Infectious outcomes of fibrin sheath disruption in tunneled dialysis catheters

Abstract

Background and objectives:

Fibrin sheath (FS) formation around tunneled central venous catheters (CVC) increases the risk of catheter-related bloodstream infections due to bacterial adherence to a biofilm. We sought to investigate whether FS disruption (FSD) at the time of CVC removal or exchange affects infectious outcomes in patients with CVC-related infections.

Design, setting, participants, and measurements:

Retrospective cohort study of 307 adult maintenance hemodialysis patients aged 18 years or older at a single center academic-based hemodialysis program (UHN, Toronto) who developed CVC-related infections requiring CVC removal or exchange between January 2000 and January 2019. Exposure was FSD at the time of CVC removal or exchange. Outcomes were infectious metastatic complications, recurrent infection with the same organism within 1 year, or death due to infection. We created a Markov Multi-State Model (MMSM) to assess patients’ trajectories through time as they transitioned between states. A time-to-event analysis was performed, adjusted for clinically relevant factors.

Results:

There was no significant relationship between FSD status at the time of CVC removal, the development of infectious complications in the multivariable model (adjusted HR = 0.71, 95% CI 0.09−5.80, p = 0.76), or mortality from infection (HR = 0.84, 95% CI 0.34−2.11, p = 0.73).

Conclusions:

FSD at the time of CVC removal was not associated with increased risk of infectious complications or death due to infection. Further prospective study is needed to determine whether FSD contributes to reducing CVC infectious related complications.

Introduction

Hemodialysis central venous catheters (CVC) are the initial vascular access type in 80% of incident hemodialysis patients in North America. ¹ Guidelines only support limited use of CVC for long-term hemodialysis due to increased risks of dysfunction, thrombosis and infection ² ; such limited use include CVCs when vasculature is unsuitable for arteriovenous access or patient choice under special circumstances. ² Patients with CVCs encounter high infectious morbidity with a 1-year risk of catheter-related bloodstream infections (CRBSI) of 9%–79%, as well as independently higher mortality rates compared to other access types.^3,4 Factors involved in the pathogenesis of CRBSI include the catheter material, virulence factors produced by infecting organisms, and host development of a fibrin sheath (FS) around the catheter. ⁵ The FS enveloping CVCs forms a biofilm base to which bacteria can adhere. ⁶ This can lead to significantly higher rates of both gram-positive and gram-negative infection and persistent bacteremia in central venous catheters with FS.^7–9

Fibrin sheath disruption (FSD), involving guide-wire directed balloon angioplasty, is a frequently employed method to treat CVC flow related dysfunction. ¹⁰ This process breaks down the adherent proteins, including fibrin and fibronectin, that form a sheath around the CVC, thus disturbing a key factor in the pathogenesis of catheter-related infections. Conversely, one could worry that separating the bacteria from the biofilm could increase the risk of septic emboli, particularly pulmonary emboli. FSD at the time of CVC exchange for catheter dysfunction has become the standard of care at many institutions; however, there is sparse literature examining the effect on infectious morbidity and mortality after this procedure, especially when CVC exchange is used to help manage suspected or present CRBSI.

Materials and methods

Study design and cohort

A retrospective review was conducted of a baseline population of adult maintenance hemodialysis patients 18 years or older at the University Health Network in-center Hemodialysis Program (UHN, Toronto). The study population included those who developed tunneled CVC-related infections requiring CVC removal or exchange from January 2000 to January 2019. Data was collected through the UHN vascular access database as well as the institutional electronic medical record. All events were included if a CVC was removed due to infection defined as a preceding positive microbiological result and confirmed through the Hemodialysis Infection Control Subcommittee at UHN which followed the Health Canada definition for intravascular device infection. ¹¹ We aimed to determine whether FSD to disrupt a potential nidus of infection affects infectious outcomes in a cohort of hemodialysis patients with confirmed CVC-related infections.

Exposures

The primary exposure was FSD status at the time of CVC removal for active infection as FSD or no FSD (control). Radiology reports at CVC removal identified absence or presence of FS and whether FSD by balloon angioplasty occurred. CVC removal where contrast angiography was not performed were classified as unknown presence of FS. There were no specific guidelines to receive antibiotics prior to FSD.

Outcomes

The primary outcome was the proportion of patients with a serious infectious complication defined as the presence of: infectious metastatic complication, recurrent infection with the same organism within 1 year from the date of original infection, or death due to infection. Infectious metastatic complications were defined as the presence of at least one of the following: septic shock, endocarditis, septic arthritis, osteomyelitis, septic emboli or thrombus, or central nervous system abscess. The date of complication was defined as the date of positive confirmatory microbiological or imaging report. The secondary outcomes were recurrent infections with any organism and type of pathogen causing invasive infection within our study period. The aim of these secondary analyses was to expand on our description of infectious morbidity, and whether certain pathogens should alert clinicians for more intensive management.

