CUBAN MEDICAL LITERATURE

Use of Recombinant Streptokinase
for Hemodialysis Catheter Recovery

JF Pérez-Oliva, MD(1);
Y Parodis, MD(1);
O Benítez, MD(1);
Y Sotolongo, MD(2);
R Vigoa, MD(1);
ME Raola, MD(1);
Ch Magrans, MD, PhD(1)

ABSTRACT

Patients with end-stage renal disease in dialysis survive thanks to tri-weekly purification of their blood supply, requiring access to blood circulation by an arteriovenous fistula, surgically created months before its use, or by central venous catheter. Malfunction of the latter can cause catheter loss and treatment interruption, requiring catheter replacement, which is not without complications. Since October 2001, 20 intraluminal Heberkinasa infusion procedures were performed in the 15 patients with such malfunction, resulting in 85% catheter recuperation, with only three catheters lost. There was good tolerance of the product, with 20% minor and temporary associated events. This study demonstrates that Heberkinasa administered in this way is safe and efficacious, which makes it a reasonable alternative for this frequent problem. It prevents final catheter loss and has positive effects on social and human cost effectiveness by avoiding potential risks of multiple catheterisms. The validity of these results has led to generalizing such practice in hemodialysis centers throughout Cuba.

Keywords: ANTICOAGULATION, CATHETER DYSFUNCTION, HEMODIALYSIS.

End-stage renal disease (ESRD) is the end road for diseases such as diabetes mellitus, high blood pressure (HBP), glomerulopathies and others associated with the aging of the world population, developing progressively towards the terminal stage, requiring dialysis or transplantation.

Hemodialysis patients survive thanks to the cleansing of their blood tri-weekly, requiring surgically created access to their blood supply, or without this, a central venous catheter. The latter represent about 15% to 25% of the total number of hemodialysis patients. Malfunction of the catheter is an important complication that causes a reduction in blood flow, interruption of hemodialysis, and loss of the catheter, necessitating replacement, which is not free from complications and leads to more risks of complications and potential mortality.[1]

This is a frequent problem and is responsible for the loss of over 1/3 of the catheters in the initial stages of their placement.[2]

To avoid catheter malfunction caused by fibrin or thrombosis, pure heparin is instilled into each branch of the catheter according to its volume, and removed prior to beginning treatment. If the amount instilled is greater than needed, the risk of anaphylactic or immunologic systemic effects increases. If the amount is less than required, it increases the risk of intra-catheter coagulation, or just as, if not more important but less studied, it may lead to peri-catheter thrombosis. This thrombosis formation contributes to catheter malfunction, formation of central vein stenosis, the appearance of embolisms and significant septic complications if it becomes infected.[3]

As an alternative to heparin instillation, which is used as an anticoagulant after every hemodialysis, other more expensive agents such as recombinant urokinase and rtPA (recombinant tissue-plasminogen activator), have been used without superior results. Faced with catheter malfunction or coagulation, several thrombolytic protocols have been used, with none appearing to offer the definitive solution to this commonly found problem in hemodialysis.[4,5]

The use of high cost, permanent tunnel catheters as the only, final alternative for patients when there is no possibility of performing an arteriovenous fistula or prosthetic graft, illustrates the need for a more urgent approach and solution to this situation. These factors prompted the study described here.

A prospective study was carried out at the Institute of Nephrology, using Cuban human recombinant streptokinase (Heberkinasa, Center for Genetic Engineering and Biotechnology, HeberBiotec S.A.), if there was no contraindication for its use, in 15 patients who presented severe catheter malfunction from October 2001 to April 2002.

Heberkinasa is used widely in Cuba for acute myocardial infarction and was used in nephrology for the treatment of arteriovenous fistula thrombosis from 1994-1996.

Blood flow and venous and arterial pressures are routinely monitored to alert for potential access problems during every hemodialysis. At the end of treatment, the lumen of each branch of the catheter is filled with pure heparin, in liquid volume amounts established by the manufacturer.

The warning sign for a poorly functioning catheter was established as a reduction of blood flow to less than 200 ml/min.

Definitions:

Severe catheter malfunction: failure to carry out hemodialysis procedure due to coagulation in catheter lines or low flow preventing its performance.

