Central venous access device (CVAD) locks are routine interventions used to prevent and treat complications, such as infection, thrombosis, and catheter occlusion.
To compare and rank lock-solutions for prevention or treatment of complications in pediatrics. Design Systematic review and network meta-analysis.
Five databases and 2 clinical trial registries were searched.
Published and unpublished randomized controlled trials that enrolled pediatric patients with a CVAD and compared the effectiveness of lock-solutions.
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.
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.
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.
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:
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?
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?
Methods
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
Literature Search and Selection
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.).
Selections Criteria
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:
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.
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
Lock Interventions
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.
Classification of Lock Solutions
Lock Solutions . | Lock 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 Solutions . | Lock 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 |
Outcomes
Primary Outcomes
CVAD-associated BSI (prevention): author definition with minimal criteria of laboratory-confirmed, positive blood or catheter tip culture.23
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.
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
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
CVAD occlusion (prevention): complete occlusion of the catheter when injecting fluids or medications.25
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.
CVAD failure: cessation of CVAD function before completion of treatment, resulting in CVAD removal and replacement vascular access.
Mortality: during the study period.
Data Extraction
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.
Quality Assessment
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.).
Statistical Analysis
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
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 and Sensitivity Analyses
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).
Assessment of the Certainty of the Evidence
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
Results
Identified Studies
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).
Characteristics of Included Studies
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%).
Characteristics of the Included Studies (N = 29 Studies)
First Author and Year of Publication . | Study Location . | Study Scale . | Randomization and Blinding . | Number of Participants/ Devices . | Inclusion Age Criteria . | Patient Population Description - Diagnostic Group . | Type of CVAD . | Lock Solutions (N of participant/ N of CVAD days) . | Lock Solution Category . | Primary Purpose . | Frequency of Administration . | |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Akyüz, 201052 | Turkey | SC | I | 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 | I | 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 | I | 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 | I | 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 | I | 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 | I | 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 | I | 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 | B | 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 | I | 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 | I | 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 | I | 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 | I | 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 | B | 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 | I | 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 | I | 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 | B | 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 | I | 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 | B | 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 | I | 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 | I | 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 | I | 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 | I | 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 | I | 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 | B | 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 | B | 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 | I | 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 | B | 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 | B | 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 Publication . | Study Location . | Study Scale . | Randomization and Blinding . | Number of Participants/ Devices . | Inclusion Age Criteria . | Patient Population Description - Diagnostic Group . | Type of CVAD . | Lock Solutions (N of participant/ N of CVAD days) . | Lock Solution Category . | Primary Purpose . | Frequency of Administration . | |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Akyüz, 201052 | Turkey | SC | I | 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 | I | 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 | I | 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 | I | 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 | I | 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 | I | 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 | I | 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 | B | 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 | I | 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 | I | 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 | I | 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 | I | 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 | B | 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 | I | 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 | I | 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 | B | 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 | I | 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 | B | 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 | I | 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 | I | 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 | I | 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 | I | 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 | I | 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 | B | 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 | B | 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 | I | 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 | B | 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 | B | 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
Quantitative Synthesis
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 6–8). 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).
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) . |
Heparin . | Comparator . | Comparator . | Comparator . | Comparator . | Comparator . | Comparator . |
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 | 5 | 9 | 12 | 10 | 5 |
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) . |
Heparin . | Comparator . | Comparator . | Comparator . | Comparator . | Comparator . | Comparator . |
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 | 5 | 9 | 12 | 10 | 5 |
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.
Downgraded because of inconsistency.
Downgraded because of imprecision.
Downgraded because of risk of bias.
Not ranked.
(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.
(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.
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 16–19). 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.
(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).
(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).
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).
Discussion
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.
Acknowledgments
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
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