Statistical analysis

Patients’ clinical and demographic characteristics were summarized as numbers (percent) and median (interquantile range) for discrete and continuous variables, respectively. In order to characterize all patients’ and their CVCs’ chronological trajectories through time without excluding patients who developed complications around the time of catheter removal, we constructed a Markov Multi-State Model (MMSM). This statistical model consisted of the following states: State (1) CVC insertion; State (2) CVC infection: positive microbiologic result; State (3) CVC removal or exchange; State (4) Infectious complication defined as either metastatic complication as evidenced by positive imaging or other investigation OR recurrent infection with the same organism within 1 year; State (5) was an absorbing state, death due to infection (Figure 1). The entry criteria for this study was CVC removal due to infection (State 3); however, once the entry criteria were met, a retrospective view was taken so the timeline of events would begin at State 1. A patient could only transition through states following the arrows in Figure 1. A patient would remain in a MMSM state if no subsequent state criteria were met; thus, after a patient experienced an infectious event that led to either CVC removal or exchange or was associated with an infectious complication, they would remain in State 3 or 4, respectively, if they did not go on to develop a subsequent CVC infection requiring CVC removal during the study period. However, patients could transition back to new CVC insertion (State 1) if that patient developed a new CVC infection requiring CVC removal (State 3) and need a new CVC. In other words, they would not transition back to State 1 unless they developed a new CVC infection requiring CVC removal and a new CVC insertion. A patient could transition from State 2 to State 4 if they developed an infectious complication prior to removal of their CVC (State 3).

Figure 1.

Diagram of states in Markov Multi-State Model (MMSM) of patients’ CVCs trajectories through time. Large arrows represent the trajectory of the majority of patients and small arrows represent the minority who developed infectious complication before CVC removal.

We assessed the association of FSD at the time of CVC removal (State 3) that transitioned to State 4 using time to event analysis (i.e. from date of CVC removal due to infection to date of infectious complication) in both univariable and multivariable models. The multivariate model adjusted for age, sex, previous infection, type of infection, and confirmed presence of fibrin sheath. Statistical analysis was conducted in R (R Core Team, 2018). p < 0.05 indicated statistical significance.

Results

Patient characteristics

During the study period, 307 patients were included with a total of 446 events of CVC removal due to infection. Demographics were compared based on total patients involved (Table 1). About 44% of patients were female. The average patient age at first infection was 58 years old. The most common causes of ESKD were diabetes (33%) and glomerulonephritis (22%).

Table 1.

Baseline patient demographic data of cohort including percentage of total patients.

	Composite results
Total patients (N)	307
Sex—N female (%)	135 (44.0)
Age (mean years ± SD)	57.8 ± 16.7
Prior CVC—N (%)	173 (56.4)
Cause of ESKD—N (%)
Diabetes mellitus	101 (32.9)
Glomerulonephritis	68 (22.1)
Hypertension	48 (15.6)
Hereditary/congenital	24 (7.8)
Other (includes diabetes and hypertension combination; other etiologies; unknown)	66 (21.5)

The unit of analysis was at the catheter level (i.e. not the patient level). Thus, characteristics of events per catheter removal were compared by FSD status at the time of CVC removal (Table 2). Specifically, there were 93 events where FSD was performed. In both groups, the most common infecting organisms were Staphylococcus aureus (40.4%) and coagulase-negative staphylococcal species (CNST) (19.7%). The majority of CVCs were located in the right (62.1%) and left (26.0%) internal jugular veins. Of the 353 CVC removals where no FSD was performed, 19 confirmed the absence of FS; the remainder included 68 CVCs exchanged over a wire, 4 confirmed present FS but did not undergo FSD, and 262 did not undergo contrast angiography to assess for FS. Less than 5% of removals occurred at the bedside.

Table 2.

Characteristics of events per catheter removal compared by fibrin sheath disruption at time of tunneled hemodialysis catheter removal.

	Fibrin sheath disruption	No fibrin sheath disruption	p-Value
Total infectious events—no.	93	353
CVC location—no. (% of group)			0.44
Right internal jugular vein	52 (55.9%)	225 (63.7%)
Left internal jugular vein	30 (32.3%)	86 (24.4%)
Right femoral vein	6 (6.5%)	17 (4.8%)
Left femoral vein	3 (3.2%)	18 (5.1%)
Right subclavian vein	2 (2.2%)	4 (1.1%)
Left subclavian vein	0	3 (0.8%)
Pathogen—no. (% of group)			<0.01
Staphylococcus aureus	30 (32.3%)	150 (42.5%)
Coagulase negative staphylococcus	32 (34.4%)	56 (15.9%)
Serratia marcescens	5 (5.4%)	31 (8.8%)
Candida species	4 (4.3%)	29 (8.2%)
Other	22 (23.7%)	87 (24.6%)
Type of Infection—no. (% of group)			0.18
Exit infection refractory to medical treatment, or candida infection	14 (15.1%)	58 (16.4%)
Tunneled infection	0	12 (3.4%)
Bacteremia	79 (84.9%)	283 (80.2%)

Figure 2 demonstrates the trajectory of patients’ CVCs through the MMSM including the number of events as they transition through states.

