Safety and Efficacy of Ethanol for Catheter Salvage and CLABSI Prophylaxis in Polyurethane Catheters in the Pediatric Intensive Care Unit

Abstract

Objective:

Ethanol lock therapy (ELT) is a potential method of central catheter salvage following central line associated blood stream infection (CLABSI) though there is potential risk of catheter damage in polyurethane (PUR) catheters. Further, there is limited efficacy data across the spectrum of common pediatric catheters and published ELT protocols describe dwell times that are not feasible for critically ill children. We sought to evaluate the safety and efficacy of ELT in PUR catheters using brief (30 minutes to 2 hours) dwell times in our pediatric intensive care unit.

Design:

Investigational pilot study using historical control data.

Setting:

Pediatric intensive care unit in a quaternary care, free-standing children’s hospital.

Interventions:

ELT in PUR central venous catheters for catheter salvage.

Results:

ELT with brief dwell times was used in 25 patients, 22 of whom were bacteremic. Ultimately 11 patients, comprising 14 catheters, were diagnosed with a primary CLABSI. The catheter salvage rate in primary CLABSI patients receiving ELT was 92% (13/14) and significantly higher than the salvage rate in patients receiving antibiotics alone (non-ELT). (62%,39/64; mean difference 0.32, 95%CI [0.14, 0.50], p=0.03). The rate of catheter fracture in all patients receiving ELT was 8% (2/25) while the rate of fracture in the non-ELT group was 13% (8/64; mean difference −0.05, 95%CI [−0.18, 0.09], p=0.72). The rate of tPA use in the ELT group was 8% (2/25) while the rate of tPA use in the non- ELT group was significantly higher at 42% (26/64; mean difference −0.34, 95%CI [−0.49, −0.17], p=0.002).

Conclusions:

The use of ELT for catheter salvage and prophylaxis in the PICU is safe in a variety of PUR catheters. Dwell times ranging from 30 minutes to 2 hours were effective in sterilizing the catheters while allowing other therapies to continue. This approach may decrease the need for frequent line changes in a medically fragile pediatric population.

Introduction

Central line-associated blood stream infections (CLABSI) increase mortality, hospital length of stay, and costs in critically ill patients. ^1,2 A failure to clear CLABSI may increase risk of harm and result in the need to remove central venous catheters (CVCs) in children with limited vascular access options. Systemic antibiotics may fail to clear CLABSI in approximately 50% of children.³ In patients with previous CLABSI, although antibiotic lock therapy is now suggested as a method of preventing recurrent CLABSI, there are no management standards for patients with a history of polymicrobial infections requiring multiple antimicrobial agents for appropriate coverage. ^3,4

Ethanol is more effective than antibiotics at penetrating biofilms across a wide range of organisms. ^5–7 Literature suggests that ethanol lock therapy (ELT) can be successfully used for catheter salvage as well as prophylaxis in children. ^8–10 Clinicians have resisted use of ELT in polyurethane (PUR) catheters due to concerns of altered catheter integrity ^11–13 despite emerging evidence supporting a favorable safety profile. ^{8–10,14–16}

There are limited data on ELT for catheter salvage therapy in PUR catheters in the pediatric critical care population, specifically with smaller non-power-injectable peripherally-inserted central catheters (PICCs). Additionally, previously described ELT salvage regimens utilize longer dwell times (4-47 hours) which are not feasible for all patients in the pediatric intensive care unit (PICU). ⁸ As part of an investigational pilot study using historical control data , we sought to explore the safety and efficacy of ELT across a variety of PUR catheters with a 30 minute to 2 hour dwell time for the purpose of PUR catheter salvage in new CLABSIs occurring in the pediatric intensive care unit (PICU). Efficacy and safety rates were compared to patients with PUR and CLABSI not receiving ELT prior to and during the study. Additionally, we evaluated the safety and efficacy of ELT for CLABSI prophylaxis in children with histories of polymicrobial CLABSIs.

Methods

We performed an investigational pilot study to utilize ELT in PUR CVCs in a convenience sample of patients within our single-center, 75-bed, medical-surgical quaternary care PICU from February 2021 to April 2023. A multidisciplinary team was established to create the protocol. The team consisted of an Interventional Radiologist (AS), PICU clinical pharmacist (KR), PICU attending (CWH) and the program manager and medical lead of the PICU vascular access team (MDW, TC). The protocol was approved by the hospital’s Drug Use Evaluation Committee. Local Institutional Review Board approved the analysis of the retrospective data as exempt from oversight: IRB number 23-021024.

