Date of most recent amendment: 23/11/1998
Date of most recent substantive amendment: 18/11/1998
Date next stage expected: / /
Contact
Dr Keith Barrington
Associate Professor
Pediatrics
University of California, San Diego
200 W Arbor Dr
San Diego
CA USA
92103-8774
Telephone 1: 1 619 543 7586
Telephone 2: 1 619 543 3759
Facsimile: 1 619 543 3812
E-mail: kbarrington@ucsd.edu
Sources of support for the review
Acknowledgements
Potential conflict of interest
None
Most NICUs now add heparin to the fluid being infused through the UAC. Several studies have examined whether this practice affects catheter occlusions or aortic thrombosis, and whether adding heparin to fluids used to intermittently flush the UAC, in place of adding heparin to the infusate, is adequate.
Heparin exposure at high dosage may be associated epidemiologically with an increased risk of intraventricular hemorrhage (Lesko 1986, Malloy 1995). It is therefore necessary to ensure that heparinization of fluids does indeed have a benefit as well as to determine whether clinically important adverse effects have been reliably assessed in newborn infants.
This review updates the existing review of Umbilical artery catheters: heparin usage, which was published in Cochrane Library, Disk Issue 4 1997 (Barrington 1997).
Types of participants
Newborn infants, both preterm and term. Entry criterion was usually
simply the 'need' for an umbilical artery catheter, as defined by the attending
medical staff.
Types of intervention
Random assignment to administration of heparin in the infusate or control
without heparin.
Random assignment to a group which received heparin in intermittent
flush solution only was considered separately.
Types of outcome measures
Catheter occlusion.
Aortic thrombosis
Death.
Intraventricular hemorrhage.
Hypertension.
Clinical ischemic events.
Each identified trial was assessed for methodological quality with respect to a) masking of allocation b) masking of intervention c) completeness of follow-up d) masking of outcome assessment.
Statistics: For categorical outcomes, typical estimates for relative risk and risk difference were calculated. For outcomes measured on a continuous scale, typical estimates for weighted mean difference were calculated. 95% confidence intervals were used. A fixed effect model was assumed.
Ankola 1993 performed a non-masked study in 30 infants who required catheter placement for clinical indications. Heparin was administered at a lower dose than any of the other studies at 0.25 units/mL. Total heparin dose received was 25 to 50 units per kg per day. Maximum heparin infusion rate was 38 (SD 7) U/kg/d. Major outcome variables were duration of catheter usability, catheter occlusion, intraventricular hemorrhage, necrotizing enterocolitis, clinical ischemic phenomena (blue discoloration of toes) and sepsis.
Bosque 1986 randomised 47 infants to receive either heparin at a dose of 1 unit/mL added to the infusate and no heparin in the solution used to flush the catheter, or no heparin in the infusate and 1 unit/mL added to the flush solution. Infants were stratified by birth weight. The group with heparin in the infusate received 80 to 220 U/kg/d of heparin, with a mean of 120 U/kg/d. The group with heparin in the flush received 0.8 to 9.8 U/kg/d with a mean of 3.9 U/kg/d. The major outcome variables were catheter occlusion, ischemic complications, prothrombin time and partial thromboplastin time.
David 1981 studied 50 infants (one later removed from analysis) randomly assigned to either 1 unit heparin/mL, in both the infusate and the flush, to no heparin in either fluid. Total heparin doses were not clearly stated but the highest dosage ranged from 125 to 200 U/kg/d. The major outcome variable of the study was the occurrence of aortic thrombi detected by single shot aortogram performed at the time of catheter removal, if the catheter had been in place for more than 24 to 72 hours. Autopsies, if available, were also used to determine aortic clots. Clotting studies were also performed
Horgan 1987 performed a trial in 111 term and preterm infants. Infants
were randomly allocated to one of four nurseries. In two nurseries heparinized
fluids were used, in the other two heparin was not used. The text also
states that allocation to a particular nursery was based on the availability
of bed space. This study may therefore have had 'haphazard' rather than
truly random allocation, and allocation was certainly not masked. Both
high and low catheters were allowed according to physician preference.
