Should Heparin Based Flushing Solutions Be Used in Preference to Saline to Maintain The

Medicines Q&As

Q&A 157.5

Should heparin based flushing solutions be used in preference to saline to maintain the patency of indwelling intravascular catheters and cannulae?

Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp Date prepared: 31 March 2016

Background

The use of peripheral intravascular catheters to provide access for the administration of medicines, fluids and parenteral nutrition, and to provide access for venepuncture and monitoring is widespread. Maintenance of their patency is important to reduce the discomfort and expense of replacement as well as to reduce any risk to continuity of treatment. It is common practice to flush the catheters with suitable solutions before and after use (phlebotomy or drug administration), in order to reduce the risk of clots forming in the lumen and hence to maintain their patency. These solutions have traditionally comprised of various strengths of heparin in saline (0.9% sodium chloride injection).

Unnecessary exposure to heparin should be avoided as there are risks and disadvantages in using these products including (1,2):

 Allergic reactions  The potential for bleeding complications  Risk of medication error  Risk of heparin induced thrombocytopenia  Cost

Another disadvantage is if a heparin based flushing solution is used then it may also be necessary to flush the device with a separate saline flush before and after administering medicines that are incompatible with heparin (2).

There is a distinction between “simple” peripheral intravenous catheters and more complex devices such as central venous or arterial catheters. Peripheral venous catheters are used to administer small volumes and, typically, are required to last only for a few hours or days during an in-patient stay. Other indwelling devices can be used to administer larger volumes and pose other problems as they may be required to remain in situ for longer periods of time whilst being accessed far less frequently.

The term “heparinised saline” is used in this document to describe solutions of heparin of various strengths (generally in range of 1-10 units per mL) in sodium chloride 0.9%. The term “normal saline” is used to describe a solution of sodium chloride 0.9%.

Answer

Devices providing peripheral venous access in adults. There are now a number of systematic reviews and meta-analyses that conclude that flushing peripheral intravenous catheters placed in adults with normal saline is as effective as using heparinised saline in terms of maintaining patency (3-6). This supports the guidance given in the British National Formulary (7) and by NICE (8) on this topic that for maintaining patency of peripheral venous catheters, sodium chloride injection 0.9% is as effective as, and is preferred to, heparin flushes.

The picture is however less clear in the following situations where more and better quality evidence is required before a definitive position can be stated on the effectiveness and safety of heparinised saline over normal saline:

Available through NICE Evidence Search at www.evidence.nhs.uk 1

Medicines Q&As

 Peripheral venous catheters in children and neonates  Central venous catheters  Arterial catheters

Devices providing peripheral venous access in children and neonates. There are a number of studies looking specifically at devices, which are generally of a narrower gauge (22 and 24 gauge), used in children and neonates. As in adults, the general conclusion of this research is that heparinised saline confers no advantage over saline (9-14). However, a recent study of 120 neonates concluded that using heparinised saline prolonged functional duration of the first catheter by 13.9h (95% CI 4.7- 23.15h) (15). A non-randomised study looking at 134 catheters in 61 babies reports a statistically significant advantage of heparinised saline over normal saline in maintaining patency of small 24- guage catheters (16). These and other studies (17,18) highlight that other determinants may affect the risk of device blockage such as the gestational age of neonates/ children, the site used for cannulation and the specific technique of flushing (e.g. post medicine administration or pre- and post-).

A systematic review looking at 13 studies in children concluded that intermittent flushing with heparinised saline showed minimal benefits in terms of longer patency and lower rates of phlebitis (the results did not reach significance). There was however no increase in heparin related side effects. Results were more positive for heparinised saline infusions (19).

A Cochrane review looked at heparinised saline versus placebo or no treatment in peripheral intravenous catheter patency in neonates. Ten eligible studies were included. The authors concluded that there was insufficient data for this intervention in neonates to make firm recommendations and that further research on the optimal dose of heparin, its effectiveness and its safety is required (20).

Central Venous Catheters. The research in this area is more limited, of variable quality and individual studies have looked at specific devices. The findings are mixed, with some studies concluding that heparinised saline provides no advantage in maintaining the patency of indwelling central venous catheters used for chemotherapy (21,22), parenteral nutrition (22), apheresis (23) and triple and/or quad lumen central catheters used in intensive care (24,25). Other studies provide variable results for Groshong catheters used for oncology in-patients and out-patients (26) and for central venous lines (27-31); these latter studies have a number of methodological limitations, differences in the concentration of heparin (up to 200-5000 units per mL) and how the flushing solutions were used (continuous or intermittent).

Two Cochrane reviews have been carried out in respect of neonates and children.

