Necessity of heparin for maintaining peripheral venous catheters: A systematic review and meta‑analysis
- Authors:
- Published online on: June 28, 2017 https://doi.org/10.3892/etm.2017.4706
- Pages: 1675-1684
Abstract
Introduction
Heparin has been widely used for the maintenance of intravascular catheters in patients requiring intravenous medications or arterial hemodynamic monitoring. The beneficial roles of heparin solution in ameliorating catheter occlusion, prolonging patency and reducing phlebitis have been investigated in a number of clinical studies (1,2). As a classical anticoagulant-medicine, heparin is considered to prevent the formation of thrombus within the indwelling catheter while being used as a flushing or locking solution (3–6). However, other studies have reported no additional benefits from heparin compared to normal saline in promoting catheter patency (7–9). A previous systematic review and meta-analysis of randomized controlled trials (RCTs) indicated that intermittent flushing with heparin was not superior to normal saline in reducing catheter occlusion, whereas low dose infusion with heparin may improve the catheter patency and prevent phlebitis (4). Furthermore, two Cochrane systematic reviews were unable to provide conclusive evidence favoring the application of heparin solution over normal saline in the maintenance of central venous and arterial catheters (10,11).
Previous studies on the use of heparin solution in peripheral venous catheters have shown controversial results. One Cochrane review that included both randomized and quasi-randomized trials reported significant heterogeneity among studies, which were not available for a meta-analysis (1). Another systematic review that focused on pediatric patients reported that continuous heparin infusion improved catheter patency, decreased infusion failures and lessened phlebitis. However, the same study showed no significant benefits of intermittent heparin flushing (3). A recent meta-analysis demonstrated similar beneficial roles of heparin solution in continuous infusion rather than intermittent flushing in adults (12).
Despite its wide use in daily practice, there are some concerns about the safety of heparin. For example, heparin has been shown to induce thrombocytopenia, and increasing bleeding risk and allergic reactions may occur following heparin infusion or flushes (13). Furthermore, a routine use of heparin for the most extensively placed peripheral venous catheters may unnecessarily increase the cost of health care when its cost-effectiveness remains unclear (14). As such, a number of RCTs with inconsistent or conflicting results have been published, prompting further debate on the use of heparin solution for peripheral venous catheter maintenance (15–17). Therefore, this updated systematic review and meta-analysis of RCTs was conducted to more precisely evaluate the role of heparin in maintaining peripheral venous catheters.
Materials and methods
Search strategy
A comprehensive literature search up to February 2016 was performed using PubMed (www.ncbi.nlm.nih.gov/pubmed), Embase (www.embase.com), Web of Science (www.isiknowledge.com) and Cochrane Central Register of Controlled Trials (www.cochranelibrary.com/about/central-landing-page.html) without language limitation. Manual searching was also used to identify eligible studies from key journals, major conference abstracts, original articles and reference lists. The following Medical Subject Headings and free text words were used: ‘Heparin’, ‘placebo’, ‘control’ and ‘peripheral’. Furthermore, the search was restricted to human studies and RCTs.
Study selection
Two investigators independently assessed the articles, and any disagreements were resolved by consensus with a third reviewer. Studies were selected if they met the following criteria: i) RCTs, ii) conducted in subjects with peripheral venous catheters, iii) compared heparin added to intravenous fluid vs. no heparin added to the similar fluid and iv) measured catheter patency, occlusion, infusion failure or phlebitis. Furthermore, studies in which the subjects received systemic anticoagulation with heparin from any other access were excluded.
Data extraction
Abstracts and full texts of the studies included were retrieved by two reviewers independently and managed in Endnote X7 (Clarivate Analytics, Philadelphia, PA, USA). Data were extracted by two reviewers and further verified by a third reviewer, who then resolved the disagreements. The following data were extracted and stored in standardized forms: First author, publication year, country, study type, population and protocol, patient and catheter numbers, catheter material and size, heparin dosage and frequency of administration, outcomes and results.
