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Heparin for prolonging peripheral intravenous catheter use in neonates:
A randomised controlled trial
Dr. Kamlesh Kumar Verma,
Department of Paediatrics
LLRM Medical College,
Garh Road, Meerut (UP)
Mob.: 09758631962
Email: drkamlesh123@gmail.com
Dr. Amit Upadhyay
(MD, DM, MNAMS)
Head, Department of Paediatrics
LLRM Medical College,
D-8, Shastri Nagar, Meerut (UP)
Mob.: 09837405009
Email: anuamit7@rediffmail.com
Dr Deepak Chawla
MD (Paediatrics), DM (Neonatology)
Assistant Professor
Department of Paediatrics
Government Medical College and Hospital
Sector 32
Chandigarh 160 030
India
Funding
Competing Interest
: None
: None
Keywords : Heparin, Functional duration of catheter, Neonates, Normal saline
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ABSTRACT
Background: Mechanical and infectious complications shorten the effective duration of
peripheral intravenous catheter. Heparin is used to prevent such complications and prolong
the usability of peripheral intravenous catheter is inconclusive.
Objective: To determine the efficacy of heparinised saline administered as intermittent flush
via peripheral intravenous catheter on functional duration of the catheter in neonates.
Method and material: Design: Randomised, double-blind placebo-controlled trial. Setting:
Level II Neonatal intensive care unit of a teaching hospital. Participants: Term and Preterm
neonates born at >32 weeks of gestation who required peripheral intravenous catheter for
intermittent administration of antibiotics after admission with expected duration of hospital
stay of >5 days. Intervention: Eligible neonates were randomized to receive 1 ml of either
heparinised saline (10U/ml) (n=53) or normal saline (n=53) every 12 hours before and after
antibiotics injection Primary outcome variable: Functional duration of 1st catheter
Result: Both groups were comparable in birth weight, sex, postnatal age, site of
catheterisation and nature of antibiotics given. Mean functional duration of 1st peripheral
intravenous catheter was more in heparinised saline group ( hours; mean difference: 15.9;
95% CI: 8.5 to 23.3). Occlusion at the catheter site was commonest indication for catheter
removal in both groups (77.3% vs. 71.7%). No difference was noted in complications related
to heparin use.
Conclusion: Heparinised saline flush increased the functional duration of peripheral
intravenous catheter without any significant side effects.
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INTRODUCTION
Neonates with systemic sepsis, meningitis or arthritis need long-term intravenous
antibiotic therapy, often without concomitant need of intravenous maintenance fluids.
Peripheral intravenous catheters (PIVC) in such neonates have intermittent usage and tend to
get blocked by blood clot at distal tip prompting frequent reinsertions. This exposes the
vulnerable newborn infants to repeated painful and stressful experiences as well as the risk of
infection due to skin breaches which might result in adverse effect on health and long-term
neurodevelopmental outcome.1 Measures to prolong the functional duration of a PIVC may
reduce the number of catheterisation attempts and save neonates from pain and stress as well
as reduce the risk of infection.2
Heparin, an anticoagulant has been administered as an intermittent injection or
continuous infusion to prevent thrombus formation and prolong catheter patency.
A
systematic review reported that heparin was not associated with prolongation in arterial or
venous catheter patency among patients of different age groups. However, only one study in
this review enrolled neonates. In addition, neonates are unique in their sensitivity to heparin
and in propensity to develop intracranial hemorrhage4. We conducted this study to evaluate
the efficacy and safety of heparinized saline flush in concentration of 10 unit/ml on functional
duration of catheter among term and preterm neonates.
MATERIAL AND METHODS
This randomized controlled study was conducted at a teaching hospital of north India from
October 2009 to September 2010. Study protocol was cleared by Institutional Ethical
Committee and informed written consent was obtained from either parent before enrolment.
Term and preterm neonates born at >32 weeks of gestation who required peripheral
intravenous catheter for intermittent administration of antibiotics with expected duration of
hospital stay >5 days were eligible for enrolment in the study. Neonates with intracranial
hemorrhage, platelet count <150,000/mm3, coagulopathy or major congenital malformation
were excluded.
Allocation of group was done by block randomization. Randomization was done in block of 8
in two groups through computer generated random numbers which were then placed in
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serially numbered opaque sealed envelopes. When a baby was eligible for enrolment a new
PIVC was put after obtaining written consent from one of the parents. Enrolled neonates were
randomized to receive immediately before and after each dose of antibiotic 1.0 ml of either
heparinized saline containing 10 unit of heparin or normal saline. Study medication
(heparinized saline or normal saline) was administered by a separately identified group of
resident physicians and treating physicians, Nurses and parents were not aware of group
allocation. Blinding was preserved by dispensing drugs and placebo in identical,
indistinguishable containers. In neonates not requiring maintenance intravenous fluid therapy
one PIVC was inserted and used for administering antibiotics only. In neonates on
maintenance intravenous fluid therapy, a separate PIVC was used for administering
antibiotics. The catheter to be given only intermittent intravenous antibiotics were included
for study. Twenty-four gauge PIVC (NEOCAN Eastern Medikit Limited, India) were used
for catheterisation in all neonates. Prior to the onset of the study, all healthcare personnel
involved in insertion and fixation of catheter in the NICU were given instructions on the
technique of insertion and fixation of PIVC. Insertion of PIVC was done by trained resident
doctor on duty and fixation was done by trained nurse or another resident doctor. Study
medication was administered immediately after catheter insertion and then immediately
before and after each antibiotics injection at interval of 12 hours in both the groups. The
catheter site was periodically monitored for development of sign of removal. The sign of
removal was defined as presence of any one of the following: Occlusion: Defined as inability
to infuse fluid. This was confirmed by resident doctor who attempted to push 1 ml of normal
saline using a 5 ml syringe. Phlebites: defined as pain, swelling, erythema or indurations at
the site of catheter with or without a palpable venous cord. Infiltration: infusate entering the
subcutaneous tissue instead of the vein leading to swelling and difficulty in pushing
antibiotics.