Any PICU patient with a PUR CVC and new bacteremia was eligible for the project. Consent for the off-label use of ethanol in PUR catheters was obtained from patients or caregivers before inclusion in the project. Eligible patients were identified through survey of daily blood culture reports received by our unit-based vascular access team and a convenience sample were consented for ELT. We included both power-injectable and non-power-injectable PICCs, tunneled cuffed CVCs and implantable ports. We excluded temporary CVCs, as these catheters are not intended for long-term use. Patients receiving ELT for CLABSIs attributed to mucosal barrier injury comprised the MBI-CLABSI cohort. An MBI-CLABSI was defined as a bacteremia from oral or intestinal bacteria in oncologic patients. ¹⁷ Those receiving ELT for CLABSI comprised the ELT CLABSI cohort, and both cohorts comprised the ELT bacteremia cohort (Figure 1).

Figure 1:

Study Cohorts

Efficacy (rate of catheter salvage) was compared between ELT CLABSI and non-ELT CLABSI cohorts. Safety (catheter breakage and tPA requirement) was compared between non-ELT CLABSI cohorts and the ELT bacteremic cohort plus patients receiving ELT prophylaxis. PICU: pediatric intensive care unit; MBI: mucosal barrier injury; CLABSI: central line-associated bloodstream infection; ELT: ethanol lock therapy; PPX: prophylaxis.

All patients received broad-spectrum systemic antibiotics in conjunction with ELT, initially empiric and then specific to the cultured microorganism. Ethanol was diluted to a final concentration of 70% (Sintetica SA, Mendrisio Switzerland). The dose volume was calculated for each catheter by using the manufactures priming volume of the catheter adjusted for the cut length of the catheter. The dwell time of the ethanol was 30 minutes up to 2 hours daily. The 30-minute minimum allowed for dwell time in patients with limited vascular access and frequent medication administrations. ¹⁸ The 2-hour maximum was set to minimize risk of harm secondary to PUR ethanol exposure, particularly non-power injectable PICCs as no prior data existed regarding ELT in these types of catheters. Prior studies suggested benefit with dwell times as short as 1 hour, thus the multidisciplinary team set the 2-hour maximum in an effort to balance risk and benefit.¹⁸ The ethanol was withdrawn at the completion of the dwell time. We treated all lumens and all catheters in the same patient unless ongoing medical therapies did not allow for appropriate ethanol dwell time. Patient demographics and bacteremia characteristics were recorded.

We retrospectively analyzed all patients with PUR and non-MBI CLABSI from February 2018 to January 2021 as well as patients during the study who were eligible but did not receive ELT (non-ELT CLABSI cohort). Patient demographics and infection characteristics were analyzed using summary statistics. Efficacy was defined as rate of catheter salvage. Safety was defined as rates of catheter fracture (leakage of fluid out the side of a lumen external to the insertion site) and tPA use while undergoing treatment. ELT has been associated with intraluminal thrombosis in smaller catheters.¹⁰ We chose to monitor tPA use as a marker for possible intraluminal catheter thrombosis.

In addition, we used ELT for CLABSI prophylaxis (PPX) in patients who had a history of polymicrobial non-MBI CLABSI or could not receive antibiotic locks for prophylaxis (ELT PPX cohort; Figure 1). Two of these patients did not have one antibiotic lock type that would cover the spectrum of bacteria in their CLABSI history. One patient in this cohort was unable to receive a traditional antibiotic lock due to the heparin it is prepared in. These patients were also locked with ethanol daily for 30 minutes to 2 hours depending on available dwell times. All patients received ELT PPX until the central catheter was removed.

Efficacy was evaluated in the non-ELT CLABSI cohort and compared to the ELT CLABSI cohort using Fisher’s exact test. Patients within the non-ELT CLABSI cohort were assessed for safety and compared to the combined ELT bacteremia and ELT PPX cohorts also using Fisher’s exact test.

Results

During the pilot study, ethanol was instilled for catheter salvage in 22 catheters across 18 patients, comprising the ELT bacteremia cohort. Of those 22 catheters receiving ELT, 14 were in patients with non-MBI bacteremia (ELT CLABSI cohort). The other 8 infections were identified as secondary bacteremias or MBI-CLABSIs and all patients received ELT. A total of three catheters had only 1 of their two lumens treated due to vasopressor infusions in the second lumen. There were 21 CVCs in 18 patients during the pilot study period did not receive ELT (only receiving systemic antibiotics for catheter salvage). Three patients had a history of polymicrobial CLABSI and received ELT (ELT PPX Cohort). The ELT bacteremia and ELT PPX cohort demographics, management and outcomes are described in (eTable 1 and Table 1). Retrospective evaluation of data extending three years prior to ELT implementation identified 44 PUR CVC CLABSI among 28 patients who would have been eligible for ELT. One of these patients had their line removed immediately upon infection identification and was excluded from efficacy and safety analysis. Together with the implementation cohort not receiving ELT, the non-ELT CLABSI cohort included 64 CVCs among 45 patients