Figure 2.

Markov Multi-State Model of patients with tunneled hemodialysis catheter-related infections requiring removal. N = number of CVCs transitioning between states through time. The dotted lines represent the small number of events that developed infectious complications prior to CVC removal. The bold box indicates that State 3 criteria must be met for entry into the study; however, once this is met, the patient begins their trajectory at State 1.

Serious infectious outcomes

Recall, serious infectious complications were categorized as infectious metastatic complications or recurrent infection with the same organism within 1 year from the date of original infection. While death is a serious infectious complication, it was captured as an absorbing state in the Markov Model. In total, there were 101 serious infectious complications: 72 (71%) developed infectious metastatic complications (Supplemental Appendix 1) and 29 (29%) were complicated by recurrent infection with the same organism within 1 year. We specifically examined the 87 serious infectious complications (State 4) that occurred after CVC removal (State 3). In this group, 20 (23%) underwent FSD at the time of CVC removal.

Time-to-event

Time-to-events were calculated for the initial states (Figure 3). After CVC insertion (State 1), the mean time to infection was 332 ± 16 days. After the date of infection (State 2), the mean time to CVC removal or to development of infectious complication was 11 ± 1 days.

Figure 3.

Average time to CVC infection and CVC removal or exchange within the multi-state model.

Fibrin sheath disruption analysis

We found no significant relationship between FSD status at the time of CVC removal (State 3) and the development of infectious complications (State 4) examined through the MMSM. This was demonstrated in a univariable model for FSD versus no FSD (control) (hazard ratio (HR) = 1.41, 95% confidence interval (95% CI) 0.86–2.32, p = 0.18). In the multivariable model adjusted for age, sex, previous infection, type of infection, and presence of fibrin sheath, there was no association between FSD and development of infectious complications (adjusted HR = 0.71, 95% CI 0.09–5.80, p = 0.76).

Infectious pathogens

Specific organisms were analyzed in a multivariable model adjusted for age, sex, previous infection, type of infection, and presence of fibrin sheath. CNST was set as the reference organism because of its indolence and prevalence. There was an increased risk of infectious complications, metastatic or recurrent infection, for both S. aureus (HR = 4.16, 95% CI 2.22–7.80, p ⩽ 0.01), and Candida species (HR = 3.10, 95% CI 1.27–7.56, p = 0.01). Bacteremic infections had a higher risk for infectious metastatic complications than exit or tunnel infections (HR = 11.18, 95% CI 3.38–37.04, p < 0.01) as no infectious metastatic complications occurred with exit or tunnel infections.

Mortality

Mortality was analyzed in the univariable model. There were 25 events that transitioned from infectious complication (State 4) to death (State 5), and FSD at CVC removal occurred in 6 (24%) of these events. We found no association between FSD at the time of CVC removal and mortality from infection (HR = 0.84, 95% CI 0.34–2.11, p = 0.73). The number of events that transitioned from CVC removal (State 3) to death (State 5) was too small to include in the analysis (Figure 2). Survival curves characterized the risk of death in patients in various states, with or without FSD (Figure 4).

Figure 4.

Survival plots of CVC removal (State 3) and infectious complication (State 4) and probability of death.

Recurrence of infections

We focused on the group of patients within the MMSM with recurrent infections with the same organism within 1 year of CVC removal or exchange. Out of the 29 patients who developed recurrent infection with the same organism within 1 year, only 8 or 27.6% (95% CI 12.7%–47.2%) had FSD at the time of the original CVC removal.

In a secondary exploratory analysis to better characterize patients who encountered multiple infections, we examined patients with recurrent CVC-related infection due to any organism, and the time to new infection could be greater than 1 year. Within the multi-state model, we analyzed all patients that transitioned back to CVC insertion (State 1) from CVC removal (State 3). In this group, there was no significant association between FSD at the time of CVC removal and development of a recurrent CVC infection either in the univariable model (HR = 1.3, 95% CI 0.82–2.11, p = 0.26) or in the multivariable model (HR = 1.20, 95% CI 0.26–5.42, p = 0.83).

Discussion

Catheter-related bloodstream infections are a major cause of morbidity and mortality among patients undergoing hemodialysis. We specifically examined cases where the CVC was removed or exchanged due to infection. Our study found no significant relationship between FSD at the time of CVC removal or exchange and the development of infectious complications or death due to infection.

