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Heparin for prolonging peripheral intravenous catheter use in neonates

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Authors

Prakeshkumar S Shah1, Eugene Ng2, Ajay K Sinha3

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs


1Department of Paediatrics and Department of Health Policy, Management and Evaluation, Rm 775A, University of Toronto, Toronto, Canada [top]
2Department of Newborn and Developmental Paediatrics, Sunnybrook Health Sciences Centre, Toronto, Canada [top]
3Department of Child Health, Queen Mary Hospital, London, UK [top]

Citation example: Shah PS, Ng E, Sinha AK. Heparin for prolonging peripheral intravenous catheter use in neonates. Cochrane Database of Systematic Reviews 2005, Issue 4. Art. No.: CD002774. DOI: 10.1002/14651858.CD002774.pub2.

Contact person

Prakeshkumar S Shah

Department of Paediatrics and Department of Health Policy, Management and Evaluation, Rm 775A
University of Toronto
600 University Avenue
Toronto Ontario M5G 1XB
Canada

E-mail: pshah@mtsinai.on.ca

Dates

Assessed as Up-to-date: 29 November 2010
Date of Search: 27 August 2010
Next Stage Expected: 29 November 2012
Protocol First Published: Issue 4, 2000
Review First Published: Issue 4, 2002
Last Citation Issue: Issue 4, 2005

What's new

Date / Event Description
29 November 2010
Updated

This review updates the existing review "Heparin for prolonging peripheral intravenous catheter use in neonates" published in the Cochrane Database of Systematic Reviews Shah 2005 .

Updated search in August 2010 found no new trials.

No changes to conclusions.

History

Date / Event Description
21 October 2008
Amended

Converted to new review format.

01 June 2006
Updated

This review updates the existing review of "Heparin for prolonging peripheral intravenous catheter use in neonates" (Shah 2002). The updated review contains information from two additional randomized controlled trials (Klenner 2003; Schultz 2002) which were eligible for inclusion.

There were no changes to the conclusions of this review.

01 June 2005
New citation: conclusions changed

Substantive amendment

Abstract

Background

Mechanical or infectious complications often necessitate their removal and/or replacement of peripheral intravenous catheters. Heparin has been shown to be effective in prolonging the patency of peripheral arterial catheters and central venous catheters, but may result in life threatening complications, especially in preterm neonates.

Objectives

The primary objective was to determine the effectiveness of heparin versus placebo or no treatment on duration of peripheral intravenous (PIV) catheter patency in neonates requiring a PIV catheter.

Search methods

A literature search was performed using the following databases: MEDLINE (1966 to February 2005), EMBASE (1980 to February 2005), CINAHL (1982 to February 2005), Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2005), and abstracts from the annual meetings of the Society for Pediatric Research, American Pediatric Society and Pediatric Academic Societies published in Pediatric Research (1991 to 2004). No language restrictions were applied.

This search was updated in 2010.

Selection criteria

Randomized or quasi-randomised trials of heparin administered as flush or infusion versus placebo or no treatment were included. Studies which included a neonatal population and reported on at least one of the outcomes were included.

Data collection and analysis

Data collection and analysis was performed in accordance with the recommendations of the Cochrane Neonatal Review Group.

Results

Ten eligible studies were identified. Heparin was administered either as a flush solution or as an additive to the total parenteral nutrition solution. Five studies reported data on the duration of use of the first catheter. Two of these studies found no statistically significant effect of heparin; two studies showed a statistically significant increase and one study showed a statistically significant decrease in the duration of PIV catheter use in the heparin group. There were marked differences between the studies in terms of the methodological quality, the dose, the timing, the route of administration of heparin and the outcomes reported. The results were not combined for meta-analysis. Individual studies did not report any significant differences between the heparin and the placebo/no treatment groups in the risks of infiltration, phlebitis and intracranial haemorrhage.

Authors' conclusions

There are insufficient data concerning the effect of heparin for prolonging PIV catheter use in neonates. Recommendations for heparin use in neonates with PIV catheters cannot be made. Further research on the effectiveness, the optimal dose, and the safety of heparin is required.

Plain language summary

Heparin for prolonging peripheral intravenous catheter use in neonates

Heparin in intravenous fluids may reduce IV tube changes needed for newborn babies in neonatal intensive care, but more research is needed to determine its safety. Babies in neonatal intensive care often need fluids intravenously (through a tube inserted into a vein). Sometimes the intravenous (IV) tube becomes blocked, as the blood clots and skin becomes swollen. Bacteria can also enter and cause serious infection. Regularly changing the tube (and which vein is used) can reduce some problems, but babies have few usable veins. The drug heparin used in the IV fluids could reduce blockages by thinning the blood, but it can have serious adverse effects. The review of trials found that more research is needed to determine whether heparin in IV fluids is advantageous for neonates without causing side effects.

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Background

Description of the condition

Intravenous infusion of drugs, fluids and nutrients has become an indispensable practice in present day medical care (Maki 1977; Lewis 1985; Tager 1983). Venous cannulation via peripheral intravenous (PIV) catheters is the simplest and most frequently used method for administration of an infusion. It is associated with inherent complications (Graham 1991) which can be mechanical or infectious (Lewis 1985; Tager 1983; Bossert 1994). Mechanical complications include thrombosis, dislodgement, extravasation, leakage, phlebitis and scar formation (Nieto-Rodrig 1992; Tomford 1984). Infectious complications include bacterial or fungal sepsis (Graham 1991). Thrombosis or phlebitis at the catheter site can act as a nidus for infection. Factors associated with the risk of these complications include duration of infusion, site of infusion, size and type of catheter, rate of flow through catheter, turbulence of fluid flow and characteristics of patients and infusate (Lewis 1985; Krafte-Jacobs 1995).

Description of the intervention

There have been various attempts to prevent or reduce PIV catheter related complications (Hecker 1992). These include designated intravenous therapy teams (Tomford 1984), frequent change in the site of catheters, placement of in-line filters (Roberts 1994), topical use of glyceryl trinitrate (Tighe 1995), hydrocortisone (Tighe 1995) or heparin (Vilardell 1999), intermittent heparinised saline flush or lock and continuous infusion of heparin (Tanner 1980; Hanson 1976; Daniell 1973; Johnstone 1991).

In a neonate, frequent change in catheter site at predetermined timings is technically challenging. In addition, repeated attempts at cannulation break the skin barrier and predispose these patients to infection by commensals in the skin such as coagulase negative staphylococcus. Such infections can be life threatening in neonates. PIV catheters are often left in situ in neonates until complications arise (Moclair 1995). Therefore, methods that can prolong the duration of viability of these catheters may be beneficial in this population.

Heparin, an anticoagulant, has been administered as intermittent injection or continuous infusion to prevent thrombus formation and consequently prolong catheter patency (Moclair 1995; Bossert 1994). However, significant effects of heparin on coagulation profiles have been observed (O'Neill 1974), even at low dose. Other adverse effects associated with heparin use include allergic reactions, bleeding complications due to dosing error, intraventricular haemorrhage in preterm infants (Malloy 1995; Lesko 1986) and heparin induced thrombocytopenia (Potter 1992).

Why it is important to do this review

The effectiveness of heparin for prolongation of PIV catheter life has been systemically reviewed previously. Goode 1991, Peterson 1991 and Randolph 1998 compared the efficacy of heparin versus normal saline in patients of all age groups. These reviews concluded that normal saline was as efficacious in prolonging catheter patency as heparin. However, only one study from these reviews studied neonates, so that the efficacy and safety of heparin was not ascertained specifically in neonates. Neonates are unique in their sensitivity and resistance to heparin (Vieira 1991) and in their higher propensity to develop intracranial haemorrhage (Lesko 1986).

Objectives

The primary objective of this review was to determine the effectiveness of heparin administered as continuous infusion or intermittent injections, via PIV catheter, versus placebo or no treatment, on duration of catheter patency (defined as number of hours of catheter use) in neonates.