Assessment of bias
The quality of the studies were evaluated using the Cochrane risk of bias tool (18), comprising of random sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and other bias. Any discrepancies were resolved by consensus with a third reviewer.
Outcomes
In the majority of the studies included, the primary outcomes of interest reported were catheter occlusion and patency duration. Secondary outcomes were infusion failure caused by any reasons, phlebitis and other major adverse events associated with the use of heparin. Phlebitis was determined when pain, induration, tenderness, erythema or palpable cord was recorded. Furthermore, major adverse events included heparin induced thrombocytopenia, allergy and major bleeding.
Data analysis
The effects of heparin solution from either continuous infusion or intermittent flushing studies were analyzed for subgroups. The total effects of dichotomous data using risk ratios (RRs) were pooled. Continuous outcomes were expressed as the mean ± standard deviation (SD) and analyzed using standard mean differences (SMDs). Furthermore, the I2 test was conducted to assess the heterogeneity among the studies. Once significant heterogeneity was found (I2>50%), the random effects models (Inversed-Variance) were used and a sensitivity analysis was performed to verify the consistency of the results. Alternatively, the fixed model (Mantel-Haenszel for dichotomous data and Inverse-Variance for continuous data) was selected for the analysis. The Egger's and Begg's tests, and funnel plots were used to assess the publication bias, and subgroup analysis and meta-regression were used to identify potential sources for heterogeneity between studies. Statistical analysis was performed with Stata (version 12; StataCorp LLC, College Station, TX, USA), using the metan, metareg and metainf commands amongst others. A two-sided P≤0.05 was considered statistically significant.
Results
Study selection and characteristics
A standard workflow of searching and selection of eligible studies according to the PRISMA statement (19) is presented in Fig. 1. In total, 629 references from electronic databases were revealed by the literature search, of which, 293 were identified as duplicates due to the overlap of the databases. The remaining 336 citations were screened for eligibility, yielding 81 studies for full-text review. Further examination of the relevant reference lists of published reviews and meta-analyses identified 15 additional citations. Finally, 32 studies were found to comply with the predefined inclusion criteria. The characteristics of the final 32 studies included in the present review are displayed in Table I, among which, there are 21 reported results for intermittent flushing (7–9,14–17,20–33) and 11 evaluated heparin for continuous infusion (34–44).
Baseline characteristics
Among the 32 studies included in the present review, the scale ranged from 16 patients/16 catheters to 451 patients/1,257 catheters. In total, 10 studies reported multiple catheters per patient (15–17,23,25,27,37–39,43), with the rest of the studies reported a single catheter per patient. The study populations included pediatric patients (14,15,21–24, 26–29,32,33,37–39,44), healthy volunteers and adults (7–9,16,17, 20,30,31,34–36,40–43), and the administered treatments in all studies primarily consisted of antibiotics and parenteral nutrition. Furthermore, the origin of countries reported included the USA (7,8,14,20,26–28,30,32,33,35,43), the UK (39,40), Germany (38), France (36), the Netherlands (22), Australia (44), Italy (17), Canada (25), Ireland (34), India (15,31) and China (16). In the infusion studies, the concentration of heparin varied between 0.1 and 2 U/ml, whereas in the intermittent flush studies the concentration used varied between 2 and 100 U/ml. Finally, the material of catheters included Teflon, polyurethane, Neoflon and polyethylene, and the size of catheters varied between 16 and 26 gauge.
Methodological quality
The majority of the studies demonstrated a low to unclear level of risk of bias, as shown in Fig. 2. In total, 10 studies did not properly address the methods for the generation of random sequence (14,21,28,29,33,36, 38,40–42). The majority of studies described an adequate method of allocation concealment, with 5 reported unclear results (8,22,31,40,43). Furthermore, all studies reported well-defined methods of blinding except for 2 studies (31,34). In terms of selective reporting and bias, however, the majority of studies did not provide a clear description. Although incomplete data were included in 5 studies, only small portions of subjects were removed following randomization. In addition, 7 studies did not provide drop-out details (28,34,40–44).
