CONTEXT

Central venous access device (CVAD) locks are routine interventions used to prevent and treat complications, such as infection, thrombosis, and catheter occlusion.

OBJECTIVE

To compare and rank lock-solutions for prevention or treatment of complications in pediatrics. Design Systematic review and network meta-analysis.

DATA SOURCES

Five databases and 2 clinical trial registries were searched.

STUDY SELECTION

Published and unpublished randomized controlled trials that enrolled pediatric patients with a CVAD and compared the effectiveness of lock-solutions.

DATA EXTRACTION

Data extraction was conducted by 2 reviewers. Odds ratio (OR) for prevention or treatment of CVAD-associated bloodstream infection (BSI), thrombosis, occlusion, CVAD-failure, and mortality were calculated, with point estimates ranking lock-solutions.

RESULTS

Twenty-nine studies were included. Chelating agents and antibiotic locks given as prevention were associated with lower odds (OR: 0.11; 95% confidence interval [CI]: 0.02–0.67; moderate-quality; OR: 0.19; 95% CI: 0.05–0.79, high-quality, respectively) of CVAD-associated BSI compared with heparinized saline (reference). Preventative thrombolytic agents had lower odds (OR: 0.64, 95% CI: 0.44–0.93; low-quality) of CVAD occlusion, whereas ethanol had higher odds (OR: 2.84, 95% CI: 1.31–6.16; high-quality) compared with heparinized saline (reference). No lock solution had effects on thrombosis prevention or treatment, CVAD-failure, CVAD-associated BSI treatment failure, or mortality.

LIMITATIONS

There was substantial uncertainty around the point estimates because of the limited number of studies for outcomes and study heterogeneity. More high-quality studies are needed to confirm the efficacy of lock solutions.

CONCLUSIONS

Chelating agents and antibiotic locks may be effective for CVAD-associated BSI prevention in pediatrics. Thrombolytic agents can be an option for CVAD occlusion prevention, whereas ethanol may not be recommended.

Central venous access devices (CVADs) are vital to deliver lifesaving treatments to the central bloodstream. However, in pediatrics, 1 in 4 CVADs becomes infected, thrombotic, or occluded during treatment.1,2  The delivery of care and the trajectory of recovery are disrupted and complicated by these events, negatively influencing morbidity and mortality.3 5 

Catheter locking is a routine intervention that maintains patency and prevents CVAD-associated adverse events. Solutions dwell in the CVAD tubing between therapy administration (between 6 hours to >8 weeks), providing a fluid-based “lock” to prevent blood from moving up through the tubing during normal movement (eg, thoracic pressure changes).6  Multiple lock solutions are used in pediatric health care and categorized by their use for primary prevention or treatment of a complication and secondary prevention. Depending on the clinician’s or author’s intention, some locks are used across these indications.

Primary preventative lock solutions are used across different CVAD types to prevent infection or thrombotic complications. In contrast, secondary prophylactic lock solutions are used in patients who have a history of infection or thrombotic complications. Historically, low-dose heparin (10–100 U/mL) was used as a prevention locking solution because of its anticoagulant properties.7  Although normal saline (0.9% sodium chloride) is chemically inactive, it is considered a primary prevention agent because it helps the turbulent movement of the solution through the catheter and physically clears the blood or fibrin build-ups. Both catheter lock solutions are recommended to be used to reduce the risk of catheter related bloodstream infection (CRBSI) by the Infusion Nurses Society and the Center for Disease Control and Prevention.8,9 

Taurolidine lock is a derivative of the amino acid taurine and is a broad-spectrum antimicrobial, including antibiotic-resistant bacteria.10  Citrate lock has an antithrombotic property through the activation of calcium-dependent coagulation pathways by chelating ionized calcium.11  It also has antimicrobial activity in higher concentrations. A combined solution, taurolidine citrate, was found to reduce infectious complications but was ineffective against thrombotic complications.12  Ethylenediaminetetraacetic acid (EDTA) is a calcium and iron chelator with anticoagulant and antimicrobial activity. Reconstituted as tetrasodium-EDTA (T-EDTA), the 4% solution has been proposed as an alternative prophylactic lock solution against catheter-associated bloodstream infection, thrombosis, and occlusion.13 15  Ethanol locks are also effective against a broad spectrum of bacteria and fungi and are inexpensive and widely available.16  However, they are ineffective for treatment and secondary prevention of catheter-associated bloodstream infection in high-risk populations and are associated with an increased risk of catheter occlusion in comparison with heparinized saline (relative risk [RR]:1.8; 95% confidence interval [CI]: 1.1–2.9).17 

Locks used to treat complications are focused on infections, thrombosis, or occlusions. Urokinase, alteplase, or recombinant tissue plasminogen activator are primarily used as a thrombolytic agent to restore CVAD patency after an occlusive event.18  Although antibiotic locks are currently recommended in immunocompetent children in conjunction with systemic antibiotic treatments for the salvage of CVADs, there is no high-quality evidence to support this.19  Concentrations of 100 to 1000 times the intravenous dose are instilled to the catheter length without systemic exposure.

Several randomized control trials (RCTs) have compared the different lock solutions. However, there is yet no meta-analysis that assessed the comparative efficacy of all available lock solutions while differentiating the purpose of use (prevention versus treatment) in pediatric healthcare. A traditional systematic review cannot compare multiple treatments simultaneously; thus, network meta-analysis is advantageous since it can compare the treatment effects indirectly among different RCTs.

The study aims to identify the best lock solution for prevention or treatment in pediatric healthcare by estimating the treatment effects through direct and indirect comparisons and generating a ranking according to the efficacy of all lock solutions in pediatric healthcare. The research questions are:

  1. Which lock solution has the highest efficacy in preventing CVAD-associated bloodstream infection (BSI), CVAD-associated thrombosis, CVAD occlusion, CVAD failure, and mortality in pediatric health care?

  2. Which lock solution has the highest efficacy used as a treatment to rescue CVAD-associated BSI, CVAD-associated thrombosis, and CVAD occlusion in pediatric health care?

The study was prospectively developed, and the protocol was registered (PROSPERO registration number: CRD42022378914). Findings of this systematic review and meta-analysis were presented according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines.20 

The original search strategy was designed in PubMed using identified keywords, index terms, and MeSH headings with the health librarian at the University of Queensland. Systematic Reviews Accelerators Polyglot Search Translation module was used with no limitation on year or language to refine search terms and transform them into suitable formats for each database.21  To achieve a comprehensive evaluation of the published evidence, the systematic search was supplemented with a forward and backward citation search as well as retrieving the first 20 similar articles from PubMed for each paper included in the searches. PubMed, Cumulative Index of Nursing and Allied Health Literature, Embase, Web of Science, Scopus, Cochrane Central Register of Controlled Trials, Australian New Zealand Clinical Trials Registry, and International Clinical Trials Registry Platform were searched. The search for unpublished studies was also completed using ProQuest Dissertations and Theses, Open Access Theses and Dissertations, and MedNar. The reference lists of all selected articles and relevant reviews were searched for additional studies. The initial search was conducted on November 25, 2022. Search terms and the full search strategy are shown in Supplemental Table 4. Titles and abstracts of all papers were uploaded to Covidence, where 2 authors (M.T. and Y.E.) independently screened the titles, abstracts, and full text. Any disagreements were resolved through a majority consensus after the involvement of the third reviewer (A.U.).

Eligible studies were published and unpublished RCTs that enrolled pediatric patients (with age inclusion defined by local guidelines) with a CVAD and compared the effectiveness of lock solutions with sufficient information for data extraction. Duplicate publications of original research and ongoing RCTs without extractable data were excluded. Study authors were contacted if pediatrics-only data were required. The study was categorized into prevention or treatment:

  1. Prevention: the use of intervention in a study population to prevent new study outcomes (CVAD-associated BSI, CVAD-associated thrombosis, or CVAD occlusion). This includes relapse and reinfections that failed secondary prophylaxis of CVAD-associated BSI.

  2. Treatment: the use of the intervention in a study population that already had 1 of the study outcomes (CVAD-associated BSI, CVAD-associated thrombosis, or CVAD occlusion), where the lock solutions were used with the aim of resolving the complication.6 

The narrowly defined lock solution categories initially chosen for the network were observed to be sparsely connected. This presents a significant problem as networks with poor connectivity may produce unreliable estimations and mis-rank treatment options. Furthermore, the lock solution may receive inconsistent rankings when the reference category is altered.

For this reason, based on clinical practice guideline summaries,6,22  the lock solutions were recategorized into heparin, chelating, saline, thrombolytic, antibiotic, ethanol and other (Table 1). Minocycline and EDTA acid have antibiotic and chelating agents but were categorized under chelating agents because of their primary agent.

