Central venous catheters that provide vascular access for haemodialysis are at high risk of luminal thrombosis. Thrombolytic agents are effective in restoring flow in occluded dialysis catheters.
Central venous catheters provide vascular access for emergency haemodialysis. Unfortunately, they are often used for chronic haemodialysis, although associated with significant complications, particularly thrombosis and infection. Ideally, dialysis catheters should be avoided or used only for a limited short period by timely creation of arteriovenous fistulae.
Dialysis catheters are of two types – short-term, or “temporary”, catheters and long-term catheters. Short-term catheters are 11–12Fr in diameter and are placed in emergency situations when dialysis is needed immediately and they can be quickly removed or exchanged. The long-term dialysis catheters, which are of larger diameter, usually 14Fr, are tunnelled under the skin, have a Dacron cuff attached to allow the catheter to embed, thus becoming fixed in the subcutaneous tissue to prevent dislodgement and reduce infection tracking up from the catheter exit site.
Generally, both types of catheter have double lumina, one to remove blood and the other to return the dialysed blood. Short-term catheters usually have a simple design and the lumen volume is approximately 1 cm3 each, whereas the lumina of long-term catheters are 1.6–1.9cm3 in volume.
Both types of catheter are at high risk of luminal thrombosis. Preventing thrombosis or managing it once established is crucial if haemodialysis activity is to be maintained. Obstruction with a loss of ability to draw back or infuse is thought to occur in up to 28% of central catheters and is a frequent source of delayed dialysis and admission to hospital, and has an economic cost.[1,2] Thrombosis is usually intrinsic to the catheter, although extrinsic obstruction due to fibrin sheath formation may be more common than acknowledged. [3,4] It presents either as a low flow rate on dialysis (<250ml/min), leading to dialysis inadequacy; or complete thrombosis, making dialysis impossible despite the use of anticoagulant lock solution, usually heparin, which is instilled into the two lumina of the catheter to prevent thrombosis in between dialyses.
Thrombolytic agents
Removal of an established thrombus requires fibrindirected therapy. Streptokinase is produced by betahaemolytic streptococcus and acts as a plasminogen activator. It was used for thrombolysis in catheter thrombosis in the early 1990s but is no longer used, mainly because of its antigenicity, which makes repeated use problematic.
Urokinase, which is a product of human kidney cells, does not have this problem and has been used successfully to treat catheter thrombosis, although since 1999 it has not been available in the USA because of concerns about its manufacture from fetal kidney cells and risks of viral contamination. However, in Europe urokinase has always been manufactured from human urine. Although withdrawn for a period of time for commercial reasons, it is currently available and is licensed in the UK (Syner-KINASE). Recombinant tissue plasminogen activator (r-tPA) is an enzyme (serine protease) that binds to fibrin in a thrombus and converts the entrapped plasminogen to plasmin, thereby initiating local fibrinolysis. Most of the recent literature from the USA, therefore, reports on use of r-tPA, and only earlier publications detail experiences of urokinase.
The primary method for restoring flow in thrombusoccluded dialysis catheters continues to be thrombolytic therapy. The two main agents used remain urokinase and r-tPA. R-tPA (alteplase or reteplase) is a shorter-acting thrombolytic agent than urokinase, and some reports suggest superior efficacy as detailed below. Critically, the thrombolytic agent has to come into direct contact with the thrombus, and this is achieved by overfilling each of the catheter lumina or by infusion.
Clinical studies
Clase and colleagues performed a systematic review of catheter thrombolysis of studies published up to 2000 and suggested that both r-tPA and urokinase were safe and efficacious in restoring patency to thrombosed haemodialysis catheters.[5] Restoration rates of 83–98% had been reported with instillation of 1–2mg/lumen r-tPA, compared with 70% with 5,000 units/lumen urokinase, suggesting that r-tPA is likely to be more effective than urokinase.
Seddon et al compared protocols using 5,000u or 2,500u urokinase to the volume of the dialysis catheter with a one-hour in-catheter dwell but, if unsuccessful, a further dose was given.[6] Clotting episodes decreased by 60% while maintaining successful catheter declotting at 74%. Low-dose urokinase was as effective as full strength.
Twardowski used an unusual approach by giving 250,000u urokinase infusion into the catheter lumina for obstruction or into the venous chamber during dialysis for catheter malfunction followed by repeat infusions if initially unsuccessful.[4] There was only one failure in overcoming catheter malfunction/obstruction out of 162 cases. Also, Twardowski used warfarin to maintain long-term catheter function. However, these approaches remain unusual.
Eyrich et al performed a retrospective review of the medical records of haemodialysis patients with central venous catheters receiving alteplase or urokinase for catheter thrombosis.[7] Patients received 1ml of 1mg/ ml alteplase or 1 ml of 5,000u/ml of urokinase in each catheter port. The effectiveness of thrombolysis was defined as achieving a post-treatment haemodialysis blood flow rate of >300ml/min, maintained for at least 30 minutes during the dialysis session. Both thrombolytic agents significantly increased the haemodialysis blood flow rates. Patients with alteplase-treated catheters were twice as likely to achieve haemodialysis blood flow rates of >300ml/min (p=0.01) and were more likely to complete haemodialysis during that session (93% versus 70%, p=0.02). However, the percentage of functioning catheters at a subsequent haemodialysis session did not significantly differ between groups (p=0.08). The majority of patients in both treatment groups did not require further interventions.
