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Continuous heparin infusion to prevent thrombosis and catheter occlusion in neonates with peripherally placed percutaneous central venous catheters

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Authors

Prakeshkumar S Shah1, Vibhuti S Shah2

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]
2Associate Professor Departments of Paediatrics and Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada [top]

Citation example: Shah PS, Shah VS. Continuous heparin infusion to prevent thrombosis and catheter occlusion in neonates with peripherally placed percutaneous central venous catheters. Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD002772. DOI: 10.1002/14651858.CD002772.pub3.

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: 04 January 2011
Date of Search: 13 September 2010
Next Stage Expected: 04 January 2013
Protocol First Published: Issue 4, 2000
Review First Published: Issue 3, 2005
Last Citation Issue: Issue 2, 2008

What's new

Date / Event Description
13 September 2010
Updated

This review updates the existing review of "Continuous heparin infusion to prevent thrombosis and catheter occlusion in neonates with peripherally placed percutaneous central venous catheters" published in the Cochrane Database of Systematic Reviews, Issue 2, 2008 (Shah 2008).

An updated search September 13, 2010 identified one new eligible study and this has been included in this update.

Conclusions have not changed.

History

Date / Event Description
09 January 2008
Amended

Converted to new review format

Abstract

Background

Complications associated with peripherally placed percutaneous central venous catheters (PCVC) in neonates include catheter thrombosis, occlusion or dislodgement and infection. Strategies to prevent catheter thrombosis and occlusion include the use of heparin. However, heparin is known to be associated with complications such as bleeding and thrombocytopenia.

Objectives

To assess the effectiveness of heparin for prevention of catheter related thrombosis.

Secondary objectives included assessment of the effectiveness of heparin on catheter occlusion, duration of catheter patency, catheter related sepsis and complications associated with the use of heparin.

Search methods

A literature search of MEDLINE, EMBASE, CINAHL from their inception to September 13, 2010, The Cochrane Library (Issue 2, 2010) and abstracts from the annual meetings of the Pediatric Academic Societies was performed.

Selection criteria

Randomized or quasi-randomised clinical trials of neonates where heparin infusion was compared to placebo or no treatment for prevention of any of the complications related to peripherally placed PCVC were included.

Data collection and analysis

We collected and analysed the data in accordance with the recommendations of the Cochrane Neonatal Review Group.

Results

Four randomised trials were identified. Three trials (including 477 infants) of adequate methodology met the eligibility criteria. There was reduced risk of catheter occlusion (typical RR 0.39, 95% CI 0.22 to 0.67; and NNT 9, 95% CI 6 to 20). There was no statistically significant difference in the duration of catheter patency; however, in one study survival analyses identified benefit with heparin (adjusted hazard ratio 0.55, 95% CI 0.36, 0.83). This could be due to higher incidence of elective removal of catheters in neonates at the completion of therapy in the heparin group in that study (63% vs. 42%; p = 0.002). There was no statistically significant differences in the risk of thrombosis (typical RR 0.93, 95% CI 0.58 to 1.51), catheter related sepsis (typical RR 0.82, 95% CI 0.43 to 1.57), or extension of intraventricular haemorrhage (typical RR 0.50, 95% CI 0.19 to 1.28) between the two groups.

Authors' conclusions

Prophylactic use of heparin for peripherally placed PCVC allows a greater number of infants to complete their intended use (complete therapy) by reducing occlusion. Evidence from this systematic review support the prophylactic use of heparin for PCVC in neonates. None of these studies was powered to evaluate a lower incidence rate of adverse events. If this therapy is adopted in routine practice, monitoring of side effects is indicated.

Plain language summary

Continuous heparin infusion to prevent thrombosis and catheter occlusion in neonates with peripherally placed percutaneous central venous catheters

There is now evidence to show beneficial effect of heparin for preventing complications when used with central catheters to give access to the tiny veins of premature and critically ill babies

Critically ill or premature babies (born before 37 weeks of pregnancy) often need medication and feeding through their veins. These veins are small and fragile so repeated injections can be hard and painful for the baby. A central catheter is a small tube that can be inserted into the vein, allowing medications and other liquids to be given to the baby for a prolonged period. It can get dislodged, blocked or infected. The drug heparin allows to complete intended therapy in more patients without increasing complications of bleeding or allergic reactions. The review found that there was now evidence to show benefit of heparin. If it is used routinely, careful monitoring of side effects is warranted.

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Background

Description of the condition

Vascular access is a major challenge in the management of preterm and critically ill term infants in neonatal intensive care units. Shaw 1973 first described the successful placement of peripherally inserted percutaneous central venous catheters (PCVC) in neonates. In sick neonates these catheters have been shown to provide long-term vascular access necessary for the prolonged administration of parenteral nutrition and intravenous medications (Dolcourt 1982; Klein 1992; Chathas 1986; Durand 1986; Loeff 1982; Puntis 1986; Harms 1992).

Despite perceived benefits in neonates, peripherally inserted PCVC are associated with mechanical and infectious complications. Mechanical complications including occlusion, extravasation, dislodgement and thrombosis occur in 15 to 48% of inserted PCVC (Harms 1992; Klein 1992; Chathas 1986; Durand 1986; Nakamura 1990). Nakamura 1990 found complete (33%) and partial (33%) occlusion in catheter tips on electron microscopic examination. In addition, 39% of all catheter tip sheaths had evidence of thrombosis. Factors that have been associated with initiation and propagation of thrombosis include endothelial damage during catheter placement, blood vessel occlusion, low flow states, turbulent flow, patient and infusate characteristics and catheter composition (Pottecher 1984; Krafte-Jacobs 1995). Infectious complications include bacterial or fungal sepsis. Thrombosis of the line can act as a nidus for infection.