Saved catheter: if the catheter remained in place three months after the event or was removed for reasons unrelated to recurrent clotting.

Loss of the catheter: if it became necessary to replace the catheter due to malfunction.

Application Protocol

Faced with the impossibility of performing hemodialysis, nursing staff halted the process and sought physician corroboration, after which the physician temporarily hospitalized the patient. The physician then instilled 375,000 IU of Heberkinasa into each catheter branch (intraluminally), with continuous cardiovascular monitoring for three hours. Afterwards, Heberkinasa was removed by aspiration, the branches washed and heparin left in them to restart hemodialysis. The dosage of anticoagulant used was specific to each case. If the malfunction persisted, the procedure was repeated. If it was effective, but was recurrent in the following hemodialysis, the procedure was carried out again, but limited to a maximum of three instillations.

The procedure was used for eight patients with permanent catheters and seven with transitory, the latter used for the development period of the arteriovenous fistula catheters.

Descriptive statistics were used for analyzing the results.

RESULTS

Of the 20 intraluminal Heberkinasa instillations administered to 15 patients with catheter malfunction, repetition of instillation was required in two patients and two more patients required three administrations, for 25% of the total instillations.

Three months after instillation, in 17 out of 20 applications (85%), there was vascular access using the saved catheter, eight of which were temporary and seven permanent, and only three of the 15 patients needed a catheter change (one catheter was permanent and two temporary).

Catheter loss occurred in 15% of the procedures, one loss occurred 67 days after the first administration (permanent catheter); the other two occurred in patients with temporary catheters. Of these, in one patient the loss occurred following two more instillations, after six and 28 days respectively. The other patient was also instilled three times (the first interrupted due to precordialgia without changes in cardiac monitoring, followed by a precarious hemodialysis, and reinfusion on the next day with catheter permanence of 35 days and a last attempt with a permanence of only five days).

The adverse events using this product were all temporary and minor. They were found in 20% of patients and consisted of sinus tachycardia (3), extrasystolic sinus arrhythmia (2), lumbar and thoracic pain (1), nausea (1), and mild increase of arterial pressure (1). It was necessary to stop the procedure in only one patient, removing the drug because of thoracic and lumbar pain without any change in cardiovascular monitoring. The procedure was repeated hours later without any modifications. More than one event was observed in four of the affected patients.

DISCUSSION

Techniques of vascular access to circulation are essential for carrying out hemodialysis and whether temporary or permanent (arteriovenous fistula, vascular graft or tunnel catheter), they are still the Achilles’ heel in guaranteeing the quality and efficiency of the purification session, despite advances achieved in recent years.[3]

If it is necessary to use a catheter as an alternative to the arteriovenous fistula, this also presents potential medical complications at the time of insertion. Other complications may appear in short or long term management such as: infection at the site of entry or of the tunnel; colonization (possibly causing a chronic micro- or systemic inflammatory state); central vein stenosis depending on the one-time or repeated placement of the catheter through the subclavian or even jugular vein; and poor flow, which may be due to twisting of the catheter or the obstruction of the blood entry/exit openings due to fibrin or clotting within or around the catheter leading to its malfunction.[1,4]

Catheter thrombosis is considered the most important cause of malfunction, and the resulting adverse effects should not be assessed only in terms of the high cost of the catheters themselves and loss of continuity and efficacy of the dialysis session, but also in terms of the potential risks of subjecting the patient to multiple traumatic interventions, with the negative implications of attendant stress, and the effect on mortality.[4]

This study describes our experience using a recombinant streptokinase infusion protocol. Streptokinase was instilled in the lumen of each hemodialysis catheter line for three hours, after which it was removed.