Bradford et al looked at the effects of intermittent flushing with heparin versus normal saline in long term central venous catheters in infants and children on a range of outcomes including the ability to draw blood from the catheter, the need for removal or re-insertion and the use of agents to clear blockages. Three trials (245 participants) of high heterogeneity were included but the review concluded that there was not enough evidence to determine the effects of flushing with heparin compared to normal saline (32).

Shah et al examined evidence about continuous heparin infusion to prevent thrombosis and catheter occlusion in neonates with peripherally placed percutaneous central venous catheters. Three trials (477 participants) were included. The authors concluded that the use of heparinised saline infusion allowed a greater proportion of neonates to complete their therapy by reducing catheter occlusion. None of the studies were powered to evaluate the incidence of adverse effects however and so monitoring of side effects is indicated (33).

A Cochrane review of the effectiveness of intermittent flushing with heparin versus normal saline in maintaining patency of central venous catheters in adults looked at six studies (1433 participants). The authors found no conclusive evidence of important differences when heparin was used for intermittent flushing when compared with normal saline flushing. They also note the wide range of concentrations of heparin employed (range 10-5000 units per mL) and variation in follow up (20-180 days) (34).

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Arterial Catheters. In these catheters, a flushing solution is continuously infused through the line. The findings of research in this area are mixed. A number of studies have found that heparinised saline confers advantages in maintaining the patency of arterial catheters and/or providing more accurate blood pressure readings (35-38). Other studies however report no difference between arterial lines flushed with heparinised saline and normal saline solutions (39-42); one of these studies noted a prolonged aPPT in patients using heparinised solutions (42).

A recent observational study expresses concerns that using normal saline rather than heparinised saline may reduce the duration of use (from a median of 102h to 72h) and increase the need for removal due to line blockage (7.9% to 41.2%). The authors acknowledge methodological limitations of this study (43,44). A review published in 2014 looked at ten papers and concluded that patency can be maintained by both normal saline and heparinised saline but if a longer duration of use is required (beyond 48h) then heparin has advantages over normal saline (45).

A Cochrane review from the same year, assessing the effectiveness of heparin versus normal saline for patency of arterial lines, looked at seven studies (606 participants). A meta-analysis was not carried out due to high levels of heterogeneity. The authors concluded that further research is required that looks at well-defined outcomes and stratifies sampling to take account of different heparin doses before firm recommendations can be made (46).

Both BNF (7) and NICE (8) reflect this lack of clarity in the evidence base for arterial and central venous catheters:  The role of heparin flushes in maintaining patency of arterial and central venous catheters is unclear (7).  When recommended by the manufacturer, implanted ports or opened-ended catheter lumens should be flushed and locked with heparin sodium flush solutions (8).

Summary

There is evidence available to address the question of whether heparin has any advantage over normal saline solution to flush peripheral intravenous catheters to reduce the risk of blockage and the need for replacement. The research identifies other issues that may impact on catheter patency including flush technique, patient’s age and site of cannulation.

 There seems to be a reasonable consensus that heparinised saline has no advantage over normal saline for maintaining peripheral intravenous catheters in adults. This is also noted in the British National Formulary and NICE guidance. However, the results from studies in children and neonates are conflicting and inconclusive.

 For arterial and for central venous catheters, the picture is less clear and more specific policies may be required depending on the individual devices in use.

Limitations The studies cited vary in their design, for example in -  The frequency of flushing of catheters  The volumes of flushing solutions used  The catheter type studied  The duration of time that catheter function was assessed  The concentration of heparin used.

