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Published on 1 May 2007

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Urokinase for managing central venous catheters

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Laurence A Goldberg
FRPharmS
Editorial Consultant
HPE
E: lag@salt.u-net.com

The patency of central venous catheters (CVCs) is vital to patients who rely on them for haemodialysis, parenteral �nutrition and regular administration of chemotherapy and antibiotics. In 2005, dialysis patients with the complications of blocked haemodialysis catheters accounted for 100,000 bed days in NHS hospitals.(1) The most common cause of catheter failure is the development of thrombi around or inside the catheter and the formation of fibrin sheaths.

The consequences of catheter dysfunction are many, including increases in morbidity and mortality, increases in expenditure and a real concern to patients who report fear of thrombosis second only to pain (see Resource). Units need to have a �strategy in place to manage occluded haemodialysis catheters.

Whilst the ideal is for every patient undergoing haemodialysis to have a functioning arteriovenous (AV) fistula, thrombolytic agents are important in preventing and reversing catheter blockage. Thrombolytics have proven efficacy and an acceptable safety profile when used appropriately to manage CVCs. The choice of agent used is governed by many factors, including availability, convenience, comparative efficacy and cost.

Urokinase
Urokinase is a naturally occurring fibrinolytic agent. It acts by converting inactive plasminogen into the proteolytic enzyme plasmin that in turn degrades fibrin, fibrinogen and other procoagulant plasma proteins.

In one study using urokinase as a “lock”, patency was restored in 81% of a series of 308 cases of blocked catheters.(2)

Urokinase was widely used as a thrombolytic agent until the late 1990s when it was withdrawn from the UK market for commercial reasons. Since then, small quantities of an unlicensed product have been available on a named-patient basis. At about the same time, other forms of urokinase were withdrawn from the US market.

A new licensed form of urokinase, Syner-KINASE(R), has recently been introduced in the UK. It is a highly purified form of human urokinase derived from human urine. As it is of human origin, it is not antigenic although allergic reactions have been reported following its use. It is the UK’s only licensed thrombolytic for use in blocked vascular access catheters. Much stricter regulations have been put into place since the initial licensing, many years ago, of the previously available products.

For Syner-KINASE production, urine is collected from donors from identifiable sources such as schools or colleges. Batch traceability and a recall system have been introduced to deal with the rare chance of donor urine being contaminated with viruses such as HIV or hepatitis B or C. New manufacturing plants in China and Italy have been built and commissioned to meet the new EU standards for good medical practice as set out in the most recent legislation (Guide to GMP-2005, part II). Evidence is now required that all batches of product are free from HIV, hepatitis B and hepatitis C (each batch undergoes polymerase chain reaction analysis to exclude viral contamination) and that there is no risk of the product transmitting animal spongiform encephalopathy agents. Product literature and labelling conform to the EU labelling regulations.

Syner-KINASE is eliminated rapidly by the liver with a half-life of up to 20 minutes and a volume of distribution of 11.5 litres. Elimination may be delayed in patients with hepatic or renal insufficiency. The fibrinolytic effect of urokinase usually disappears within a few hours but increased thrombin time, decreased plasma levels of fibrinogen and plasminogen and increased levels of the degradation products of fibrinogen and fibrin may persist for up to 12-24 hours following discontinuation of an IV infusion. Small amounts of urokinase are eliminated in the urine and via the bile. It is not known if urokinase crosses the placenta or is transferred into breast milk.

Undesirable effects include local sensations of warmth, dull ache or pain in the vessel being treated. Overt bleeding and haemorrhagic complications may occur and pyrexia and haematuria have been reported. Embolic episodes have been noted after clot fragments have been released. Allergic reactions, though rare, have been reported.

Syner-KINASE is currently available in vials containing 25,000 IU or 100,000 IU. It is offered in the form of a freeze-dried powder that can be stored at room temperature and is reconstituted with sterile saline. It has the additional benefit of not containing human albumin. The drug can be administered as a catheter “lock” or by infusion. The recommended dose for clearing thrombosed intravascular catheters is 5,000-25,000 IU dissolved in 2 ml of sterile saline, which is then “locked” for up to four hours. The procedure can be repeated if poor blood flow persists. An infusion during or between dialysis sessions may be administered over three hours where “locking” has proved to be ineffective.

Other thrombolytics

Tissue-type plasminogen activator (tPA)
Recombinant tPA is a powerful fibrinolytic, licensed for use in acute myocardial infarction and pulmonary embolism but not for catheter clearance or peripheral vascular occlusion. A study in 20 patients suggested that infusions of 2 mg/h were effective in restoring catheter patency. However, in 10 patients who received 4 mg/h, the authors reported one case of rectal bleeding and two cases of minorhaemorrhaging around the eyes. They concluded that the safety margins might not be acceptable.(3)

Streptokinase
Streptokinase is an exogenous fibrinolytic agent derived from beta-haemolytic streptococci. It has similar thrombolytic properties to urokinase but its clinical application is limited as allergic complications develop with repeated use. It has also been associated with erratic responses and drug resistance. Therefore there is little evidence to support the use of streptokinase for catheter clearance.(4)

According to Professor Donal O’ Donaghue, the recently appointed “renal tsar” at the UK’s Department of Health, the reintroduction of urokinase is a good opportunity for renal units to evaluate their protocols for dealing with occluded venous access catheters. The availability of a licensed product provides the rationale for undertaking new work to steer the direction of national guidelines, which have been limited until now by lack of good data. Evidence from multicentre audits and trials should inform recommendations about techniques of catheter lock and infusions in terms of the optimum amount of thrombolytic agent to use and the correct timing for such procedures.(5) Syner-KINASE is the only UK-licensed thrombolytic for use in vascular access catheters. It contains no human albumin, does not require cold chain distribution or storage and is not covered by a black triangle. There are no licensed alternatives in the UK.

References

  1. Renal Association. UK Renal Registry: eighth annual report, December 2005. Bristol: RA; 2005. Available from: www.renalreg.com/report%202005/Cover_Frame2.htm
  2. Moss AH, et al. Use of a silicone dual-lumen catheter with a Dacron cuff as a long-term vascular access for haemodialysis patients. Am J Kidney Dis 1990;16:211-5.
  3. Davies J, et al. Restoration of flow following haemodialysis catheter thrombus: analysis of rt-PA �infusion in tunnelled dialysis catheters. J Clin Pharm Ther 2004;29:517-20
  4. Clase CM, et al. Thrombolysis for restoration of �patency to haemodialysis central venous catheters: a systematic review. J Thromb Thrombolysis 2001;11:127-36.
  5. Kumwenda M, O’Donoghue D. The changing options for managing blocked haemodialysis catheters. Br J Ren Med 2006;11 Sponsored Suppl 4:2-4.

Resource
National Kidney Foundation
KDOQI Guidelines
W: www.kidney.org/professionals/kdoqi/guidelines.cfm



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