Secondary objectives were to determine the effects of heparin on:

  1. Complications relating to PIV catheters:
    1. Catheter blockage (defined as inability to infuse fluid or medication);
    2. Phlebitis or thrombophlebitis developing at the site of or above the catheter (defined as pain, swelling, erythema or induration at the site of catheter with or without a palpable venous cord above the catheter site);
    3. Catheter related sepsis (defined as signs and symptoms suggestive of sepsis with positive blood culture growing the same organism in samples obtained from venipuncture at a different sterile site and from the catheter or catheter tip);
    4. Number of additional PIV catheter insertions.
  2. Complications relating to heparin:
    1. Abnormality of coagulation profile;
    2. Incidence of allergic reactions to heparin;
    3. Heparin induced thrombocytopenia (development of thrombocytopenia {platelet count < 150, 000 per cubic litre} after starting heparin in an infant with previously normal platelet count after exclusion of all other causes of thrombocytopenia and positive serotonin release test { Warkentin 1990});
    4. Intraventricular/intracranial haemorrhage (development of recent onset of haemorrhage or extension of preexisting haemorrhage after starting heparin, according to the classification of Papile 1978).
  3. Mortality

Subgroup analyses were planned a priori according to the method of heparin administration (continuous versus intermittent), and gestational age [preterm (less than 37 weeks gestation) versus term (more than or equal to 37 weeks gestation)]. A comparison of effects of different heparin doses was also planned if sufficient numbers of studies or trials using different dosage regimens were identified.

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Methods

Criteria for considering studies for this review

Types of studies

Randomised and quasi-randomised controlled trials in which heparin administration was compared to placebo or no treatment for the prevention of thrombosis or occlusion of PIV catheter.

Types of participants

Term or preterm infants who required PIV catheter as determined by the attending physicians during their stay in neonatal intensive care unit.

Types of interventions

Heparin by infusion or intermittent injections via PIV catheter, versus placebo or no treatment. Heparin or placebo must have been administered during the entire duration of the catheter being in situ.

Types of outcome measures

Studies that report on one or more of the following outcomes:

Primary outcomes
  1. Number of hours of catheter use, measured as time until catheter was removed.
Secondary outcomes
  1. Complications associated with PIV catheters including:
    1. occlusion of the catheter (identified by inability to infuse fluids);
    2. incidence of phlebitis or thrombophlebitis (one episode per patient);
    3. catheter related sepsis (one episode per patient);
    4. number of additional PIV catheters needed.
  2. Complications related to heparin
    1. abnormal coagulation profile;
    2. allergic reactions;
    3. heparin induced thrombocytopenia;
    4. intracranial or intraventricular haemorrhage.
  3. Neonatal mortality
    1. In this review, only data from the first catheter, retrieved either from the published studies or directly from the study authors, were used in reporting outcomes concerning the efficacy of heparin.

Search methods for identification of studies

The standard search methods of the Cochrane Neonatal Review Group were used.

Electronic searches

MEDLINE was searched (1966 to February 2005) using MeSH terms: heparin, infant, newborn, peripheral intravenous catheter, silastic catheter, indwelling catheter.

Other databases that were searched included: EMBASE (1980 to February 2005); CINAHL (1982 to February 2005); the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2005) and the reference lists of identified trials and abstracts from the annual meetings of the Society of Pediatric Research, American Pediatric Society and Pediatric Academic Societies published in Pediatric Research (1991 to 2004). No language restrictions were applied.

This search was updated in August, 2010. See: Appendix 1

Searching other resources

The following types of articles were excluded: letters, editorials/commentaries, reviews, lectures.

Data collection and analysis

The standard methods of the Cochrane Neonatal Collaborative Review Group were used for data collection and analysis.

Selection of studies

All published articles identified as potentially relevant by the literature search were assessed for inclusion in the review.

Data extraction and management

We attempted to obtain data from the primary author where published data provided inadequate information for the review, or the study population included all age groups and neonatal data could not be abstracted. No studies were identified which were reported only as abstracts. Retrieved articles were assessed and data were abstracted independently by all the reviewers. Discrepancies between reviewers were resolved by consensus.

Assessment of risk of bias in included studies

The standard methods of the Cochrane Neonatal Review Group were employed. The methodological quality of the studies were assessed using the following key criteria: allocation concealment (blinding of randomisation), blinding of intervention, completeness of follow-up, and blinding of outcome measurement/assessment. For each criterion, assessment was yes, no, can't tell. Two review authors separately assessed each study. Any disagreement was resolved by discussion. This information was added to the Characteristics of Included Studies table.

For the update in 2010, the following issues were evaluated and entered into the Risk of Bias table:

  1. Sequence generation (checking for possible selection bias). Was the allocation sequence adequately generated?For each included study, we categorized the method used to generate the allocation sequence as:
    • adequate (any truly random process e.g. random number table; computer random number generator);
    • inadequate (any non random process e.g. odd or even date of birth; hospital or clinic record number);
    • unclear.
  2. Allocation concealment (checking for possible selection bias). Was allocation adequately concealed?
    For each included study, we categorized the method used to conceal the allocation sequence as:
    • adequate (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);
    • inadequate (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);
    • unclear.
  3. Blinding (checking for possible performance bias). Was knowledge of the allocated intervention adequately prevented during the study? At study entry? At the time of outcome assessment?
    For each included study, we categorized the methods used to blind study participants and personnel from knowledge of which intervention a participant received. Blinding was assessed separately for different outcomes or classes of outcomes. We categorized the methods as:
    • adequate, inadequate or unclear for participants;
    • adequate, inadequate or unclear for personnel;
    • adequate, inadequate or unclear for outcome assessors.
  4. Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations). Were incomplete outcome data adequately addressed?
    For each included study and for each outcome, we described the completeness of data including attrition and exclusions from the analysis. We noted whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes.Where sufficient information was reported or supplied by the trial authors, we re-included missing data in the analyses. We categorized the methods as:
    • adequate (< 20% missing data);
    • inadequate (greater than/or equal to 20% missing data):
    • unclear.
  5. Selective reporting bias. Are reports of the study free of suggestion of selective outcome reporting?
    For each included study, we described how we investigated the possibility of selective outcome reporting bias and what we found. We assessed the methods as:
    • adequate (where it is clear that all of the study’s pre-specified outcomes and all expected outcomes of interest to the review have been reported);
    • inadequate (where not all the study’s pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);
    • unclear.
  6. Other sources of bias. Was the study apparently free of other problems that could put it at a high risk of bias?
    For each included study, we described any important concerns we had about other possible sources of bias (for example, whether there was a potential source of bias related to the specific study design or whether the trial was stopped early due to some data-dependent process). We assessed whether each study was free of other problems that could put it at risk of bias as:
    • yes;no;or unclear.

If needed, we planned to explore the impact of the level of bias through undertaking sensitivity analyses.

Measures of treatment effect

Statistical methods included relative risk (RR), risk difference (RD), number needed to treat (NNT) and weighted mean difference (WMD) as appropriate. Ninety five percent confidence intervals were used for these estimates of treatment effects.

Unit of analysis issues

Because a catheter may be changed owing to blockage, because of routine practice to avoid blockage, or because it is no longer needed, analysis of number of catheters used may not reflect an effect due to heparin use. Accordingly, we developed three potential approaches to statistical analysis. 1) We attempted to assess duration of the first catheter used by each patient and the reasons for discontinuation. Duration of patency before occlusion is a valid measure of effect. These data can be analysed using mean difference in duration between the treated and untreated patients, or if hazard ratios are reported in the individual trials, these can be analysed using the relative risk statistical procedure for meta-analysis. 2) If there are several catheters per patient, with different durations of patency for each and they are known to have become occluded, the mean duration of all catheters for each patient were to be obtained and analysed as a mean of means. This procedure has the advantage of using more of each patient's data than simply relying on duration of the first catheter. 3) If trials report the number of occluded catheters for each patient, excluding those removed which were unoccluded, these data were to be analysed using the mean number of catheters used.

Assessment of heterogeneity

We estimated the treatment effects of individual trials and examined heterogeneity between trials by inspecting the forest plots and quantifying the impact of heterogeneity using the I-squared statistic. If we detected statistical heterogeneity, we planned to explore the possible causes (for example, differences in study quality, participants, intervention regimens, or outcome assessments) using post hoc sub group analyses.

Data synthesis

If appropriate, meta-analysis was performed using Review Manager software (RevMan 5), supplied by the Cochrane Collaboration. For estimates of typical relative risk and risk difference, we used the Mantel-Haenszel method. For measured quantities, we used the inverse variance method. All meta-analyses were done using the fixed effect model.