References

Medicines Q&As

1. Aronson JK, editor Meyler’s Side Effects of Drugs 15th Ed. London: Elsevier; 2006; 1590- 1591. 2. Barrett PJ, Lester RL. Heparin versus saline flushing solutions in a small community hospital. Hosp Pharm. 1990;25:115-118. 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. British Medical Journal 1998;316:969-975. 4. Goode CJ, Titler M, Rakel B et al. A meta-analysis of effects of heparin flush and saline flush: quality and cost implications. Nurs Res 1991;40(6):324-30. 5. Peterson FY, Kirchhoff KT. Analysis of the research about heparinized versus nonheparinized intravascular lines. Heart Lung 1991;20:631-40. 6. Toft B. The dangers of heparin flushes. Qual Saf Health Care 2010;18:84-5. 7. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. Accessed 30 March 2016 via http://www.evidence.nhs.uk/. 8. National Institute for Care Excellence. NICE Clinical Guideline CG139 March 2012. Healthcare-associated infections: prevention and control in primary and community care. Accessed online via: www.nice.org.uk/guidance/cg139 on 21/04/16. 9. Mok E, Kwong TKY, Chan MF. A randomized controlled trial for maintaining peripheral intravenous lock in children. Int J Nurs Prac 2007;13:33-45. 10. Robertson J. Intermittent intravenous therapy: a comparison of two flushing solutions. Contemp Nurse 1994;3(4):174-179. 11. Paisley MK, Stamper M, Brown J et al. The use of heparin and normal saline flushes in neonatal intravenous catheters. Pediatr Nurs 1997;23(5):521-524,527. 12. Kotter RW. Heparin vs saline for intermittent intravenous device maintenance in neonates. Neonatal Netw 1996;15(6):43-47. 13. LeDuc K. Efficacy of normal saline solution versus heparin solution for maintaining patency of peripheral intravenous catheters in children. J Emerg Nurs 1997;23:306-9. 14. White ML, Crawley J, Rennie EA, Lewandowski LA. Examining the effectiveness of 2 solutions used to flush capped pediatric peripheral intravenous catheters. J Infusion Nursing 2011;34(4):260-270. 15. Upadhyay A, Verma KK, Lal P et al. Heparin for prolonging peripheral intravenous catheter use in neonates: a randomized controlled trial. J Perinatology 2015;35:274-277. 16. Mudge B, Forcier D, Slattery MJ. Patency of 24-gauge peripheral intermittent infusion devices: a comparison of heparin and saline flush solutions. Pediatr Nurs 1998;24(2):142- 145. 17. Cook L, Bellini S, Cusson RM. Heparinized saline vs normal saline for maintenance of intravenous access in neonates. Advances in Neonatal Care 2011;11(3):208-215. 18. Arnts IJJ, Heijnen JA, Wilbers HTM et al. Effectiveness of heparin solution versus normal saline in maintaining patency of intravenous locks in neonates: a double blind randomized controlled study. J Advanced Nursing 2011;67(12):2677-2685. 19. Kumar M, Vandermeer B, Bassler D, Mansoor N. Low-dose heparin use and the patency of peripheral IV catheters in children: a systematic review. Pediatrics 2013;131;e864-e872. 20. Shah PS, Ng E, Sinha AK. Heparin for prolonging peripheral intravenous catheter use in neonates. Cochrane Database of Systematic Reviews. 2005, Issue 4. Art. No.: CD002774. 21. Smith S, Dawson S, Hennessey R, Andrew M. Maintenance of the patency of indwelling central venous catheters: is heparin necessary? Am J Pediatric Hematol Oncol 1991;13(2):141-143. 22. Bertoglio S, Solari N, Meszaros P et al. Efficacy of normal saline versus heparinized saline solution for locking catheters of totally implantable long-term central vascular access devices in adult cancer patients. Cancer Nursing 2012;35(4):E35-E42. 23. Stephens LC, Haire WD, Tarantolo S et al. Normal saline versus heparin flush for maintaining central venous catheter patency during apheresis collection of peripheral blood stem cells (PBSC). Transfus Sci 1997;18 (2):187-193. 24. Fuentes i Pumarola C, Casademont Mercader R, Colomer Plana Met al. Comparative study of maintenance of patency of triple lumen central venous catheter. Enferm Intensiva 2007;18(1):25-35. 25. Schallom ME, Prentice D, Sona C et al. Heparin or 0.9% sodium chloride to maintain central venous catheter patency: a randomized trial. Crit Care Med 2012;40(6):1820-1826.

