Normal saline (0.9% sodium chloride) versus heparin intermittent flushing for the prevention of occlusion in long‐term central venous catheters in infants and children

Natalie K Bradford; Rachel M Edwards; Raymond J Chan

doi:10.1002/14651858.CD010996.pub3

Lavado intermitente con solución salina normal (cloruro de sodio al 0,9%) versus heparina para la prevención de la oclusión en catéteres venosos centrales a largo plazo en lactantes y niños

Authors' declarations of interest

Version published: 30 April 2020 Version history

https://doi.org/10.1002/14651858.CD010996.pub3

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Resumen

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Antecedentes

Las guías y la práctica clínica para la prevención de las complicaciones asociadas con los catéteres venosos centrales (CVC) en todo el mundo varían enormemente. La mayoría de las instituciones recomiendan el uso de la heparina para prevenir la oclusión; sin embargo, existe un debate en torno a la necesidad de la heparina y hay evidencia que indica que la solución salina normal (cloruro de sodio al 0,9%) puede ser igual de eficaz. El uso de la heparina no está exento de riesgos, puede ser innecesario y también se asocia a un aumento de los costos. Esta es una actualización de la revisión publicada en 2015.

Objetivos

Evaluar los efectos clínicos (efectos beneficiosos y perjudiciales) de el lavado intermitente con solución salina normal versus heparina para prevenir la oclusión en los catéteres venosos centrales a largo plazo en lactantes y niños.

Métodos de búsqueda

El especialista en información del Grupo Cochrane Vascular (Cochrane Vascular Group) buscó en el Registro especializado del grupo, en las bases de datos CENTRAL, MEDLINE, Embase y CINAHL; en la World Health Organization International Clinical Trials Registry Platform y en el registro de ensayos ClinicalTrials.gov hasta el 9 de abril de 2019. También se realizó una verificación de las referencias, una búsqueda de citas y se estableció contacto con los autores de los estudios para identificar estudios adicionales.

Criterios de selección

Se incluyeron los ensayos controlados aleatorizados (ECA) que compararon la eficacia del lavado intermitente con solución salina normal versus heparina para prevenir la oclusión de los CVC a largo plazo en lactantes y niños de hasta 18 años de edad. Se excluyeron los CVC temporales y los catéteres centrales de inserción periférica.

Obtención y análisis de los datos

Dos autores de la revisión, de forma independiente, aplicaron los criterios de inclusión, evaluaron la calidad de los ensayos ensayos y extrajeron los datos. La calidad de los estudios se evaluó con la herramienta de "Riesgo de sesgo" de Cochrane. Para los resultados dicotómicos se calculó el cociente de tasas (CT) y el correspondiente intervalo de confianza (IC) del 95%. Los datos se agruparon mediante un modelo de efectos aleatorios y se utilizó GRADE para evaluar la certeza general de la evidencia que respalda los resultados evaluados en esta revisión.

Resultados principales

Se identificó un nuevo estudio en esta actualización, con lo que el número total de estudios incluidos asciende a cuatro (255 participantes). Los cuatro ensayos compararon directamente el uso de la solución salina normal y la heparina; sin embargo, todos los estudios utilizaron protocolos diferentes para los brazos de intervención y control, y todos utilizaron diferentes concentraciones de heparina. También se informó de diferentes frecuencias de lavados entre los estudios. Además, no todos los estudios informaron sobre todos los resultados. La certeza de la evidencia varió de moderada a muy baja porque no hubo cegamiento; la heterogeneidad e inconsistencia entre los estudios fue alta y los IC fueron amplios. En los cuatro ensayos se evaluó la oclusión del CVC. Fue posible agrupar los resultados de dos ensayos sobre los resultados de la oclusión del CVC y la bacteriemia asociada con el CVC. El CT calculado para la oclusión del CVC por 1000 días de catéter entre los grupos de solución salina normal y heparina fue 0,75 (IC del 95%: 0,10 a 5,51; dos estudios, 229 participantes; evidencia de certeza muy baja). El CT calculado para la bacteriemia asociada con el CVC fue 1,48 (IC del 95%: 0,24 a 9,37; dos estudios, 231 participantes; evidencia de certeza baja). Se informó de que la duración de la colocación del catéter fue similar en los dos brazos del estudio en un estudio (203 participantes; evidencia de certeza moderada), y no se informó al respecto en los estudios restantes.

Conclusiones de los autores

La revisión encontró que no hubo evidencia suficiente para determinar los efectos del lavado intermitente con solución salina normal versus heparina para prevenir la oclusión de los catéteres venosos centrales a largo plazo en lactantes y niños. Sigue sin estar claro si la heparina es necesaria para prevenir la oclusión, la bacteriemia asociada con el CVC o los efectos de la duración de la colocación del catéter. Todavía no hay acuerdo entre las instituciones de todo el mundo con respecto al cuidado y mantenimiento adecuados de estos dispositivos.