Total heparin doses ranged from 0.46 to 3.4 U/kg/hr, with a mean of 0.9
U/kg/hr. Outcome variables reported were aortic thrombi determined
by ultrasound, catheter occlusion, intraventricular hemorrhage of grade
3 or 4, sustained hypertension, (systolic pressure above 100 mm Hg or mean
>85 mm Hg in term infants and >70 mm Hg in premature infants).
Rajani 1979 performed a well masked randomized study with the randomization
code maintained by pharmacy until the end of the study. 62 infants, term
and preterm, were randomized to either heparin or placebo added at 1 unit/ml
to the catheter infusate. Fluids ran at a minimum of 5 mL/hr in all but
one infant, giving a total heparin dose in excess of 5 units/hr for all
except one infant in the treatment group. It was noted in the discussion
that patients received between 100 and 200 U/kg/d. Outcome variables were
duration of catheter 'life-span', incidence of occlusion, clotting studies,
and clinical ischemic phenomena defined as blue toes lasting for more than
8 hours.
Chang 1997 reported a prospective masked trial of heparin usage in umbilical catheters. This study assessed the effects of the use of heparin in both umbilical arterial and venous catheters, at a concentration of 1 unit/mL. The study only included preterm infants at risk for development of intraventricular hemorrhage by reason of a gestational age of less than 31 completed weeks gestational age. The study period was from birth to the fifth day of life, and heparin doses received by the infant averaged 4.3 U/kg/hr (no standard deviation given). The primary outcome variable was the occurrence of intraventricular hemorrhage, of any grade. Hemostatic variables were also determined and compared between groups. Mortality rates and severe intracentricular hemorrhage rates were reported and are included in the meta-analysis.
Bosque 1986
Masking of Allocation
Allocation was determined by a table of random numbers and "a separate
pad of paper was used for each weight group". There does not appear to
have been adequate allocation concealment.
Masking of Intervention
Not attempted
Completeness of follow up
All infants appear to have been accounted for
Masking of outcome
Not attempted
Other Comments
Hypothesis not described. Study was stopped when it was found that
all of the occlusions were in the flush only group, and that the difference
was statistically significant.
David 1981
Masking of allocation
Allocation clearly described: A pad containing randomly ordered group
designations was used, the top page torn off for each patient, assignments
not visible until torn off.
Masking of intervention
Not attempted
Completeness of follow up
Yes
Masking of outcome
Not attempted for most outcomes, aortograms were read by a radiologist
unaware of group assignment.
Horgan 1987
Masking of Allocation
Not attempted
Masking of Intervention
Not attempted
Completeness of follow up
All infants appear to have been accounted for. The numbers of
infants who actually had ultrasounds is not stated, even though two infants
had aortic thrombosis diagnosed by clinical symptoms alone.
Masking of outcome
Not attempted
Other comments
Hypotheses stated, authors do not describe how they arrived at a sample
size.
Rajani 1979
Masking of allocation
This appears to have been adequate
Masking of intervention
This was placebo controlled fully masked study
Completeness of follow up
All infants accounted for
Masking of outcome
Yes
Other comments
Hypothesis stated, No sample size determination is described. Life
table analysis of catheters with and without heparin was performed.
Chang 1997
Masking of allocation
Randomization was revealed only to the pharmacist involved and therefore
this appears to have been adequate.
Masking of intervention
This was a placebo controlled masked study.
Completeness of follow up
Outcomes are described for all except 5 infants deleted from analysis
as they contravened exclusion criteria.
Masking of outcome
It appears that the interpretation of the ultrasounds was performed
by a single masked radiologist, and this was therefore adequate.
Other comments
Both venous and arterial lines were studied in this trial.
Using heparin solely in the flush solution and not in the infusate does
not appear to be effective in preventing catheter occlusion (Bosque 1986).
A concentration of 0.25 units/mL, in comparison to no heparin, was
effective in one trial (Ankola 1993), and appears to have a similar efficacy
to higher concentrations but has not been directly compared to a higher
concentration.
The duration of catheter usability was reported by several of the studies by the use of life table analysis. (David 1981, Rajani 1979, Ankola 1993). All showed a significant prolongation of the life of the catheter with heparinization.
Aortic thrombosis incidence, however, does not appear to be affected by heparin use. Neither of the 2 studies that examined this showed an effect (David 1981, Horgan 1987). The overall relative risk was 0.71; 95% CI 0.42, 1.22.