Subgroup analysis and investigation of heterogeneity

Subgroup analyses were planned a priori according to the method of heparin administration (continuous versus intermittent), and gestational age [preterm (less than 37 weeks gestation) versus term (more than or equal to 37 weeks gestation)]. A comparison of effects of different heparin doses was also planned if sufficient numbers of studies or trials using different dosage regimens were identified.

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Results

Description of studies

Ten studies were included in this review (Alpan 1984; Golberg 1999; Heilskov 1998; Klenner 2003; Kotter 1996; Moclair 1995; Mudge 1998; Paisley 1997; Schultz 2002; Treas 1992). Clinical details concerning the participants, interventions and outcomes are given in the table, Characteristics of Included Studies.

Alpan 1984 performed a randomised controlled trial involving addition of heparin to total parenteral nutrition (TPN) solution in preterm infants. Preterm infants needing TPN were eligible for inclusion in the study. The treatment group received 1 IU/ml of heparin added to their TPN solution and the control group received no heparin in their TPN solution. All patients were cannulated using 22-gauge catheters. A total of 26 patients were enrolled, 13 infants in each group. These infants received 227 PIV catheters during the study period (105 in the heparin group and 122 in the control group) and all the catheters were managed according to the originally allocated policy. Baseline patient characteristics did not differ statistically significantly between the two groups. The duration of each catheter in situ was recorded. In addition, the incidences of phlebitis, local inflammation, intraventricular haemorrhage and septicaemia were reported. Only the incidence of intraventricular haemorrhage was reported per patient and was used for this review; all other outcomes were reported per PIV catheter.

Golberg 1999 performed a randomised controlled trial comparing intermittent flush of heparinized normal saline (4 IU/ml) with normal saline via PIV catheters in neonates. A total of 60 neonates were randomised; however, 13 infants were removed from the analysis because of possible contamination. Of the remaining 47 neonates 23 were randomised to the heparinised normal saline and 24 to normal saline group. Baseline characteristics did not differ between the two groups. All patients received 24-gauge intravenous catheters. The duration of catheter patency and the incidence of phlebitis were the only outcomes used for this review.

Heilskov 1998 performed a randomised double-blind controlled 3-arm trial in which neonates requiring PIV catheters were enrolled. Neonates who were receiving anticoagulant medication via another site were excluded. Ninety neonates were randomised to receive intermittent flush of low dose heparinised saline at 2 IU/ml (n = 28), high dose heparinized saline at 10 IU/ml (n = 35) or normal saline (n = 27) via PIV catheters. Only one catheter per patient was included in the study. Baseline patient characteristics were not statistically significantly different among groups. The duration of catheter patency and the incidence of PIV infiltration were reported in the study and were used for the purpose of this review.

Klenner 2003 performed a randomised controlled trial involving addition of heparin to intravenous infusion fluids in neonates who were anticipated to need intravenous infusion for > 5 days. Neonates > 1 kg birth weight were eligible for inclusion in the study. The treatment group received 0.5 IU/ml of heparin added to their intravenous infusion solution and the control group received no heparin in their intravenous infusion solution. Patients were cannulated using 24 or 26 gauge catheters. A total of 296 patients were enrolled, 145 infants in heparin group and 151 patients in control group. These infants received 1257 PIV catheters during the study period (565 in the heparin group and 692 in the control group) and all the catheters were monitored carefully. The catheters were removed if there were signs of infection, phlebitis or extravasation. Baseline patient characteristics did not differ statistically significantly between the two groups. The duration of each catheter in situ was recorded. In addition, the incidences of phlebitis, infiltration/extravasation, thrombus formation and accidental dislodgement were reported. Patients were evaluated for heparin induced thrombocytopenia antibody assay at 1, 7, 14, 21 and 28 days (108 patients from heparin group and 105 patients from the control group) and for intraventricular haemorrhage at 1, 3, 7, 14, 28 and 42 days age if they were still in hospital. Outcomes were reported as per catheter. Additional outcomes on first catheter not reported were obtained from the study author.

Kotter 1996 performed a randomised study comparing intermittent flush of heparinised saline (10 IU/ml) and normal saline via PIV catheters in neonates. Eighty-four neonates were enrolled, and data were collected for a total of 227 catheters. However, 109 of these catheters were excluded from the analysis because they were used for continuous infusion for a period of time before converting to intermittent use (heparin was not used for continuous infusion, so data from these catheters cannot be used for analysis), or were removed while patent. The authors reported data on the remaining 118 catheters from 51 patients. Each catheter was managed according to the patient's original group allocation. The primary outcome reported was duration (hours) of catheter patency. Other outcomes reported were incidence of catheter occlusion, phlebitis and leakage. All outcomes were reported per catheter and thus were not used for this review.

Moclair 1995 performed a randomised dose comparison study of heparin in neonates comparing the addition of various doses of heparin or no heparin to peripheral TPN solution. Patients receiving a central venous catheter during the study period were withdrawn from the study (the actual number not reported in the study). Ninety-seven neonates were randomised, but seven patients were excluded from analysis due to death or transfer to another hospital. The remaining 90 neonates were randomly allocated to one of five groups; 0.1 IU/ml heparin group (n = 15 with 35 PIV catheters), 0.25 IU/ml heparin group (n = 16 with 47 PIV catheters), 0.5 IU/ml heparin group (n = 23 with 61 PIV catheters), 1 IU/ml heparin group (n = 16 with 30 PIV catheters) and a heparin free control group (n = 20 with 72 PIV catheters). Subsequent catheters in the neonates were managed according to the original allocation. All neonates received 24-gauge catheters during the study. Baseline patient characteristics were not reported. Primary outcome was survival of PIV catheters, as indicated by number of PIV catheters required per neonate, duration of patency (hours) of each catheter, and the "survival curve" for catheter patency for each group. The duration of catheter patency was reported per number of catheters, and the authors were not able to provide the data on the first catheters only, so none of the outcome data were used for this review.

Mudge 1998 performed a quasi-randomised blinded trial comparing intermittent flush of heparinised saline (10 IU/ml) and normal saline via PIV catheters. Both neonatal and paediatric patients were included. A total of 61 patients with 134 PIV catheters were enrolled. Fifty-six catheters were flushed with heparinised saline and 78 with saline. The frequency of flushing was not controlled. The primary outcome was catheter duration, defined as the time from catheter insertion or conversion from continuous to intermittent infusion to catheter removal or conversion from intermittent to continuous infusion. Other outcomes reported were incidence of catheter-related complications (erythema, edema, occlusion, leakage, and discomfort). The author when contacted provided data on the 15 neonates in the heparin group and the 25 neonates in the saline group. Duration of catheter patency for the first catheter, incidence of catheter occlusion and incidence of phlebitis were used for this review.

Paisley 1997 performed a quasi-randomised study comparing heparinised saline flushes (0.6 ml of heparin solution containing 10 IU/ml of heparin) and 0.6 ml of normal saline via PIV catheters. Infants 32 weeks gestation or greater were eligible. Thirty-three infants received heparin and 54 patients received saline flushes. A total of 159 PIV catheters were studied. The data were reported per first PIV catheter and per all PIV catheters. Subsequent catheters in the same patient were managed according to the patient's original group allocation. The primary outcome was duration of catheter patency. Other outcomes reported were heparin induced thrombocytopenia, catheter blockade, phlebitis, infiltration and leaking. Duration of catheter patency and incidence of heparin induced thrombocytopenia were used for this review.

Schultz 2002 performed a randomised controlled trial involving heparinised flushes vs normal saline flushes. Neonates < 30 days of age were eligible for inclusion in the study. Twenty patients received 0.5 ml of heparinised saline (2 IU/ml) flushes and twenty nine patients received 0.5 ml of normal saline flushes. All patients were cannulated using 24-gauge catheters. Only one catheter per patient were included in the study. Baseline patient characteristics did not differ statistically significantly between the two groups. The duration of each catheter in situ was recorded. In addition, the incidences of occlusion, phlebitis (redness and edema) and extravasation were reported and were used for this review.

Treas 1992 performed a quasi-randomised study comparing heparinised saline (0.5 IU/ml) and normal saline via PIV catheters in neonates. All neonates were cannulated using size 24-gauge catheters. Only the first three catheters used in a neonate were included in the study. In the treatment group, heparin was added to a continuous infusion or as intermittent flush solution. In the control group, saline was used as intermittent flush solution. Sixty-three neonates with 131 PIV catheters were in the heparin group, and 49 neonates with 122 PIV catheters were in the control group. Subsequent catheters in the same patient were managed according to the patient's original group allocation. Baseline characteristics were not different between the two groups. The primary outcome was duration of catheter patency. Other outcomes reported were incidence of phlebitis, catheter-related infection, and bleeding. Outcomes were reported per catheter. The author (personal communication) provided data on the duration of patency for the first catheter and this was the only outcome used for this review.