Description of the intervention

Heparin has been administered by intermittent injection or continuous infusion to prevent thrombus formation and prolong catheter patency (Randolph 1998; Schmidt 1988; Brismar 1982). In a systematic review involving all ages including neonates, Randolph 1998 evaluated the effectiveness of heparin (administered intermittently or as continuous infusion) on catheter patency and prevention of complications associated with peripheral arterial or venous catheters. The authors concluded that the use of heparin flushes at concentrations of 10 units/ml demonstrated no effect on catheter patency for peripheral venous lines; however, low dose heparin infusion through peripheral arterial catheters prolonged the patency of the catheter. The benefits of using heparin have to be weighed against the risks involved. Risks include allergic reactions, bleeding complications due to dosing error and occurrence of heparin-induced thrombocytopenia which has been described in 3% of patients exposed to heparin (Spadone 1992).

In a systematic review, Barrington 2000 documented that heparin infusion is effective in improving umbilical arterial catheter patency in neonates, with no statistically significant evidence of adverse outcomes. The effectiveness of heparin use to prevent thrombosis in neonates with peripherally placed PCVC has not been systematically evaluated.

Why it is important to do this review

The aim of this review was to determine the benefits and risks of continuous infusion of heparin in neonates with a peripherally inserted PCVC.

Objectives

The primary objective of this review was to determine the effect of heparin infusion in neonates with a peripherally inserted PCVC on the incidence of thrombosis along the length of, or at the tip of the catheter.

Secondary objectives were to determine the effect of heparin infusion on:

  1. occlusion of catheter (defined as inability to infuse fluids through the catheter due to blockage);
  2. number of days of catheter patency (duration of patency of first catheter);
  3. episodes of catheter related sepsis (defined as symptoms and signs suggestive of sepsis, accompanied by positive blood cultures obtained from a normally sterile site different to the central line, and from the line or catheter tip, each growing the same microorganism);
  4. number of additional peripheral intravenous catheter insertions;
  5. arrhythmia (defined as abnormal rhythm on electrocardiogram while catheter is in situ);
  6. abnormality of coagulation profile;
  7. allergic reactions to heparin;
  8. heparin induced thrombocytopenia (development of thrombocytopenia after starting heparin in an infant with previously normal platelet count after exclusion of all other causes of thrombocytopenia);
  9. intraventricular/intracranial haemorrhage [development of recent onset of haemorrhage or extension of preexisting haemorrhage after starting heparin, according to the classification of Papile 1978];
  10. mortality.

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Methods

Criteria for considering studies for this review

Types of studies

Randomized and quasi-randomised controlled trials of heparin infusion in neonates with peripherally placed PCVC. Studies in which the unit of randomisation was catheter, the primary authors were to be contacted to obtain data for the first catheter after randomisation and only those data were to be included. If authors were unable to provide the data or could not be contacted the study were to be described and only data on long term outcome such as intraventricular haemorrhage were included.

Types of participants

Term or preterm infants who required peripherally placed PCVC during their stay in neonatal intensive care unit.

Types of interventions

Heparin infusion versus control (placebo or no treatment), without restriction to specific dosage regimen. Heparin or placebo infusion must have been administered during the entire duration of catheter placement.

Types of outcome measures

Studies that reported on one or more of the following outcomes among all randomised:
  • Thrombosis of the catheter (along the length of, or at the tip of the catheter) as determined by Doppler ultrasonography or contrast venography.
  • Occlusion of the catheter (identified by inability to infuse fluids).
  • Days of catheter patency (duration of patency of first catheter in days).
  • Episodes of catheter related sepsis (infants with one or more episode).
  • Number of additional peripheral intravenous catheters needed.
  • Arrhythmia.
  • Side effects of heparin (allergic reactions, haemorrhage, heparin-induced thrombocytopenia, abnormal coagulation profile).
  • Extension of intraventricular haemorrhage (IVH) in patients with pre-existing IVH or appearance of new IVH.
  • Mortality during stay in neonatal intensive care unit.

Search methods for identification of studies

As per Cochrane Neonatal Collaborative Group search strategy

No language restrictions were applied. The following types of articles were excluded: letters, editorials/commentaries, reviews, lectures.

Electronic searches

Search strategy:

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

Ovid MEDLINE(R) 1950 to September 13, 2010

Serach strategy
  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. ("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. Heparin/ or (Heparinic Acid or Liquaemin or Sodium Heparin or Heparin, Sodium or Heparin Sodium or alpha-Heparin or alpha Heparin).mp
  4. Central Catheterization/ or (Catheterization, Central or Catheterizations, Central or Central Catheterizations or Central Venous Catheterization or Catheterizations, Central Venous or Central Venous Catheterizations or Venous Catheterizations, Central or Venous Catheterization, Central or Catheter, In-Dwelling or Catheters, In-Dwelling or In Dwelling Catheters or In-Dwelling Catheter). mp
  5. 3 and 4
  6. 1 and 2
  7. 5 and 6