TABLE 1

Classification of Lock Solutions

Lock SolutionsLock Solution Category
Heparinized saline Heparin 
Normal saline Saline 
Vancomycin and amikacin Antibiotic 
Antibiotic Antibiotic 
Fusidic acid Antibiotic 
Vancomycin Antibiotic 
Amikacin Antibiotic 
Taurolidine and citrate Chelating 
Minocycline and Edetic acid Chelating 
Urokinase Thrombolytic 
Tissue Plasminogen Activator Thrombolytic 
Ethanol Ethanol 
Ascorbic acid Other 
Lock SolutionsLock Solution Category
Heparinized saline Heparin 
Normal saline Saline 
Vancomycin and amikacin Antibiotic 
Antibiotic Antibiotic 
Fusidic acid Antibiotic 
Vancomycin Antibiotic 
Amikacin Antibiotic 
Taurolidine and citrate Chelating 
Minocycline and Edetic acid Chelating 
Urokinase Thrombolytic 
Tissue Plasminogen Activator Thrombolytic 
Ethanol Ethanol 
Ascorbic acid Other 

Primary Outcomes

  1. CVAD-associated BSI (prevention): author definition with minimal criteria of laboratory-confirmed, positive blood or catheter tip culture.23 

  2. CVAD-associated BSI treatment failure: ongoing CVAD-associated BSI (including persistence of the symptoms) during the treatment phase where interventions have been used as a treatment after initial BSI or relapse of CVAD-BSI with the same organism during the follow-up period.

  3. CVAD-associated thrombosis(prevention): a symptomatic thrombosed CVAD containing blood vessel or fibrin sheath occluding venous lumen diagnosed via ultrasound or venography. “Symptomatic” was defined by the study authors.24 

  4. CVAD-associated thrombosis treatment failure: ongoing CVAD-associated thrombosis during the treatment phase where interventions have been used as a treatment after initial CVAD-associated thrombosis.

Secondary Outcomes

  1. CVAD occlusion (prevention): complete occlusion of the catheter when injecting fluids or medications.25 

  2. CVAD occlusion treatment failure: persistent clinically relevant CVAD dysfunction after treatment with the intervention requiring an alternative intervention, modification of CVAD use, or removal of the CVAD.

  3. CVAD failure: cessation of CVAD function before completion of treatment, resulting in CVAD removal and replacement vascular access.

  4. Mortality: during the study period.

Data extraction was performed by M.T. and Y.E. The data extracted from the included studies were year, country of study, study population, follow-up time, number of patients, catheters, device type, presence and frequency of CVAD complications, and CVAD dwell days. The study authors were contacted to see if further data or clarifications were needed. The data were extracted into the form designed for this review on Microsoft Excel.

The risk of bias was assessed according to the Cochrane Collaboration Risk of Bias Tool for RCT 2.026  by 2 reviewers (M.T., Y.E.). The tool assesses the risk of bias related to random sequence generation, allocation concealment, selective reporting, blinding, incomplete data, and attrition rate. The items were evaluated as having a high, low, or unclear risk of bias. Any disagreements were resolved by the third reviewer (A.U.).

Descriptive statistics for the eligible trials, including study population characteristics and types of interventions, were summarized. The proportion of treated individuals with different locks who achieved the outcome(s) of interest (as described above) was estimated for each trial, and the odds ratio (OR) of the outcome after the lock intervention. An automated generalized pair-wise modeling (GPM) framework was used to generate mixed treatment effects against heparin saline. The method involves (1) pooling effect sizes for direct comparisons between each combination of 2 treatments using meta-analysis; (2) performing indirect comparisons by an automated generation of all possible closed loops of 3 treatments such that 1 is common to 2 studies; and (3) pooling all direct and indirect effects using meta-analysis to give a final effect size comparing each treatment to the common comparator. The pool estimates were estimated using the inverse variance heterogeneity model,27  which uses a quasi-likelihood-based variance structure without distributional assumptions. The transitivity assumption underlying the network meta-analysis was evaluated by assessing the patient, intervention, and study design features by 2 clinicians (M.T., A.U.). Coherence was evaluated based on the CI of the difference in comparative effect size between direct and indirect comparisons.28 30 

Sensitivity analyses were performed to assess the impact of the risk of bias on the results (using a quality effects model). The presence of adequate safeguards for the domains from the Risk of Bias Tool for RCT 2.0 was evaluated as low risk (1-point), some concern (0.5-points), and high risk (0-points). The scores were added up for an overall risk of bias score with a maximum of 5-points and were incorporated into the quality effects model.31  Additionally, all analyses were rerun using the random effects model within a multivariate frequentist framework for comparison.

Posthoc subgroup analyses were conducted for CVAD-BSI (prevention) outcome by CRBSI and CLABSI definitions.32  Posthoc sensitivity analyses were conducted for CVAD-BSI (prevention), (1) assessing only taurolidine in the chelating agent groups, and (2) assessing only the oncology and hematology patient group.

Publication bias was assessed using ”comparison-adjusted” funnel plots, which show the difference of each study’s observed ln(OR) (natural logarithm of OR) versus the comparison’s mean ln(OR) obtained from meta-analysis on the horizontal axis. In the absence of small-study effects, studies are expected to form an inverted funnel centered at 0. GPM framework analyses were conducted using MetaXL version 5.3 (EpiGear Int Pty Ltd.; Brisbane, Australia). Assumption testing, sensitivity analyses, and funnel and network plots were conducted in Stata version 14.1 (College Station, TX, USA).

We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the evidence certainty associated with outcomes across the 5 criteria (individual risk of bias, study inconsistency, indirectness of evidence, imprecision, and publication bias), categorized as between high to very low.33 

We identified 1910 studies from the databases, and 1637 studies were removed after screening the title and abstract. A total of 200 studies were assessed for eligibility for full texts; 29 met the inclusion criteria for the systematic review and were included in the network meta-analysis (Fig 1).

FIGURE 1

PRISMA flow diagram of study selection for quantitative synthesis.

FIGURE 1

PRISMA flow diagram of study selection for quantitative synthesis.

Close modal

The 29 included studies were published between 1990 and 2022, including 2970 patients and 3053 devices (Table 2, Supplemental Table 5). Studies were conducted in United States (11 studies, 37.9%), Europe (Belgium, Denmark, Germany, Italy, Netherlands, Poland; 8 studies, 27.6%), South America (Brazil and Mexico; 5 studies, 17.2%), Asia (Korea and Turkey; 2 studies, 6.9%), Africa (Egypt; 1 study, 3.4%), Australia (1 study, 3.4%), and international collaborations (USA and Australia; 1 study, 3.5%).

TABLE 2

Characteristics of the Included Studies (N = 29 Studies)