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26. Mayo DJ, Horne McD K, Summers BL et al. The effects of heparin flush on patency of the Groshong® catheter: A pilot study. Oncol Nurs Forum 1996;23(9):1401-1405. 27. Rabe C, Gramann T, Sons X et al. Keeping central venous lines open: a prospective comparison of heparin, vitamin C and sodium chloride sealing solutions in medical patients. Intensive Care Med 2002;28:1172-1176. 28. de Neef M, Heijboer H, van Woensel JBM, de Haan RJ. The efficacy of heparinization in prolonging patency of arterial and central venous catheters in children: A randomized double- blind trial. Pediatr Hematol Oncol 2002;19:553-560. 29. Bowers L, Speroni KG, Jones LA, Atherton M. Comparison of occlusion rates by flushing solutions for peripherally inserted central catheters with positive pressure luer-activated devices. J Inf Nurs 2008;31(1),22-27. 30. Cesaro S, Tridello G, Cavaliere M et al. Prospective randomized trial of two different modalities of flushing central venous catheters in pediatric patients with cancer. J Clin Oncol 2009;27(12):2059-2065. 31. Jonker MA, Osterby KR, Vermeulen LC et al. Does low-dose heparin maintain central venous access device patency? A comparison of heparin versus saline during a period of heparin shortage. J Parenteral and Enteral Nutrition 2010;34(4):444-449. 32. Bradford NK, Edwards RM, Chan RJ. Heparin versus 0.9% sodium chloride intermittent flushing for the prevention of occlusion in long term central venous catheters in infants and children. Cochrane Database of Systematic Reviews. 2015, Issue 11, CD010996. 33. Shah PS, Shah VS. Continuous heparin infusion to prevent thrombosis and catheter occlusion in neonates with peripherally placed percutaneous central venous catheters (Review). Cochrane Database of Systematic Reviews. 2008, Issue 2. CD002772. 34. López-Briz E, Ruiz Garcia V, Cabello JB et al. Heparin versus 0.9% sodium chloride intermittent flushing for prevention of occlusion in central venous catheters in adults (Review). Cochrane Database of Systematic Reviews. 2014, Issue 10. CD008462. 35. Dennis Clifton G, Branson P, Jeanette Kelly H et al. Comparison of normal saline and heparin solutions for maintenance of arterial catheter patency. Heart Lung 1991;20:115-118. 36. Kulkarni M, Elsner C, Ouellet D, Zeldin R. Heparinized saline versus normal saline in maintaining patency of the radial artery catheter. Can J Surg 1994;37(1):37-42 37. Zevola DR, Dioso J, Moggio R. Comparison of heparinized and nonheparinized solutions for maintaining patency of arterial and pulmonary artery catheters. Am J Crit Care 1997;6(1):52- 55 38. American Association of Critical-Care Nurses. Evaluation of the effects of heparinized and nonheparinized flush solutions on the patency of arterial pressure monitoring lines: the AACN Thunder Project®. Am J Crit Care 1993;2(1):3-15. 39. Alizadehasl A, Ziyaeifard M, Peighambari M et al. Avoiding heparinization of arterial line and maintaining acceptable arterial waveform after cardiac surgery: A randomized clinical trial. Res Cardiovasc Med 2015;4 (3):e28086. 40. Sang Sook H, Jee Eun P, Nam Eun K, Hwa Ja K. Effects of normal saline for maintenance of arterial lines of surgical patients. J Korean Acad Nurs 2012;42(6);791-798. 41. Whitta RKS, Hall KFM, Bennetts TM et al. Comparison of normal or heparinised saline flushing on function of arterial lines. Crit Care Resusc 2006;8(3):205-208 42. Del Cotillo M, Grané N, Llavoré M, Quintana S. Heparinized solution vs. saline solution in the maintenance of arterial catheters: a double blind randomized clinical trial. Int Care Med 2008;34:339-343. 43. Tully RP, McGrath BA, Moore JA et al. Observational study of the effect of heparin-containing flush solutions on the incidence of arterial catheter occlusion. J Intensive Care Soc 2014;15(3):213-215. 44. Tully RP, Moore JA, Rigg J et al. Problems with saline flush for arterial lines. Anaesthesia 2016 ?2014?;69:87-88. 45. Kordzadeh A, Austin T, Panayiotopoulos Y. Efficacy of normal saline in the maintenance of the arterial lines in comparison to heparin flush: a comprehensive review of the literature. J Vasc Access 2014;15(2):123-127. 46. Robertson-Malt S, Malt GN, Farquhar V, Greer W. Heparin versus normal saline for patency of arterial lines (Review). Cochrane Database of Systematic Reviews. 2014, Issue 5. CD007364.

Medicines Q&As

Quality Assurance

Prepared by Trevor Beswick, South West Medicines Information and Training

Date Prepared 30th March 2016

Checked by Michèle Skipp, South West Medicines Information and Training

Date of check 5th May 2016

Search strategy EMBASE 1. EMBASE; HEPARIN/; 121397 results. 2. EMBASE; CATHETER/; 44031 results. 3. EMBASE; 1 AND 2; 1514 results. 4. EMBASE; 3 [Limit to: (Year Published Last 3 Years)]; 461 results. 5. EMBASE; flush.ti,ab [Limit to: (Year Published Last 3 Years)]; 1044 results. 6. EMBASE; 4 AND 5 [Limit to: (Year Published Last 3 Years)]; 5 results. 7. EMBASE; (venous AND catheter).ti,ab [Limit to: (Year Published Last 3 Years)]; 5051 results. 8. EMBASE; INTRAVENOUS CATHETER/ [Limit to: (Year Published Last 3 Years)]; 1392 results. 9. EMBASE; 1 AND 8 [Limit to: (Year Published Last 3 Years)]; 77 results. 10. EMBASE; (arterial AND catheter).ti,ab [Limit to: (Year Published Last 3 Years)]; 3019 results. 11. EMBASE; ARTERY CATHETER/ [Limit to: (Year Published Last 3 Years)]; 916 results. 12. EMBASE; 1 AND 11 [Limit to: (Year Published Last 3 Years)]; 94 results.

MEDLINE 13. Medline; heparin.ti,ab; 67587 results. 14. Medline; VASCULAR ACCESS DEVICES/; 842 results. 15. Medline; 13 AND 14; 21 results.

NHS Evidence “heparin flush”