Table 1:

Ethanol Prophylaxis Cohort

Patient	Catheter	Infectious Organisms	CVC Dwell Days	EtOH Dwell Time (minutes)	Ethanol Doses	Recurrent Infection (yes/no)	Catheter Complication
1	PICC Bard 4Fr DL	-Escherichia coli -Acinetobacter baumannii -Entercoccus faecalis -Staphylococcus haemolyticus -Staphylococcus Aureus -Klebsiella oxytoca	116	60	30	no	none
2	PICC Bard 5Fr TL	-Enterococcus faecium (unable to receive antibiotic lock)	185	120	58	no	tPA
3	PICC Bard 5Fr TL	-Enterobacter cloacae -Achromobacter -Serratia marcescens -Staphylococcus epidermidis	30	120	30	no	none

PICC- peripherally inserted central catheter; CLABSI- central line associated bloodstream infection; tPA- tissue plasminogen activator, DL- double lumen, TL- triple lumen

The rate of catheter salvage within the ELT CLABSI cohort was 92% (13/14). The patient without successful salvage was the only patient with a fungal infection (Candida glabrata). One patient had a repeat CLABSI later in their hospital course with a different organism. The rate of catheter salvage within the non-ELT CLABSI cohort was 62% (39/64; mean difference 0.32, 95%CI [0.14, 0.50], p=0.03). Nine of this cohort had repeat CLABSI later in their hospital course with 4/9 having the same organism as the original CLABSI.

The rate of catheter fracture during treatment within the combined ELT bacteremia and ELT PPX cohorts was 8% (2/25) and the rate of tPA requirement was 8% (2/25). The two fractured lines were 2.6 French non-power-injectable double lumen PICCs which leaked within 3-6 hours of ELT initiation All catheters were removed in one intact unit. There were no episodes of interrupted therapies due to ELT. The remainder of ELT catheters were removed at completion of therapy and no catheter fracture was encountered.

The rate of catheter fracture during treatment within the non-ELT Abx cohort was 13% (8/64). Among the fractured CVCs, 3 were 2.6 French non-power-injectable double lumen PICCs. The rate of tPA use in the non-ELT CLABSI cohort during the course of systemic antibiotic therapy was 42% (27/64). The rate of tPA use was significantly higher compared to the combined ELT bacteremia and ELT PPX cohorts (mean difference −0.34, 95%CI [−0.49, −0.17], p=0.002), but the rate of catheter fracture was not significant between cohorts (mean difference −0.05, 95%CI [−0.18, 0.09], p=0.72). None of the three patients treated with ELT for prophylaxis due to history of polymicrobial CLABSI developed CLABSI while receiving ELT.

Discussion

In PICU patients with PUR catheters and suspected or confirmed non-MBI CLABSI, our data suggest that ethanol locks are safe and effective for catheter salvage. Within our pilot study, ELT increased catheter salvage rates compared to similar patients with PUR CVCs receiving systemic antibiotics alone. Although the ELT PPX cohort had a small sample size, no children with history of polymicrobial CLABSI treated with prophylactic ELT developed CLABSI during treatment. ELT with a dwell time of ≤ 2 hours allowed for the continued delivery of essential therapies and may reduce the risk of subsequent infection within our critically ill population.

Historical data suggest ethanol decreases the integrity of PUR catheters leading to premature failure due to plasticizers eluted from their interaction with high concentration alcohols. ^11,12 Since those initial reports, more recent studies have investigated the in vitro effects of ethanol on 4 and 5 French PUR catheters and discovered no appreciable impact on the mechanical integrity of the catheters.¹⁹ Similarly, no structural differences were noted in PUR catheters exposed to ethanol when assessed with scanning electron microscopy, although investigation with mass spectroscopy revealed very low amounts of PUR compounds released after exposure to ethanol.²⁰ Thus, it appears that the newer formulations of PUR catheters may be less effected by ethanol than those of previous generations with little effect on surface properties in relation to bacterial adhesion.^21,22

With growing confidence of ethanol safety in PUR catheters and its success in CLABSI prevention with silicone catheters ²³, lock therapy has been introduced as a potential method of improving CLABSI prevention in outpatient PUR catheters. One of the first populations evaluated with ELT were children with intestinal failure, a specific group of patients with a high risk of infection, morbidity and mortality. A regimen of ethanol prophylaxis 3-7 times per week for 4-24 hour dwell times resulted in fewer catheter fractures in the polyurethane catheters compared to the silicone catheters and similar CLABSI reduction between catheter groups. ¹⁴ Ashkenazi-Hoffnung et al.³ evaluated ethanol for catheter salvage in pediatric oncology patients with PICCs, venous ports and tunneled cuffed central venous catheters using a dwell time of 4 – 48 hours. They found a significant increase in catheter salvage in this high-risk population when using ELT compared to systemic antibiotics alone (78% vs. 54%, p<0.001) with minimal adverse events.