First Author and Year of PublicationStudy LocationStudy ScaleRandomization and BlindingNumber of Participants/ DevicesInclusion Age CriteriaPatient Population Description - Diagnostic GroupType of CVADLock Solutions (N of participant/ N of CVAD days)Lock Solution CategoryPrimary PurposeFrequency of Administration
Akyüz, 201052  Turkey SC NC 97/97 NC Pediatric oncology patients NR Heparinized saline (48/ NR)/ taurolidine and citrate (49/NR) Heparin/ chelating Prevention NR 
Aquino, 200253  United States SC DB 74/74 Age 1 to up to 21 y old NR Tunneled noncuffed catheter Normal saline (34/667)/ urokinase (40/12 300) Saline/ thrombolytic Prevention NR 
Araujo, 201154  Brazil SC OL 133/133 NICU All newborns Peripherally inserted central catheter Heparinized Saline (64/839)/ normal saline (69/1000) Heparin or saline Prevention Every 4 h 
Atkinson, 199834  United States SC OL 63/63 NC - children Department of surgery or pediatrics Port or totally implanted device; tunneled-cuffed catheter (eg, Hickmans) Normal saline (30/unclear)/ urokinase (33/unclear) Saline/ thrombolytic Treatment 12 hourly 
Bracho-Blanchet, 201055  Mexico SC NC 76/76 <18 y of age Inpatient NR Heparinized saline (38/unclear)/ normal saline (38/unclear) Heparin/ saline Prevention Daily 
Cesaro, 200956  Italy MC OL 203/203 <17 y of age Malignant or nonmalignant hematologic or oncologic disease Tunneled-cuffed catheter (eg, Hickmans) Heparinized saline (101/38 425)/ normal saline (102/36 796) Heparin/ saline Prevention Twice a week 
Choi, 202057  Korea SC NC 22/22 Unclear Allogeneic HSCT Tunneled-cuffed catheter (eg, Hickmans) Heparinized saline (11/unclear)/ normal saline (11/unclear) Heparin/ saline Prevention Unclear 
Dümichen, 201258  Germany SC NC 71/71 1–18 y Hematologic malignancies Tunneled-cuffed catheter (eg, Hickmans) Heparinized Saline (36/7233)/ taurolidine and citrate (35/6576) Heparin/ chelating Prevention Weekly 
Daghistani, 199659  United States SC DB 61/64 <22 y of age Diagnosis of malignancy NR Normal saline (33/10 033)/ vancomycin and amikacin (28/9814) Saline/ antibiotic Prevention NR 
Decembrino, 201435  Italy SC NC 13/13 3–18 y Oncology hematology Peripherally inserted central catheter; port or totally implanted device; tunneled-cuffed catheter (eg, Hickmans) Ethanol (9/ NR)/ antibiotic (4/NR) Ethanol/ antibiotic Prevention NR 
Ferreira Chacon, 201160  Brazil SC OL 50/50 Unclear (children) Cancer and undergoing chemotherapy and clinically stable Port or totally implanted device Heparinized saline (26/3016)/ minocycline and edetic acid (24/4587) Heparin/ chelating Prevention After each chemo session 
Filippi, 200736  Italy SC NC 103/103 Neonates - no age limit NICU Peripherally inserted central catheter; UVC Fusidic acid (50/456)/ heparinized saline (53/522) Antibiotic/ heparin Prevention Once a day 
Garland, 200561  United States SC DB 90/90 Neonates Neonate admitted to NICU alive at 48 h Peripherally inserted central catheter Normal saline (43/unclear) / vancomycin (42/unclear) Saline/ antibiotic Prevention 2–3 times a day 
Giacomozzi, 202244  Brazil SC OL 152/152 29 d to 14 y PICU/ hemato-oncology Peripherally inserted central catheter Ascorbic acid (79/unclear)/ normal saline (73/unclear) Other/ saline Prevention Max 4 doses per day/ CVAD route 
Goossens, 201362  Belgium SC OL 28/28 Older than 1 y Oncology patient Port or totally implanted device Heparinized saline (17/unclear)/ normal saline (11/unclear) Heparin/ saline Prevention NR 
Handrup, 201337  Denmark SC OL 113/130 <19 y of age Oncology patient Port or totally implanted device; tunneled-cuffed catheter (eg, Hickmans) Normal saline (65/18 571)/ taurolidine and citrate (64/17 500) Saline/ chelating Prevention NR 
Henrickson, 200063  United States MC DB 126/153 <20 y of age Presence of a primary or secondary immunodeficiency Tunneled-cuffed catheter (eg, Hickmans) Normal saline (80/10 840)/ vancomycin (35/8059) Saline/ antibiotic Prevention NR 
Jones, 200138  United States SC NC 578/578 Unclear (children) Children treated with malignancies Port or totally implanted device; tunneled-cuffed catheter (eg, Hickmans) Heparinized saline (289/unclear)/ urokinase (289/unclear) Heparin/ thrombolytic Prevention Every 2 weeks 
LaQuaglia, 199443  United States SC DB 41/41 <19 y of age Oncology patient Tunneled-cuffed catheter (eg, Hickmans) Normal saline (18/unclear)/ urokinase (23/unclear) Saline/ thrombolytic Treatment Every 12 h 
Lopes, 201945  Brazil SC NC 80/80 0–5 y NICU or pediatric ICU within the preceding 24 h Nontunneled catheter Ethanol (35/346)/ normal saline (39/464) Ethanol/ saline Prevention Daily 
Lyszkowska, 201939  Poland SC NC 86/97 <2 y of age Surgical treatment with observation Peripherally inserted central catheter; port /totally implanted device; tunneled-cuffed catheter (eg, hickmans); tunneled non-cuffed catheter; non-tunneled catheter Normal saline (49/976)/ taurolidine and citrate (48/942) Saline/ chelating Prevention Daily 
Onder, 200840  United States SC OL 42/59 2–21 y Pediatric hemodialysis unit Tunneled-cuffed catheter (eg, Hickmans); nontunneled catheter Heparinized saline (12/unclear)/ tissue plasminogen activator (12/unclear) Heparin/ thrombolytic Treatment NR 
Rackoff, 199564  United States SC NC 63/63 <18 y of age Inpatient Tunneled-cuffed catheter (eg, Hickmans) Normal saline (31/4780)/ vancomycin (32/4378) Antibiotic/ saline Prevention Once a day 
Schoot, 201541  Netherlands MC DB 307/307 <18 y of age Oncology patient Port or totally implanted device; tunneled-cuffed catheter (eg, Hickmans) Ethanol (153/20 916)/ heparinized saline (154/19 915) Ethanol/ heparin Prevention Max once a week 
Schwartz, 199065  United States SC DB 45/53 <20 y of age Hematology/ oncology Tunneled-cuffed catheter (eg, Hickmans) Normal saline (24/4792)/ vancomycin (29/6303) Saline/ antibiotic Prevention At least daily 
Seliem, 201066  Egypt SC DB 83/83 Neonates All neonates (term and preterm) admitted to the unit UVC Amikacin (41/unclear)/ normal saline (42/unclear) Antibiotic/ saline Prevention Twice daily 
Smith, 199167  United States SC Other: crossover NC 14/14 <21 y of age Oncology patient Tunneled-cuffed catheter (eg, Hickmans) Heparinized saline (14/1515)/ normal saline (14/1514) Heparin/ saline Prevention Once a week 
Ullman, 202242  Australia SC OL 61/61 <18 y of age Oncology patient Peripherally inserted central catheter; port/ totally implanted device; tunneled-cuffed catheter (eg, Hickmans) Heparinized saline (29/3850)/ normal saline (30/4036) Heparin/ saline Prevention When not in use for more than 24 h 
Wolf, 201817  United States and Australia MC DB 95/95 0.5–25 y Cancer or a hematologic disorder or undergoing haemopoietic stem-cell transplantation Port or totally implanted device; tunneled-cuffed catheter (eg, Hickmans) Ethanol (48/unclear)/ heparinized saline (46/unclear) Ethanol/ heparin Treatment NR 
First Author and Year of PublicationStudy LocationStudy ScaleRandomization and BlindingNumber of Participants/ DevicesInclusion Age CriteriaPatient Population Description - Diagnostic GroupType of CVADLock Solutions (N of participant/ N of CVAD days)Lock Solution CategoryPrimary PurposeFrequency of Administration
Akyüz, 201052  Turkey SC NC 97/97 NC Pediatric oncology patients NR Heparinized saline (48/ NR)/ taurolidine and citrate (49/NR) Heparin/ chelating Prevention NR 
Aquino, 200253  United States SC DB 74/74 Age 1 to up to 21 y old NR Tunneled noncuffed catheter Normal saline (34/667)/ urokinase (40/12 300) Saline/ thrombolytic Prevention NR 
Araujo, 201154  Brazil SC OL 133/133 NICU All newborns Peripherally inserted central catheter Heparinized Saline (64/839)/ normal saline (69/1000) Heparin or saline Prevention Every 4 h 
Atkinson, 199834  United States SC OL 63/63 NC - children Department of surgery or pediatrics Port or totally implanted device; tunneled-cuffed catheter (eg, Hickmans) Normal saline (30/unclear)/ urokinase (33/unclear) Saline/ thrombolytic Treatment 12 hourly 
Bracho-Blanchet, 201055  Mexico SC NC 76/76 <18 y of age Inpatient NR Heparinized saline (38/unclear)/ normal saline (38/unclear) Heparin/ saline Prevention Daily 
Cesaro, 200956  Italy MC OL 203/203 <17 y of age Malignant or nonmalignant hematologic or oncologic disease Tunneled-cuffed catheter (eg, Hickmans) Heparinized saline (101/38 425)/ normal saline (102/36 796) Heparin/ saline Prevention Twice a week 
Choi, 202057  Korea SC NC 22/22 Unclear Allogeneic HSCT Tunneled-cuffed catheter (eg, Hickmans) Heparinized saline (11/unclear)/ normal saline (11/unclear) Heparin/ saline Prevention Unclear 
Dümichen, 201258  Germany SC NC 71/71 1–18 y Hematologic malignancies Tunneled-cuffed catheter (eg, Hickmans) Heparinized Saline (36/7233)/ taurolidine and citrate (35/6576) Heparin/ chelating Prevention Weekly 
Daghistani, 199659  United States SC DB 61/64 <22 y of age Diagnosis of malignancy NR Normal saline (33/10 033)/ vancomycin and amikacin (28/9814) Saline/ antibiotic Prevention NR 
Decembrino, 201435  Italy SC NC 13/13 3–18 y Oncology hematology Peripherally inserted central catheter; port or totally implanted device; tunneled-cuffed catheter (eg, Hickmans) Ethanol (9/ NR)/ antibiotic (4/NR) Ethanol/ antibiotic Prevention NR 
Ferreira Chacon, 201160  Brazil SC OL 50/50 Unclear (children) Cancer and undergoing chemotherapy and clinically stable Port or totally implanted device Heparinized saline (26/3016)/ minocycline and edetic acid (24/4587) Heparin/ chelating Prevention After each chemo session 
Filippi, 200736  Italy SC NC 103/103 Neonates - no age limit NICU Peripherally inserted central catheter; UVC Fusidic acid (50/456)/ heparinized saline (53/522) Antibiotic/ heparin Prevention Once a day 
Garland, 200561  United States SC DB 90/90 Neonates Neonate admitted to NICU alive at 48 h Peripherally inserted central catheter Normal saline (43/unclear) / vancomycin (42/unclear) Saline/ antibiotic Prevention 2–3 times a day 
Giacomozzi, 202244  Brazil SC OL 152/152 29 d to 14 y PICU/ hemato-oncology Peripherally inserted central catheter Ascorbic acid (79/unclear)/ normal saline (73/unclear) Other/ saline Prevention Max 4 doses per day/ CVAD route 
Goossens, 201362  Belgium SC OL 28/28 Older than 1 y Oncology patient Port or totally implanted device Heparinized saline (17/unclear)/ normal saline (11/unclear) Heparin/ saline Prevention NR 
Handrup, 201337  Denmark SC OL 113/130 <19 y of age Oncology patient Port or totally implanted device; tunneled-cuffed catheter (eg, Hickmans) Normal saline (65/18 571)/ taurolidine and citrate (64/17 500) Saline/ chelating Prevention NR 
Henrickson, 200063  United States MC DB 126/153 <20 y of age Presence of a primary or secondary immunodeficiency Tunneled-cuffed catheter (eg, Hickmans) Normal saline (80/10 840)/ vancomycin (35/8059) Saline/ antibiotic Prevention NR 
Jones, 200138  United States SC NC 578/578 Unclear (children) Children treated with malignancies Port or totally implanted device; tunneled-cuffed catheter (eg, Hickmans) Heparinized saline (289/unclear)/ urokinase (289/unclear) Heparin/ thrombolytic Prevention Every 2 weeks 
LaQuaglia, 199443  United States SC DB 41/41 <19 y of age Oncology patient Tunneled-cuffed catheter (eg, Hickmans) Normal saline (18/unclear)/ urokinase (23/unclear) Saline/ thrombolytic Treatment Every 12 h 
Lopes, 201945  Brazil SC NC 80/80 0–5 y NICU or pediatric ICU within the preceding 24 h Nontunneled catheter Ethanol (35/346)/ normal saline (39/464) Ethanol/ saline Prevention Daily 
Lyszkowska, 201939  Poland SC NC 86/97 <2 y of age Surgical treatment with observation Peripherally inserted central catheter; port /totally implanted device; tunneled-cuffed catheter (eg, hickmans); tunneled non-cuffed catheter; non-tunneled catheter Normal saline (49/976)/ taurolidine and citrate (48/942) Saline/ chelating Prevention Daily 
Onder, 200840  United States SC OL 42/59 2–21 y Pediatric hemodialysis unit Tunneled-cuffed catheter (eg, Hickmans); nontunneled catheter Heparinized saline (12/unclear)/ tissue plasminogen activator (12/unclear) Heparin/ thrombolytic Treatment NR 
Rackoff, 199564  United States SC NC 63/63 <18 y of age Inpatient Tunneled-cuffed catheter (eg, Hickmans) Normal saline (31/4780)/ vancomycin (32/4378) Antibiotic/ saline Prevention Once a day 
Schoot, 201541  Netherlands MC DB 307/307 <18 y of age Oncology patient Port or totally implanted device; tunneled-cuffed catheter (eg, Hickmans) Ethanol (153/20 916)/ heparinized saline (154/19 915) Ethanol/ heparin Prevention Max once a week 
Schwartz, 199065  United States SC DB 45/53 <20 y of age Hematology/ oncology Tunneled-cuffed catheter (eg, Hickmans) Normal saline (24/4792)/ vancomycin (29/6303) Saline/ antibiotic Prevention At least daily 
Seliem, 201066  Egypt SC DB 83/83 Neonates All neonates (term and preterm) admitted to the unit UVC Amikacin (41/unclear)/ normal saline (42/unclear) Antibiotic/ saline Prevention Twice daily 
Smith, 199167  United States SC Other: crossover NC 14/14 <21 y of age Oncology patient Tunneled-cuffed catheter (eg, Hickmans) Heparinized saline (14/1515)/ normal saline (14/1514) Heparin/ saline Prevention Once a week 
Ullman, 202242  Australia SC OL 61/61 <18 y of age Oncology patient Peripherally inserted central catheter; port/ totally implanted device; tunneled-cuffed catheter (eg, Hickmans) Heparinized saline (29/3850)/ normal saline (30/4036) Heparin/ saline Prevention When not in use for more than 24 h 
Wolf, 201817  United States and Australia MC DB 95/95 0.5–25 y Cancer or a hematologic disorder or undergoing haemopoietic stem-cell transplantation Port or totally implanted device; tunneled-cuffed catheter (eg, Hickmans) Ethanol (48/unclear)/ heparinized saline (46/unclear) Ethanol/ heparin Treatment NR 