Coagulation studies were described in several reports (David 1981, Horgan 1987, Bosque 1985, Rajani 1979, Chang 1997). The timing of performance of the studies, methodologic details and detail of reporting of the results varied so greatly that a meta-analysis was not performed. However, in general terms none of the studies showed a significant prolongation of prothrombin or partial thromboplastin times. Horgan 1987 and Chang 1997 did not show an effect on fibrinogen concentrations; David 1981 did not show an effect on thrombin or reptilase times; and Rajani 1979 did not show an effect on antithrombin 3 concentrations, whereas Chang 1997 showed a decrease in antithrombin 3 concentrations at the end of the study in the heparin group.
Grade 3 and 4 Intraventricular hemorrhage was not affected (Ankola 1993, Horgan 1987, Chang 1997), relative risk 1.07; 95% CI 0.58, 1.99.
Hypertension was reported by only one of the studies (Horgan 1987) and was significantly reduced by the addition of heparin, relative risk 0.05; 95% CI 0.00, 0.78.
Clinical ischemic phenomena were reported by 3 of the studies; none reported a significant effect of heparinization. The overall RR was 1.28; 95% CI 0.22, 2.48.
Mortality was reported in 4 studies (Ankola 1993, Horgan 1987, Rajani 1979, Chang 1997). Each failed to show a significant difference between heparinized and non-heparinized fluids. The overall relative risk was 0.87; 95% CI 0.50, 1.49. David 1981 mentioned that mortality was not significantly different between groups, but did not give figures. (Ankola 1993 mentioned that one control patient died "during the period of this data collection").
Heparinization of the infusate appears to be effective in reducing the incidence of catheter occlusion. This leads to an increase in the usable lifespan of the catheter. There is not a statistically significant effect of heparinization on the frequency of aortic thrombi. However, the confidence intervals for this effect are wide, as only 134 infants have been evaluated for this common and important outcome. Thus it remains possible that a decrease in aortic thrombosis of as much as 50% could have been missed in the studies published to date. The lack of documented effect of heparin on aortic thrombosis, if confirmed in further studies, may suggest that mechanical factors may be more important, or that systemic anticoagulation may be necessary to prevent this complication. Clinically apparent ischemic phenomena were also unaffected by heparinization, again suggesting that mechanical factors may be most important in determining the frequency of blue or white toes.
There was no effect of routine use of heparin on mean values of coagulation tests or on analyses of clotting factors. The decrease in AT3 demonstrated by Chang 1997 is of questionable significance, in general heparin administration has been associated with an increase in AT3 levels, so a slight decrease, which remained within the accepted normal range is of uncertain significance. The wide range of administered heparin doses means that there remains a possibility of an effect of heparin on coagulation in that group of infants who receive greater volumes of heparinized fluids.
Adverse effects were not noted. The incidence of intraventricular hemorrhage was not different between groups, but it must be remembered that almost all of these studies included infants of all gestational ages, many of whom would be at very low risk for this complication. A relatively small number of infants have been evaluated for extensive intracranial hemorrhage (n=254). The confidence intervals for effect on intracranial hemorrhage are very wide and still include the possibility that routine addition of heparin to umbilical artery catheters doubles the incidence of grade 3 and 4 hemorrhages! The actual total dose of heparin differed widely because of varying infusion rates, and was not standardized between groups. Infants who receive the highest doses of heparin may be at increased risk for intraventricular hemorrhage as suggested by two epidemiologic studies (Lesko 1986, Malloy 1995).
Mortality was also not significantly affected by heparinization (n evaluated = 316), but again the confidence intervals are very wide. There are no clear data on the frequency of necrotising enterocolitis which was an outcome variable in only one study (the incidence in both groups was zero, Ankola 1993).
Study: Bosque 1986
Method: Randomised single center study. Masking of allocation;
appears not to have been done. Masking of intervention; No. Completeness
of follow up; Yes. masking of outcome; No.
Participants: 47 preterm and term infants stratified by birth
weight.
Interventions: Infants received either heparin at a dose of
1 unit/mL added to the infusate and no heparin in the solution used to
flush the catheter, or no heparin in the infusate and 1 unit/mL to the
flush solution.