Platelet count was obtained at time of enrolment and then every day starting fifth day of study
enrolment till end of enrollment. Heparin induced thrombocytopenia (HIT) was defined using
standard definition.5,6,7 Coagulation profile was done at the time of stopping study drug or if
coagulation abnormality was suspected clinically. Study medication was stopped if neonates
developed thrombocytopenia or coagulation defect or intracranial bleed. Intracranial
hemorrhage was recognized by ultrasound which was obtained before enrolment, on clinical
suspicion, on seventh day and at discharge from hospital.
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Primary outcome variable was functional duration of first PIVC defined as the time between
insertion and removal of the catheter. Secondary outcome variables were average catheter
duration, was defined as numbers of hours of catheterization divided by total number of
catheterizations. Other outcomes included complications associated with PIVC including
occlusion, phlebitis or infiltration, abnormal coagulation profile, allergic reaction to study
medication (fever, high blood pressure, heart rate >160/minute, respiratory distress, skin
rashes consisting of red spot), heparin induced thrombocytopenia (HIT) defined as platelet
count < 150000/mm3 after exclusion of other cause of thrombocytopenia.
Sample size was calculated on the basis of a pilot study conducted in our hospital. We needed
to enrol 50 subjects in each group to detect a 25% increase in functional duration of PIVC
with 90% power with 95% confidence. To account for some unforeseen cases we decided to
randomised 120 babies in two equal groups.
All base line and outcome data were recorded prospectively on a pretested data form. The
data were checked daily for completion, consistency and accuracy. Intention to treat analysis
was performed by using software Stata version 11. Categorical variables were compared with
chi square test and student t test was used for discrete and continuous variables. p value of
<0.05 was considered significant.
Observation and result
Of the 130 eligible neonates 120 were randomized to two groups of 60 neonates
each. All 60 babies were analysed on intension to treat analysis, seven babies in each group
were could not completed the study protocols. In heparinised group 6 babies developed
deceased platelet count and increased PT and APTT and their septic work up was positive
and 1 expired during study period without blockage of catheter. In normal saline group 5
babies developed sepsis with decrease platelet count and increased PT and APTT and their
septic work up was positive and two babies expired during study period without blockade of
catheter according to defined criterion (Fig1). The groups were comparable with respect to
postnatal age, sex, birth weight, mode of delivery, nature of IV antibiotics, site of
catheterisation, person inserting catheter (Table 1).
Primary outcome: There was a statistically significant increase in functional duration of 1st
catheter in neonates in heparinized saline group as compared to normal saline group. Mean
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functional duration of 1st catheter was more in heparinized saline group, mean (SD) of
79.2(18.3) hours as compare to 63 (20.0) hours in normal saline group (p<.005). Between two
groups mean difference(95%CI) in functional duration of catheter was 15.9(8.5 to 23.3 hours)
in favour of heparinized saline group (fig 2).
Secondary outcome: (1) Average catheter duration was also more in heparinized saline
group, mean (SD) of 77.99 (19.56) hours in compare to 58.73 (12.09) hours in normal saline
group (p<0.005). Between two groups mean difference (95% CI) in average catheter duration
was 19.26 (13.0 to 25.53 hours) in favour of heparinized saline group (fig 3). Occlusion at
catheter site was commonest indication for catheter removal in both groups (77.3% vs
71.7%). There was no adverse effect on platelet count and coagulation profile, intra cranial
bleed and allergic reaction in either group.
DISCUSSION
Our study demonstrated that use of heparinized saline flush (10 unit/ml) resulted in
prolonged functional duration of 24-gauge catheter in neonates by almost 16 hours without
affecting incidence of occlusion and phlebitis. There is limited evidence in neonatal age that
use of heparin in peripheral intravenous catheter will prolong their life and utility in neonatal
age.