B, Block (stratified); DB, double blinded; HSCT, hematopoietic stem cell transplantation; I, individual; MC, multicenter; NC, not clear; NR, not reported; OL, open label; SC, single center; UVC, umbilical venous catheter.

There were 17 studies that studied tunneled-cuffed catheters (58.6%), 10 studies on totally implanted devices (34.5%), 7 studies on peripherally inserted central catheters (24.1%), 3 studies for nontunneled catheters (10.3%), 2 studies each (6.9%) for tunneled noncuffed catheters and umbilical venous catheters (UVCs), and 3 studies did not specify the type of CVADs (10.3%). Ten studies had multiple CVAD devices included.17,34 42 

Five studies used lock solutions to treat CVAD-BSI.17,34,35,40,43  No studies used a lock solution for rescuing occlusion and thrombosis. The most frequently investigated outcomes were BSIs (n = 22 studies), occlusion (n = 12), device failure (n = 10), thrombosis (n = 9), treatment failure after short course treatment (n = 5), and mortality (n = 5). Only 5 studies used the lock solution for treatment purposes, and all 5 studies only assessed the outcome of CVAD-associated BSI.

Patient setting and diagnosis included oncology and hematology (18 studies; 62.1%), followed by NICU and neonates only (5 studies; 17.2%), pediatric intensive care, surgery, and all pediatrics (2 studies each, 6.9%), and renal and unknown (1 study, 3.4%). Two studies had mixed settings and diagnoses.44,45 

CVAD-BSI (Prevention)

Based on 22 studies examining prevention of CVAD-BSI, when heparinized saline was used as the reference category, the ranking was chelating agent, antibiotic, ethanol, thrombolytic agents, and saline (Table 3, Fig 2; Supplemental Tables 68). Chelating and antibiotic lock had significantly lower odds of CVAD-BSI (OR: 0.11; 95% CI: 0.02–0.67; moderate evidence-quality and OR: 0.19; 95% CI: 0.05–0.79; high evidence-quality, respectively). Ethanol (OR: 0.48; 95% CI: 0.05–0.79), thrombolytic agents (OR: 0.62; 95% CI: 0.02–23.98), and saline (OR: 0.73; 95% CI: 0.11–4.82) locks had lower odds estimate with low evidence-quality, however with wide CIs. Comparison-adjusted funnel plots demonstrated little evidence of asymmetry (Fig 2). The H-index of 1.90 indicates a moderate level of centrality or importance for the network node. The ranking from GPM was the same as to multivariate frequentist OR except for thrombolytic and saline, and the effect estimates from the quality effects (QE) model were similar to GPM (Supplemental Table 9).

TABLE 3

Summary Table of the Odds Ratio of Lock Solutions Category for Multiple Outcomes (Reference Group: Heparinized Saline)

Outcomes, Odds Ratio (95% CI), and Certainty of the Evidence (GRADE)
CVAD-Associated BSI (prevention)CVAD-Associated BSI Treatment Failured (Supplemental Fig 1)CVAD-associated Thrombosis (Prevention)d (Supplemental Fig 2)CVAD Occlusion (Prevention)d (Fig 3)CVAD Failured (Supplemental Fig 3)Mortalityd (Supplemental Fig 4)
HeparinComparatorComparatorComparatorComparatorComparatorComparator
Chelating 0.11 (0.02–0.67)⊕⊕⊕⊝moderatea — 2.27 (0.52–9.97)⊕⊕⊝⊝lowb — 1.52 (0.79–2.94)⊕⊕⊝⊝lowb 1.71 (0.26–11.26)⊕⊕⊝⊝lowb 
Antibiotic 0.19 (0.05–0.79)⊕⊕⊕⊕high 2.81 (0.04–194.42)⊕⊕⊝⊝low - imprecisionb — 0.88 (0.10–7.74)⊕⊕⊝⊝lowb — 1.34 (0.54–3.35)⊕⊝⊝⊝very lowb,c 
Ethanol 0.48 (0.05–4.24)⊕⊕⊝⊝lowb 1.33 (0.42–4.19)⊕⊕⊝⊝lowb 0.74 (0.25–2.20)⊕⊕⊝⊝lowb 2.84 (1.31–6.16)⊕⊕⊕⊕high 1.63 (0.71–3.76)⊕⊕⊝⊝lowb 0.50 (0.09–2.75)⊕⊕⊝⊝lowb 
Thrombolytic 0.62 (0.02–23.98)⊕⊕⊝⊝lowb 1.00 (0.02–54.46)⊕⊕⊝⊝lowb  0.64 (0.44–0.93)⊕⊕⊝⊝lowc 0.95 (0.12–7.73)⊕⊕⊝⊝lowb — 
Saline 0.73 (0.11–4.82)⊕⊕⊝⊝lowb 1.05 (0.02–62.55)⊕⊝⊝⊝very lowb,c 3.71 (0.51–26.87)⊕⊕⊝⊝lowb 0.54 (0.10–3.05)⊕⊕⊝⊝lowb 1.05 (0.56–1.95)⊕⊕⊝⊝lowb 1.68 (0.19–15.20)⊕⊕⊝⊝lowb 
Other — — 5.14 (0.33–80.81)⊕⊕⊝⊝lowb 0.44 (0.05–4.21)⊕⊕⊝⊝lowb 1.09 (0.46–2.62)⊕⊕⊝⊝lowb — 
Number of studies 22 12 10 
H-index 1.90 1.00 1.00 1.00 1.06 1.00 
Outcomes, Odds Ratio (95% CI), and Certainty of the Evidence (GRADE)
CVAD-Associated BSI (prevention)CVAD-Associated BSI Treatment Failured (Supplemental Fig 1)CVAD-associated Thrombosis (Prevention)d (Supplemental Fig 2)CVAD Occlusion (Prevention)d (Fig 3)CVAD Failured (Supplemental Fig 3)Mortalityd (Supplemental Fig 4)
HeparinComparatorComparatorComparatorComparatorComparatorComparator
Chelating 0.11 (0.02–0.67)⊕⊕⊕⊝moderatea — 2.27 (0.52–9.97)⊕⊕⊝⊝lowb — 1.52 (0.79–2.94)⊕⊕⊝⊝lowb 1.71 (0.26–11.26)⊕⊕⊝⊝lowb 
Antibiotic 0.19 (0.05–0.79)⊕⊕⊕⊕high 2.81 (0.04–194.42)⊕⊕⊝⊝low - imprecisionb — 0.88 (0.10–7.74)⊕⊕⊝⊝lowb — 1.34 (0.54–3.35)⊕⊝⊝⊝very lowb,c 
Ethanol 0.48 (0.05–4.24)⊕⊕⊝⊝lowb 1.33 (0.42–4.19)⊕⊕⊝⊝lowb 0.74 (0.25–2.20)⊕⊕⊝⊝lowb 2.84 (1.31–6.16)⊕⊕⊕⊕high 1.63 (0.71–3.76)⊕⊕⊝⊝lowb 0.50 (0.09–2.75)⊕⊕⊝⊝lowb 
Thrombolytic 0.62 (0.02–23.98)⊕⊕⊝⊝lowb 1.00 (0.02–54.46)⊕⊕⊝⊝lowb  0.64 (0.44–0.93)⊕⊕⊝⊝lowc 0.95 (0.12–7.73)⊕⊕⊝⊝lowb — 
Saline 0.73 (0.11–4.82)⊕⊕⊝⊝lowb 1.05 (0.02–62.55)⊕⊝⊝⊝very lowb,c 3.71 (0.51–26.87)⊕⊕⊝⊝lowb 0.54 (0.10–3.05)⊕⊕⊝⊝lowb 1.05 (0.56–1.95)⊕⊕⊝⊝lowb 1.68 (0.19–15.20)⊕⊕⊝⊝lowb 
Other — — 5.14 (0.33–80.81)⊕⊕⊝⊝lowb 0.44 (0.05–4.21)⊕⊕⊝⊝lowb 1.09 (0.46–2.62)⊕⊕⊝⊝lowb — 
Number of studies 22 12 10 
H-index 1.90 1.00 1.00 1.00 1.06 1.00 