PICOs

Population

Intervention

Comparison

Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Resumen en términos sencillos

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Sustituir el lavado con heparina por el lavado con solución salina para prevenir complicaciones en los catéteres venosos centrales a largo plazo en los niños

Antecedentes

Un catéter venoso central (CVC) es un tubo largo, delgado y flexible que se inserta en una gran vena central. Este permite el acceso a la sangre para que los pacientes con problemas médicos graves puedan recibir fármacos y líquidos, así como para la recogida de muestras de sangre. Los CVC a largo plazo se utilizan para acceder al sistema sanguíneo en niños con afecciones médicas complejas como el cáncer. Para evitar que el catéter se bloquee es habitual utilizar heparina, un fármaco que evita la formación de coágulos, para limpiar el catéter. Sin embargo, algunos estudios han demostrado que la heparina no es necesaria, y que en su lugar se puede utilizar con seguridad una solución salina normal (una solución estéril de agua salada). La heparina se puede asociar con complicaciones, como hemorragias e infecciones, junto con mayores costos para los profesionales sanitarios. Si bien las complicaciones como las infecciones y las oclusiones son poco frecuentes, las prácticas varían en todo el mundo y hay muchas inconsistencias en cuanto a la mejor solución de lavado que se debe utilizar para prevenir las complicaciones en los catéteres a largo plazo.

Características de los estudios y resultados clave

Esta revisión incluyó ensayos controlados aleatorizados (estudios clínicos en los que las personas se asignaron al azar a uno de dos o más grupos de tratamiento) que compararon el uso de solución salina y heparina para prevenir la obstrucción y otras complicaciones relacionadas con los catéteres a largo plazo. La evidencia está actualizada hasta el 9 de abril de 2019. Dos autores de la revisión examinaron los estudios de forma independiente. En la revisión se incluyeron cuatro estudios con un total de 255 participantes. Los cuatro ensayos se realizaron en grandes hospitales docentes (terciarios) y compararon directamente el uso de la solución salina y la heparina. Sin embargo, los estudios fueron muy diferentes en cuanto a la forma en que compararon la solución salina y la heparina, con diferentes concentraciones de heparina y diferentes frecuencias de lavados informadas. Fue posible combinar los resultados de dos estudios: el análisis mostró resultados poco precisos del bloqueo de los catéteres y de las infecciones de la sangre para la solución salina normal versus la heparina. Un estudio informó que la duración de la colocación del catéter fue similar entre los dos brazos de estudio.

Certeza de la evidencia

La certeza general de la evidencia varió de moderada a muy baja. Hubo un alto riesgo de sesgo de cegamiento, hubo diferencias entre los métodos e intervenciones de los estudios, resultados inconsistentes entre los estudios y no todos los estudios informaron de todos los resultados de interés. Se determinó que no hubo suficiente evidencia para determinar qué solución, salina o heparina, es más eficaz para reducir las complicaciones. Se necesitan estudios de investigación adicionales y es probable que tengan una importante repercusión en esta área. Esta revisión es una actualización de una revisión publicada por primera vez en 2015.

Authors' conclusions

Implications for practice

There is insufficient evidence to determine the effects of intermittent flushing with normal saline versus heparin to prevent occlusion in long‐term central venous catheters in infants and children. It remains unclear whether heparin is necessary to prevent occlusion, CVC‐associated blood stream infection or the effects of prolonged catheter placement. Lack of agreement remains between institutions around the world regarding the appropriate care and maintenance of these devices.

Implications for research

Given the results of this review, there is a need for healthcare organisations to consider undertaking further research in this area to contribute to the evidence base. Ultimately this would facilitate the development of evidence‐based clinical practice guidelines and consistency of practice. Careful attention to study design is required, including blinding and proper sample size calculations to detect clinically meaningful differences, and ensuring only one aspect of the intervention is changed in the intervention arm (flushing frequency, concentration of heparin or use of normal saline). Additionally, reporting on variables that may influence outcomes, such as catheter maintenance processes, infection control processes and packaging of flush solutions, would assist with evaluation. Such studies would generate evidence and ensure results could be appraised and generalised to address the current gaps in knowledge. Consistency of outcome reporting would aid interpretation of results. No studies measured the costs associated with the intervention or control arms. If efficacy is similar between both normal saline and heparin, then the use of heparin incurs costs to health systems with no advantages; cost analysis would be a useful addition to future studies. Alternatively, decision models could be used to ascertain what differences in complication rates would make a meaningful difference in costs or outcomes.

Summary of findings

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Summary of findings 1. Does normal saline flushing in long‐term central venous catheters (CVC) prevent occlusion compared to heparin flushing in infants and children?

Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	No. of participants (RCTs)	Certainty of the evidence (GRADE)	Comments
Normal saline versus heparin flushing for prevention of occlusion in long‐term CVC in infants and children
Patient or population: infants and children with a long‐term CVC Settings: tertiary hospitals Intervention: normal saline flush Control: heparin flush
Outcomes	Risk with heparin flush	Risk with normal saline flush	Relative effect (95% CI)	No. of participants (RCTs)	Certainty of the evidence (GRADE)	Comments
CVC occlusion rate per 1000 catheter days: ability to infuse solution through CVC Follow‐up: 3029 to 115,991 at‐risk days	Study population		Rate ratio 0.75 (0.10 to 5.51)	229 (2 RCTs)	⊕⊝⊝⊝ very low^1,2,3
	551 per 1000	507 per 1000 (99 to 1000)	Rate ratio 0.75 (0.10 to 5.51)	229 (2 RCTs)	⊕⊝⊝⊝ very low^1,2,3
CVC‐associated blood stream infection rate per 1000 catheter days: incidence of positive blood culture Follow‐up: 3029 to 115,991 at‐risk days	Study population		Rate ratio 1.48 (0.24 to 9.37)	231 (2 RCTs)	⊕⊕⊝⊝ low^1,3,4,5
	93 per 1000	209 per 1000 (103 to 425)	Rate ratio 1.48 (0.24 to 9.37)	231 (2 RCTs)	⊕⊕⊝⊝ low^1,3,4,5
Duration of CVC placement (days) Follow up: median 360 days	See comment			203 (1 RCT)	⊕⊕⊕⊝ moderate^1,4	Cesaro 2009 reported this in terms of survival, not in days. Mean survival was reported as 77% (95% CI 66% to 84%) in the normal saline group and 69% (95% CI 53% to 80%) in the heparin group. No differences were found in cause or frequency of premature removal of catheter between study arms. The remaining studies did not report on this outcome.
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; CVC: Central venous catheter; RCTs: Randomised controlled trial
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹No blinding in either study. Performance and detection bias is high in both studies ²Heterogeneity and inconsistency between studies is high ³Confidence intervals were wide and included the null hypothesis ⁴Results could be attributed to other factors associated with the use of heparin ⁵The outcomes could also be attributed to the use of positive pressure cap in the Cesaro 2009 study

Background

Description of the condition

A central venous catheter (CVC) is a long, thin, flexible tube which is inserted into a large central vein, with the tip of the catheter ideally placed within the superior vena cava (Schuster 2000). This enables the administration of medications and fluids, as well as the collection of blood specimens, and avoids multiple venipunctures. CVCs are commonly known as 'central lines' or by their brand name including Broviac, Hickman, and Port‐a‐Cath. The use of long‐term CVCs for the management of chronic medical conditions in infants and children has greatly improved the quality and safety of care provision. Long‐term CVCs are typically inserted when the administration of intravenous medication or nutritional support is required over a considerable time period. Hypertonic medications such as vesicant chemotherapy drugs, certain antibiotics, other supportive drugs and parenteral nutrition cannot be safely administered through peripheral venous catheters. For children with cancer and other chronic medical conditions who require such medications, this safety issue is overcome by the insertion of a CVC which commonly remains in place for the duration of treatment (Gonzalez 2012). There are three types of long‐term CVCs: tunnelled catheters; totally implanted catheters; and peripherally inserted central catheters (PICC). A tunnelled CVC is surgically inserted under the skin, with the catheter lumen(s) typically exiting from the chest or neck. A totally implanted catheter is also surgically inserted, but is placed entirely under the skin and commonly referred to as a 'port'. The port reservoir is accessed with a needle through the skin. A PICC line is inserted into a central vein through the arm and thus is a narrower catheter.

Adverse events associated with CVCs may cause complications in up to 46% of children (Athale 2012). Adverse events in the scope of this review include mechanical failure, catheter fracture, infections and intravascular thrombosis, all of which can affect patient morbidity and mortality (Baskin 2009; Fratino 2005; Stocco 2012; Wong 2012). Mechanical failure is often attributed to catheter occlusion. Over time, it is common for a fibrin sheath to develop at the tip of the catheter. The fibrin sheath may prevent aspiration of blood from the catheter and cause resistance when infusing fluids. An intraluminal clot can also occur, which can totally occlude the catheter. Intraluminal clots may occur as a result of precipitate from medications, which would not be prevented by use of heparin; or from blood refluxing into the catheter lumen and forming a clot. Occlusion can result in the need for the catheter to be removed (and replaced), interrupting and delaying treatment of the underlying disease (Shah 2007). Occlusions of CVCs are estimated to occur in 14% to 36% of patients within one to two years of catheter insertion (Fratino 2005); or at an incidence rate of 1.35 per 1000 catheter days (95% confidence interval (CI) 1.10 to 1.63) (Revel‐Vilk 2010). Incidence rates of central‐line‐associated blood stream infection differ depending upon the type of catheter, with rates reported between 1.40 per 1000 catheter days (95% CI 1.06 to 1.82) and 0.46 per 1000 catheter days (95% CI 0.29 to 0.69). Intravascular thrombosis is the rarest adverse event reported in children, with a lower incidence rate of 0.08 per 1000 catheter days (95% CI 0.04 to 0.16), and can only be diagnosed by radiographic methods (Fratino 2005). Intravascular thrombosis may or may not occur concurrently with other complications.