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

Search Strategy:
  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. Heparin/ or (Heparinic Acid or Liquaemin or Sodium Heparin or Heparin, Sodium or Heparin Sodium or alpha-Heparin or alpha Heparin).mp
  3. Central Catheterization/ or (Catheterization, Central or Catheterizations, Central or Central Catheterizations or Central Venous Catheterization or Catheterizations, Central Venous or Central Venous Catheterizations or Venous Catheterizations, Central or Venous Catheterization, Central or Catheter, In-Dwelling or Catheters, In-Dwelling or In Dwelling Catheters or In-Dwelling Catheter). mp
  4. 4 1 and 2

EMBASE < 1980 to 2010 Week 32>

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 (intrauterine 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. Central Catheterization/ or (Catheterization, Central or Catheterizations, Central or Central Catheterizations or Central Venous Catheterization or Catheterizations, Central Venous or Central Venous Catheterizations or Venous Catheterizations, Central or Venous Catheterization, Central or Catheter, In-Dwelling or Catheters, In-Dwelling or In Dwelling Catheters or In-Dwelling Catheter). mp
  5. 1 and 2
  6. 3 and 4
  7. 4 and 5

Searching other resources

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 (2007 to 2010).

Clinical trials registries were also searched for ongoing or recently completed trials (ClinicalTrials.gov, Controlled-Trials.com External Web Site Policy, and WHO International Clinical Trials Registry Platform (ICTRP) External Web Site Policy).

Data collection and analysis

We collected and analysed data in accordance with the recommendations of the Cochrane Neonatal Review Group.

Selection of studies

All published articles identified as potentially relevant by the literature search were assessed for inclusion in the review by two reviewers. In order to be included the trial had to meet the following criteria: 1) the study population had to be term or preterm infants admitted to a neonatal intensive care unit 2) the intervention had to be heparin infusion in addition to regular maintenance fluid via peripherally placed PCVC, compared to placebo or no treatment 3) the study had to be a randomised or quasi-randomised controlled trial and 4) one or more primary or secondary outcome measures were reported.

Data extraction and management

We attempted to collect the data from the primary author when published data provided inadequate information for the review. Retrieved articles were assessed and data were abstracted independently by the reviewers. Discrepancy was resolved by consensus.

Assessment of risk of bias in included studies

Standard methods of the Cochrane Neonatal Review Group were used to assess methodological quality of studies.

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.

In addition, 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:
  2. adequate (any truly random process e.g. random number table; computer random number generator);
  3. inadequate (any non random process e.g. odd or even date of birth; hospital or clinic record number);
  4. unclear.
  5. Allocation concealment (checking for possible selection bias). Was allocation adequately concealed?
  6. For each included study, we categorized the method used to conceal the allocation sequence as:
  7. adequate (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);
  8. inadequate (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);
  9. unclear.
  10. 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:
  11. adequate, inadequate or unclear for participants;
  12. adequate, inadequate or unclear for personnel;
  13. adequate, inadequate or unclear for outcome assessors.
  14. 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:
  15. adequate (< 20% missing data);
  16. inadequate (greater than/or equal to 20% missing data):
  17. unclear.
  18. 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:
  19. 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);
  20. 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);
  21. unclear.
  22. 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:
  23. 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) when appropriate as per the methods of the Cochrane Neonatal Review Group.

Assessment of heterogeneity

We planned to estimate the treatment effects of individual trials and examine 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 subgroup analyses.

Data synthesis

The meta-analysis was been 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

No subgroup analysis was planned a priori.

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Results

Description of studies

Four studies were identified (Birch 2010; Kamala 2002; Shah 2007; Betremieux 1988). Three studies met eligibility criteria for this review (Kamala 2002, Shah 2007; Birch 2010).

Kamala 2002: Randomized 68 neonates (36 neonates in heparin group and 32 neonates in no heparin group). Each infant received only one catheter for the purpose of the study. The eligible neonates were stratified in three groups according to birth weight before randomisation. Neonates in the heparin group received 1 IU of heparin per ml of parenteral nutrition solution. The neonates in the no heparin group did not receive heparin in the parenteral nutrition solution. Premicath (27G) and Epicutaneocava (23 G) silicone catheters were used depending upon the size of infants. All patients were monitored for hyperbilirubinaemia, hypertriglyceridaemia, coagulation profile and platelet counts prior to insertion of catheter, at four days and eight days after catheter insertion or on removal of catheter if it was removed before four days. Catheter blockage was diagnosed (a) when there was inability to infuse fluid and (b) when clots were noted at the time of removal of catheter. The duration of catheter patency was defined as number of days the catheter stayed in situ. Catheter related sepsis was diagnosed when clinical symptoms and signs of sepsis were associated with positive catheter tip culture and blood culture for the same organism. There was protocol violation for two patients (one in each group). The details of the patients enrolled in this study are described in the table Characteristics of Included Studies.