Risk of bias in included studies

For each study included in the review, assessments of methodological quality are given in the table, Characteristics of Included Studies.

The methodological details for studies were extracted from the published information and personal contact with the authors.

Alpan 1984
Randomization was performed by a table of random numbers and was blinded. Masking of intervention and outcome measures was ensured. Outcomes were reported on all catheters and all neonates enrolled in the study.

Golberg 1999
Randomization was performed centrally in the pharmacy. The study medication was centrally supplied as premixed vials, and the vial stoppers were all punctured to ensure that the intervention was masked. Outcomes were reported on 47 of the 60 neonates enrolled.

Heilskov 1998
Randomization was performed using a random allocation list. The study solutions were coded to ensure masking of the intervention. Outcomes were reported on all catheters and all neonates enrolled in the study.

Klenner 2003
Randomization was performed centrally in the pharmacy. The study solution was centrally supplied in premixed form to ensure masking of intervention. Outcomes were reported as per catheter, however, data on first catheter were obtained from the author.

Kotter 1996
Randomization was performed by random selection of sealed envelopes. Color-coded cards and data sheets were used to separate the two groups; however, the treatment allocation was concealed, thus ensuring masking of intervention and outcome measures. Outcomes were reported on 51 (118 catheters) of 84 (227 catheters) neonates enrolled.

Moclair 1995
Randomization was performed centrally by allocation of codes in the pharmacy. TPN solutions were prepared with heparin added according to the code assigned. Masking of intervention and outcome measures were ascertained. Outcomes were reported on 90 of 97 neonates who completed the study.

Mudge 1998
Allocation was based on the month of entry. All patients enrolled in a given month received the same flush solution (labelled solution A or B). Masking of intervention and outcome measures were ascertained. Outcomes were reported on all catheters of all patients studied.

Paisley 1997
Allocation was based on last digit of infant's hospital number. Masking of allocation or outcome assessment was not performed. Outcomes were reported separately on the first catheters and all catheters.

Schultz 2002
Randomization was performed centrally in the pharmacy. The study medication was centrally supplied as premixed vials to ensure that the intervention was masked. Outcomes were reported on all neonates enrolled. Only one catheter per patient was included in the study.

Treas 1992
Allocation was based on sequential hospital number given by the admitting office. Masking of intervention and outcome measures were not performed (personal communication). Outcomes were reported on all enrolled neonates and their first three catheters.

Effects of interventions

In many studies included in this review, the outcomes were reported per catheter rather than per patient. However, most patients received more than one PIV catheter during the study period. Attempts were made to contact the primary authors in order to obtain data of the first catheter of each patient. Where such data were not available only the long-term outcomes such as intracranial haemorrhage were included in the review.

After reviewing the studies, it was observed that a number of catheters were removed electively. An attempt was made to obtain individual patient data which was not successful.

Primary outcome: Number of hours of use of first catheter

Seven studies (Heilskov 1998; Paisley 1997; Mudge 1998; Treas 1992; Golberg 1999; Klenner 2003; Schultz 2002) reported on duration of use for the first catheter in each patient. Three studies found no statistically significant difference, three studies showed a statistically significant increase and one study showed a statistically significant decrease in the duration of catheter use in the heparin group. Heilskov 1998 found that the duration of use was not statistically different between the groups [mean (SD) catheter duration was 66.1 (32.1) hours in the heparin group vs 67.1 (33.1) hours in the control group]; Paisley 1997 also found that there was no statistically significant difference between the two groups [mean (SD) catheter duration was 66.2 (42.8) hours in the heparin group vs 76.4 (125.7) hours in the control group]. Mudge 1998 found that the duration of catheter use was statistically significantly increased in the heparin group [mean (SD) catheter duration was 50.8 (16.2) hours in the heparin group vs 38.0 (21.1) hours in the control group]; Treas 1992 also found that there was a statistically significant increase in the duration of catheter use in the treatment group [mean (SD) catheter duration was 62.8 (29.9) hours in the heparin group vs 27.3 (15.3) hours in the control group]. Golberg 1999 found that the duration of catheter use was statistically significantly shorter in the heparin group [mean (SD) catheter duration was 25.6 (22.7) hours in heparin group vs 56.5 (46.1) hours in control group]. Klenner 2003 found that the duration of catheter use was statistically significantly increased in the heparin group [mean (SD) catheter duration was 46.9 (27.9) hours in the heparin group vs 35.0 (17.8) hours in the control group]. Schultz 2002 found that the duration of use was not statistically different between the groups [mean (SD) catheter duration was 38.5 (33.3) hours in the heparin group vs 34.4 (27.3) hours in the control group]. However, there was strong evidence of heterogeneity for the treatment effect (p < 0.001) across these seven studies. In addition, there were important differences between the studies in terms of dosages of heparin, concentrations of heparin, timings of flushing of catheters, size of the catheters and methodology of the studies. After reviewing these differences among the studies, a decision was made not to report a summary measure of treatment effect.

Secondary outcomes:

1. Complications associated with PIV catheters:

Occlusion of the catheter (identified by inability to infuse fluids):

Four studies (Heilskov 1998; Mudge 1998; Klenner 2003; Schultz 2002) reported on this outcome for the first catheter placement. There was no statistically significant difference in the rate of catheter occlusion and subsequent infiltration (pooled RR 1.00 [95% CI 0.85, 1.16] and RD 0.00 [95% CI -0.09, 0.09]. There was evidence of heterogeneity for the treatment effect; p=0.01).

Incidence of phlebitis or thrombophlebitis:

Four studies (Golberg 1999; Mudge 1998; Klenner 2003; Schultz 2002 ) reported on this outcome for the first catheter placement. There was no statistically significant difference in the rate of phlebitis or thrombophlebitis (pooled RR 0.74 [95%CI 0.50, 1.10] and RD -0.06 [95% CI -0.13, 0.02]; p = 0.65).

Catheter related sepsis and number of additional PIV catheters needed:

None of the included studies reported on these outcomes.

2. Complications related to heparin:

Abnormal coagulation profile:

None of the studies reported on the incidence of abnormal coagulation profile. However, Alpan 1984 reported on the mean prothrombin time and mean partial thromboplastin time and there was no significant difference between the groups.

Allergic reactions and heparin induced thrombocytopenia:

Paisley 1997 and Klenner 2003 reported that none of the infants in their study developed heparin induced thrombocytopenia. No other study has reported on this outcome. Klenner 2003 prospectively evaluated 213 (those patients who received heparin for > 5 days) of the total 296 patients for heparin induced thrombocytopenia at specified intervals and did not observe any difference in mean optical density at 405 nm (enzyme linked immunosorbent assay) between groups (0.020 vs 0.019; p = 0.78).

Intracranial or intraventricular haemorrhage:

Two studies Alpan 1984 and Klenner 2003 reported on the incidence of intraventricular haemorrhage in their study patients. There was no statistically significant difference between the groups (pooled RR 0.37 [95% CI 0.12, 1.17] and RD -0.04 [95% CI -0.08, 0.00]).

3. Mortality:

No study reported on this outcome.

Included studies but no analysable outcomes:

Kotter 1996 reported all the outcomes per number of catheters.

Moclair 1995 did not report any of the outcomes per number of patients. The results were expressed per number of catheters so were not included in the analysis. Survival curves for control group and all the heparin doses were calculated, based on all catheters, and the authors reported that addition of heparin prolongs the infusion site survival at concentration of 0.25 IU/ml. They also reported that the effect of heparin is sigmoidal with onset at 0.1 IU/ml and flattening at 0.5 IU/ml.

Discussion

There is an extensive literature on the use of heparin to prolong the patency of PIV catheters. Randolph 1998 performed a systematic review on the use of heparin for PIV catheters in all age groups, and concluded that low dose heparin infusion was effective in prolonging patency of peripheral arterial catheters but not PIV catheters. The present review includes nine additional studies aiming to test the effectiveness of heparin use for PIV catheters in the neonatal population.