Description of the intervention

A flush refers to a solution of 0.9% sodium chloride (normal saline) injected to clear or 'rinse' the catheter of blood or fibrin build‐up. This is commonly used when the catheter is accessed, between administration of medications, or before and after collection of blood specimens. A lock is used to instil fluid into the catheter when the catheter will not be accessed for a period of time. A positive pressure lock refers to the technique used to ensure blood does not flow back into the catheter after it is flushed, which may otherwise clot and cause occlusion. Tunnelled CVCs and PICC lines are typically flushed and locked weekly, while implanted ports are flushed and locked every 4 to 6 weeks. A typical lock solution for tunnelled catheters in children is to use between 1 mL to 3 mL (depending on the volume of the catheter) of 10 units/mL of heparin for a 24‐hour to 7‐day lock. For implanted ports, 5 mL of 100 units/mL is typically used as a lock solution for a 30‐day lock (Davis 2013). There is debate, however, regarding the effectiveness of heparin to prevent occlusion over such time periods, given its short half‐life (Young 2008). The evidence to support the use of heparin to prevent occlusion in adult CVCs is inconclusive and there is growing evidence to support the use of normal saline to lock CVCs, particularly in the paediatric population (Bertoglio 2012; Lee 2005). In paediatrics, there is an additional risk of bleeding due to overdose of heparin from frequent flushing or incorrect dilution.

How the intervention might work

Heparin is used to prevent occlusion because of its anticoagulant properties which are believed to prevent thrombus forming in the catheter. Alternatively normal saline, when used with pulsatile (push‒pause rather than continuous) flushing techniques and a positive pressure lock or positive displacement device, may be as effective in preventing thrombus formation in catheters—eliminating the need for heparin to be used (Bertoglio 2012).

Why it is important to do this review

Catheter maintenance practices vary among institutions because of the lack of evidence regarding best practice to prevent occlusion of CVCs. Variations include the quantity of flush and lock solutions, the proportional volume of heparin lock solution, the concentration of heparin, and the frequency of flushes and locks. The use of heparin is not risk free and in certain instances may actually cause harm, including infection (Shanks 2005), and heparin‐induced thrombocytopenia (HIT) (Barclay 2012). The mechanism of haemostasis in children is different when compared to adults, particularly in infants and very young children; and the evidence suggests algorithms used in adults are unlikely to be valid in children (Monagle 2010). Additionally, treatments for diseases such as cancer involve the use of medications which can affect coagulation. In the absence of specific data related to paediatrics, using evidence based on adults may be inappropriate and there is a need for paediatric‐specific studies (Monagle 2010). For these reasons the use of heparin to prevent CVC occlusion should be judicious and evidence based. While the risks of adverse effects from the use of heparin may be regarded as less than those which might arise from occlusion of a catheter and subsequent replacement, it is important to ensure interventions are based on evidence.

In the adult population, there have been several trials investigating heparin versus normal saline to prevent occlusions in CVCs, six of which are summarised in a Cochrane Review (Lopez‐Briz 2018). As evidence from adult studies is not directly transferable to paediatrics, systematic reviews focused on infants and children are required. A review published in 2014 that did relate specifically to paediatrics did not identify all relevant studies and made recommendations based on the current practice of several institutions (Conway 2014). These recommendations were not evidence based, and are contrary to the practice of many other institutions. It is important, therefore, to systematically appraise the evidence for the use of normal saline compared with heparin to prevent occlusion of CVCs. This is an update of a previously published systematic review (Bradford 2015).

Objectives

To assess the clinical effects (benefits and harms) of intermittent flushing of normal saline versus heparin to prevent occlusion in long‐term central venous catheters in infants and children.

Methods

Criteria for considering studies for this review

Types of studies

We considered all randomised controlled trials (RCTs) that compared the efficacy of normal saline with heparin for the prevention of occlusion of central venous catheters (CVCs). Due to potential bias, we excluded studies that used alternative methods (quasi‐randomised) to allocate participants to an intervention or control group.

Types of participants

We included study populations comprising infants and children aged 0 to 18 years, who had a CVC (tunnelled catheter or totally implanted catheter) inserted for long‐term venous access. Because midline catheters are not placed in the same position as a CVC (superior or inferior vena cava), and PICC have narrow lumens which require specific care, studies of infants or children with midline catheters or PICCs were beyond the scope of this review and we excluded them. We placed no restrictions on the insertion site, or catheter tip placement site (superior or inferior vena cava). We placed no restrictions on the healthcare setting in which the study was conducted, for example tertiary hospital or community setting. Where studies had a mixed population that included infants, children and adults, we included data from infants and children only. If information was not presented in the article, we contacted the study authors to attempt to obtain age‐stratified results. If we were unable to contact the study authors, and children and infants comprised a proportion greater than 20% of the study population, we included the appropriate proportion of participants to represent the paediatric component. If we were unable to obtain any information regarding the proportion of infants and children in the study population, we excluded the study from the review.

Types of interventions

We included studies where the intervention of interest was the intermittent (any time frequency) flushing of normal saline (alone, or in combination with pulsatile flushing techniques, positive displacement devices or positive pressure lock) compared with intermittent flushing with heparin (any dose or concentration) delivered with the intention to prevent occlusion of the CVC.