Shah 2007: Randomized 201 neonates (100 neonates in heparin group and 101 neonates in no heparin group) at four centres in Ontario, Canada. One catheter per patients was studied. The eligible neonates were stratified in two groups according to gestational age (GA) before randomisation (< 30 weeks GA and greater than/or equal to 30 weeks GA). Neonates in the heparin group received 0.5 IU/kg/hr of unfractionated heparin mixed in 5% or 10% dextrose solution (depending upon plasma glucose level) via a separate infusion pump but “Y”ed in to the running solution (TPN or normal saline). The solution was infused at 0.5 ml/hr (for neonates < 30 weeks GA and 1 ml/hr for infants > 30 weeks GA). Neonates in the placebo group received either 5% or 10% dextrose solution (depending upon plasma glucose level) running at similar rate as heparin infusions. Neo-PICC, L-cath, V-cath or Per-Q-cath catheters were used depending upon the choice and availability of catheter at study sites. All patients were monitored for clinical signs of sepsis and thrombosis. The primary outcome was duration of catheter use was defined as the time between insertion and removal (elective or because of complications) of the catheter in hours. Secondary outcomes included catheter occlusion defined as inability to infuse fluid; catheter-related sepsis defined as symptoms and signs suggestive of sepsis with a positive blood culture obtained from catheter fluid and a normally sterile site (blood, urine, or cerebrospinal fluid) for the same organism; thrombosis was defined as the detection of a thrombus along the catheter path diagnosed by ultrasonography and Doppler examination within 72 hours after catheter removal and/or when clinically indicated (distal swelling and persistent thrombocytopenia); and other causes of catheter removal such as accidental dislodgment, leakage, extravasation, or breakage of the catheter. Each infant was monitored for haemorrhage from > 2 noncontiguous sites and heparin-induced thrombocytopenia (HIT), defined as a platelet count of < 50, 000/mL after exclusion of other causes of thrombocytopenia and a positive antibody test. Duration of catheter patency was compared using survival analyses (Kaplan Meir curve and Log-rank test).

Birch 2010: Randomized 243 neonates (118 neonates in heparin group and 125 neonates in no heparin group). It appears that one catheter per patient was studied. The eligible neonates were stratified in three groups according to birth weight (< 850 g, 850 to 2000 g and > 2000 g). Sixteen patients in heparin group and 17 patients in no heparin group were excluded after randomisation due to no need for long line, inability to place long line, death before long line insertion, lack of parental consent and commencement of non-protocol infusion. Neonates in the heparin group (n = 102) received 0.5 IU/ml of unfractionated heparin mixed in total parenteral solution (TPN). The solution was infused at rates prescribed by attending team. Neonates in the control group received TPN without heparin. Epicutaneo Cava Katheter (23 gauge) and PremiCath (27 gauge) were used depending upon the choice of inserting physician. All patients were monitored for clinical signs of sepsis and extravasation. The primary outcome was number of episodes of catheter related sepsis and rate of catheter related sepsis per 1000 long line days. Secondary outcomes were bacteraemic episodes with organisms not commonly associated with line sepsis, definite or probable candida line infection, progression of IVH, catheter removal due to extravasation or occlusion and elective removal of catheter. Definite catheter related sepsis was defined as two positive blood cultures for the same organism taken from two separate sites within 72 hours of each other. Probable sepsis was defined as single positive blood culture and a peak C-reactive protein level > 9 mg/l recorded from 24 hours before or 72 hours after the positive culture was drawn. Possible catheter related sepsis was defined as a single positive blood culture without elevation of C reactive protein.

Another study relevant to the objectives of this review (Betremieux 1988) was identified. It was published in French and was translated to English for this review. The trial did not meet the entry criteria specified a priori for this review. The reasons for exclusion of this study are given in the table Characteristics of excluded studies.

Risk of bias in included studies

Kamala 2002 performed a double blind placebo controlled randomised trial of use of heparin for peripherally inserted central venous catheters in neonates. The randomisation was done by one of the investigators (pharmacist) from previously prepared randomisation cards. No other investigators were aware of the treatment allocation. The heparin was mixed in the parenteral nutrition fluid. One patient each from both heparin and placebo group was removed from analysis because of the protocol violation. The authors have not reported masking of outcome assessment; however, the attending team was unaware of allocation when making decision regarding discontinuation of the catheter among the patients in whom the randomisation codes were not broken. The randomisation codes were broken prior to completion of the study in 13 patients (n = 5 heparin group and n = 8 no heparin group). The reasons for the breaking the code were development of bleeding tendencies (n = 2 heparin group and n = 4 no heparin group) and thrombocytopenia (n = 3 heparin group and n = 4 no heparin group). After breaking the code heparin was removed from the parenteral solutions from patients in heparin group and none of the patients developed blocked catheters. None of the patients were described to have more than one outcome.

Shah 2007 performed a multicenter double blind placebo controlled randomised trial of the use of heparin for peripherally inserted central venous catheters in neonates. The randomisation was done centrally by pharmacist at all four hospitals from non-transparent sealed envelopes. No investigators or parents were aware of the treatment allocation. The heparin and placebo were delivered in identical containers labelled as study medication. Investigators and parents were unaware of randomisation through out the study. Two randomisation envelopes (one each in heparin and placebo group) were inadvertently opened for patients who did not have central venous catheters. These were excluded from analyses. Outcome assessment was masked. Radiologist reporting ultrasonography was unaware of treatment allocation. The randomisation codes were not broken for safety reasons in any patient. Primary outcome data were complete for all patients. Secondary outcome data especially for ultrasonography were missing for patients transferred to community centres or due to non-availability of machines and/or technicians.

Birch 2010 performed a single centre double blind placebo controlled randomised trial of the use of heparin for peripherally inserted central venous catheters in neonates. The randomisation was done centrally by a pharmacist. Neither investigators nor parents were aware of the treatment allocation. The heparin was added to the total parenteral solution. Of 243 patients randomised, 33 (16 in heparin group and 17 in control group) were excluded because of various reasons (catheter no longer required, inability to place catheter, death before catheter placement, lacked consent, initiation of non study nutrition). These were excluded from analyses and pragmatically speaking this should not have affected validity of the study. Outcome assessment was masked. Primary outcome data were complete for all patients. Secondary outcome data especially for ultrasonography were missing for some patients in both groups.