Two more studies were identified in this update in addition to eight studies identified in previous version (Shah 2002). Despite large number of studies identified, the total number of neonatal patients included in this systematic review was 721. The methodology of the systematic review process was hampered by many studies reporting outcomes per catheter rather than per patient; this practice leads to non-independence of multiple measures of the same outcome in the same patients, and thus creates potential bias in data analysis. Therefore, in performing this review, only data from the first catheters were considered.

This review was further limited by the significant variability amongst included studies in clinical details, methodological quality, and outcomes reported, thus precluding the reviewers from combining data on the primary outcome to estimate an overall effect size. The dose and method of administration of heparin varied widely, with concentrations varying from 0.1 to 10 IU/ml of heparin administered as either intermittent flush solution or as an additive in parenteral nutrition solutions, and frequency of flush was not always specified by the investigators. Catheter size was not uniform across the studies and may have affected the duration of catheter patency or the likelihood of the complications. The methodological quality of studies were variable, from randomised, double-blinded controlled trials to quasi-randomised studies, with some studies having inadequate or no blinding of intervention or outcome assessment, and incomplete follow up. The outcomes reported were different among the studies. Although seven of the ten studies reported on the primary outcome of PIV catheter patency, few reported on secondary outcomes such as short and long term adverse effects of heparin, or complications related to PIV catheter insertions. It is noteworthy that none of the neonates developed heparin induced thrombocytopenia which was examined in two studies (n = 300).

It was not possible from the published reports to assess the effect of heparin among patients who had multiple catheter placements. Individual patient data, required for the planned analyses among patients having multiple catheters, were not available. Future studies should report the duration of catheter use separately for catheters removed because of occlusion, removed electively, or removed for other reasons. These data should be reported for the first catheter and for all catheters.

Because of heterogeneity among included studies, and despite the best effort of data collection and analysis, the question of the effectiveness and safety of heparin use in PIV catheters in neonates was unable to be definitively answered by this review.

Authors' conclusions

Implications for practice

No conclusive evidence is available from this systematic review on which to evaluate the effectiveness of heparin to prolong PIV catheter life in the neonatal population. Although limited data did not suggest significant adverse effects from heparin use, the safety of such practice has not been thoroughly investigated.

Implications for research

A randomised, controlled trials of sufficient power is needed to evaluate the efficacy of heparin in neonates with PIV catheters. Studies to identify the minimal effective dose of heparin and to evaluate the safety of heparin administration in this setting will also be necessary before routine use can be recommended in neonates, particularly in the preterm population. A detailed history of all catheters should be recorded, including the reason for catheter removal (blocked, suspected or proven infection, routine or elective replacement, no longer needed). Time until catheter blockage should be assessed by "survival" function analysis.

Acknowledgements

We would like to thank the primary authors (Moclair 1995, Mudge 1998, Treas 1992, Hanrahan 2000, LeDuc 1997, Taylor 1989, Klenner 2003) for providing additional data from their studies. We are also grateful for Dr. Arne Ohlsson's valuable input in the revision of this manuscript.

Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN267200603418C.

Contributions of authors

Dr. P S Shah

Literature search and identification of trials
Evaluation of methodological quality of trials
Data collection
Verification of data and entry in Revman
Writing the text of review

Dr. E Ng

Literature search and identification of trials
Evaluation of methodological quality of trials
Data collection
Verification of data
Revision of the review

Dr. A Sinha

Literature search and identification of trials
Evaluation of methodological quality of trials
Data collection
Verification of data
Revision of the review

The August 2010 search was conducted by Dr. P S Shah, Dr. E Ng and Dr. A Sinha. The November 2010 update was conducted centrally by the Cochrane Neonatal Review Group staff (Yolanda Montagne, Diane Haughton, and Roger Soll). This update was reviewed and approved by PS.

Declarations of interest

  • None noted.

Differences between protocol and review

  • None noted.

Additional tables

  • None noted.

Potential conflict of interest

  • None noted.

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Characteristics of studies

Characteristics of Included Studies

Alpan 1984

Methods

Randomization - yes
Single centre study
Blinding of randomisation - yes
Blinding of intervention - yes
Blinding of outcome assessment - yes
Complete follow up - yes

Participants

Preterm infants admitted to NICU
Group 1: n=13, Mean (SD) GA 32.0 (2.2) weeks
Mean (SD) BW 1397 (543) g
Group 2: n=13, Mean (SD) GA 31.2 (3.1) weeks
Mean (SD) BW 1361 (627) g

Interventions

Group 1: heparin 1 IU/ml in TPN infusate
Group 2: no heparin

Outcomes

Duration of catheter use
Phlebitis
Septicemia
Coagulation parameters (PT and PTT)

Notes

Only long-term outcome such as intraventricular haemorrhage reported per number of patients while others are reported per number of catheters

Risk of bias table
Item Judgement Description
Adequate sequence generation? Unclear
Allocation concealment? Yes

Blinding of randomisation - yes

Blinding? Yes

Blinding of intervention - yes
Blinding of outcome assessment - yes

Incomplete outcome data addressed? Yes

Complete follow up - yes

Free of selective reporting? Unclear
Free of other bias? Unclear

Golberg 1999

Methods

Randomization - yes
Single centre study
Blinding of randomisation - yes (by pharmacist)
Blinding of intervention - yes (multidose vial)
Blinding of outcome assessment - yes
Complete follow up - no

Participants

All patients in the NICU who required PIV catheters
Group 1: n=24
Group 2: n=23
Mean (SD) GA of the cohort 35.07 (5.4) weeks
Mean (SD) BW of the cohort 2664 (1175.6) g

Interventions

Group 1: heparin 4 IU/ml
Group 2: normal saline
Dose 1 ml flush at least every 6 hours

Outcomes

Duration of catheter use
Phlebitis

Notes

Positive pressure technique for flushing

Risk of bias table
Item Judgement Description
Adequate sequence generation? Unclear
Allocation concealment? Yes

Blinding of randomisation - yes (by pharmacist)

Blinding? Yes

Blinding of intervention - yes (multidose vial)
Blinding of outcome assessment - yes

Incomplete outcome data addressed? No

Complete follow up - no

Free of selective reporting? Unclear
Free of other bias? Unclear

Heilskov 1998

Methods

Randomization - yes
Single centre study
Blinding of randomisation - yes
Blinding of intervention - yes (treatment solution with the code number)
Blinding of outcome assessment - yes
Complete follow up - yes

Participants

All neonates admitted to NICU or intermediate care nursery who required PIV catheter
Exclusion criteria: Neonates who had received anticoagulant within the last 48 hours, BW < 800 grams, Parents - non English speaking
Group 1: n=27, Mean (SD) BW 2323 (816) g
Group 2: n=28, Mean (SD) BW 2521 (891) g
Group 3: n=35, Mean (SD) BW 2677 (998) g

Interventions

Group 1: heparin 2 IU/ml
Group 2: heparin 10 IU/ml
Group 3: normal saline
Catheter flushed at least every 6 hours

Outcomes

Duration of catheter use
Infiltration

Notes

Positive pressure technique for flushing
Many canula had IV fluid running through prior to locking for intermittent use

Risk of bias table
Item Judgement Description
Adequate sequence generation? Unclear
Allocation concealment? Yes

Blinding of randomisation - yes

Blinding? Yes

Blinding of intervention - yes (treatment solution with the code number)
Blinding of outcome assessment - yes

Incomplete outcome data addressed? Yes

Complete follow up - yes

Free of selective reporting? Unclear
Free of other bias? Unclear

Klenner 2003

Methods

Randomization - yes
Single centre study
Blinding of randomisation - yes
Blinding of intervention - yes
Blinding of outcome assessment - yes
Complete follow up - yes

Participants

Infants with anticipated need for intravenous infusion for >5 days and birth weight >1000g and postnatal age < 28 days
Group 1: n=145, Mean (SD) GA 35.3 (3.5) weeks
Mean (SD) BW 2400 (890) g
Group 2: n=151, Mean (SD) GA 35.6 (3.3) weeks
Mean (SD) BW 2416 (737) g

Interventions

Group 1: heparin 0.5 IU/ml in intravenous infusion
Group 2: saline

Outcomes

Duration of catheter use
Extravasation/infiltration
Phlebitis
Thrombosis
Heparin induced thrombocytopenia

Notes
Risk of bias table
Item Judgement Description
Adequate sequence generation? Unclear
Allocation concealment? Yes