Types of outcome measures

We did not consider outcome measures to be a part of eligibility criteria.

Primary outcomes

Occlusion of the CVC, determined by the inability to infuse fluids through the catheter
CVC‐associated blood stream infection or colonisation of the catheter (as defined by studies)
Duration in days of catheter placement

Secondary outcomes

Inability to withdraw blood from the CVC
Any use of urokinase or recombinant tissue plasminogen such as alteplase
Incidence of removal/re‐insertion of the catheter
CVC‐related thrombosis
Other CVC‐related complication (e.g. dislocation of CVCs, tunnel or site infection, allergic reaction, haemorrhage, heparin‐induced thrombocytopenia, elevated hepatic enzymes)

Search methods for identification of studies

Electronic searches

The Cochrane Vascular Information Specialist conducted systematic searches of the following databases for randomised controlled trials and controlled clinical trials without language, publication year or publication status restrictions.

Cochrane Vascular Specialised Register via the Cochrane Register of Studies (CRS Web searched on 9 April 2019)
Cochrane Central Register of Controlled Trials (CENTRAL) Cochrane Register of Studies Online (CRSO 2019, 3)
MEDLINE (Ovid MEDLINE® Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE® Daily and Ovid MEDLINE®) (searched from 1 January 2017 to 9 April 2019)
Embase Ovid (searched from 1 January 2017 to 9 April 2019)
CINAHL EBSCO (searched from 1 January 2017 to 9 April 2019)
AMED Ovid (searched from 1 January 2017 to 9 April 2019)

The Information Specialist modelled search strategies for other databases on the search strategy designed for CENTRAL. Where appropriate, they were combined with adaptations of the Highly Sensitive Search Strategy designed by Cochrane for identifying randomised controlled trials and controlled clinical trials (as described in the Cochrane Handbook for Systematic Reviews of Interventions, Chapter 6, Lefebvre 2011). Search strategies for major databases are provided in Appendix 1.

The Information Specialist searched the following trials registries on 9 April 2019.

World Health Organization (WHO) International Clinical Trials Registry Platform (who.int/trialsearch)
ClinicalTrials.gov

Searching other resources

Two review authors (NB, RE) screened the reference lists of retrieved articles for additional studies. We attempted to contact authors of any studies identified in unpublished literature to obtain further data.

Data collection and analysis

Selection of studies

Two review authors (NB, RE) independently reviewed all titles and abstracts of retrieved articles using Covidence software (Covidence), to assess eligibility against inclusion criteria. When disagreement arose regarding the inclusion of a study, the third author (RC) acted as arbitrator. We obtained the full text of all potentially eligible studies and contacted authors of primary studies to clarify data if necessary. We used a flowchart based upon the PRISMA statement to document results (Moher 2009). We recorded data on the results of all searches undertaken including database searched, date, limiters, and number of results. We recorded the reasons for exclusion of studies.

Data extraction and management

Two review authors (NB, RC) extracted the data independently using the Cochrane Vascular Group forms for dichotomous and continuous data. In the updated review, we also used Covidence to extract data (Covidence). Where available, we collected data regarding the:

lead author and year of study;
country where the study was undertaken;
participant inclusion criteria;
participant age and gender;
study design;
description of interventions;
setting of study;
number of participants in each arm;
attrition or losses to follow‐up;
variables associated with catheter maintenance (e.g. preparation of injectables (pre‐filled or not), caregiver level of education);
outcome measures.

We resolved any disagreement regarding data extraction by discussion between all review authors (NB, RE, RC).

Assessment of risk of bias in included studies

We assessed bias within studies using the tool described in the Cochrane Handbook for Systematic Reviews of Interventions and reported on the following domains: sequence generation; allocation concealment; blinding; incomplete data; selective outcome reporting; and other biases (Higgins 2011b). If necessary, primary authors were contacted to clarify any information. Two review authors (NB, RC) independently undertook the risk of bias assessment. We resolved disagreement regarding the assessment of bias by discussion between review authors (NB, RC).

Measures of treatment effect

As dichotomous outcomes such as occlusion or central‐line‐associated blood stream infection could occur more than once for individual participants (e.g. once in each lumen of a double lumen CVC), we calculated count data per time at risk of outcome (per 1000 catheter days) and reported rate ratios (RR) with 95% confidence intervals (CI). Using section 9.4.8 of the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2011), we also calculated the formula for the log of the standard error (SE) for each RR. We used descriptive statistics, including mean differences (MD) with 95% CI, for any continuous data. We planned to report time‐to‐event data as hazard ratios (HR) with 95% CI. We analysed data with Review Manager software (RevMan Web 2019).

Unit of analysis issues

We identified the unit of analysis in each study at either the patient or the catheter level. We planned to analyse studies separately for different units of analysis. Where results were reported from cluster RCTs, cross‐over trials or repeated measurements of the same outcome, we took the appropriate design effect into consideration to avoid unit of analysis error.

Dealing with missing data

We contacted primary authors of studies to attempt to obtain any missing data. We assessed all data for potential mislabelling and made no assumptions regarding missing data in order to include these in the analysis. Where data were missing and proved to be irretrievable, we excluded them from the analysis.