Effects of interventions

HEPARIN VS. NO HEPARIN GROUP (COMPARISON 1):

Occlusion of the catheter (identified by inability to infuse fluids) (Outcome 1.1):

There was statistically significant difference in the incidence of catheter occlusion between heparin and no heparin group (typical RR 0.39, 95% CI 0.22 to 0.67; and typical RD -0.11, 95% CI -0.16 to -0.05) in favour of heparin group. Number of infants needed to treat to prevent one catheter occlusion by heparin was 9 (95% CI 6 to 20). This was translated in clinically meaningful outcome of ability to complete intended therapy in the study by Shah 2007. A statistically significantly higher proportion of catheters were removed electively in heparin group vs. placebo group (63% vs. 42%; p = 0.002; RR 1.5, 95% CI 1.2 to 2.0; RD -0.21, 95% CI -0.34 to -0.07, NNT 5, 95% CI 3 to 14). However, there was no difference in the number of infants who had elective removal of catheter (62% vs. 58%; RR 1.06, 95% CI 0.85 to 1.32; RD 0.03, 95% CI -0.10 to 0.17) in Birch 2010.

Thrombosis of the catheter (along the length of, or at the tip of the catheter) as determined by Doppler ultrasonography or contrast venography (Outcome 1.2):

There was no statistically significant differences in the incidence of thrombosis between heparin and no heparin group (typical RR 0.93, 95% CI 0.58 to 1.51; and typical RD -0.01, 95% CI -0.11 to 0.08). Kamala 2002 identified thrombosis by flushing the catheter after removal and observing the presence of clots. Shah 2007 performed ultrasonography within 72 hours of catheter removal and when clinically indicated.

Days of catheter patency (duration of patency of first catheter) (Outcome 1.3):

There was no statistically significant difference in the duration of catheter patency between heparin and no heparin group (WMD 0.87 days, 95% CI -0.66 days to 2.39 days). However, this analysis is confounded due to the fact that many observations were censored in both groups (i.e. catheters were removed at the completion of therapy or death of patients). Shah 2007 analysed this data using survival analysis and identified that the adjusted hazard ratio was in favour of infants in the heparin group compared with the placebo group (P < 0.005; hazard ratio: 0.55, 95% CI 0.36 to 0.83).

Episodes of catheter related sepsis (infants with one or more episode) (Outcome 1.4):

There was no statistically significant difference in the incidence of catheter related sepsis between heparin and no heparin group (typical RR 0.82, 95% CI 0.43 to 1.57; and typical RD -0.01, 95% CI -0.06 to 0.03).

Number of additional peripheral intravenous catheters needed

This outcome was not reported in either study.

Arrhythmia

This outcome was not reported in either study.

Side effects of heparin (allergic reactions, haemorrhage, heparin-induced thrombocytopenia, abnormal coagulation profile) (Outcome 1.5):

There was no statistically significant difference in the activated partial thromboplastin time between heparin and no heparin group (MD -5.7 sec, 95% CI -22.2 sec to 10.8 sec). Birch 2010 reported that none of the neonates in their trial were unblinded because of bleeding diathesis or thrombocytopenia.

Extension of pre-existing IVH or appearance of new IVH (Outcome 1.6):

There was no statistically significant difference in the appearance of new IVH between heparin and no heparin group (typical RR 0.50, 95% CI 0.19 to 1.28; and typical RD -0.03, 95% CI -0.07 to 0.01) as reported by Kamala 2002 and Birch 2010 whereas Shah 2007 reported no new or extension of haemorrhage in any of their patients.

Mortality during stay in neonatal intensive care unit (Outcome 1.7):

There was no statistically significant difference in the mortality between heparin and no heparin group (typical RR 0.83, 95% CI 0.33 to 2.09; and typical RD -0.01, 95% CI -0.04 to 0.02).

Discussion

In our previous version (Shah 2007) of this systematic overview, two randomised controlled studies (Kamala 2002; Shah 2007) were identified. In our current update, another adequately powered randomised controlled trial (Birch 2010) was identified. All three studies are of good methodological quality. The combined estimate of effect reveals that addition of heparin for percutaneously placed central venous catheters allows completion of intended therapeutic use of catheter in neonates. There is reduced risk of catheter occlusion. The duration of catheter use was not significantly different between heparin and placebo groups (duration of catheter patency was not different); however, this could be explained by the fact that these catheters are removed at the end of their intended use and duration. Traditional continuous outcome assessment may not capture this adequately. Survival analysis with censoring of data is probably the correct method for such analysis (Shah 2007). The authors reported a hazard ratio of 0.55 (95% CI 0.36 to 0.83) for catheter usability in favour of heparin. This difference is clinically meaningful and strongly indicates efficacy.