Chelating, chelating agent (taurolidine and citrate/minocycline and edetic acid); antibiotic, (vancomycin and amikacin/antibiotic/fusidic acid/vancomycin/amikacin); ethanol, ethanol; thrombolytic, thrombolytic agent (urokinase/tissue plasminogen activator); saline, normal saline; other (ascorbic acid). Assumption testing found that transitivity assumption is likely to hold in our analysis. BS, bloodstream infection; —, not applicable.

a

Downgraded because of inconsistency.

b

Downgraded because of imprecision.

c

Downgraded because of risk of bias.

d

Not ranked.

FIGURE 2

(A) Network Forest plot based on 21 studies ranking comparison based on their odds ratio; (B) network plot of 7 lock solutions for CVAD-associated BSI (prevention); and (C) Funnel plot of network meta-analysis for CVAD-associated BSI (prevention) (Reference group: heparinized saline). Chelating, chelating agent (taurolidine and citrate/minocycline and edetic acid); antibiotic, (vancomycin and amikacin/antibiotic/fusidic acid/vancomycin/amikacin); ethanol, ethanol; thrombolytic, thrombolytic agent (urokinase/tissue plasminogen activator); saline, normal saline.

FIGURE 2

(A) Network Forest plot based on 21 studies ranking comparison based on their odds ratio; (B) network plot of 7 lock solutions for CVAD-associated BSI (prevention); and (C) Funnel plot of network meta-analysis for CVAD-associated BSI (prevention) (Reference group: heparinized saline). Chelating, chelating agent (taurolidine and citrate/minocycline and edetic acid); antibiotic, (vancomycin and amikacin/antibiotic/fusidic acid/vancomycin/amikacin); ethanol, ethanol; thrombolytic, thrombolytic agent (urokinase/tissue plasminogen activator); saline, normal saline.

Close modal

Exploring difference between CLABSI versus CRBSI outcome definitions, comparisons found similar ORs to the main analysis (Supplemental Table 10). The result was similar when only taurolidine and citrate locks were included in the analysis (OR: 0.12; 95% CI: 0.01–1.57; Supplemental Table 11). However, the ranking changed when only oncology and hematology patients were included in the analysis, where thrombolytic agents (OR: 0.22; 95% CI: 0.05–0.93) came second after chelating agent (OR: 0.12; 95% CI: 0.02–0.62), and antibiotic became less precise (OR: 0.69; 95% CI: 0.12–3.91; Supplemental Table 12).

CVAD-associated BSI Treatment Failure

We had 5 studies comparing 4 lock solutions when heparinized saline was referent (Table 3, Supplemental Fig 4; Supplemental Tables 13 and 14). The ranking was antibiotic (OR: 2.81; 95% CI: 0.04–194.42), ethanol (OR: 1.33; 95% CI: 0.42–4.19), thrombolytic agents (OR: 1.00; 95% CI: 0.02–54.46), and saline (OR: 1.05; 95% CI: 0.02–62.55). None of the lock solutions evaluated in the study demonstrated statistically significant effect estimates and all had low to very low evidence-quality. The CI for the effect estimates were wide, indicating a lack of precise estimates for the effectiveness of these lock solutions. H index was 1.000. The funnel plot has little evidence of asymmetry (Supplemental Fig 4). The ranking from GPM was the same as the multivariate frequentist OR, and the effect estimates from the QE model were similar to GPM (Supplemental Table 15).

CVAD-associated Thrombosis (Prevention)

Nine studies compared 5 lock solutions as thrombosis prevention with heparinized saline as reference (Table 3, Supplemental Fig 5, Supplemental Tables 1619). The ranking was ethanol (OR: 0.74; 95% CI: 0.25–2.20), chelating (OR: 2.27; 95% CI: 0.52–9.97), saline (OR: 3.71; 95% CI: 0.51–26.87), and other (OR: 5.14; 95% CI: 0.33–80.81). However, the effect estimates were not statistically significant and had low evidence-quality. H-index was 1.00. The funnel plot had slight asymmetry, with more studies reporting higher effect sizes (Supplemental Fig 5). The ranking from GPM was mostly the same as multivariate frequentist OR except for other solution and saline, and the effect estimates from the QE model was similar to GPM (Supplemental Table 18).

No studies examined catheter lock solutions for the treatment of existing CVAD-associated thrombosis.

CVAD Occlusion (Prevention)

Twelve studies comparing 6 lock solutions for CVAD occlusion prevention with heparinized saline as referent (Table 3, Fig 3; Supplemental Tables 19 and 20). The ranking was other (OR: 0.44; 95% CI: 0.05–4.21), saline (OR: 0.54; 95% CI: 0.10–3.05), thrombolytic agent (OR: 0.64, 95% CI: 0.44–0.93), antibiotic (OR: 0.88, 95% CI: 0.10–7.74), and ethanol (OR: 2.84, 95% CI: 1.31–6.16). Ethanol results were high and others were low evidence-quality. The consistency H-index was 1.00. The funnel plot had little evidence of asymmetry (Fig 3). The ranking from GPM was the same as to multivariate frequentist OR, and the effect estimates from the QE model were similar to GPM (Supplemental Table 21). When analysis was restricted to oncology and hematology patients, the precisions improved for other (ascorbic-acid; OR: 0.16; 95% CI: 0.03–0.98), and saline group (OR: 0.17; 95% CI: 0.04–0.74; Supplemental Table 22). No studies examined catheter lock solutions for the treatment of CVAD-associated occlusion.

FIGURE 3

(A) Network Forest plot based on 12 studies ranking comparison based on their odds ratio; (B) network plot of 6 lock solutions for CVAD occlusion (prevention); and (C) funnel plot of network meta-analysis for CVAD occlusion prevention (Reference group: heparinized saline). Antibiotic, (vancomycin and amikacin/antibiotic/fusidic acid/vancomycin/amikacin); ethanol, ethanol; thrombolytic, thrombolytic agent (urokinase/tissue plasminogen activator); saline, normal saline; other (ascorbic acid).

FIGURE 3

(A) Network Forest plot based on 12 studies ranking comparison based on their odds ratio; (B) network plot of 6 lock solutions for CVAD occlusion (prevention); and (C) funnel plot of network meta-analysis for CVAD occlusion prevention (Reference group: heparinized saline). Antibiotic, (vancomycin and amikacin/antibiotic/fusidic acid/vancomycin/amikacin); ethanol, ethanol; thrombolytic, thrombolytic agent (urokinase/tissue plasminogen activator); saline, normal saline; other (ascorbic acid).