Assessment of heterogeneity

Where feasible, we assessed heterogeneity between effect sizes of included studies by visual inspection of forest plots and the Chi² test (P value < 0.05). We planned to describe inconsistency between trials by assessing the I² statistic and the variability between the effect estimates (Higgins 2003), with an I² value of 50% considered to represent substantial heterogeneity (Higgins 2011a). Additionally we considered the clinical heterogeneity of studies where the frequency of interventions or catheter type differed between studies.

Assessment of reporting biases

Where appropriate, we planned to assess publication bias using funnel plots and Egger's test (Egger 1997; Sterne 2011). Additionally, we reduced possible reporting bias by searching multiple electronic databases, proceedings of conferences and scientific meetings, and trial registries. We excluded duplicates of the same trial to avoid duplicate publication bias.

Data synthesis

The primary author (NB) entered data into RevMan Web (RevMan Web 2019), and undertook analysis according to recommended guidelines (Deeks 2011). We planned to combine effect sizes across studies using a fixed‐effect model and CI limits set at 95%. Where substantial heterogeneity existed, we pooled data using the random‐effects model. Where it was not appropriate to combine results, we presented a narrative review descriptively summarising the results.

Subgroup analysis and investigation of heterogeneity

We planned to conduct subgroup analysis where appropriate with:

type of CVC (tunnelled catheter or implanted port);
insertion site or catheter tip placement site, or both;
age group;
oncology or other diagnosis;
use of systemic heparin.

We were unable to do this as data were not available.

Sensitivity analysis

We planned to undertake sensitivity analyses to examine the effects of different trials and their methodology including: number of participants (≥ 50 vs < 50 participants); concentration of heparin; and duration of follow‐up. We were unable to do this as data were not available.

Summary of findings and assessment of the certainty of the evidence

We present the main findings of the review results concerning the certainty of evidence, the magnitude of effect of the interventions examined, the sum of available data for the primary outcomes CVC occlusion rate, and CVC‐associated blood stream infection and duration in days of catheter placement in summary of findings Table 1, according to Schünemann 2011 and Atkins 2004. We used GRADEprofiler (GRADEpro) software to assist in the preparation of the 'Summary of findings' table (GRADEpro GDT).

Results

Description of studies

Results of the search

See Figure 1.

Figure 1

Study flow diagram.

We identified one new study for this update (da Silva 2018); and included three studies from the previous version (Cesaro 2009; Goossens 2013; Smith 1991). We excluded 12 new studies (Arauj 2011; Arnts 2011; Brito 2018; Heidari Gorji 2015; Klein 2017; Klein 2018; NCT01343680; NCT00001518; NCT02354118; NCT02923830; Reichardt 2002; Schallom 2012).

Included studies

Based on the review of full texts, four studies met eligibility criteria and we have included them in the final updated review (Cesaro 2009; da Silva 2018; Goossens 2013; Smith 1991) (see Table: Characteristics of included studies). The studies undertaken by Cesaro 2009 and Goossens 2013 were of medium duration (25 and 23 months respectively) and included follow‐up periods of 14 and six months respectively. The Smith 1991 study was a cross‐over study of two time periods, each of three‐and‐a‐half months (total duration seven months) and did not include a follow‐up period. We were not able to ascertain if this study was analysed as paired data or not, and no information was available regarding the first cross‐over period. The da Silva 2018 study was a dissertation thesis and was undertaken over a period of 180 days without a follow‐up period. All studies had obtained ethical approval from their relevant institutions.

Population

The four included trials involved a total of 255 participants, with the majority of participants (203) coming from Cesaro 2009. Of the other three studies, Goossens 2013 contributed 28 participants, Smith 1991 contributed 14 participants and da Silva 2018 10 participants. Goossens 2013 and da Silva 2018 were not trials specific to children; Goossens 2013 had more participants in the control arm (n = 17) compared to the intervention arm (n = 11); and child participant numbers were balanced between the intervention and control arms in da Silva 2018. All participants had a long‐term central venous catheter (CVC), and were undergoing treatment for haematology or oncology conditions, or undergoing stem cell transplantation. Cesaro 2009 was undertaken in Italy, Goossens 2013 in Belgium, Smith 1991 in Canada and da Silva 2018 in Brazil. Participants in Smith 1991 and Cesaro 2009 had Broviac tunnelled CVCs inserted, da Silva 2018 participants all had Hickman catheters inserted, whereas all participants in Goossens 2013 had totally inserted catheters (ports) placed. All studies were undertaken in developed nations in tertiary referral centres, i.e. large hospitals that provide specialist health care after referral from the providers of primary care and secondary care. Both Cesaro 2009 and Goossens 2013 undertook power size calculations to obtain sample sizes; it is important to note, however, that children comprised only 3.5% of the Goossens 2013 study population, thus this study was not powered to analyse the results of children separately. Smith 1991 was a small study with only 14 participants. da Silva 2018 recruited only 17 of a planned 100 participants, of which 10 were children aged less than 18 years.