While the literature is sparse, our findings are in keeping with previous clinical studies examining the consequences of FSD. In a single-center retrospective study, Shanaah et al. ¹² examined 168 procedures for catheter dysfunction through catheter exchange with FSD (n = 28), catheter exchange with no fibrin sheath present (n = 56), or de novo placement of a CVC (n = 84). The authors found no statistically significant relationship in the development of infection between the groups. In another single-center retrospective study, Valliant et al. ¹³ examined the incidence of bacteremia after 163 catheter exchanges for catheter dysfunction with FSD (n = 3/67) and without (n = 3/96) and found no significant association between the groups. We similarly found no increased risk of infection after FSD, and no increased risk of infectious metastatic complications or mortality.

Crucially, our study differed from the remainder of the literature in that we specifically examined patients wherein the cause for CVC removal or exchange was due to confirmed infection. At present, FSD is primarily considered a strategy to treat CVC dysfunction. ¹⁰ While barriers to routine angiography to detect FS include increased procedural time and cost, FSD at the time of catheter exchange rather than CVC removal alone appears to significantly prolong catheter patency. ¹⁴ Prolonging CVC patency is essential in patients where a permanent CVC is appropriate, to help avoid subsequent CVC insertions at different locations and the risk of central venous stenosis, limiting access options. ¹⁵ Epidemiologically, infection is a common indication for CVC removal.^16,17 When a CVC is removed in the presence of an unknown infected fibrin sheath, this potentially places the patient at risk of ongoing infection, as the nidus of infection has not been managed. Inserting another CVC simply introduces a new foreign object for biofilm to adhere to. Our findings could highlight CVC infection as a routine indication for contrast angiography to determine the presence of fibrin sheath at the time of CVC exchange. If present, FSD may eliminate the nidus of infection and is not associated with more infectious complications when compared to no FSD.

Indeed, in our secondary analysis, those with FSD at the time of CVC removal appeared less likely to develop recurrent infection with the same organism within 1 year. This supports the theoretical advantage to disrupting the biofilm to prevent persistent infection. However, these findings should be interpreted with caution as they were not analyzed in the MMSM thus lacking the intricacies of our other results. Certainly, this signal toward protectivity from recurrent infection should be evaluated in prospective studies.

Our study demonstrated that S. aureus and Candida species were more likely to result in severe or recurrent infection compared to other pathogens. This finding is in keeping with current literature. The Infectious Diseases Society of America advises that CVCs should be removed in the event of CRBSIs due to S. aureus, Candida sp., and others such as Pseudomonas sp. due to the virulent nature of these pathogens. ¹⁸

While not specifically examined in our study, it is important to note the non-infectious complications of FSD. ¹⁹ Given that the FS is formed from adherent proteins and clot, pulmonary embolism is a potential complication of FSD that should be evaluated further in prospective studies.

This study had several limitations. Through its retrospective nature, this study relied on complete and accurate recording of pertinent information within the vascular access database and electronic medical record. However, this data was reviewed on a regular basis by the UHN Hemodialysis Infection Control Committee, a multidisciplinary team consisting of a nephrologist, vascular access coordinator, infection control practitioner, pharmacist, and others as needed (e.g. input from microbiologist). Secondly, the capture of FS presence or disruption at the time of removal is limited by the high number of removals that did not assess for FS with contrast angiography, thus limiting the ability to make inferences about the impact of FSD on reducing recurrent infectious complications. Thirdly, FSD generally occurred when the radiologists were prompted to perform the procedure, suggesting that the referring clinicians may have been more concerned about a FS contributing to ongoing infectious symptoms. As mentioned above, contrast angiography may be more routinely performed for malfunctioning CVCs compared to CVCs being removed due to infection. This could translate to a non-random cohort of patients selected by ordering physicians who felt the procedure would be medically appropriate. While the vast majority of cases that did not undergo FSD had an unknown presence or absence of FS, this reflects real life practice as this retrospective study occurred over a long timeframe when practices were evolving. Where FSD has principally been employed for catheter dysfunction, growing literature that was produced over this retrospective study period raised the possibility that infection could be an additional indication for FSD. ²⁰ Fourthly, there may have been an element of selection bias for more severe infections as we only included cases of CVC-related infections where the CVC was removed or exchanged. While the nidus of infection was removed, these patients may have been more prone to infectious complications or death due to the severity of their infections. Conversely, the true impact of infected fibrin sheaths may be underestimated. Further, our findings may not be generalizable to cases where CVC salvage is initially attempted. Finally, our results had wide confidence intervals owing to the small sample size and should be interpreted carefully.

In conclusion, we found that FSD at the time of CVC removal or exchange for management of infection was not associated with an increased risk of serious infectious complications. Prospective and randomized trials are necessary to evaluate the role of routine contrast angiography identification of FS and its disruption in the strategy of managing CVC related infections and subsequent outcomes.