Ethics
This prospective clinical trial was approved by the Ethics Committee of the University Hospital Tuebingen prior to recruitment (394/2014MPG23). Before randomization, written consent was acquired from all patients or their legal representative prior to study inclusion. If the patient was incapable to provide informed consent but no advanced directive regarding the legal representative was made, a formal legal guardianship was requested at the respective dependency court. If a legally binding informed consent was absent prior to the first study intervention, the patients were excluded from the study. The study was registered in Clinical Trial Database (NCT02134769).
Study setting, population and sample size
The study was performed as a simple, single-center randomized controlled trial at tertiary, university hospital intensive care unit. The study included patients requiring a central venous catheter or an arterial cannula for monitoring or therapy.
Inclusion and exclusion criteria
Inclusion criteria were 18 years of age or older, admission to the intensive care unit, the necessity for a central venous catheter or arterial line, anticipated ICU treatment for more than 5 days and informed consent by the legal representative. Exclusion criteria included ICU stay for less than 3 days (including non-survival), positive blood cultures prior to first infusion line change, the unknown time point of catheter placement, catheter placement at a referring hospital or absence of informed consent. Patients with intellectual disability were also excluded from the study.
Primary and secondary endpoint
The primary endpoint of our study was the number of CRBSI. Secondary endpoints were bacterial colonization of intravascular catheter line entry ports.
Definition of catheter-related bloodstream infections and clinical criteria
In line with international guidelines [6, 7], CRBSI was diagnosed when the following criteria were met: bacteremia/fungemia in a patient with an intravascular catheter with at least one positive blood culture obtained from a peripheral vein, catheter tip colonization, no apparent source for the bloodstream infection except the catheter and clinical manifestations of infection. Clinical criteria for an infection were fever (body temperature > 38 °C), tachycardia, tachypnea, hypotension or increase of vasopressors by more than 50% in 24 h, chills in the presence of elevated inflammatory markers (C-reactive protein > 5 mg/dl postoperatively, procalcitonin > 0.5 ng/ml).
Study protocol and randomization
Intravascular catheters were either placed in the operating room just prior to ICU admission or after ICU admission under sterile conditions. Patients received intravascular catheter solely for the management of the underlying disease. On day 3 after ICU admission, the attending intensivist on call screened patients for inclusion or exclusion criteria and enrolled the patients if applicable. If patients were included in the study, patients were randomized into either the NFC group or the control group. Numbered, concealed envelopes were used for randomization based on a randomization list generated by the Institute of Biometrics at the University of Tuebingen. In the treatment group, we replaced caps by NFCs (Fig. 1). All staff involved in patient care received training in the use of NFCs used in our study (Vygon Bionecteur®) prior to the study.
The study protocol entailed a programmed change of the central venous pressure infusion lines and arterial pressure infusion line every 72 h. We collected a set of blood cultures prior to the change of infusion lines for the first time. Simultaneously to infusion line changes, microbiological samples were collected from each port of the CVC or arterial lines. Before each handling of the ports, spray disinfection before application of medication or before changing infusion lines was performed. All infusion hubs of a four-way stopcock were capped by a sterile cap.
Microbiological analysis was performed by the Institute of Medical Microbiology at the University Tuebingen according to routine standard-operating procedures. The medical microbiologist was blinded to the study group.
Staff training
Before the study, all nursing staff and physicians of our intensive care unit were trained in the handling of NFCs. In a first step, the manufacturer of Bionecteur, Vygon Inc®, trained senior critical care nurses, who also hold a certificate as practical nursing trainers. Then, the nursing care trainers served as proxies and subsequently trained all other staff within a 4 weeks’ time frame. The study protocol was initiated after all personnel had completed training in NFC handling.
Access-ports nursing care
Before handling, NFCs were sprayed with a 70% propranolol-based antiseptic solution and then scrubbed for 15 s. After an additional wait period of 15 s to allow the antiseptic solution to dry, the NFC entry ports were then handled.
In the control group, the three-way stopcocks were also sprayed with a 70% propranolol-based antiseptic solution after uncapping and before infusion lines were connected or medication injected. A new, sterilely packed end-cap was placed on the three-way stopcock after each handling.
Regardless of the study group, both systems were flushed with a bolus of several milliliters of normal saline after injection of medication.
Statistical analysis
Statistical planning and evaluation were performed by the Institute of Biometrics at the University of Tuebingen. The data were analyzed by Mann-Whitney and T test. A p value of < 0.05 was considered significant.