Intervention

Participants in all four included studies received standard care except where stated as follows.

All included studies involved an intervention arm where normal saline solution was used in place of heparinised saline when the CVC was not being used. As well as changing the type of solution used to flush the CVC, Smith 1991 increased the duration between flushes in the intervention arm. Participants in the control arm received standard care with CVCs flushed twice daily. In the intervention arm, the duration between flushes was increased to weekly. Similarly, Cesaro 2009 increased the duration between flushes in the intervention arm compared to standard care from twice per week to weekly. Cesaro 2009 also introduced a positive pressure cap into the intervention arm. These changes confound the interventions so it is not possible to associate outcomes with the use of the solution alone. Goossens 2013 and da Silva 2018 were the only two studies included in this review where the only difference between the intervention and control arm was the use of normal saline (intervention) or heparin (control) solution to flush the CVC under positive pressure. In da Silva 2018, it was not clear when participants received either solution; participants were inpatients and four syringes were prepared daily with either normal saline or heparin. However there is no information about when these syringes were administered, or if all four were administered each day. The intervention arm in da Silva 2018 may have received up to four catheter locks of normal saline each day. These catheter locks were administered whenever a catheter was not used.

Control

In all studies, participants randomised to the control arm received various concentrations of heparinised saline to flush their CVC. Participants in Smith 1991 received 5 mL of 10 units/mL heparinised saline (i.e. 50 units of heparin) twice daily. Participants in Cesaro 2009 received 3 mL of 200 units/mL heparinised saline (i.e. 600 units of heparin) twice weekly. In Goossens 2013, participants in the control arm received maintenance care (normal saline pulsatile flushes after infusions, blood sampling, etc.), and their CVC was flushed with 3 mL of 100 units/mL heparin (i.e. 300 units of heparin) under positive pressure at least every eight weeks when the CVC was not in use. In da Silva 2018, the control arm received up to four syringes daily of 3 mL containing 50 units of heparin per mL (150 units of heparin per syringe).

Outcomes

The primary outcome of interest, occlusion of CVC, was measured in all four studies included in this review. In Smith 1991, occlusion was defined as blockage of the catheter and measured by both echocardiogram to determine thrombus formation and inability to infuse fluids. Smith 1991 also recorded CVC‐associated blood stream and exit site infections. Blood stream infections were defined by Smith 1991 as the presence of systemic infection and positive blood cultures, and exit site infections were defined as the presence of infection and positive culture from the exit site. Cesaro 2009 defined CVC occlusion as the inability to withdraw blood or infuse fluids, or both. Cesaro 2009 also measured CVC‐associated blood stream infection, CVC mechanical issues and CVC‐related thrombosis. CVC‐associated blood stream infection was defined by Cesaro 2009 as one or more positive blood cultures obtained through the CVC in patients with signs of infection. CVC mechanical issues included dislodgement of the CVC tip or cuff, fracture or accidental CVC self‐removal by the patient; these outcomes were evaluated by visual inspection and chest X‐ray. CVC‐related thrombosis was measured where clinically indicated by ultrasound, computed tomography or magnetic resonance imaging. Goossens 2013 measured CVC occlusion as a secondary end point, their primary outcome was partial occlusion defined by easy infusion, difficulty withdrawing from CVC. Other secondary outcome measures in Goossens 2013 were CVC‐associated blood stream infection and other CVC mechanical issues. CVC‐associated blood stream infection was defined by Goossens 2013 as positive blood cultures from the CVC and peripheral veins, and fever or chills in the absence of other infection sources. CVC mechanical issues encompassed all other functional problems encountered with each access. da Silva 2018 measured CVC occlusion daily on both lumens of the CVC, defined as the inability to aspirate fluids/blood. If no fluids/blood could be withdrawn following repositioning, normal saline was injected. If there was resistance or pressure present, the CVC was noted as having a partial occlusion. If no fluids could be infused, the CVC was deemed to have a 'complete occlusion' and the lumen involved was then finished in the study. As the lumens of Hickman catheters are independent, the other lumen could remain in the study until it too occluded, or the study ended. As participants could experience outcomes more than once, all studies except da Silva 2018 reported the number of catheter days that participants in either study arm were at risk of experiencing an outcome.

Excluded studies

For this update, 12 studies were excluded as they did not meet the eligibility criteria (Arauj 2011; Arnts 2011; Brito 2018; Heidari Gorji 2015; Klein 2017; Klein 2018; NCT00001518; NCT01343680; NCT02354118; NCT02923830; Reichardt 2002; Schallom 2012). Six studies were excluded from the previous version (De Neef 2002; Geritz 1992; Kaneko 2004; Pumarola 2007; Rabe 2002; Schultz 2002), making a total of 18 excluded studies. Most studies were excluded because they were adult studies with no children (Arauj 2011; Arnts 2011; Heidari Gorji 2015; Kaneko 2004; Klein 2017; Klein 2018; NCT00001518; NCT01343680; NCT02354118; NCT02923830; Rabe 2002; Reichardt 2002; Schallom 2012). One study was not a RCT (Brito 2018); and one study was terminated after recruiting only two participants (NCT01343680). Geritz 1992 and Schultz 2002 reported trials investigating peripheral catheters; De Neef 2002 and Kaneko 2004 investigated arterial catheters; and Pumarola 2007 and Rabe 2002 investigated temporary central venous catheters. See Characteristics of excluded studies.