Meta-analysis
OcclusionOf the included studies, 21 reported the rates of occlusion per catheter, whereas 11 studies presented the occlusion rates per patient. The use of heparin in intermittent flushing lead to a 20% reduced risk in catheter occlusion [RR, 0.80; 95% confidence interval (CI), 0.66–0.98; P<0.05], and a similar reduction of the occlusion rate was exhibited in continuous heparin infusion studies (RR, 0.82; 95% CI, 0.69–0.98; P<0.05). In addition, the use of heparin also significantly decreased the overall risk of occlusion (RR, 0.81; 95% CI, 0.71–0.93; P<0.01). Finally, no significant heterogeneity was observed among the studies (intermittent, I2=26.9%; continuous, I2=5.5%; overall, I2=17.8%; Fig. 3) and no publication bias was noticed among the studies as indicated by Egger's (continuous, P=0.962; intermittent, P=0.801; overall, P=0.560) and Begg's (continuous, P=0.624; intermittent, P=0.464; overall, P=0.554) tests.
Duration of catheter patency
The duration of catheter patency was reported in 22 studies, including 6 of continuous infusion and 16 of intermittent flushing. These studies described the duration in h (mean ± SD), which were summarized in Table I. In some studies, elective removal was issued for a quantity of catheters, which were separately recorded in the results. Other studies directly combined results from both elective and non-elective catheter removals. As shown in Fig. 4, continuous infusion of heparin solution in peripheral intravenous catheters significantly increased the duration of catheter patency (SMD, 0.90; 95% CI, 0.48–1.32; P<0.001) whereas intermittent flushing with heparin did not display significant differences compared with placebo (SMD, 0.11; 95% CI, −0.05–1.27; P=0.165; Fig. 4A). Furthermore, between-sample heterogeneities were significant in both groups (continuous, I2=92.4%; intermittent, I2=72.0%), therefore potential sources of these observations were sought. The continuous infusion studies demonstrated no publication bias, as assessed by Egger's (P=0.11) and Begg's (P=0.57) tests. However, in the intermittent flushing studies, the Egger's test showed significant publication bias (P<0.05) whereas the Begg's test did not display any significant difference. Notably, subgroup analysis revealed that both the duration of catheter patency (SMD, 0.30; 95% CI, 0.17–0.42; P<0.01) and occlusion profile (RR, 0.64; 95% CI, 0.48–0.86; P<0.01) were significantly improved when a higher concentration of heparin (100 U/ml) was used as an intermittent flushing solution.
Furthermore, a population-based subgroup analysis was conducted in the intermittent flushing studies and no significant changes of catheter patency by heparin were detected in children (SMD, 0.10; 95% CI, −0.07–0.27; P=0.25) or adult population (SMD, 0.14; 95% CI, −0.25–0.52; P=0.49). Homogeneity tests showed persistent between-study heterogeneity in both children (I2=63.6%) and adults (continuous, I2=85.3%; Fig. 4B). Additionally, a univariate meta-regression test showed that the publication year, generation of random sequence, censor of elective catheter removal as well as catheter/patient ratio did not contribute significantly to the heterogeneity observed in the duration of patency.
Infusion failureA total of 7 studies utilizing continuous infusion of heparin solution and 11 studies testing intermittent flushing with heparin presented this outcome as dichotomous data. A usage-based subgroup meta-analysis was performed for each group. Accordingly, only continuous application of heparin significantly reduced the risk of infusion failure in peripheral intravenous catheters (RR, 0.83; 95% CI, 0.76–0.92; P<0.001), whereas intermittent flushing with heparin failed to show a statistical difference (RR, 0.93; 95% CI, 0.81–1.06; P=0.28). Nevertheless, heparin demonstrated a significant overall effect on decreasing infusion failure in peripheral intravenous catheters (RR, 0.86; 95% CI, 0.80–0.93; P<0.001). Further analysis showed no significant between-study heterogeneities (continuous, I2=0%; intermittent, I2=49.5%; overall, I2=37.2%; Fig. 5A). There was also no evidence of potential publication bias among the studies included as assessed by Begg's (continuous, P=0.453; intermittent, P=0.938; overall, P=0.678) and Egger's tests (continuous, P=0.261; intermittent, P=0.425; overall, P=0.935).