In another study using the now withdrawn urokinase in the USA, Haire et al randomised 50 patients with dysfunctional central venous catheters to be injected with either 2mg r-tPA or 10,000u urokinase and allowed to dwell for two hours.[8] A second dose was allowed if catheter function was not restored with the first injection. Thirteen of 22 catheters randomised to urokinase had their full function restored compared with 25 of 28 catheters randomised to r-tPA (p=0.01). Radiographic contrast injection showed seven catheters randomised to urokinase had complete resolution of the thrombus, compared with 17 randomised to r-tPA (p=0.042). t-PA (2 mg) restored catheter function more reliably and dissolved thrombi faster than twice the “standard” dose of urokinase.
A further comparison of alteplase with urokinase in re-establishing adequate blood flow through partially or completely occluded vascular catheters was performed by Zacharias et al in 30 patients using a 30- minute push protocol to administer thrombolytics.[9] The proportion of completely occluded catheters achieving post-thrombolytic blood flows ≥200ml/min was significantly better with alteplase than with urokinase: 15/17 (88.2%), against 6/14 (42.8%), respectively (p=0.018). No significant difference was observed with partially occluded catheters.
In all these early trials of urokinase with r-tPA, dose equivalence of the two agents was not tested. Clase et al suggested that 1mg r-tPA was likely to be equivalent to 36,000u urokinase, which few centres have used.[5] Further trials with the new formulation of urokinase need to be performed. There are, however, many publications on the use of r-tPA, mainly alteplase but also more recently reteplase, in unblocking dialysis catheters. Davies et al evaluated the efficacy of r-tPA in 20 patients who required 57 infusions in 38 lumens.[10] For completely blocked lines it was infused at 2mg/h for four hours, achieving an 85% success rate. For inadequate flow (<250ml/min) r-tPA was infused at 1mg/h for four hours, achieving an 88% success rate.
Hyman et al investigated the use of reteplase 0.4u to occluded lumens in 59 patients who could not complete dialysis because of poor arterial blood flow, with a further dose after 30 minutes dwell time if flow could not be sufficiently re-established.[11] Eighty-five per cent (50/59) of the patients were able to complete their haemodialysis session following reteplase administration, with 70% (41/59) able to sustain blood flow rates of ≥250ml/min. Of the 50 patients who successfully completed dialysis, 66% (33/50) required only one 0.4- unit dose of reteplase per lumen, while 34% (17/50) required a second dose. No instances of bleeding or allergic reactions were noted.
The Cardiovascular thrombolytic to Open Occluded Lines study (COOL) analysed the safety and efficacy of alteplase after administration of a maximum of two 2mg/2ml doses to thrombosed catheters.[12] In this paper, a combined analysis of two pivotal prospective phase-III clinical trials involving 80 centres was performed. Alteplase (2mg/2ml) was instilled into the lumen of the dysfunctional non-dialysis central venous catheters and allowed to dwell for 120 minutes with a further 2 mg/ml given if necessary. One thousand and sixty-four patients with dysfunctional catheters, with an age range of 2–91 years, were treated and function was restored in 798 patients (75.0%) after one dose and in 905 patients (85.1%) after two doses. Efficacy rates were similar among catheter types (single-, double- and triple-lumen catheters and ports). Other studies using r-tPA are more encouraging.[13–17]
A contrary view of the benefits of thrombolysis was published by Macrae et al, who compared short dwell or long dwell, 1h or >48 h, with subsequent haemodialysis session r-tPA dwell.[18] Whilst a 78% overall catheter patency rate was observed at the subsequent haemodialysis session, and although this fell to 48% patency at two weeks, there was no statistically significant difference between the short and long r-tPA dwell groups for catheter patency (76.9% vs 79.4%) or at two weeks (42.3% vs 52.9%). Multivariate analysis demonstrated that the use of r-tPA on two or more previous occasions was a predictor of r-tPA failure both at the subsequent dialysis session and at two weeks. R-tPA instillation achieved a median catheter function time of only 14 days, after which catheter dysfunction reoccurred. They concluded that strategies that employ r-tPA for catheter dysfunction are temporary and allow a two-week window during which more definitive therapies for dialysis access should be sought.
Conclusion
Whilst there is sufficient evidence to suggest that thrombolytics, urokinase or r-tPA, are effective in restoring flow in occluded dialysis catheters, the ideal dose of agent, whether it should be dwell or infusion, and for how long or how frequently treatment should be undertaken remain uncertain. After limited success with repeated luminal installations, an infusion may be more efficacious. This stepwise escalation of intervention appears effective and well tolerated.
KDOQI guidelines 7.1 and European Best Practice guideline 11.1 support the use of thrombolytic agents.[19,20]
However, the literature contains few large-scale randomised controlled trials and relies on small case series with their methodological limitations, which preclude robust recommendations regarding precise use of these very effective agents. Further trials are therefore necessary.
Author
Ali Bakran
Consultant Transplant and Vascular Surgeon, The Royal Liverpool, University Hospital, Liverpool UK
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19 http://www.kidney.org/PROFESSIONALS/kdoqi/ guidelines.cfm
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