Risk of bias in included studies

See Figure 2, Figure 3 and Characteristics of included studies.

Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

There was low risk of selection bias in the Cesaro 2009, Goossens 2013 and da Silva 2018 studies; these investigators reported using computerised random sequencing and concealing allocation until participants had been recruited and provided consent. Smith 1991 did not provide any details regarding how participants were randomised and we therefore judged it to be of unclear risk of selection bias.

Blinding

da Silva 2018 was the only study that reported blinding participants, clinicians and researchers to which arm the participant was allocated and we deemed it to have low risk for performance bias and detection bias. Goossens 2013 stated blinding was not possible for logistical reasons. All outcomes were objectively measured, but in Cesaro 2009, Goossens 2013 and Smith 1991 there is the possibility clinicians may have modified their technique depending on the arm to which the participant had been allocated. We therefore assessed these three studies at high risk of both performance and detection bias.

Incomplete outcome data

All four studies included in this review reported full results for all participants who were randomised. A flowchart of participant progress through the study was provided by Goossens 2013. There were no protocol violations reported by Goossens 2013 or Cesaro 2009. In Goossens 2013 there was a 4.9% dropout rate which was not statistically different between the two groups and all analysis was based on intention to treat. This dropout rate relates to the adult participants and not the children included in this review. In Cesaro 2009, 22% (n = 44) of CVCs required premature removal; there were, however, no statistical differences between study arms. Attrition of two participants due to death also occurred in this study but no losses to follow‐up occurred. Smith 1991 and da Silva 2018 reported no losses to follow‐up. We assigned Cesaro 2009, da Silva 2018 and Smith 1991 a low risk of attrition bias, and Goossens 2013 an unclear risk.

Selective reporting

All studies reported on their primary and secondary outcome measures. There was a study protocol for da Silva 2018; we therefore deemed risk of reporting bias for this study to be low. Neither Cesaro 2009 nor Goossens 2013 had a published protocol and so we deemed them at unclear risk. Smith 1991 reported data in a basic format with no results from statistical tests. It is not clear if paired analysis was undertaken; we assessed this study as being at high risk for reporting bias.

Other potential sources of bias

In both the Cesaro 2009 and Smith 1991 studies, there is a high concern for confounding of results. Both these studies altered the frequency between flushes for the intervention arm as well as the concentration of the heparin solution. Additionally, the intervention arm included the use of a positive pressure cap in Cesaro 2009. It is not possible therefore to attribute the outcome to the use of the solution alone: the outcome could plausibly also be attributed to the frequency of flushes or the use of a positive pressure cap. It may therefore be more appropriate to view the intervention as a component of a bundle of care. Further bias may exist in the subset of unpublished data of paediatric participants provided by Goossens 2013; we were not able to determine if the characteristics of this subset of participants were subject to other biases. As it is a cross‐over study, there may have been a carry‐over effect of the intervention from one arm to the other in Smith 1991. It is not clear if the study authors considered this. da Silva 2018 recruited only 17 of a planned 100 participants: this small sample size reduced precision of the findings. Additionally it was not clear how long participants remained in the study. These other potential sources of bias across all four studies are substantial and they are all at high risk of bias for this domain.

Effects of interventions

See: Summary of findings 1 Does normal saline flushing in long‐term central venous catheters (CVC) prevent occlusion compared to heparin flushing in infants and children?

See summary of findings Table 1 for the three primary outcomes: CVC occlusion; CVC‐associated blood stream infection or colonisation; and duration in days of catheter placement. See Additional Table 1 for summary of outcome rates per 1000 catheter days.

Open in table viewer

Table 1. Rate per 1000 catheter days for primary and secondary outcomes

Outcome	Normal saline	Heparin	Normal saline	Heparin	Normal saline	Heparin
	Smith 1991		Cesaro 2009		Goossens 2013
CVC occlusion rate per 1000 catheter days	1.32	0.66	2.16	1.11	2.62	10.35
CVC‐associated blood stream infection rate per 1000 catheter days	1.32	0.66	0.62	0.24	0.32	1.04
Inability to withdraw blood	Not reported	Not reported	Not reported	Not reported	3.42	10.60
CVC dislodgement	0.33	1.65	0.47	0.54	Not reported	Not reported
CVC site infection	2.31	0.33	0.26	0.38	Not reported	Not reported
CVC‐related thrombosis	0.66	0.66	0.30	0.30	Not reported	Not reported

CVC: Central venous catheter

da Silva 2018 not included in table as rate per 1000 catheter days not able to be calculated

We were not able to ascertain if Smith 1991 analysed data as paired data or not, and no information was available regarding the first cross‐over period. We were not able to obtain data regarding the child participants in da Silva 2018, or information regarding the number of catheter days. We therefore did not pool results from these two studies with the others.