There were no significant side effects reported in study by Shah 2007 and Birch 2010, whereas 20% of patients required opening of randomisation code because of safety issues in Kamala 2002. Increased incidences of complications (bleeding tendencies and thrombocytopenia) reported in this study (Kamala 2002) may have resulted due to higher dose of heparin used. Infants in the heparin group received heparin in the dose of 1 IU/ml of parenteral nutrient solution, which could result in on an average > 100 IU/kg/d of heparin delivered to those infants. Most of the studies of heparin for peripheral intravenous catheters and umbilical artery catheters have used 0.25 to 0.5 IU/kg/hr resulting in a maximum of 12 IU/kg/d delivered to infants and have shown no increase in these complications. Birch 2010 used half dose 0.5 IU/ml than Kamala 2002 and did not observe increased incidence of side effects. A dose of 0.5 U/kg/hr used by Shah 2007 resulted in elimination of such side effects; however, it must be recognized that neither studies were adequately powered to detect side effects, which are rare. There is heterogeneity between studies in terms of dose of heparin used; however, this keeps in with clinical heterogeneity in practice that we see in neonatal units. Shah 2007 showed an increase in longevity of catheter and higher numbers of patients were able to complete the intended use (0.5 IU/kg/hr) whereas Birch 2010 showed reduction in incidence of catheter related sepsis (0.5 IU/ml of total parenteral solution). Thus, it will be difficult to generalize a specific dose; however, we can indicate that use of heparin is efficacious.

Barrington 2000 has evaluated the effectiveness of heparin for umbilical arterial catheter placement in a systematic review. Even in concentrations as low as 0.25 units/ml heparin was found to prolong umbilical artery catheter patency without significant adverse outcomes. However, the data from that review cannot be extrapolated to PCVC placement as the size of the catheters (internal diameter) used for umbilical arterial catheters is larger than that used for PCVC placement. In addition, the flow patterns in the aorta, where umbilical catheters are usually placed, differ from the relatively sluggish circulatory states of the venous system in which PCVC are placed, thus making PCVCs more prone to thrombus formation. In another systematic review, Randolph 1998 found that heparin was effective in preventing complications for peripheral arterial catheters but not for venous catheters. However, that review was not limited to the neonatal population.

With the new information available from this updated review, it could be concluded that heparin is effective in allowing increased number of patients to complete their therapy or intended use of PCVC, and reduces the risk of catheter occlusion. It is important that if this practice is adopted a careful reporting of side effects associated with the use of heparin for PCVC is indicated.

Authors' conclusions

Implications for practice

Prophylactic use of heparin for peripherally placed PCVC allows higher number of infants to complete their intended use (complete therapy). Heparin reduces catheter occlusion. Evidence from this systematic review support the use of heparin for PCVC in neonates.

Implications for research

With increasing survival of extreme preterm infants, the need for peripherally placed PCVC is growing. None of these studies was powered to evaluate a lower incidence rates of adverse events. If this therapy is adopted in clinical practice, monitoring of side effects is indicated.

Acknowledgements

Authors acknowledge Dr. Y Diambomba for translation of the Betremieux 1988 study from French to English.

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
Writing the text of review

Dr. V. Shah

Literature search and identification of trials
Evaluation of methodological quality of trials
Revision of the review

Declarations of interest

After concluding in the first version of the review (Shah 2001) that there were no randomised controlled trials on the subject, the authors initiated a randomised controlled trial evaluating this intervention, results of which are incorporated in this version (Shah 2007).

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

Birch 2010

Methods

Double blind randomised controlled study

  1. Masking of randomisation: Yes
  2. Masking of intervention: Yes
  3. Completeness of follow-up: Yes
  4. Masking of outcome assessment: Yes
Participants

Infants who needed peripherally inserted central venous catheters were enrolled.
Patients were stratified according to birth weight (< 850g, 850 - 2000g and > 2000g) after parental consent.
Heparin group (102 neonates): Mean (SD) birth weight was 1261 (672) g and gestational age was 28.7 (3.6) weeks
No heparin group (108 neonates): Mean (SD) birth weight was 1308 (720) g and gestational age was 29.0 (4.2) weeks
Exclusion criteria: Neonates with previous successful use of peripherally inserted central venous catheter

Interventions

Heparin group: Neonates in the heparin group received heparin in the parenteral nutrition solution at a concentration of 0.5 IU/ml.
No heparin group: no heparin was added to the parenteral solution in this group of patients.

Outcomes

Number of episodes of catheter related sepsis

Rates of catheter related sepsis episode/1000 catheter days

Bacteremia with organisms not commonly associated with catheter sepsis

Definite or probable Candida catheter sepsis

Mortality

Progression of intraventricular haemorrhage

Catheter removal due to extravasation or occlusion

Elective catheter removal

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

Double blind randomised controlled study
Masking of randomisation: Yes

Blinding? Yes

Masking of intervention: Yes
Masking of outcome assessment: Yes

Incomplete outcome data addressed? Yes

Completeness of follow-up: Yes

Free of selective reporting? Yes
Free of other bias? Yes

Kamala 2002

Methods

Double blind randomised controlled study

  1. Masking of randomisation: Yes
  2. Masking of intervention: Yes
  3. Completeness of follow-up: Yes
  4. Masking of outcome assessment: Yes
Participants

Infants who needed peripherally inserted central venous catheters were enrolled.
Patients were stratified according to birth weight (< 1250, 1250 - 2500 and > 2500 grams) after parental consent.
Heparin group (35 neonates): Mean (SD) birth weight was 1454 (600) g and gestational age was 30.9 (3.9) weeks
No Heparin group (31 neonates): Mean (SD) birth weight was 1430 (630) g and gestational age was 31.9 (4.2) weeks
Exclusion criteria: Neonates with clinical evidence of bleeding tendencies, severe intraventricular haemorrhage grade 3/4, thrombocytopenia (platelet count < 100), prolonged activated partial thromboplastin time > 51s for term infants and > 74s for preterm infants

Interventions

Heparin group: Neonates in the heparin group received heparin in the parenteral nutrition solution at a concentration of 1 IU/ml.
No heparin group: no heparin was added to the parenteral solution in this group of patients.