Mudge et al8 has earlier demonstrated the effectiveness of heparin flush solutions in
maintaining the patency of 24-gauge peripheral intermittent infusion devices. It was however
a non-randomized, sequential, but blinded study. The Kaplan Meier Survival demonstrate that
the median duration of catheter flushed with heparin was 42 hours and with saline was 35.3
hours (p = 0.02). Kotter et al10 in 1996 reported that there was no statistically significant
difference in average duration of patency between NS-flushed catheters and 10 unit/ml of
HS-flushed catheters. Phlebitis, occlusion, infiltration, and leaking occurred with equal
frequency for both solutions. Our study also demonstrated that with increasing gestational
maturity functional duration of peripheral intravenous catheter also increases. This could be
because at lower gestational age walls of veins are immature, thin with poor vascular tone
Gupta et al11 studied variables affecting life span of a peripheral IV catheter in a NICU of a
developing country. The median survival time of an IV catheter, as expressed by KaplanMeir survival analysis, was 40 hours (SE, 2.49; 95% CI, 35.12 to 44.88 hours). Birth weight,
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gestation, application of splint, fluid and glucose infusion rate, site of catheterisation and
administration of antibiotics, phenobarbitone, blood products, or calcium gluconate did not
influence the median life span of IV catheter.
In our study mean functional duration was more then as reported by Gupta et al.11 This
probably because only IV antibiotics were give thorough peripheral IV cannlae (cefotaxime,
ceftriaxone , pipercillin tazobactum) and no other irritant fluid was being administered.
In our study 7 babies could not be analysed in each group. In heparinised group six babies
developed clinical sepsis with feature of DIC (decreased platelate count and increased PT and
APTT) before catheter blockage as defined criterion in our study and one baby expired before
catheter blockage. In normal saline group five babies developed clinical sepsis and feature of
DIC and two babies expired before completion of study.
In conclusion it can be stated that administration of heparinised saline in concentration of 10
unit/ml increases the functional duration of peripheral intravenous catheter in neonates
without any effect on platelate count and coagulation profile.
Competing interest: none
Ethics approval: Ethics committee approval was obtained from ethics committee, LLRM
Medical College Meerut, India
WHAT IS ALREADY KNOWNUse of heparin for increasing functional duration of arterial catheter is all ready documented,
but its use for peripheral intravenous catheter especially in neonates is very debatable.
WHAT THIS STUDY ADDSUse of heparinized flush increases the functional duration of peripheral intravenous catheter.
No significant side effect could be related to use of heparin
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REFERENCES
1.
Johnston CC, Stevens BJ. Experience in a neonatal intensive care unit affects pain
response. Paediatrics 1996; 98:925–30.
2.
Batton DG, Maisels MJ, Appelbaum P. Use of peripheral intravenous catheters in
premature infants: a no-splinted study. Paediatrics 1982; 70:487–9.
3.
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.
4.
Lesko 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.
5.
Ahmed I, Majeed A, Powell R (September 2007). “Heparin induced thrombocytopenia:
diagnosis and management update”. Postgrad Med J83 (983): 575-82.
6.
Warkentin TE “Think of HIT”. Hematology Am Soc Hematol Educ Program 2006:
408-14.
7.
Warkentin TE, Aird WC, Rand JH. “Platelet-endothelial interactions: sepsis, HIT, and
antiphospholipid syndrome”. Hematology Am Soc Hematol Educ Program (2003): 497519.
8.
Mudge B, Forcier D, Slattery MJ Pediatr Nurs. 1998;24(2):142-5, 149.
9.
Shah P, Ng, Sinha A, Shah P. Heparin for prolonging peripheral intravenous catheter
use in neonates. Cochrane Database Syst Rev. 2005;(4) :CD002774.
10.
Kotter RW Neonatal Netw. 1996 Sep;15:43-7.
11.
Gupta P, Rai R, Basu S, et al. Life span of peripheral intravenous catheter in a neonatal
intensive care unit of a developing country. J Pediatrics
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Table 1 Base line characteristics of neonates enrolled in two groups
Base line variable
Post natal age* (days)
Birth weight (gms) **
Heparinised group
(n=53)
5.74
2180
(1610-3315)
Normal saline
group(n=53)
4.6
2130
(1410-3215)
23(43.3%)
30(56.6%)
28(52.8%)
25(58.2%)
37(68.5%)
31(55.3%)
62(68.8%)
18(20.0%)
10(11.1%)
53(60.9%)
22(25.2%)
12(13.7%)
72(80%)
18(20%)
67(77.0%)
20(33.0%)
10(18.8%)
40(75.4%)
03(5.6%)
53(100%)
15(28.3%)
37( 69.8%)
1(1.8%)
53(100%)
Mode of deliveries**
Cesarian
Others
Sex
Male
Site of catheterisation**
Extensor surface of hand
Flexor surface of fore arm
Others
Canula insertor
Junior resident 2 years
Junior resident 3 years
Antibiotics
Cefotaxime
Ceftrixone
Piperacilline
Amikacin
Date express as *mean (SD), ** Median (range)
Data express as value (n=%)
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Fig. 1 Flow diagram of participant’s enrolment
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Fig 2 : Kaplan Mayer survival estimates for comparison of functional duration of first catheter
in two groups (Group 1= Normal saline , Group 2= Heparinized saline group )
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Fig 3: Box and Whishker plot for average duration of cathetere in the two groups (G –avg
= Average cannula duration, group 1 = normal saline group, group 2 = heparinized saline
group)
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