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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
  1. Pita Birch1,
  2. Simon Ogden2,
  3. Michael Hewson3
  1. 1Newborn Services, Auckland City Hospital, Auckland, New Zealand
  2. 2Department of Pharmacy, Wellington Hospital, Wellington, New Zealand
  3. 3Wellington Neonatal Unit, Wellington Hospital, Wellington, New Zealand
  1. Correspondence to Dr Pita Birch, Newborn Services, Level 9, Support Building, Auckland District Health Board, Private Bag 92 024, Auckland, New Zealand; pitabirch{at}gmail.com

Abstract

Background Infections are common complications of neonatal long lines. Heparin has been shown to prolong the effective duration of neonatal long lines and to reduce the ability of bacteria to adhere to foreign surfaces, but the effect of heparin on rates of infection is uncertain.

Objective The goal of this study was to evaluate the effect of heparin on the frequency of episodes of catheter-related sepsis (CRS) in infants receiving total parenteral nutrition (TPN) through a neonatal long line.

Design/Methods This randomised, controlled, double blind, single-centre clinical trial compared heparin at 0.5 IU/ml with no heparin in TPN infused through a neonatal long line, with episodes of CRS as the primary outcome.

Results 210 infants were enrolled (TPN with heparin n=102, TPN without heparin n=108). There was a statistically significant reduction in all episodes of culture-positive CRS in those infants with heparin added to the TPN compared with those without heparin (p=0.04; RR 0.57, 95% CI 0.32 to 0.98; number needed to treat 9, 95% CI 4.6 to 212.4).

Conclusions The addition of heparin at 0.5 IU/ml to TPN infused through a neonatal long line reduces the incidence of culture-positive CRS.

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Neonatal long lines are essential for providing long-term intravenous total parenteral nutrition (TPN) to sick or preterm neonates or those with surgical problems prohibiting enteral feeding. However, long lines are associated with significant complications, particularly catheter-related sepsis (CRS) with staphylococcal species. Nosocomial infections are common in neonatal units, with reported rates of between 4.6 and 62 infections per 1000 patient-days with rates higher in smaller, more preterm infants.1,,3 Infection with coagulase-negative staphylococcal species (CONS) represented 57.1% of reported episodes of late-onset sepsis in Australian and New Zealand neonatal units from 1991 to 2000.4

CONS, in particular Staphylococcus epidermidis, secrete a highly adhesive extracellular material that inhibits phagocytosis and reduces susceptibility to antibiotic therapy.5,,7 Microthrombi on the tips of long lines can act as foci for infection and make it difficult to eradicate the organism.8 9 Heparin reduces microthrombus formation and reduces the ability of staphylococcal species to adhere to and colonise foreign surfaces.7 10,,12

What is already known on this topic

  • ▶. Heparin as a continuous infusion prolongs the duration of long line usability and reduces catheter obstruction without any increase in adverse effects.

  • ▶. Heparin reduces the ability of bacteria to adhere to foreign surfaces.

What this study adds

  • ▶. The use of heparin in TPN when infused through a neonatal long line reduces the incidence of CRS without any adverse effects.

  • ▶. It is also possible that by reducing the incidence of CRS it protects extremely low birthweight infants weighing less than 850 g from the progression of IVH.

Heparin as a continuous infusion prolongs the duration of long line usability and reduces catheter obstruction without any increase in adverse effects.13 Heparin has been shown to reduce central line sepsis in adults receiving TPN,14 but a statistically significant reduction in CRS has not been found in neonates.13 15 16 The objective of this study was to determine whether the addition of heparin to TPN prevented CRS in neonates as determined by a positive blood culture with an organism commonly associated with long line infection.

Methods

We conducted a prospective, randomised, double blind, controlled clinical trial of heparin compared with no heparin added to TPN infused through a neonatal long line. The study took place in the tertiary care neonatal unit at Wellington Hospital between March 2004 and October 2007. Written consent was obtained from one or both parents of all infants who entered the trial before insertion of the long line. The research was approved by the Wellington Ethics Committee.

Study population

Infants requiring a long line for TPN as judged by the clinical team were eligible for the trial. Infants were excluded if they had had a previous long line successfully inserted and utilised.