When heparin was used as intermittent flushing, no significant difference of infusion failure was noted in either children (RR, −0.06; 95% CI, −0.20–0.08; P=0.40) or adult (RR, −0.34; 95% CI, −0.92–0.24; P=0.26) populations, as indicated by population-based subgroup tests (Fig. 5B). Further analysis of meta-regression indicated no significant association between the years of publication, catheter/patient ratios, censoring for catheter removal, generation of random sequence and the heterogeneity noticed in infusion failure.
PhlebitisThe majority of included studies reported phlebitis as an outcome in binary format. According to the meta-analysis, the use of heparin significantly lowered the rates of phlebitis in both intermittent flushing (RR, 0.70; 95% CI, 0.56–0.86; P<0.01) and continuous infusion (RR, 0.66; 95% CI, 0.58–0.75; P<0.001) as compared with the placebo. The overall effect of heparin on reducing phlebitis was also statistically significant (RR, 0.67; 95% CI, 0.60–0.75; P<0.001). Furthermore, the tests for homogeneity revealed a low level of heterogeneity among studies (continuous, I2=21.1%; intermittent, I2=30.3%; overall, I2=21.9%; Fig. 6), and no significant publication bias was indicated by Egger's (continuous, P=0.105; intermittent, P=0.230; overall, P=0.589) and Begg's (continuous, P=0.095; intermittent, P=0.807; overall, P=0.527) tests.
Major adverse events
One study reported adverse events, one of which reported 10 intracranial bleeding events, and 23 episodes of heparin-induced thrombocytopenia in neonates (38). Other studies only reported mild-bleedings, and no onset of sepsis or allergic reaction was noted (17,25,38).
Discussion
Heparin has been utilized as an antithrombotic agent for maintaining catheters for four decades. Anticoagulation by heparin is predominantly mediated through antithrombin III in plasma (45). Due to rapid pharmacokinetics and a relatively lower cost, heparin is widely and routinely used in clinical practice. In some countries and medical facilities, flushing and locking catheters with heparin solutions are becoming standard procedures. However, a number of clinical trials studying heparin in catheter maintenance failed to find significance of its efficacy (8,9,14,23,26). Therefore, several systematic reviews and meta-analyses are conducted but their results remain controversial (3,4,11). Whereas many studies focus on central venous catheters, only a few have investigated the role of heparin in peripheral catheters. The present study performed an updated systematic review and meta-analysis of the efficacy of heparin solution used as both continuous infusion and intermittent flushing in peripheral venous catheters.
The results of the current meta-analysis demonstrated that the addition of heparin significantly reduced the rate of catheter occlusion, infusion failure and prolonged the duration of catheter patency in continuous infusion of a peripheral venous catheter. Conversely, heparin also showed a border effect on reducing occlusion and failed to display improvements in the duration of patency as well as infusion failure as an intermittent flushing solution. Nevertheless, a significant decrease was observed in the rate of phlebitis in both intermittent and continuous use of heparin.
The majority of infusion studies used low concentrations of heparin (1 U/ml) (34–39,41–44), whereas the majority of intermittent flushing studies used higher concentrations (10–100 U/ml). It is speculated that the difference of effects between these two distinctive modes of heparin usage may be due to discrepancies of concentrations. Notably, it was revealed that there were significant benefits in catheter patency when heparin was used for intermittent flushing at the highest concentration of 100 U/ml. In addition, the pooled effect demonstrated that a higher frequency of flushing with heparin did not bring any further advantages in catheter patency. Additionally, one study of intermittent flushing with heparin showed no significant difference in catheter patency between concentrations of 1 and 10 U/ml (21). Conversely, an intergroup difference corresponding to concentration gradients of heparin was reported in one study using heparin as a continuous infusion (39).