Close modal

CVAD Failure

Ten studies compared 6 lock solutions with heparinized saline as a referent (Table 3, Supplemental Fig 6, Supplemental Tables 23 and 24). The ranking was thrombolytic agents (OR: 0.95; 95% CI: 0.12–7.73), saline (OR: 1.05; 95% CI: 0.56–1.95), other (OR: 1.09; 95% CI: 0.46–2.62), chelating agents (OR: 1.52; 95% CI: 0.79–2.94), and ethanol (OR:1.62; 95% CI: 0.71–3.76), all with low evidence-quality. Although having less precision, chelating agents and ethanol had 52% to 62% increased odds of having CVAD failure. The H index was 1.06. The funnel plot was observed to be symmetrical (Supplemental Fig 6). The ranking from GPM was similar to multivariate frequentist OR except that other solution had a lower OR than saline in the multivariate frequentist model, and the effect estimates from the QE model were similar to GPM (Supplemental Table 25). When the analysis was restricted to oncology and hematology patients, the ranking changed to thrombolytic (OR: 0.92; 95% CI: 0.11–7.60), other (OR: 1.06; 95% CI: 0.43–2.61); saline (OR: 1.17; 95% CI: 0.64–2.11), ethanol (OR: 1.26; 95% CI: 0.57–2.77), and chelating agents (OR: 1.75; 95% CI: 0.68–4.53; Supplemental Table 26).

Mortality

Five studies compared 5 lock solutions when heparinized saline was referent (Table 3, Supplemental Fig 7, Supplemental Tables 27 and 28). The ranking was ethanol (OR: 0.50; 95% CI: 0.09–2.75), antibiotic (OR: 1.34; 95% CI: 0.54–3.35), saline (OR: 1.68; 95% CI: 0.19–15.20), and chelating agents (OR: 1.71; 95% CI: 0.26–11.26), with low to very low evidence-quality. H index was 1.000. The funnel plot has little evidence of asymmetry (SupplementalFig 7). The ranking from GPM was the same as the multivariate frequentist OR, and the effect estimates from the QE model were similar to GPM (Supplemental Table 29).

Children undergoing complex treatments requiring CVADs have a high risk of infective and thrombotic complications.1  To prevent and treat these complications, clinicians are searching for a safe and effective catheter lock solution. This first network metanalysis involving 29 clinical trials, including 2970 children across the last 32 years, demonstrates the complexity of choosing between the range of locking solutions. Chelating and antibiotic locks appeared effective in preventing CVAD-associated BSI for children in comparison with heparinized saline solutions. Additionally, there are some early signals that thrombolytic agents and ethanol locks may have a potential benefit. Thrombolytic agents were potentially effective in preventing CVAD occlusion, whereas ethanol increased the risk of occlusion, in comparison with heparinized saline. No lock solutions were significantly associated with CVAD-associated BSI treatment failure, CVAD-associated thrombosis prevention, CVAD failure, or mortality. Children who are at high risk for 1 complication, are at increased vulnerability for the sequelae.46  The ideal CVAD lock solution needs to be effective across all types of CVAD complications to ensure this high-risk population can receive harm-free, uninterrupted therapies.

Our analysis of 22 studies on the prevention of CVAD-associated BSI showed that chelating and antibiotic locks had a significantly lower odds ratio of CVAD-associated BSI when compared with heparinized saline, whereas thrombolytic agents and ethanol locks did not have statistically significant results. The result is similar to the previous network meta-analysis using 13 studies comprising 1335 patients, which demonstrated taurolidine and heparin were effective in the prevention of CRBSI in pediatric patients compared with heparin (RR: 0.21, 95% CI: 0.09–0.51).47  Although the authors found no significant reduction in antibiotics groups, amikacin (RR: 0.79; 95% CI: 0.12–5.21), fusidic acid (RR: 0.24; 95% CI: 0.06–1.03), and vancomycin (RR: 0.55; 95% CI: 0.25–1.21) had lower RRs when heparin was referent. When all of the antibiotics were grouped together, this explains the improved precision and higher evidence certainty. However, compared with our review, this meta-analysis study mixed the studies that used lock solutions for prevention and treatment.47  In the previous meta-analysis of 4 studies, taurolidine demonstrated a statistically significant reduction in the total number of CRBSI compared with the control (RR: 0.23; 95% CI: 0.13–0.40).10  In the meta-analysis of 14 RCTs (adult and children) comparing the efficacy of taurolidine solution to other lock solutions for prevention of CVAD-associated BSI, the incident rate ratio was 0.36 (95% CI: 0.18–0.71), also favoring taurolidine over heparin-only lock solutions.48  Overall, our result for chelating agents and antibiotics are concordant with previous evidence.

In the treatment of CVAD-associated BSI, none of the lock solutions demonstrated certainty of performance, with very low to low evidence-quality across all lock solutions. Previous systematic review and meta-analysis (19 studies; mixed prospective and retrospective cohort) of catheter salvage strategies in children with CRBSI and CLABSI, reported the recurrence was low with both antibiotic (6%; 95% CI: 1–15) and ethanol lock (6%; 95% CI: 2–11).32  To gain more accurate insights and assess the potential impact of lock solutions on the treatment of CVAD-associated BSI, further research or studies with larger sample sizes would be necessary. Additionally, it is important to report outcomes clearly, distinguishing between short-term treatment failure and long-term failure, including relapse (for both treatment and secondary prophylaxis) and reinfection (for primary and secondary prophylaxis approaches). This categorization is crucial for accurately determining whether the lock solutions are more effective for both treatment and prophylaxis purposes.

For the prevention of CVAD occlusion, there was high evidence-quality that ethanol increased the odds of occlusion. Ethanol might cause occlusion by precipitating plasma proteins or heparin in flushes used between locks, or might interact adversely with microbial biofilm.49  In the previous systematic review, which assessed adverse effects associated with ethanol catheter lock solutions, it was reported that the use of ethanol locks was associated with structural changes in catheters and elution of molecules from the catheter polymers.50  The review also reported that clinical studies revealed systemic toxicity, increased catheter occlusion, and breaches in catheter integrity.50  The Infusion Nurses Society Standards6  recommends that practitioners follow catheter manufacturers’ instructions for intraluminal locking with ethanol, as these structural changes have been observed in CVADs made of polyurethane, but not silicone, and have led to catheter rupture and splitting. The European Society for Clinical Nutrition and Metabolism (ESPEN) guideline, albeit for adults, also recommends not to use ethanol for CVAD locking.22 

The Infusion Nurses Society Standards6  recommends either heparin 10 U per mL or preservative-free 0.9% sodium chloride for locking CVADs in children. Antimicrobial locking solution for therapeutic and prophylactic purposes is recommended for use in patients with long-term CVADs, patients with a history of multiple CRBSIs, high risk patient populations, and in facilities with unacceptably high rates of CLABSI, despite other methods of CLABSI reduction in in place. Antiseptic locking solutions include ethanol, taurolidine, citrate, 26% sodium chloride, methylene blue, fusidic acid, and T-EDTA are recommended to be used alone or in combination. Although antibiotics have shown benefits in the prevention of CRBSI, their use can contribute to the overuse of antibiotics, which in turn can lead to the development of antibiotic resistance.51  To address this concern, further studies are needed to explore the potential of antiseptic agents, including chelating agents, as alternatives to antibiotics for CVAD-associated BSI prevention. By investigating the effectiveness of chelating agents, we can potentially reduce the reliance on antibiotics and mitigate the risk of antibiotic resistance.

Our study has limitations. First, there was substantial uncertainty around the point estimates of the different lock solutions for the various outcomes examined in this review. This could be because of the limited number of studies available for some outcomes and the variability in the quality of the evidence. In addition, the heterogeneity among the studies in terms of patient characteristics, catheter types, and study designs could have contributed to the observed uncertainty. Therefore, it is important to interpret the findings of this study with caution and to consider the limitations of the available evidence. More high-quality studies are needed to confirm the efficacy and safety of different lock solutions for the prevention and management of catheter-related complications in pediatric patients. Future reviews should examine the effectiveness of alternative management interventions, including routine disinfection, and the influence of intrinsic risk factors.

In conclusion, this network meta-analysis provides some evidence to support the use of chelating and antibiotic locks for the prevention of CVAD-associated BSI in pediatric patients. Thrombolytic agents may be a preferred option for preventing CVAD occlusion, whereas ethanol may not be recommended for this purpose. However, further research is needed to confirm these findings and to evaluate the efficacy and safety of these and other lock solutions for various catheter-related complications in pediatric patients.

We extend our deepest gratitude to Linda Nguyen for her invaluable contribution to formatting the figures for this article.

Ms Takashima and Ms Ezure conceptualized and designed the study, designed the data collection instruments, collected data, conducted the initial analyses, and drafted the initial manuscript; Mr Dufficy collected data; Dr Ullman conceptualized and designed the study; Dr Furyua-Kanamori conceptualized and designed the study and coordinated and supervised data collection; and all authors critically reviewed and revised the manuscript, approved the final manuscript as submitted, and agree to be accountable for all aspects of the work.

FUNDING: This review article was funded by the Cancer Council Queensland (ACCR-118).

CONFLICT OF INTEREST DISCLOSURES: The authors have indicated they have no conflicts of interest to disclose.