Randomisation and blinding

Participants were stratified on the basis of birth weight (<850 g, 850–2000 g, >2000 g) and were randomly allocated to either heparin added to TPN or no heparin by computer-generated random numbers software performed by an independent statistician and balanced within blocks of random length. Randomisation tables were held in the pharmacy and the trial physicians, parents and clinical staff were blinded to the heparin content of the TPN.

The majority of infants were randomly assigned once consent was obtained and before the insertion of the long line, but in some cases infants were randomly assigned before consent was obtained in order to avoid delays in the initiation of TPN.

Intervention

Heparin was added to the TPN in the pharmacy using a sterile technique at a concentration of 0.5 IU/ml.17 TPN was stored under refrigerated conditions and individually identified using patient labels.

Long lines were inserted according to current unit practice using an aseptic technique and all lines were secured using medical adhesive and covered with a non-adhesive dressing. Two types of catheters were used: Epicutaneo Cava Katheter, 23-gauge (Vygon, Aachen, Germany) and PremiCath, 27-gauge (Vygon). The choice of catheter was determined by the inserting physician. Following insertion the lines were secured and dressed and were either attached directly to a bag of TPN or to an infusion of normal saline while waiting for the confirmation of the position of the line. Radiographs were taken with contrast to check line placement.

Cranial ultrasound scans (USS) were performed according to institution practice and clinical indication and all scans were reported by an independent radiologist. Intraventricular haemorrhage (IVH) was graded according to the grading system of Papile et al.18

Outcomes

The primary outcomes were the number of episodes of CRS per total number of infants and rates of CRS episodes per 1000 long line days.

The secondary outcomes were: (1) bacteraemic episodes with organisms not commonly associated with line sepsis; (2) definite or probable Candida line infections; (3) progression of IVH; (4) long line removal because of extravasation or occlusion; and (5) long line removal because the line was no longer required.

The endpoints for removal of the infant from the trial were: (1) definite or probable CRS with bacteria as defined below or Candida; (2) death of the infant; (3) trial violation; (4) parental withdrawal of consent; (5) transfer out of the unit with long line in situ; (6) removal from the trial by the clinician; or (7) removal of the long line. The reasons for removal of the line were only included as endpoints if they were the primary reason for the removal of the long line.

An a priori decision was made to analyse two composite outcomes: definite or probable CRS and definite, probable and possible CRS. Possible CRS was not an endpoint so an infant could have two or more episodes of possible CRS or an episode of possible CRS and then an episode of definite or probable CRS. In this case we would only use one episode for the outcome of the number of episodes of CRS per total number of catheters, but counted each episode when calculating rates of CRS per 1000 long line days.

Definitions

A positive blood culture was defined as any blood culture growing one or more organism drawn from insertion of the long line to 24 h after the line was removed. CRS was defined as positive blood culture growing CONS, Staphylococcus aureus, Acinetobacter species or Candida. Definite CRS was defined as two positive blood cultures with the same organism taken from two separate sites within 72 h of each other.19 Probable CRS was defined as a single positive blood culture and a peak C-reactive protein level greater than 9 mg/l recorded from 24 h before to 72 h after the positive culture was drawn. Possible CRS was defined as a single positive blood culture without elevation of C-reactive protein.

Bacteraemia with organisms not commonly associated with line sepsis was defined as a single positive blood culture with the following organisms: streptococcal species, Gram-negative organisms and enterococci. Two or more blood cultures positive for the same organism and less than 7 days apart were considered to be the same single bacteraemic episode. This event was not a trial endpoint and the infant continued to remain in the trial until an endpoint was reached.

IVH progression during the trial was defined as an increase on either side from grade 0–2 to grade 3–4 between the ‘worst initial IVH’ and the ‘worst post-trial IVH’. The ‘worst initial IVH’ was the worst IVH grade before starting the trial or, if no pretrial cranial USS was performed, the first cranial USS performed during the trial period. The ‘worst post-trial scan’ is defined as the worst IVH after starting TPN and before discharge or, if no scan was done before starting TPN, the worst IVH after that first scan and before discharge.