Blinding of randomisation - yes

Blinding? Yes

Blinding of intervention - yes
Blinding of outcome assessment - yes

Incomplete outcome data addressed? Yes

Complete follow up - yes

Free of selective reporting? Unclear
Free of other bias? Unclear

Kotter 1996

Methods

Randomization - yes (pharmacist)
Single centre study
Blinding of intervention - yes
Blinding of outcome assessment - not stated
Complete follow up - no

Participants

All NICU patients under one month of age who required intermittent PIV catheter locks
Group 1: n= 27 (75 catheters)
Group 2: n=24 (43 catheters)
Mean GA of the cohort 36.2 weeks
Mean BW of the cohort 2581 g

Interventions

Group 1: heparin 10 IU/ml
Group 2: normal saline
Dose: 0.5 ml after each infusion and every 4 hours

Outcomes

Duration of catheter use
Infiltration
Phlebitis
Occlusion
Leaking

Notes

The outcomes were reported per number of catheters

Risk of bias table
Item Judgement Description
Adequate sequence generation? Unclear
Allocation concealment? Yes

Randomization - yes (pharmacist)

Blinding? Unclear

Blinding of intervention - yes
Blinding of outcome assessment - not stated

Incomplete outcome data addressed? No

Complete follow up - no

Free of selective reporting? Unclear
Free of other bias? Unclear

Moclair 1995

Methods

Randomization - yes (pharmacist)
Single centre study
Blinding of randomisation - yes
Blinding of intervention - yes
Blinding of outcome assessment - not stated
Complete follow up - no (97 entered the study, 7 dropped due to death or transfer)

Participants

All NICU patients receiving TPN through peripheral intravenous catheter
Group 1: n=20 (72 catheters)
Group 2: n=15 (35 catheters)
Group 3: n=16 (47 catheters)
Group 4: n=23 (61 catheters)
Group 5: n=16 (30 catheters)

Interventions

Group 1: heparin 0.1 IU/ml
Group 2: heparin 0.25 IU/ml
Group 3: heparin 0.5 IU/ml
Group 4: heparin 1 IU/ml
Group 5: no heparin
added to TPN infusate

Outcomes

Duration of catheter use
Extravasation of catheters

Notes
Risk of bias table
Item Judgement Description
Adequate sequence generation? Unclear
Allocation concealment? Yes

Blinding of randomisation - yes

Blinding? Unclear

Blinding of intervention - yes
Blinding of outcome assessment - not stated

Incomplete outcome data addressed? No

Complete follow up - no (97 entered the study, 7 dropped due to death or transfer)

Free of selective reporting? Unclear
Free of other bias? Unclear

Mudge 1998

Methods

Quasi-randomized
Single centre study
Blinding of randomisation - no
Blinding of intervention - yes
Blinding of outcome assessment - yes
Complete follow up - no (40 out of 42 infants)

Participants

Patients admitted to NICU or general paediatric units
Group 1: Total of 78 patient randomised to control group of which 25 were neonates
Group 2: Total of 56 patients randomised to heparin group of which 15 were neonates
Mean BW of the neonatal cohort was 2164.8 g

Interventions

Group 1: heparin 10 IU/ ml
Group 2: normal saline
Dose: 1 ml flush, frequency not specified

Outcomes

Duration of catheter use
Occlusion of catheter
Phlebitis

Notes

Allocation was based on the month of the study
Data on neonates was provided by primary author

Risk of bias table
Item Judgement Description
Adequate sequence generation? Unclear
Allocation concealment? No

Blinding of randomisation - no

Blinding? Yes

Blinding of intervention - yes
Blinding of outcome assessment - yes

Incomplete outcome data addressed? No

Complete follow up - no (40 out of 42 infants)

Free of selective reporting? Unclear
Free of other bias? Unclear

Paisley 1997

Methods

Quasi-randomized
Single centre study
Blinding of randomisation - no
Blinding of intervention - no
Blinding of outcome assessment - no
Complete follow up - yes

Participants

Infants > 32 weeks gestation admitted to NICU and continuing care nursery
Group 1: 33 infants
Group 2: 54 infants
Mean (SD) gestational age of the group 38.46 (2.48) weeks

Interventions

Group 1: heparin 10 IU/ml
Group 2: normal saline flushes
Dose: 0.6 ml flush every 4 hours

Outcomes

Duration of catheter use
Heparin induced thrombocytopenia
Occlusion
Leaking
Phlebitis
Infiltration

Notes

Allocation was based on the last digit of the hospital number
All the outcomes apart from duration of catheter patency were reported in the combined group (treatment and control)

Risk of bias table
Item Judgement Description
Adequate sequence generation? No

Allocation was based on the last digit of the hospital number

Allocation concealment? No

Blinding of randomisation - no

Blinding? No

Blinding of intervention - no
Blinding of outcome assessment - no

Incomplete outcome data addressed? Yes

Complete follow up - yes

Free of selective reporting? Unclear
Free of other bias? Unclear

Schultz 2002

Methods

Randomization - yes
Single centre study
Blinding of randomisation - yes
Blinding of intervention - yes
Blinding of outcome assessment - yes
Complete follow up - yes

Participants

All neonates who required intermittent intravenous catheter locks
Group 1: n=20, Mean (SD) GA 33.2 (3.7) weeks
Mean (SD) BW 2020 (830) g
Group 2: n=29, Mean (SD) GA 33.7 (4.0) weeks
Mean (SD) BW 2170 (910) g

Interventions

Group 1: heparin 2 IU/ml
Group 2: normal saline flushes
Dose: 0.5 ml flush every 3 hours

Outcomes

Duration of catheter use
Occlusion
Extravasation
Phlebitis

Notes
Risk of bias table
Item Judgement Description
Adequate sequence generation? Unclear
Allocation concealment? Yes

Blinding of randomisation - yes

Blinding? Yes

Blinding of intervention - yes
Blinding of outcome assessment - yes

Incomplete outcome data addressed? Yes

Complete follow up - yes

Free of selective reporting? Unclear
Free of other bias? Unclear

Treas 1992

Methods

Quasi-randomized
Single centre study
Blinding of randomisation - no
Blinding of intervention - no
Blinding of outcome assessment - no
Complete follow up - yes

Participants

Infants admitted to NICU
Group 1: n=63 (catheter 131)
Mean (SD) GA 33.8 (3.0) weeks
Mean (SD) BW 1977 (595) g
Group 2: n=49 (catheters 122)
Mean (SD) GA
34.7 (3.2) weeks
Mean (SD) BW 2300 (806)g

Interventions

Group 1: infusion containing 0.5 IU/ml of heparin or flush containing 0.5 IU/ml of heparin
Group 2: normal saline
Dose: Volume of flush not specified

Outcomes

Duration of catheter use
Infection
Infiltration
Leaking
Phlebitis

Notes

Allocation was based on hospital number
All the outcomes were reported per number of catheters
Data for the first catheters were provided by the author

Risk of bias table
Item Judgement Description
Adequate sequence generation? No

Allocation was based on hospital number

Allocation concealment? No

Blinding of randomisation - no

Blinding? No

Blinding of intervention - no
Blinding of outcome assessment - no

Incomplete outcome data addressed? Yes

Complete follow up - yes

Free of selective reporting? Unclear
Free of other bias? Unclear
GA = Gestational age
BW = Birth weight
TPN = Total parenteral nutrition
NICU = Neonatal Intensive Care Unit
SD = standard deviation
IU = International Unit
PIV = peripheral intravenous

Characteristics of excluded studies

Danek 1992

Reason for exclusion

Data on neonates not available

Hanrahan 2000

Reason for exclusion

Non-randomised

LeDuc 1997

Reason for exclusion

Data on neonates not available

McMullen 1993

Reason for exclusion

Data on neonates not available

Nelson 1998

Reason for exclusion

Data on neonates not available

Taylor 1989

Reason for exclusion

Compared heparin flush with heparin infusion

[top]

References to studies

Included studies

Alpan 1984

Alpan G, Fabian E, Springer C, Glick B, Goder K, Armon J. Heparinization of alimental solutions administered through peripheral veins in premature infants: a controlled study. Pediatrics 1984;74:375-8.

Golberg 1999

Golberg M, Sankaran R, Givelichan L, Sankaran K. Maintaining patency of peripheral intermittent infusion devices with heparinized saline and saline. Neonatal Intensive Care 1999;12:18-22.

