The occurrence of CR-BSI has important implications for patient morbidity and mortality as well as healthcare costs. Potentially severe systemic complications may increase mortality rates associated with CR-BSI; for example, sepsis is lethal in 20%–50% of severely affected patients, and sepsis is currently the tenth leading cause of death overall in the United States.15
Bloodstream infections can also lead to costly hospitalizations. In this context, CR-BSIs are associated with healthcare costs approaching $60,000 per infection, resulting in an estimated cumulative cost of $300 million to more than $2 billion annually.16
Therefore, reducing the risk of CR-BSI is an important goal of therapy for PAH.
In this observational study, implementing a closed-hub system and maintaining dry infusion line connections decreased the overall incidence of CR-BSI among pediatric patients with PAH treated with IV prostanoid therapy. Of note, the introduction of preventive measures significantly reduced the rate of CR-BSI among patients receiving treprostinil, including a reduction in the incidence of gram-negative infection, which appeared to be more common among treprostinil-treated patients. The reasons for the increased risk of CR-BSI caused by gram-negative pathogens with treprostinil, compared with epoprostenol, are unknown but have been suggested potentially to be related to differences in patient behavior or to differences in medication properties.4
The terminal elimination half-life of treprostinil is much longer than that of epoprostenol (approximately 4 hours vs approximately 6 minutes).17,18
Although unproven, patients who receive treprostinil may be more apt to disconnect the infusion line from their CVC because of the medication’s longer half-life, which may increase the risk of catheter hub contamination during exposure to air or moisture.4
The difference in the storage and preparation of the treprostinil and epoprostenol may potentially influence CR-BSI rates, because treprostinil is a multiuse vial and epoprostenol is a single-use vial. However, treprostinil vials contain 0.3% metacresol, and multiple vials and cassettes from treprostinil-treated patients with CR-BSI were negative for bacteria.
In addition, the pH of treprostinil is neutral (6.0–7.2),17
and the treprostinil was reconstituted with sterile water for injection or 0.9% normal saline, whereas epoprostenol reconstituted with Flolan sterile diluent for injection has an alkaline pH (10.2–10.8).18
The package insert for treprostinil was recently changed to allow its use with Flolan sterile diluent on the basis of a study showing that treprostinil (0.004 mg/mL) is stable for 52 hours in this diluent (pH, 10.5).19
As part of the same study, antimicrobial tests showed log reductions of 4.20 and 4.53 in Escherichia coli
and Pseudomonas aeruginosa
populations, respectively. A previous study demonstrated little change in populations of the same bacteria in treprostinil with sterile saline diluent. Of interest, treprostinil with Flolan sterile diluent or normal saline are both bactericidal against Staphylococcus aureus
The effect of increasing the pH of the treprostinil infusion on the incidence of CR-BSI will be tracked in the future.
The results of our study are consistent with a previous report by Akagi et al11
in which protection of the catheter hub connection led to a significant reduction in the risk of CR-BSI. Use of a closed-hub system may minimize bacterial contamination by limiting exposure of the catheter connection to the environment.11
Although the treprostinil group had a significant decrease in CR-BSI, the decrease noted in the epoprostenol group did not reach statistical significance. There was, however, a trend toward further improvement that may be clinically important. Before implementation of the closed-hub system, the higher pH of epoprostenol may have provided some antimicrobial protection, especially against gram-negative bacteria.
Different types of catheter hub systems are available. However, split-septum devices may be preferred over mechanical valve devices, but mechanical valve devices with a flat, smooth surface amenable to preaccess disinfection may be considered.21
In another study by Rupp et al,22
a transition from a split-septum device to a positive-pressure displacement valve led to an approximate 3-fold increase in the rate of BSI (approximately 4 infections per 1,000 CVC-days to approximately 12 infections per 1,000 CVC-days). After a transition back to the split-septum device, CR-BSI rates returned to normal levels. These data demonstrate the importance of selecting access devices that minimize exposure to potential contaminants and that can be adequately disinfected.
Our study suggests that, in addition to the implementation of a closed-hub system, the waterproofing of catheter hub connections during showering may be an effective preventive measure for managing the risk of CR-BSI among patients with PAH. The catheter hub is often the point of entry for pathogens that cause CR-BSI,13,14
and hub connections may be exposed to hydrophilic gram-negative pathogens (eg, Pseudomonas, Stenotrophomonas, Acinetobacter
, or Serratia
species) during showering.21
None of the currently available closed-hub systems provide a waterproof seal for the catheter hub threads. Further investigation into newer hubs that prevent water contamination is warranted. If a connection is exposed to water, patients should be counseled to not disconnect to change out their system until the threads are dry, because this appears to be the point at which contamination occurs. We found that protecting the catheter hub connection with a sealable wrap during showering effectively kept it dry, which may have contributed to the observed reduction in the incidence of CR-BSI.
Interpretation of this study is limited by several factors, including the observational study design. Increased education and surveillance with regard to catheter-related infection may have also influenced our results. Patient complacency with regard to aseptic technique must also be considered. Guidelines for the prevention of catheter-related infection16,21
recommend proper hand hygiene (ie, washing hands with conventional antiseptic-containing soap and water or with waterless alcohol-based gels or foams) and the use of gloves when manipulating the CVC. In addition, wiping the access port with 70% alcohol and accessing the port only with sterile devices may minimize contamination. These guidelines were again addressed with patients and caregivers. In addition, the number of catheter-days after implementation of the interventions was a relatively small proportion of the overall experience (approximately 20%). Nevertheless, there was a robust CVC duration overall, with a mean of more than 2 catheter-years per patient. Also, we did not measure patient compliance with respect to maintaining dry connections. Finally, only BSIs determined by the investigators to be attributed to the catheter were included, although these infections likely accounted for the majority of BSIs reported in the PAH population.
In summary, we report that the implementation of a closed-hub system and the waterproofing of catheter hub connections during showering reduced the rate of CR-BSI in our cohort of pediatric patients who were receiving IV prostanoid therapy, including a significant decrease in the rate of infections caused by gram-negative pathogens. Further investigation with regard to the use of the closed-hub system and to improvements in protecting the delivery system against contamination is warranted to establish best practices for managing the risk of CR-BSI among patients who require long-term indwelling CVCs. In addition, there is a need to track the impact of increasing the pH of treprostinil with Flolan sterile diluent on CR-BSI. Implementing current evidence-based recommendations for the prevention of CR-BSI16,21
is encouraged for all PAH centers.