Sample size

The primary outcome was all episodes of CRS using a composite of definite, probable or possible CRS. A previous local audit found that 35% of infants with a long line in situ for the delivery of TPN had an episode of CRS defined as a single positive blood cultures with an organism commonly associated with CRS. For this trial we estimated that in order to see a clinically significant reduction in CRS from 35% to 23% we would require 204 infants (α=0.05, β=0.20)

Statistical analysis

Continuous variables were analysed using Student's t test or the Mann–Whitney U test. Nominal data were analysed using Fisher's exact test or the χ2 test. A p value of less than 0.05 was considered statistically significant. Survival data were calculated using a Kaplan–Meier survival curve and compared using the log-rank test. Random numbers were generated using the ranuni function of SAS (SAS Institute Inc, Cary, North Carolina, USA) software. An a priori decision was made to perform subgroup analysis according to weight stratification. Interim analysis was performed by an independent statistician once complete data on the first 100 infants were available.

Results

A total of 210 infants was recruited between March 2004 and October 2007 (figure 1). Baseline characteristics were similar between the groups (table 1).

Figure 1

Numbers of infants eligible for the study randomly assigned to receive total parenteral nutrition (TPN) with heparin or TPN without heparin and stratified according to birth weight.

Table 1

Baseline characteristics of the study population

Blood culture results

A total of 264 blood cultures was taken from 113 infants. This corresponded to 184 blood culture episodes (114 episodes had a single blood culture taken and 70 episodes had two or more blood cultures taken within 72 h of the original blood culture). One hundred and thirty-eight (75%) of the blood culture episodes had no growth in any of the cultures taken. Forty-six (25%) had a positive culture in one or more of the blood cultures taken; S aureus three (7%), S epidermidis 18 (39%), pure growth of other CONS 17 (37%), mixed growth of CONS species six (13%), Enterococcus one (2%) and Acinetobacter one (2%); 89% of positive blood culture in this cohort grew CONS.

Primary outcomes

Outcomes for the entire cohort are reported in table 2. There was a statistically significant reduction in culture-positive CRS in those infants who had heparin added to the TPN compared with those without heparin (p=0.04; RR 0.57, 95% CI 0.32 to 0.98; number needed to treat (NNT) nine, 95% CI 4.6 to 212.4). There was a statistically significant reduction in episodes of definite CRS in infants under 850 g (p=0.045; absolute risk reduction 14.3%, 95% CI 1.3% to 27.3%; NNT seven, 95% CI 3.7 to 75.5). Outcomes for infants under 850 g are reported in table 3.

Table 2

Outcomes for all stratifications

Table 3

Outcomes for subgroup of infants under 850 g

Rates of all episodes of CRS per 1000 days catheter in situ (12.3 vs 20.3; p=0.10; RR 0.61, 95% CI 0.33 to 1.11) and rates of definite CRS per 1000 days catheter in situ (2.3 vs 6.8; p=0.09; RR 0.34, 95% CI 0.09 to 1.24) were reduced in those infants receiving heparin, but the result did not reach statistical significance.

Secondary outcomes

There was a single episode of bacteraemia (in the heparin group) with an organism not commonly associated with line sepsis (Enterococcus faecalis) and no episodes of Candida infection during the trial. There was no statistically significant difference in the rates of progression of IVH between the two groups overall. For infants under 850 g there was a statistically significant reduction in the incidence of progression of IVH in the group receiving heparin (p=0.041; absolute RR 14.8%, 95% CI 1.4% to 28.2%; NNT seven, 95% CI 3.5 to 70.7). No infants were removed from the trial or unblinded because of bleeding diatheses or thrombocytopaenia. There were no statistically significant differences in the incidence of catheter obstruction, extravasation or elective catheter removal between the two groups. There was a trend towards longer survival free from all CRS and survival free from definite infection in the heparin group (see figure 2).

Figure 2

(A) Survival free from any catheter-related sepsis (CRS) and (B) survival free from definite CRS.

Discussion

Heparin added to TPN at a concentration of 0.5 IU/ml reduced episodes of culture-positive CRS in neonates without any adverse effects. There were no statistically significant differences in the incidence of catheter obstruction, extravasation or elective line removal, or in overall survival of the catheter.

This trial was conducted as a ‘per protocol analysis’ rather than by ‘intention to treat’ as in clinical practice either all or no infants would receive heparin in the TPN as per the protocol of the individual unit.

In this trial the primary outcome includes definite, probable and possible CRS. Within the possible CRS group and to a lesser extent the probable group, there may be episodes that represent contamination rather than true CRS. However, there is a large, but non-statistically significant trend towards a reduction in episodes of definite CRS in those infants receiving heparin. In infants under 850 g, heparin added to TPN reduced episodes of definite CRS. However, this study was not powered to show differences in this subgroup analysis. Moreover, the lower rate of definite CRS in the heparin group may be partly due to the lower number of blood culture episodes with two separate blood cultures in the heparin group.