Data are limited regarding ethanol use in the pediatric critical care setting. Valentine reported a 92% clearance and 77% salvage rate in 26 CVCs receiving ELT, though wide ranges in both dwell-time (4-48 hours) and doses (50% receiving single dose). ¹⁰ McGrath et al. described the use of ELT in PICU patients with dwell times up to 47 hours, but it was not clear if the extended dwell times were used only for silicone catheters or included PUR catheters. ⁸ Across studies, ELT catheter salvage rates with both PUR and silicone catheters range from 78-92% compared to 24-66% of those who receive systemic antibiotics alone. ^{3,8–10,24,25}

Our data support ELT as an effective method of PUR catheter salvage in critically ill children, including patients with non-power-injectable PICCs, a catheter type used in our smallest patients. This utility has not been previously reported in ELT studies. Our baseline salvage rates in patients treated with systemic antibiotics alone was 62%, consistent with previously reported rates in the pediatric literature. Importantly, our study is the first to evaluate catheter salvage with strict limits on lock therapy duration (≤ 2 hours) in the PICU setting. We demonstrated that even short exposure to ethanol can provide PUR catheter salvage benefit to patients (92%), similar to studies using longer dwell times. Efficacy of a shorter dwell time is supported by data demonstrating in vitro clearance of biofilm with just 1 minute of exposure to ethanol. ⁵ There was only one case of repeat CLABSI in a patient who underwent ELT, but with a different organism than the original CLABSI. New data in the adult hemodialysis population also support a shorter dwell time of ethanol for catheter salvage.¹⁸ Our data suggest that ethanol provides effective PUR catheter sterilization.

Our findings are particularly relevant to the critically ill pediatric patients who (1) often have limited vascular access options, (2) may have increased risks in both transfer for and placement of new vascular access devices and (3) often receive multiple life-sustaining therapies through their vascular access devices, resulting in limited dwell time for catheter salvage interventions. When developing our protocol, we hypothesized that any exposure to ELT would be beneficial and therefore allowed patients to be enrolled even if they only had 30 minutes for ELT dwell time. Within the study patients, only one patient had such a limited dwell time and we preferentially allowed for times up to 2 hours when possible.

Regarding our safety metrics, two ELT PUR CVCs demonstrated fracture, both of which were small-caliber non-power-injectable PICCs. Since ELT has not been evaluated in non-power-injectable PICCs prior to our quality improvement intervention, we empirically limited our dwell time in all PUR CVCs to 2 hours. The proportion of ELT catheter fractures in this type of PUR catheter (2/25; 8%) was slightly higher than the rate in the non-ELT cohort with the same type of catheter (3/64; 5%) and remains an important outcome measure for future ELT studies. Our other safety metric, use of tPA, is a surrogate marker for clot risk. There was no evidence of increased use of tPA in ELT patients.

Limitations of this study include the small sample size and single-center nature of the work. Another limitation is the large historical fraction of non-ELT patients who did not receive care contemporaneously with the ELT patients. This was necessary to provide a comparison sample within the scope of our study design. Further, as a means of treating patients promptly, ELT was started as soon as a positive blood culture was noted. It is possible that some of these patients may have cleared their bacteremia with systemic antibiotics alone even prior to ELT initiation.

Conclusion

The use of ethanol lock therapy with short dwell times for catheter salvage and prophylaxis in critically ill patients with CLABSI was safe in a variety of PUR catheters and demonstrated efficacy when compared to treatment with systemic antibiotics alone. Larger studies are necessary to further validate the safety of ELT in small caliber or non-power injectable PUR PICCs often utilized in the care of our smallest patients.

Supplementary Material

eTable - supplemental

eTable 1 Ethanol Lock Therapy Cohort

PICC- peripherally inserted central catheter; tPA- tissue plasminogen, SL- single lumen, DL- double lumen, TL- triple lumen

Research in Context.

• Ethanol locks have been used successfully to both prevent and treat central line associated blood stream infections.

• Historically, ethanol has compromised the integrity of older generations of polyurethane catheters.

• In this study the use of ethanol locks for catheter salvage therapy was both safe and effective for children in the PICU with a wide range of newer generation polyurethane catheters.

At the Bedside.

• Ethanol locks can be used in a wide range of polyurethane catheters commonly used in PICU patients.

• The success of catheter salvage therapy increased from 62% using systemic antibiotics alone to 92% following the implementation of ethanol locks.

• Given the high success rate, ethanol catheter salvage therapy should be considered in PICU patients with CLABSI in conjunction with systemic antibiotics.