BSI

blood stream infections

CI

confidence interval

CRBSI

catheter-related bloodstream infection

CVAD

central venous access device

EDTA

ethylenediaminetetraacetic acid

GPM

generalized pairwise modelling

GRADE

Grading of Recommendations Assessment, Development and Evaluation

OR

odds ratio

QE

quality effects model

RCT

randomized controlled trials

RR

relative risk

T-EDTA

tetrasodium ethylenediaminetetraacetic acid

UVC

umbilical venous catheter

1
Ullman
AJ
,
Marsh
N
,
Mihala
G
,
Cooke
M
,
Rickard
CM
.
Complications of central venous access devices: a systematic review
.
Pediatrics
.
2015
;
136
(
5
):
e1331
e1344
2
Ullman
AJ
,
Gibson
V
,
Takashima
MD
, et al
.
Pediatric central venous access devices: practice, performance, and costs
.
Pediatr Res
.
2022
;
92
(
5
):
1381
1390
3
Athale
UH
,
Siciliano
S
,
Cheng
J
,
Thabane
L
,
Chan
AK
.
Central venous line dysfunction is an independent predictor of poor survival in children with cancer
.
J Pediatr Hematol Oncol
.
2012
;
34
(
3
):
188
193
4
Deitcher
SR
,
Gajjar
A
,
Kun
L
,
Heideman
RL
.
Clinically evident venous thromboembolic events in children with brain tumors
.
J Pediatr
.
2004
;
145
(
6
):
848
850
5
Forbrigger
Z
,
Kulkarni
K
.
Use of tissue plasminogen activator as a surrogate measure for central venous catheter dysfunction and survival outcome in children with cancer: a population-based retrospective cohort study
.
Pediatr Hematol Oncol
.
2020
;
37
(
7
):
554
560
6
Gorski
LA
,
Hadaway
L
,
Hagle
ME
, et al
.
Infusion therapy standards of practice, 8th ed
.
J Infus Nurs
.
2021
;
44
(
1S Suppl 1
):
S1
S224
7
Bradford
NK
,
Edwards
RM
,
Chan
RJ
.
Heparin versus 0.9% sodium chloride intermittent flushing for the prevention of occlusion in long term central venous catheters in infants and children
.
Cochrane Database Syst Rev
.
2015
;
11
(
11
):
CD010996
8
Gorski
LA
.
The 2016 infusion therapy standards of practice
.
Home Healthc Now
.
2017
;
35
(
1
):
10
18
9
O’Grady
NP
,
Alexander
M
,
Burns
LA
, et al
.
Guidelines for the prevention of intravascular catheter-related infections
.
Clin Infect Dis
.
2011
;
52
(
9
):
e162
e193
10
Sun
Y
,
Wan
G
,
Liang
L
.
Taurolidine lock solution for catheter-related bloodstream infections in pediatric patients: a meta-analysis
.
PLoS One
.
2020
;
15
(
4
):
e0231110
11
Mai
H
,
Zhao
Y
,
Salerno
S
, et al
.
Citrate versus heparin lock for prevention of hemodialysis catheter-related complications: updated systematic review and meta-analysis of randomized controlled trials
.
Int Urol Nephrol
.
2019
;
51
(
6
):
1019
1033
12
Clark
JE
,
Graham
N
,
Kleidon
T
,
Ullman
A
.
Taurolidine–citrate line locks prevent recurrent central line–associated bloodstream infection in pediatric patients
.
Pediatr Infect Dis J
.
2019
;
38
(
1
):
e16
e18
13
Hill
J
,
Garner
R
.
Efficacy of 4% tetrasodium ethylenediaminetetraacetic acid (T-EDTA) catheter lock solution in home parenteral nutrition patients: a quality improvement evaluation
.
J Vasc Access
.
2021
;
22
(
4
):
1533
539
14
Percival
SL
,
Kite
P
,
Eastwood
K
, et al
.
Tetrasodium EDTA as a novel central venous catheter lock solution against biofilm
.
Infect Control Hosp Epidemiol
.
2005
;
26
(
6
):
515
519
15
Liu
F
,
Hansra
S
,
Crockford
G
, et al
.
Tetrasodium EDTA is effective at eradicating biofilms formed by clinically relevant microorganisms from patients’ central venous catheters
.
mSphere
.
2018
;
3
(
6
):
e00525
18
16
Rahhal
R
,
Abu-El-Haija
MA
,
Fei
L
, et al
.
Systematic review and meta-analysis of the utilization of ethanol locks in pediatric patients with intestinal failure
.
JPEN J Parenter Enteral Nutr
.
2018
;
42
(
4
):
690
701
17
Wolf
J
,
Connell
TG
,
Allison
KJ
, et al
.
Treatment and secondary prophylaxis with ethanol lock therapy for central line-associated bloodstream infection in paediatric cancer: a randomised, double-blind, controlled trial
.
Lancet Infect Dis
.
2018
;
18
(
8
):
854
863
18
da Costa
ACC
,
Vieira
NNP
,
Vasques
CI
,
Ferreira
EB
,
Guerra
ENS
,
dos Reis
PED
.
Interventions for occluded central venous catheters: a meta-analysis
.
Pediatrics
.
2019
;
144
(
6
):
e20183789
19
Schoot
RA
,
van Dalen
EC
,
van Ommen
CH
,
van de Wetering
MD
.
Antibiotic and other lock treatments for tunnelled central venous catheter‐related infections in children with cancer
.
Cochrane Database Syst Rev
.
2013
;(
6
):
CD008975
20
Page
MJ
,
McKenzie
JE
,
Bossuyt
PM
, et al
.
The PRISMA 2020 statement: an updated guideline for reporting systematic reviews
.
BMJ
.
2021
;
372
:
n71
21
Clark
J
,
Glasziou
P
,
Del Mar
C
,
Bannach-Brown
A
,
Stehlik
P
,
Scott
AM
.
A full systematic review was completed in 2 weeks using automation tools: a case study
.
J Clin Epidemiol
.
2020
;
121
:
81
90
22
Pironi
L
,
Arends
J
,
Bozzetti
F
, et al
.
ESPEN guidelines on chronic intestinal failure in adults
.
Clin Nutr
.
2016
;
35
(
2
):
247
307
23
Gaur
AH
,
Bundy
DG
,
Werner
EJ
, et al
.
A Prospective, holistic, multicenter approach to tracking and understanding bloodstream infections in pediatric hematology-oncology patients
.
Infect Control Hosp Epidemiol
.
2017
;
38
(
6
):
690
696
24
Ullman
A
,
Kleidon
T
,
Gibson
V
, et al
.
Innovative dressing and securement of tunneled central venous access devices in pediatrics: a pilot randomized controlled trial
.
BMC Cancer
.
2017
;
17
(
1
):
595
25
Goossens
GA
,
De Waele
Y
,
Jérôme
M
, et al
.
Diagnostic accuracy of the Catheter Injection and Aspiration (CINAS) classification for assessing the function of totally implantable venous access devices
.
Support Care Cancer
.
2016
;
24
(
2
):
755
761
26
Higgins
JPTSJ
,
Savović
J
, et al
.
RoB 2: A revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:4898
27
Doi
SA
,
Barendregt
JJ
,
Khan
S
,
Thalib
L
,
Williams
GM
.
Advances in the meta-analysis of heterogeneous clinical trials I: the inverse variance heterogeneity model
.
Contemp Clin Trials
.
2015
;
45
(
Pt A
):
130
138
28
Shim
S
,
Yoon
BH
,
Shin
IS
,
Bae
JM
.
Network meta-analysis: application and practice using Stata
.
Epidemiol Health
.
2017
;
39
:
e2017047
29
Cipriani
A
,
Furukawa
TA
,
Salanti
G
, et al
.
Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis
.
Lancet
.
2009
;
373
(
9665
):
746
758
30
Salanti
G
.
Indirect and mixed-treatment comparison, network, or multiple-treatments meta-analysis: many names, many benefits, many concerns for the next generation evidence synthesis tool
.
Res Synth Methods
.
2012
;
3
(
2
):
80
97
31
Doi
SA
,
Thalib
L
.
A quality-effects model for meta-analysis
.
Epidemiology
.
2008
;
19
(
1
):
94
100
32
Buonsenso
D
,
Salerno
G
,
Sodero
G
, et al
.
Catheter salvage strategies in children with central venous catheter-related or -associated bloodstream infections: a systematic review and meta-analysis
.
J Hosp Infect
.
2022
;
125
:
1
20
33
Schünemann
HJ
,
Higgins
JP
,
Vist
GE
,
Glasziou
P
,
Akl
EA
,
Skoetz
N
, et al
.
Completing ‘Summary of findings’ tables and grading the certainty of the evidence. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA, eds. Cochrane Handbook for Systematic Reviews of Interventions;
2019
:
375
402
34
Atkinson
JB
,
Chamberlin
K
,
Boody
BA
.
A prospective randomized trial of urokinase as an adjuvant in the treatment of proven Hickman catheter sepsis
.
J Pediatr Surg
.
1998
;
33
(
5
):
714
716
35
Decembrino
N
,
Brandolini
M
,
Pagani
M
, et al
.
Lock-therapy with ethanol for the salvage of colonized long-term central venous catheter: experience in oncohematological pediatric patients
.
Bone Marrow Transplant
.
2014
;
49
:
S467
36
Filippi
L
,
Pezzati
M
,
Di Amario
S
,
Poggi
C
,
Pecile
P
.