The instillation frequency used was in the same range as that of other reports using different thrombolytic agents.[6,7]

Our frequency of catheter change was similar to the one reported by Welik et al. also using recombinant streptokinase,[2] but we reported slightly inferior results than those for other more modern anticoagulants. Nevertheless, we must take into account that the time factor is essential when considering efficacy, since different authors using different thrombolytic agents and/or different protocols report efficacy in different ways, even the possibility of carrying out hemodialysis immediately with tPA in 87.5%.[8]

Takeda[5] used urokinase with an 84% catheter survival after 34 days, which is similar to our results. Webbs,[9] using a systemic urokinase infusion followed by permanent oral anticoagulants, reported 95% recovery after three months.[9]

The most commonly used drugs for catheter malfunction, in the order they appeared are increasingly more expensive: streptokinase, urokinase and recombinant tissue plasminogen activator (tPA).[10]

Clase points out the safety, efficacy (streptokinase 70%; urokinase 80%; tPA 83-98%), and increasing costs of each.[11]

We did not find important adverse effects, even when the procedure was interrupted for thoracic and lumbar pain and repeated some hours later in one patient. All this is caused by the passage of small amounts of recombinant streptokinase through a catheter opening. We did not find allergic reactions or severe effects related to its use as reported by others.[11]

Analyzing the cost of recombinant streptokinase when compared to the catheter, and considering the efficacy achieved, our results show a positive cost-benefit balance. Even more so if we consider that Heberkinasa is produced in Cuba; the use of other thrombolytic agents is prohibitive because of their very high prices in the international market.[10,11]

In short, this study, in which a protocol of simple Heberkinasa intraluminal instillation is used for hemodialysis catheter malfunction, showed that it is safe, well-tolerated and efficacious. This makes it a reasonable, cost-effective alternative, in our circumstances, for solving this important and frustrating problem. It also avoids definitive catheter loss, and thus has a positive impact on cost-effectivity and patient care, reducing complications and mortality caused by repeated venous interventions, which also lead to irreversible vessel loss.

REFERENCES

1. Beathard, GA. “Catheter thrombosis.” Semin Dial 14(6), November-December, 2001; 441-445.
2. Welik, RA; Josselson, J; Shen, SY; Reed, WR; Sadler, JH. “Repeated low-dose streptokinase infusions into occluded permanent, central-venous hemodialysis catheters.” Kidney Int 31(5), May, 1987: 1210-1212.
3. National Kidney Foundation-Dialysis Outcomes Quality Initiative. “NKF-DOQI clinical practice guidelines for vascular access.” Am J Kid Dis 30(4Suppl. 3): S150–191.
4. Jos, N; Barendregt, M; Jan, H; Tordoir, M; Karel; Leunissen, L. “Antithrombotic measures for indwelling intravenous haemodialysis catheters— Columbus’ egg yet to be found.” Nephrol Dial Transplant 14, 1999: 1834-1835.
5. Takeda, K; Harada, A; Kubo, M. “Successful use of single-lumen, urokinase immobilized femoral catheters as a temporary access for haemodialysis.” Nephrol Dial Transplant 13: 130-133.
6. Matuszkiewicz-Rowinska, J; Billip-Tomecka, Z; Rowinski, W; Sicinski, A. “Systemic streptokinase infusion for declotting of hemodialysis arteriovenous fistulas.” Nephron 66(1), 1994: 67-70
7. Twardowski, ZJ. “High-dose intradialytic urokinase to restore the patency of permanent central vein hemodialysis catheters.” Am J Kidney Dis 31(5), May 1998: 841-847.
8. Daeihagh, P; Jordan, J; Chen, J; Rocco, M. “Efficacy of tissue plasminogen activator administration on patency of hemodialysis access catheters.” Am J Kidney Dis 36(1), Jul 2000: 75-79.
9. Webbs, A; Mubarak, A; Russell, GI. “A protocol of infusion and warfarin for the management of the thrombosed haemodialysis catheters.” Nephrol Dial Transplant
10. Jean, G; Himmelfarb. “Pharmacologic prevention of vascular access stenosis.” Curr Opin Nephrol Hypertens 8(5), September 1999: 569-572.
11. Clase, CM; Crowther, MA; Ingram, AJ; Cina, CS. “Thrombolysis for restoration of patency to haemodialysis central venous catheters: a systematic review.” J Thromb Thrombolysis 11(2), April 2001: 127-136.

This paper was originally presented at the 2002 Science and Technology Forum, Havana.

THE AUTHORS

1. JF Pérez-Oliva, MD, Y Parodis, MD, O Benítez, MD, R Vigoa, MD, ME Raola, MD, and Ch Magrans, MD, PhD, nephrologists at the Institute of Nephrology, Havana, Cuba.
2. Y Sotolongo, MD, anesthesiologist at the Institute of Nephrology, Havana, Cuba.