Heilskov 1998

Published and unpublished data

Heilskov J, Kleiber C, Johnson K, Miller J. A randomized trial of heparin and saline for maintaining intravenous locks in neonates. Journal of the Society of Pediatric Nurses 1998;3:111-6.

Klenner 2003

Published and unpublished data

Klenner AF, Fusch C, Rakow A, Kadow I, Beyersdorff E, Eichler P, Wander K, Lietz T, Greinacher A. Benefit and risk of heparin for maintaining peripheral venous catheters in neonates: a placebo-controlled trial. Journal of Pediatrics 2003;143:741-5.

Kotter 1996

Kotter RW. Heparin vs saline for intermittent intravenous device maintenance in neonates. Neonatal Network 1996;15:43-7.

Moclair 1995

Published and unpublished data

Moclair A, Bates I. The efficacy of heparin in maintaining peripheral infusions in neonates. European Journal of Pediatrics 1995;154:567-70.

Mudge 1998

Published and unpublished data

Mudge B, Forcier D, Slattery MJ. Patency of 24-gauge peripheral intermittent infusion devices: a comparison of heparin and saline flush solutions. Pediatric Nursing 1998;24:142-5.

Paisley 1997

Paisley MK, Stamper M, Brown J, Brown N, Ganong LH. The use of heparin and normal saline flushes in neonatal intravenous catheters. Pediatric Nursing 1997;23:521-7.

Schultz 2002

Schultz AA, Drew D, Hewitt H. Comparison of normal saline and heparinized saline for patency of IV locks in neonates. Applied Nursing Research 2002;15:28-34.

Treas 1992

Published and unpublished data

Treas LS, Latinis-Bridges B. Efficacy of heparin in peripheral venous infusion in neonates. Journal of Obstetric, Gynecologic, and Neonatal Nursing 1992;21:214-9.

Excluded studies

Danek 1992

Published and unpublished data

Danek GD, Noris EM. Pediatric IV catheters: efficacy of saline flush. Pediatric Nursing 1992;18:111-3.

Hanrahan 2000

Published and unpublished data

Hanrahan KS, Kleiber C, Berends S. Saline for peripheral intravenous locks in neonates: evaluating change in practice. Neonatal Network 2000;19:19-24.

LeDuc 1997

Published and unpublished data

LeDuc K. Efficacy of normal saline solution versus heparin solution for maintaining patency of peripheral intravenous catheters in children. Journal of Emergency Nursing 1997;23:306-9.

McMullen 1993

McMullen A, Fioravanti ID, Pollack V, Rideout K, Sciera M. Heparinized saline or normal saline as a flush solution in intermittent intravenous lines in infants and children. MCN. The American Journal of Maternal Child Nursing 1993;18:78-85.

Nelson 1998

Nelson JJ, Graves SM. 0.9% Sodium chloride injection with and without heparin for maintaining peripheral indwelling intermittent-infusion devices in infants. American Journal of Health-System Pharmacy 1998;55:570-3.

Taylor 1989

Taylor J, Shanon R, Kilbride H. Heparin lock intravenous line use in newborn infants: a controlled trial. Clinical Pediatrics 1989;28:237-40.

Studies awaiting classification

  • None noted.

Ongoing studies

  • None noted.

Other references

Additional references

Bossert 1994

Bossert E, Beecroft PC. Peripheral intravenous lock irrigation in children: current practice. Pediatric Nursing 1994;20:346-9, 355.

Daniell 1973

Daniell HW. Heparin in the prevention of infusion phlebitis: a double-blind controlled study. JAMA : The Journal of the American Medical Association 1973;226:1317-21.

Goode 1991

Goode CJ, Titler M, Rakel B, Ones DS, Kleiber C, Small S, Triolo PK. A meta-analysis of effects of heparin flush and saline flush: quality and cost implications. Nursing Research 1991;40:324-30.

Graham 1991

Graham DR, Keldermans MM, Klemm LW, Semenza NJ, Shafer ML. Infectious complications among patients receiving home intravenous therapy with peripheral, central, or peripherally placed central venous catheters. The American Journal of Medicine 1991;91:95s-100s.

Hanson 1976

Hanson RL, Grant AM, Majors KR. Heparin-lock maintenance with ten units of sodium heparin in one milliliter of normal saline solution. Surgery, Gynecology & Obstetrics 1976;142:373-6.

Hecker 1992

Hecker JF. Potential for extending survival of peripheral intravenous infusions. BMJ 1992;304:619-24.

Johnstone 1991

Johnstone JM. Heparinised saline - is the heparin really necessary? The Australian Nurses' Journal 1991;20:31-2.

Krafte-Jacobs 1995

Krafte-Jacobs B, Sivit CJ, Mejia R, Pollack MM. Catheter-related thrombosis in critically ill children: comparison of catheters with and without heparin bonding. Journal of Pediatrics 1995;126:50-4.

Lesko 1986

Lesko SM, Mitchell AA, Epstein MF, Louik C, Giacoia GP, Shapiro S. Heparin use as a risk factor for intraventricular hemorrhage in low-birth-weight infants. New England Journal of Medicine 1986;314:1156-60.

Lewis 1985

Lewis GBH, Hecker JF. Infusion thrombophlebitis. British Journal of Anaesthesia 1985;57:220-33.

Maki 1977

Maki DG. Preventing infection in intravenous therapy. Anesthesia and Analgesia 1977;56:141-53.

Malloy 1995

Malloy MH, Cutter GR. The association of heparin exposure with intraventricular hemorrhage among very low birth weight infants. Journal of Perinatology 1995;15:185-91.

Nieto-Rodrig 1992

Nieto-Rodriguez JA, Garcia-Martin MA, Barreda-Hernandez MD, Hervas MJ, Cano-Real O. Heparin and infusion phlebitis: a prospective study. The Annals of Pharmacotherapy 1992;26:1211-4.

O'Neill 1974

O'Neill TJ, Tierney LM Jr, Proulx RJ. Heparin lock-induced alterations in the activated partial thromboplastin time. JAMA : The Journal of the American Medical Association 1974;227:1297-8.

Papile 1978

Papile L, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weight less than 1500 grams. Journal of Pediatrics 1978;92:529-34.

Peterson 1991

Peterson FY, Kirchhoff KT. Analysis of the research about heparinized versus nonheparinized intravascular lines. Heart Lung 1991;20:631-40.

Potter 1992

Potter C, Gill JC, Scott JP, McFarland JG. Heparin-induced thrombocytopenia in a child. Journal of Pediatrics 1992;121:135-8.

Randolph 1998

Randolph AG, Cook DJ, Gonzales CA, Andrew M. Benefit of heparin in peripheral venous and arterial catheters: systematic review and meta-analysis of randomised controlled trials. BMJ 1998;316:969-75.

Roberts 1994

Roberts GW, Holmes MD, Staugas REM, Day RA, Finlay CF, Pitcher A. Peripheral intravenous line survival and phlebitis prevention in patients receiving intravenous antibiotics: heparin/hydrocortisone versus in-line filters. The Annals of Pharmacotherapy 1994;28:11-6.

Tager 1983

Tager IB, Ginsberg MB, Ellis SE, Walsh NE, Dupont I, Simchen E, Faich GA. An epidemiologic study of the risks associated with peripheral intravenous catheters. American Journal of Epidemiology 1983;118:839-51.

Tanner 1980

Tanner WA, Delaney PV, Hennessy TP. The influence of heparin on intravenous infusions: a prospective study. The British Journal of Surgery 1980;67:311-2.

Tighe 1995

Tighe MJ, Wong C, Martin IG, McMahon MJ. Do heparin, hydrocortisone, and glyceryl trinitrate influence thrombophlebitis during full intravenous nutrition via a peripheral vein? JPEN. Journal of Parenteral and Enteral Nutrition 1995;19:507-9.

Tomford 1984

Tomford JW, Hershey CO, McLaren CE, Porter DK, Cohen DI. Intravenous therapy team and peripheral venous catheter-associated complications. a prospective controlled study. Archives of Internal Medicine 1984;144:1191-4.

Vieira 1991

Vieira A, Berry L, Ofosu F, Andrew M. Heparin sensitivity and resistance in the neonate: an explanation. Thrombosis Research 1991;63:85-98.