Fusidic acid and heparin lock solution for the prevention of catheter-related bloodstream infections in critically ill neonates: a retrospective study and a prospective, randomized trial
.
Pediatr Crit Care Med
.
2007
;
8
(
6
):
556
562
37
Handrup
MM
,
Møller
JK
,
Schrøder
H
.
Central venous catheters and catheter locks in children with cancer: a prospective randomized trial of taurolidine versus heparin
.
Pediatr Blood Cancer
.
2013
;
60
(
8
):
1292
1298
38
Jones
GR
,
Dillon
PW
,
Bagnall-Reeb
H
,
Buckley
J
,
Haase
GM
.
Urokinase for prevention of central venous catheter occlusions and infections: results of the children’s cancer group study CCG-S921
.
Pediatr Res
.
2001
;
49
(
4
):
215A
39
Lyszkowska
M
,
Kowalewski
G
,
Szymczak
M
,
Polnik
D
,
Mikolajczyk
A
,
Kalicinski
P
.
Effects of prophylactic use of taurolidine-citrate lock on the number of catheter-related infections in children under 2 years of age undergoing surgery
.
J Hosp Infect
.
2019
;
103
(
2
):
223
226
40
Onder
AM
,
Chandar
J
,
Simon
N
, et al
.
Comparison of tissue plasminogen activator-antibiotic locks with heparin-antibiotic locks in children with catheter-related bacteraemia
.
Nephrol Dial Transplant
.
2008
;
23
(
8
):
2604
2610
41
Schoot
RA
,
van Ommen
CH
,
Stijnen
T
, et al
.
Prevention of central venous catheter-associated bloodstream infections in paediatric oncology patients using 70% ethanol locks: a randomised controlled multi-centre trial
.
Eur J Cancer
.
2015
;
51
(
14
):
2031
2038
42
Ullman
AJ
,
Edwards
R
,
Walker
R
, et al
.
Routine catheter lock solutions in pediatric cancer care: a pilot randomized controlled trial of heparin vs saline
.
Cancer Nurs
.
2022
;
45
(
6
):
438
446
43
La Quaglia
MP
,
Caldwell
C
,
Lucas
A
, et al
.
A prospective randomized double-blind trial of bolus urokinase in the treatment of established Hickman catheter sepsis in children
.
J Pediatr Surg
.
1994
;
29
(
6
):
742
745
44
Giacomozzi
LM
,
Silva
RPVC
,
Danski
MTR
,
Carreiro
JE
, et al
.
Efetividade do ácido ascórbico e solução fisiológica no acesso venoso central pediátrico: ensaio clínico randomizado
.
Cogitare Enfermagem
.
2022
;
27
:
1139
1151
45
Lopes
BC
,
Borges
P
,
Gallindo
RM
,
Tenório
TBS
,
Machado
LB
,
de Orange
FA
.
Ethanol lock therapy for the prevention of nontunneled catheter-related bloodstream infection in pediatric patients
.
JPEN J Parenter Enteral Nutr
.
2019
;
43
(
8
):
1044
1052
46
Baskin
JL
,
Pui
C-H
,
Reiss
U
, et al
.
Management of occlusion and thrombosis associated with long-term indwelling central venous catheters
.
Lancet
.
2009
;
374
(
9684
):
159
169
47
Guo
Q
,
Lv
Z
,
Wang
H
, et al
.
Catheter lock solutions for reducing catheter-related bloodstream infections in paediatric patients: a network meta-analysis
.
J Hosp Infect
.
2021
;
118
:
40
47
48
Van Den Bosch
CH
,
Jeremiasse
B
,
Van Der Bruggen
JT
, et al
.
The efficacy of taurolidine containing lock solutions for the prevention of central-venous-catheter-related bloodstream infections: a systematic review and meta-analysis
.
J Hosp Infect
.
2022
;
123
:
143
155
49
Schilcher
G
,
Schlagenhauf
A
,
Schneditz
D
, et al
.
Ethanol causes protein precipitation–new safety issues for catheter locking techniques
.
PLoS One
.
2013
;
8
(
12
):
e84869
50
Mermel
LA
,
Alang
N
.
Adverse effects associated with ethanol catheter lock solutions: a systematic review
.
J Antimicrob Chemother
.
2014
;
69
(
10
):
2611
2619
51
Dixon
JJ
,
Steele
M
,
Makanjuola
AD
.
Anti-microbial locks increase the prevalence of Staphylococcus aureus and antibiotic-resistant Enterobacter: observational retrospective cohort study
.
Nephrol Dial Transplant
.
2012
;
27
(
9
):
3575
3581
52
Akyüz
C
,
Küpeli
S
,
Yagci-Küpeli
B
, et al
. Prophylactic taurolidine use in central venous catheters of pediatric cancer patients: a prospective randomized study from single center. In: Proceedings from the 42nd Congress of the International Society of Pediatric Oncology, SIOP 2010; 21 to 24 October,
2010
; Boston, MA United States.
949
53
Aquino
VM
,
Sandler
ES
,
Mustafa
MM
,
Steele
JW
,
Buchanan
GR
.
A prospective double-blind randomized trial of urokinase flushes to prevent bacteremia resulting from luminal colonization of subcutaneous central venous catheters
.
J Pediatr Hematol Oncol
.
2002
;
24
(
9
):
710
713
54
Araujo
MC
,
Silva
JSE
,
Barros
MMd
.
Intermittent heparin is not effective at preventing the occlusion of peripherally inserted central venous catheters in preterm and term neonates
.
Rev Bras Ter Intensiva
.
2011
;
23
(
3
):
335
340
55
Bracho-Blanchet
E
,
Cortés-Sauza
J
,
Dávila-Pérez
R
,
Lezama-Del Valle
P
,
Villalobos-Alfaro
C
,
Nieto-Zermeño
J
.
Usefulness of intravenous heparin to prevent thrombosis of central venous catheter in children
.
Cir Cir
.
2010
;
78
(
5
):
423
429
56
Cesaro
S
,
Tridello
G
,
Cavaliere
M
, et al
.
Prospective, randomized trial of two different modalities of flushing central venous catheters in pediatric patients with cancer
.
J Clin Oncol
.
2009
;
27
(
12
):
2059
2065
57
Choi
ES
,
Im
HJ
,
Kim
H
, et al
.
Comparison of normal saline with heparin solution for flushing central venous catheter in pediatric patients
.
Pediatr Blood Cancer
.
2020
;
67
(
SUPPL 4
)
58
Dümichen
MJ
,
Seeger
K
,
Lode
HN
, et al
.
Randomized controlled trial of taurolidine citrate versus heparin as catheter lock solution in paediatric patients with haematological malignancies
.
J Hosp Infect
.
2012
;
80
(
4
):
304
309
59
Daghistani
D
,
Horn
M
,
Rodriguez
Z
,
Schoenike
S
,
Toledano
S
.
Prevention of indwelling central venous catheter sepsis
.
Med Pediatr Oncol
.
1996
;
26
(
6
):
405
408
60
Ferreira Chacon
JM
,
Hato de Almeida
E
,
de Lourdes Simoes
R
, et al
.
Randomized study of minocycline and edetic acid as a locking solution for central line (port-a-cath) in children with cancer
.
Chemotherapy
.
2011
;
57
(
4
):
285
291
61
Garland
JS
,
Alex
CP
,
Henrickson
KJ
,
McAuliffe
TL
,
Maki
DG
.
A vancomycin-heparin lock solution for prevention of nosocomial bloodstream infection in critically ill neonates with peripherally inserted central venous catheters: a prospective, randomized trial
.
Pediatrics
.
2005
;
116
(
2
):
e198
e205
62
Goossens
GA
,
Jérôme
M
,
Janssens
C
, et al
.
Comparing normal saline versus diluted heparin to lock non-valved totally implantable venous access devices in cancer patients: a randomised, non-inferiority, open trial
.
Ann Oncol
.
2013
;
24
(
7
):
1892
1899
63
Henrickson
KJ
,
Axtell
RA
,
Hoover
SM
, et al
.
Prevention of central venous catheter-related infections and thrombotic events in immunocompromised children by the use of vancomycin/ciprofloxacin/heparin flush solution: a randomized, multicenter, double-blind trial
.
J Clin Oncol
.
2000
;
18
(
6
):
1269
1278
64
Rackoff
WR
,
Weiman
M
,
Jakobowski
D
, et al
.
A randomized controlled trial of the efficacy of a heparin and vancomycin flush solution in preventing central venous catheter infections in children
.
J Pediatr
.
1995
;
127
(
1
):
147
151
65
Schwartz
C
,
Henrickson
KJ
,
Roghmann
K
,
Powell
K
.
Prevention of bacteremia attributed to luminal colonization of tunneled central venous catheters with vancomycin-susceptible organisms
.
J Clin Oncol
.
1990
;
8
(
9
):
1591
1597
66
Seliem
W
,
Abdel-Hady
H
,
El-Nady
G
.
Amikacin-heparin lock for prevention of catheter-related bloodstream infection in neonates with extended umbilical venous catheters use: a randomized controlled trial
.
J Neonatal Perinatal Med
.
2010
;
3
(
1
):
33
41
67
Smith
S
,
Dawson
S
,
Hennessey
R
,
Andrew
M
.
Maintenance of the patency of indwelling central venous catheters: is heparin necessary?
Am J Pediatr Hematol Oncol
.
1991
;
13
(
2
):
141
143

Supplementary data