In 1991, two meta-analyses including randomized and quasi-randomized studies were published, which reported that heparin solution was not superior to normal saline in maintaining patency of vascular catheters (46,47). Another meta-analysis from 1998, which included only RCTs, demonstrated different results, in which heparin improved catheter patency during continuous infusion rather than intermittent flushing (4). However, in subgroup analysis, the authors revealed that a higher concentration of heparin exerted substantial benefits in catheter patency compared with the placebo. This result is in accordance with the present findings that a higher concentration of heparin was beneficial in intermittent flushing. More recently, two updated meta-analyses reported the efficacy of heparin on catheter patency in adults and children, respectively. In the first study, which focused on pediatric patients, heparin was shown to improve catheter patency while being continuously infused (3). In the second study, which focused on adult patients, inclusion of heparin in continuous infusion solutions resulted in improved patency outcomes and less phlebitis (12). Nonetheless, neither study reported significant benefits of heparin in intermittent application. Another systemic review by Shah and Shah (1) focused in neonates but did not conduct a meta-analysis due to high heterogeneity among the studies included, in which both semi-randomized and randomized trials were included.
Besides similar observations of phlebitis in the use of heparin as a continuous infusion, the present study demonstrated significant beneficial effects of heparin on preventing phlebitis as an intermittent flushing solution. Considering a similar duration of patency and occlusion profiles in the intermittent use of heparin compared with placebo was demonstrated in the present results, this improvement in phlebitis by heparin may be independent of catheter patency. Traditionally, phlebitis is considered to be caused by thrombosis and is usually called ‘thrombophlebitis’ (48). The observations of the present study that heparin showed additional benefits in preventing phlebitis besides anticoagulation may be explained by its anti-inflammatory role, which has been reported in sports injuries and inflammatory bowel disease (49,50). Notwithstanding these benefits, administration of heparin may result in potential complications such as bleeding, thrombocytopenia and allergy (51–53). These drawbacks may discourage the clinical use of heparin at higher concentrations, although the morbidity of the complications has been low in previous observations (7,13,16,51,53).
The meta-analysis of the present study showed improved outcomes of patency in the continuous infusion; however, the results must be interpreted with caution due to a series of limitations. First of all, high heterogeneity was observed in the analysis of duration of catheter patency. Furthermore, a subsequent meta-regression of the catheter/patient ratio, proper generation of randomization, year of publication and censoring for elective withdrawal failed to identify significant sources of heterogeneity. Additionally, since SMD was used as pooled effects for the continuous data as h, the discrepancies in the acquisition of outcomes among different studies may compromise the homogeneity of the results. Also, it is not possible to delineate the effects of the catheter material on the current observations in the present meta-analysis due to insufficient catheter information. The lack of sub-group studies with concentration gradients made it difficult to pool a concentration-dependent outcome. Additionally, there are other causes of bias in this review. For instance, a few studies included multiple groups that used other agents in combination with heparin (36,42,43), and some other studies reported a considerable drop-out rate of the subjects (9,35,42). Furthermore, one study reported the median rather than the mean and SD, and only effect size can be obtained from another (39,44). It is noteworthy that one study with a large number of patients used cluster randomization instead of the classical randomization method (17). In addition, multi-center or large-scale RCTs were not identified for inclusion in the current meta-analysis. All of these factors may contribute to the heterogeneity and bias among the studies and affect the quality of the meta-analysis.
In conclusion, this updated systematic review and meta-analysis demonstrated that the use of heparin as a continuous infusion may significantly improve the patency of peripheral intravenous catheters, whereas intermittent flushing with heparin only reduces the rate of occlusion but shows no significant benefit on the duration of patency and infusion failure. Furthermore, the present findings suggest that both intermittent and continuous uses of heparin in peripheral intravenous catheters ameliorate phlebitis.
Acknowledgements
The authors are grateful to Dr Li Zhu (Soochow University; Suzhou, China) for his contributions to the search updates and manuscript preparation.
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