Outcomes

Number of blocked catheters
Number of patients who had elective removal of catheter (completed administration of parenteral solution)
Phlebitis
Catheter related septicaemia
Mortality
Duration of peripherally inserted central venous catheter in situ
Coagulation abnormality

Notes

1 patient each in both group had protocol violation

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

Double blind randomised controlled study

Masking of randomisation: Yes

Blinding? Yes

Masking of intervention: Yes
Masking of outcome assessment: Yes

Incomplete outcome data addressed? Yes

Completeness of follow-up: Yes

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

Shah 2007

Methods

Double blind randomised controlled study

  1. Masking of randomisation - Yes
  2. Masking of intervention - Yes
  3. Completeness of follow up - Yes
  4. Masking of outcome assessment - Yes
Participants

Infants who needed peripherally inserted central venous catheters were enrolled.
Patients were stratified according to GA (< 30 weeks and greater than/or equal to 30 weeks) after parental consent.
Heparin group (100 neonates): Mean (SD) birth weight was 1011 (467) g and GA was 28 (3) weeks
Placebo group (101 neonates): Mean (SD) birth weight was 1095 (565) g and gestational age was 28 (4) weeks
Exclusion criteria: Neonates who had grade 3/4 intraventricular haemorrhage, recent onset of presumed or confirmed sepsis (within 48 hours of initiation of antimicrobial therapy), bleeding diathesis, disseminated intravascular coagulation, thrombocytopenia (most recent platelet count of < 100, 000/mL), arrhythmia, preexisting liver disease

Interventions

Heparin group: Neonates in the heparin group received heparin in 5% or 10% dextrose at dose of 0.5 IU/kg/hr running at 0.5 ml/hr (for neonates < 30 weeks GA and 1 ml/hr for neonates greater than/or equal to 30 weeks).

The solution was “Y”ed in with the ongoing solution.
Placebo group: Normal saline was added to the parenteral solution in this group of patients. The infusion rate was similar to heparin group.

Outcomes

Duration of peripherally inserted central venous catheter in situ

Catheter occlusion

Catheter related sepsis

Catheter related thrombosis

Other causes of catheter removal

Bleeding tendency

Heparin induced thrombocytopenia

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

Double blind randomised controlled study

Masking of randomisation - Yes

Blinding? Yes

Masking of intervention - Yes

Masking of outcome assessment - Yes

Incomplete outcome data addressed? Yes

Completeness of follow up - Yes

Free of selective reporting? Yes
Free of other bias? Yes

Characteristics of excluded studies

Betremieux 1988

Reason for exclusion
  1. The infants were randomised to heparin or control at the time of insertion of umbilical catheters and later on when they needed the placement of PCVC they were kept in the same treatment group. There was no separate randomisation at the time of PCVC placement.
  2. The results are expressed based on number of catheters rather than infants. Four infants had multiple catheter insertions and separate data were not available for first catheter placement.

PCVC = Percutaneous central venous catheter

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References to studies

Included studies

Birch 2010

Birch P, Ogden S, Hewson M. A randomised controlled trial of heparin in total parenteral nutrition to prevent sepsis associated with neonatal long lines: the Heparin in Long Line Total Parenteral Nutrition (HILLTOP) trial. Archives of Diseases of Childhood Fetal and Neonatal Edition 2010;95:F252-7.

Kamala 2002

Kamala F, Boo NY, Cheah FC, Birinder K. Randomized controlled trial of heparin for prevention of blockage of peripherally inserted central catheters in neonates. Acta Paediatrica 2002;91:1350-6.

Shah 2007

Shah PS, Kalyn A, Satodia P, Dunn MS, Parvez B, Daneman A, Salem S, Glanc P, Ohlsson A, Shah V. A randomized, controlled trial of heparin versus placebo infusion to prolong the usability of peripherally placed percutaneous central venous catheters (PCVCs) in neonates: the HIP (Heparin Infusion for PCVC) study. Pediatrics 2007;119:e284-91.

Excluded studies

Betremieux 1988

Betremieux P, Odent S, Prigent JY, Dabadie A, Roussey M, Lefrancois C, Le marec B. Study of continuous infusion of low doses of heparin in the prevention of complications of catheters during the neonatal period [Etude de la perfusion continue de faibles doses d'heparine dans la prevention des complications liees aux catheters dans la periode neonatale]. La Revue de Pediatrie 1988;14:311-5.

Studies awaiting classification

  • None noted.

Ongoing studies

  • None noted.

Other references

Additional references

Barrington 2000

Barrington KJ. Umbilical artery catheters: heparin usage. Cochrane Database of Systematic Reviews 2000, Issue 2. Art. No.: CD000507. DOI: 10.1002/14651858.CD000507.