Vilardell 1999

Vilardell M, Sabat D, Arnaiz JA, Bleda MJ, Castel JM, Laporte JR, Vallve C. Topical heparin for the treatment of acute superficial phlebitis secondary to indwelling intravenous catheter: a double-blind, randomized, placebo-controlled trial. European Journal of Clinical Pharmacology 1999;54:917-21.

Warkentin 1990

Warkentin TE, Kelton JG. Heparin and platelets. Hematology/oncology Clinics of North America 1990;4:243-64.

Other published versions of this review

Shah 2002

Shah P, Ng E, Sinha AK. Heparin for prolonging peripheral intravenous catheter use in neonates. Cochrane Database of Systematic Reviews 2002, Issue 4. Art. No.: CD002774. DOI: 10.1002/14651858.CD002774.

Shah 2005

Shah P, Ng E, Sinha AK. Heparin for prolonging peripheral intravenous catheter use in neonates. Cochrane Database of Systematic Reviews 2005, Issue 2. Art. No.: CD002774. DOI: 10.1002/14651858.CD002774.pub2.

[top]

Data and analyses

1 Heparin versus control (normal saline or no treatment)

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Duration of catheter patency (hours), first catheter 7 Mean Difference (IV, Fixed, 95% CI) No totals
1.2 Catheter occlusion, first catheter 4 475 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.85, 1.16]
1.3 Phlebitis or thrombophlebitis, first catheter 4 432 Risk Ratio (M-H, Fixed, 95% CI) 0.74 [0.50, 1.10]
1.4 Intracranial hemorrhage 2 322 Risk Ratio (M-H, Fixed, 95% CI) 0.37 [0.12, 1.17]
1.5 Heparin induced thrombocytopenia 2 300 Risk Ratio (M-H, Fixed, 95% CI) Not estimable

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Sources of support

Internal sources

  • Mount Sinai Hospital, University of Toronto, Toronto, Canada
  • Sunnybrook and Women's College Health Sciences Center, Canada
  • Department of Child Health, Queen Mary University of London, London, UK

External sources

  • No sources of support provided.

Appendices

1 Search Strategy August 2010

Medline, CCTR and Embase were searched using the following strategies.

Ovid MEDLINE(R) 1950 to August 27, 2010

Serach strategy
  1. 1 Infant, newborn/ or infant, low birth weight/ or infant, small for gestational age/ or infant, very low birth weight/ or infant, premature/ or exp Infant, Newborn, Diseases/ or pregnancy, high-risk/ or quadruplets/ or quintuplets/ or superfetation/ or triplets/ or twins/ or twins, dizygotic/ or twins, monozygotic/ or (infan: or neonat: or newborn: or prematur: or iugr or sga or vlbw or lbw or elbw).ti, ab. or ((intrauterine adj2 growth adj2 restrict:) or (intrauterine adj2 growth adj2 retard:)).ti, ab.
  2. 2 ("clinical trial, all" or clinical trial).pt. or clinical trials as topic/ or clinical trial, phase i.pt. or clinical trials, phase i as topic/ or clinical trial, phase iii.pt. or clinical trials, phase iii as topic/ or clinical trial, phase iv.pt. or clinical trials, phase iv as topic/ or controlled clinical trial.pt. or controlled clinical trials as topic/ or meta-analysis.pt. or meta-analysis as topic/ or multicenter study.pt. or multicenter studies as topic/ or randomized controlled trial.pt. or randomized controlled trials as topic/ or evaluation studies as topic/ or validation studies as topic/ or evaluation study.pt. or validation study.pt. or case-control studies/ or retrospective studies/ or cohort studies/ or longitudinal studies/ or follow-up studies/ or prospective studies/ or cross-sectional studies/ or double-blind method/ or random allocation/ or single-blind method/ or ((singl* or doubl* or tripl* or trebl*) adj5 (blin or mask or blinded or masked)).ti, ab.
  3. 3 Heparin/ or (Heparinic Acid or Liquaemin or Sodium Heparin or Heparin, Sodium or Heparin Sodium or alpha-Heparin or alpha Heparin).mp
  4. 4 Intravenous catheter/ or (Catheter, Indwelling or Indwelling Catheter or Indwelling Catheters or In-Dwelling Catheters or Catheter, In-Dwelling or Catheters, In-Dwelling or In Dwelling Catheters or In-Dwelling Catheter or Intravenous infusion or Intravenous Infusions or Infusion, Intravenous or Intravenous Infusion or Intravenous Drip). mp
  5. 5 3 and 4
  6. 6 1 and 2
  7. 7 5 and 6

EBM Reviews - Cochrane Central Register of Controlled Trials < 1st Quarter 2010>

Search Strategy:
  1. 1 Infant, newborn/ or infant, low birth weight/ or infant, small for gestational age/ or infant, very low birth weight/ or infant, premature/ or exp Infant, Newborn, Diseases/ or pregnancy, high-risk/ or quadruplets/ or quintuplets/ or superfetation/ or triplets/ or twins/ or twins, dizygotic/ or twins, monozygotic/ or (infan: or neonat: or newborn: or prematur: or iugr or sga or vlbw or lbw or elbw).ti, ab. or ((intrauterine adj2 growth adj2 restrict:) or (intrauterine adj2 growth adj2 retard:)).ti, ab.
  2. 2 Heparin/ or (Heparinic Acid or Liquaemin or Sodium Heparin or Heparin, Sodium or Heparin Sodium or alpha-Heparin or alpha Heparin).mp
  3. 3 Intravenous catheter/ or (Catheter, Indwelling or Indwelling Catheter or Indwelling Catheters or In-Dwelling Catheters or Catheter, In-Dwelling or Catheters, In-Dwelling or In Dwelling Catheters or In-Dwelling Catheter or Intravenous infusion or Intravenous Infusions or Infusion, Intravenous or Intravenous Infusion or Intravenous Drip). mp
  4. 4 1 and 2

EMBASE < 1980 to 2010 Week 30>

Search Strategy:
  1. newborn/ or newborn period/ or low birth weight/ or extremely low birth weight/ or small for date infant/ or very low birth weight/ or Prematurity/ or exp newborn disease/ or multiple pregnancy/ or twin pregnancy/ or twins/ or dizygotic twins/ or monozygotic twins/ or human triplets/ or intrauterine growth retardation/ or small for date infant/ or (infan: or neonat: or newborn: or prematur: or iugr or sga or vlbw or lbw or elbw or (intrautrine adj2 growth adj2 restrict:) or (intrauterine adj2 growth adj2 retard:)).ti, ab. (774681)
  2. ct.fs. or clinical trial/ or controlled clinical trial/ or multicenter study/ or phase 1 clinical trial/ or phase 2 clinical trial/ or phase 3 clinical trial/ or phase 4 clinical trial/ or cohort analysis/ or double blind procedure/ or single blind procedure/ or triple blind procedure/ or meta analysis/ or randomized controlled trial/ or "systematic review"/ or case control study/ or longitudinal study/ or prospective study/ or retrospective study/ or multicenter study/ or validation study/ or (((evaluation or validation) adj2 study) or ((evaluation or validation) adj2 studies)).ti, ab. (882179)
  3. Heparin/ or (Heparinic Acid or Liquaemin or Sodium Heparin or Heparin, Sodium or Heparin Sodium or alpha-Heparin or alpha Heparin).mp
  4. Intravenous catheter/ or (Catheter, Indwelling or Indwelling Catheter or Indwelling Catheters or In-Dwelling Catheters or Catheter, In-Dwelling or Catheters, In-Dwelling or In Dwelling Catheters or In-Dwelling Catheter or Intravenous infusion or Intravenous Infusions or Infusion, Intravenous or Intravenous Infusion or Intravenous Drip). mp
  5. 1 and 2
  6. 3 and 4
  7. 4 and 5

We also searched reference lists of identified trials, and abstracts from the annual meetings of the Society for Pediatric Research, American Pediatric Society and Pediatric Academic Societies published in Pediatric Research (2002-2009). No language restrictions were applied.

ClinicalTrials.gov

Search Strategy:

Heparin AND (neon* OR infant OR newborn)

Limited: Child (birth - 17 years)

Controlled-Trials.com External Web Site Policy

Search Strategy:

Heparin AND (neon* OR infant OR newborn)

No limits applied


This review is published as a Cochrane review in The Cochrane Library, Issue 1, 2011 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review.