Previous randomised controlled trials have not shown any significant effect of heparin on CRS. Shah et al13 found a non-significant increase in the incidence of CRS (p=0.243, 5% vs 2%) and suspected CRS (p=0.722, 5% vs 4%) when infusing heparin at 0.5 IU/kg/h. CRS was not a primary endpoint and the incidence of CRS in both groups was very low.

Whereas the study of Shah et al13 used a separate heparin infusion at a rate of 0.5 IU/kg/h, in this trial we added heparin to the TPN at a concentration of 0.5 IU/ml based on evidence that the maximal effect in prolonging the life of peripheral intravenous catheters could be achieved at a minimal concentration of 0.5 IU/ml.17 Infants in this trial thus received a rate of heparin that was approximately sixfold greater than the dose used by Shah et al13 (at a TPN rate of 150 ml/kg per day). We speculate that this higher dose of heparin is required to reduce the incidence of CRS.

In a smaller study Kamala et al16 using a CRS definition that required both a positive culture from the tip of the catheter and a blood culture growing the same organism found no reduction in CRS with heparin added to the TPN at a concentration of 1 IU/ml.

Shah et al13 found heparin to prolong the duration of catheter use and to reduce the incidence of catheter occlusion. In this trial we showed neither a reduction in catheter occlusion, nor prolonged usability of the line. The incidence of catheter occlusion was 5% in the heparin group and 3% in the group not receiving heparin compared with 6% and 31% in the trial of Shah et al.13 Whereas in our neonatal intensive care unit long lines are never used for sampling including the drawing of blood cultures, Shah et al13 included a culture drawn from the line in their definition of CRS. We speculate that blood sampling from long lines increases the risk of catheter occlusion, which is ameliorated by infusing low-dose heparin.

There were no adverse heparin-related effects noted in this trial. In adults heparin has been associated with heparin-induced thrombocytopaenia and subsequent thrombotic complications,20 although this appears to be a rare occurrence in the neonate.21

There was no increase in the progression of IVH in the heparin group overall or in the most at-risk babies—under 850 g or weighing 2000 g or less. Indeed, there was a trend towards fewer episodes of progression of IVH in all infants receiving heparin and there was a significant reduction in IVH progression in the infants under 850 g who received heparin (NNT seven). Evaluating only those infants under 850 g, none of the infants in the heparin group had progression of IVH and of the four infants in the non-heparin group to have IVH progression, two had definite infection, one had a possible infection and one had the long line removed because of extravasation (often attributed to local infection).22 In the entire cohort two infants with heparin in TPN had progression of IVH, although neither had infection, whereas out of the seven in the non-heparin group to have IVH progression, two had definite infection, one probable infection, one possible infection, one extravasation and two had elective line removal without complications. Sepsis is a risk factor in evolving IVH and it is possible that the protective effect of heparin in reducing CRS in turn reduces the risk of the progression of IVH.

It is important to note when adding heparin to an infusate that system-based error prevention strategies are required to reduce the risk of substitution errors.23

Conclusions

The use of heparin in TPN at a concentration of 0.5 IU ml when infused through a neonatal long line reduces the incidence of CRS without any adverse effects. It is also possible that by reducing the incidence of CRS it protects extremely low birthweight infants under 850 g from the progression of IVH.

Acknowledgments

The authors would like to acknowledge the statistical support of statistician Gordon Purdie and Professor Lex Doyle, the involvement of the pharmacy department and the support from the medical and nursing staff at the Wellington Neonatal Unit.

References

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Footnotes

  • Funding This study was supported by grants from the New Zealand Grants Advisory Subcommittee of the Royal Australasian College of Physicians and the Baxter Clinical Nutrition Grant 2004.

  • Competing interests None.

  • Patient consent Obtained from parents.

  • Ethics approval This study was conducted with the approval of the Wellington Ethics Committee, Ministry of Health, PO Box 5013, approval number: WGT/03/08/079, Wellington.

  • Provenance and peer review Not commissioned; externally peer reviewed.

    This trial was registered on 4 October 2005 (trial start date 5 March 2004) with the Australian New Zealand Clinical Trials Registry (ACTRN12605000579695).

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