Brismar 1982

Brismar B, Hardstedt C, Jacobson S, Kager L, Malmborg AS. Reduction of catheter-associated thrombosis in parenteral nutrition by intravenous heparin therapy. Archives of Surgery 1982;117:1196-9. [MEDLINE: 6810843]

Chathas 1986

Chathas MK. Percutaneous central venous catheters in neonates. Journal of Obstetrics, Gynecological and Neonatal Nursing 1986;15:324-32. [MEDLINE: 3638348]

Dolcourt 1982

Dolcourt JL, Bose CL. Percutaneous insertion of silastic central venous catheters in newborn infants. Pediatrics 1982;70:484-6. [MEDLINE: 6810302]

Durand 1986

Durand M, Ramanathan R, Martinelli B, Tolentino M. Prospective evaluation of percutaneous central venous silastic catheters in newborn infants with birth weights of 510 to 3, 920 grams. Pediatrics 1986;78:245-50. [MEDLINE: 3090511]

Harms 1992

Harms K, Herting E, Kruger T, Compagnone D, Speer CP. Percutaneous silastic catheters in newborn and premature infants. A report of experience with 497 catheters in 5 years. Monatsschrift fur Kinderheilkd 1992;140:464-71. [MEDLINE: 1435805]

Klein 1992

Klein JF, Shahrivar F. Use of percutaneous silastic central venous catheters in neonates and the management of infectious complications. American Journal of Perinatology 1992;9:261-4. [MEDLINE: 1627216]

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. [MEDLINE: 7815223]

Loeff 1982

Loeff DS, Matlak ME, Black RE, Overall JC, Dolcourt JL, Johnson DG. Insertion of a small central venous catheter in neonates and young infants. Journal of Pediatric Surgery 1982;17:944-9. [MEDLINE: 6819354]

Nakamura 1990

Nakamura KT, Sato Y, Erenberg A. Evaluation of a percutaneously placed 27-gauge central venous catheter in neonates weighing less than 1200 grams. Journal of Parenteral and Enteral Nutrition 1990;14:295-9.

Papile 1978

Papile L, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1, 500 grams. Journal of Pediatrics 1978;92:529-34.

Pottecher 1984

Pottecher T, Forrler M, Picardat D, Krause D, Bellocq JP, Otteni JC. Thrombogenicity of central venous catheters: prospective study of polyethylene, silicone and polyurethane catheters with phlebography or postmortem examination. European Journal of Anaesthesiology 1984;1:361-5. [MEDLINE: 6536520]

Puntis 1986

Puntis JW. Percutaneous insertion of central venous feeding catheters. Archives of Diseases of Childhood 1986;61:1138-40. [MEDLINE: 3098187]

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. British Medical Journal 1998;316:969-75. [MEDLINE: 9550955]

Schmidt 1988

Schmidt B, Andrew M. Neonatal thrombotic disease: prevention, diagnosis, and treatment. Journal of Pediatrics 1988;113:407-10. [MEDLINE: 3294364]

Shaw 1973

Shaw JCL. Parenteral nutrition in the management of sick low birth weight infants. Pediatric Clinics of North America 1973;20:333-58.

Spadone 1992

Spadone D, Clark F, James E, Laster J, Hoch J, Silver D. Heparin-induced thrombocytopenia in the newborn. Journal of Vascular Surgery 1992;15:306-11. [MEDLINE: 1735891]

Other published versions of this review

Shah 2001

Shah P, Shah V. Continuous heparin infusion to prevent thrombosis and catheter occlusion in neonates with peripherally placed percutaneous central venous catheters. Cochrane Database of Systematic Reviews 2001, Issue 2. Art. No.: CD002772. DOI: 10.1002/14651858.CD002772.

Shah 2005

Shah P, Shah V. Continuous heparin infusion to prevent thrombosis and catheter occlusion in neonates with peripherally placed percutaneous central venous catheters. Cochrane Database of Systematic Reviews 2005, Issue 3. Art. No.: CD002772. DOI: 10.1002/14651858.CD002772.pub2.

Shah 2007

Shah PS, Shah VS. Continuous heparin infusion to prevent thrombosis and catheter occlusion in neonates with peripherally placed percutaneous central venous catheters. Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD002772. DOI: 10.1002/14651858.CD002772.pub3.

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Data and analyses

1 Heparin versus no heparin group

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Catheter occlusion 3 477 Risk Ratio (M-H, Fixed, 95% CI) 0.39 [0.22, 0.67]
1.2 Thrombosis 2 267 Risk Ratio (M-H, Fixed, 95% CI) 0.93 [0.58, 1.51]
1.3 Days of catheter patency (duration of patency of first catheter in days) 3 477 Mean Difference (IV, Fixed, 95% CI) 0.87 [-0.66, 2.39]
1.4 Episodes of catheter related sepsis 3 477 Risk Ratio (M-H, Fixed, 95% CI) 0.82 [0.43, 1.57]
1.5 Abnormality in coagulation 1 66 Mean Difference (IV, Fixed, 95% CI) -5.70 [-22.19, 10.79]
1.5.1 Activated partial thromboplastin time (sec) 1 66 Mean Difference (IV, Fixed, 95% CI) -5.70 [-22.19, 10.79]
1.6 Appearance of new IVH or extension of IVH in infants examined 3 412 Risk Ratio (M-H, Fixed, 95% CI) 0.50 [0.19, 1.28]
1.7 Mortality 3 477 Risk Ratio (M-H, Fixed, 95% CI) 0.83 [0.33, 2.09]

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Figures

  • None noted.

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Sources of support

Internal sources

  • Department of Paediatrics, University of Toronto, Canada
  • Department of Paediatrics, Mount Sinai Hospital, Toronto, Canada

External sources

  • No sources of support provided.

This review is published as a Cochrane review in The Cochrane Library, Issue 2, 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.