Outcomes: Clotting studies (PT and PTT), incidence of catheter
occlusion, duration of catheter usability.
Study: Chang 1997
Method: Single center masked prospective controlled trial. Masking
of allocation; yes. Masking of intervention; yes. Completeness of follow
up; yes. Masking of outcome; yes.
Participants: Preterm infants, <31 weeks gestational age,
who had umbilical catheters placed. Either arterial or venous catheters
or both were acceptable.
Interventions: Addition of heparin 1 unit/mL to the infusate,
compared to placebo. No heparin in the flush solution.
Outcomes: Intraventricular hemorrhage diagnosed by a head ultrasound
at 1 week of age was the primary outcome variable. Secondary outcomes included
clotting times (PT, PTT) and coagulation factor assays (fibrinogen, AT3).
Study: David 1981
Method: Single center randomized study. Masking of allocation;
Yes. Masking of intervention; No. Completeness of follow up; Yes. Masking
of outcome; No.
Participants: 50 term and preterm infants requiring umbilical
arterial catheterisation for clinical care.
Interventions: Heparin at 1 unit/mL in the infusate and the
flush compared to no heparin in either the infusate or the flush.
Outcomes: Clinical ischemic phenomena, hematuria, clotting studies,
Aortic thrombi on aortograms performed after 24 to 72 hours or at autopsy.
Study: Horgan 1987
Method: Single center randomized study. Masking of allocation;
No. Masking of intervention; No. Completeness of follow up; Yes. Masking
of Outcome; No.
Participants: 111 infants "randomly" allocated to one of four
nurseries, two of which used heparin and two of which didn't.
Interventions: Heparin at 1 unit/mL in the infusate, running
at 2 mL/hr. The flush solutions did not contain heparin.
Outcomes: Frequency of catheter occlusion. Aortic thrombosis
by ultrasound within 12 to 24 hours after catheter removal, PT and PTT.
Study: Rajani 1979
Method: Single center randomized study. Masking of allocation;
yes. Masking of intervention; Yes. Completeness of follow-up; Yes. Masking
of outcome; Yes.
Participants: 62 term and preterm infants requiring umbilical
arterial catheterisation for clinical therapy.
Interventions: Heparin at 1 unit/mL or placebo (5% dextrose)
added to UAC fluid. No heparin was added to the flush solution.
Outcomes: Clinical ischemic phenomena, catheter occlusion,
PT and PTT
Bosque E, Weaver L. Continuous versus intermittent heparin infusion of umbilical artery catheters in the newborn infant. J Pediatr 1986;108:141-143.
Chang GY, Lueder FL, DiMichele DM et al. Heparin and the risk of intraventricular hemorrhage in premature infants. J Pediatr 1997;131:362-6.
David RJ, Merten DF, Anderson JC, Gross S. Prevention of umbilical artery catheter clots with heparinized infusates. Dev Pharmacol Ther 1981;2:117-126.
Horgan MJ, Bartoletti A. Effect of heparin infusates in umbilical arterial catheters on frequency of thrombotic complications. J Pediatr 1987;111:774-8.
Rajani K, Goetzman B, Wennberg RP, Turner E, Abildgaard C. Effect of heparinization of fluids infused through an umbilical artery catheter on catheter patency and frequency of complications. Pediatrics 1979;63:552-556.
Malloy MH, Cutter GR. The association of heparin exposure with intraventricular hemorrhage among very low birth weight infants. J Perinatol 1995; 15:185-91.
01.01.00 Catheter occlusion prior to removal (RR)
01.01.00 Catheter occlusion prior to removal (RD)
01.01.01 Studies comparing heparin in the infusate to no heparin
01.01.02 Studies comparing heparin in the infusate to heparin only in the flush
01.02.00 Aortic thrombosis (RR)
01.02.00 Aortic thrombosis (RD)
01.03.00 Hypertension (RR)
01.03.00 Hypertension (RD)
01.04.00 Intraventricular hemorrhage, grade 3 and 4 (RR)
01.04.00 Intraventricular hemorrhage, grade 3 and 4 (RD)
01.05.00 Clinical ischemic phenomena (RR)
01.05.00 Clinical ischemic phenomena (RD)
01.06.00 Death (RR)
01.06.00 Death (RD)