In the past 20 years, vascular access devices (VADs)

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1 Maria Eulàlia Juvé, RN Intravenous Catheter Declotting Same Outcomes With Lower Dose Urokinase? Abstract This study aims to assess, in terms of catheter salvage and economic cost, the effect of a low dose (2000 IU) urokinase lock technique to clear multilumen central venous catheters (CVC) and peripherally inserted central catheters (PICCs) when occluded. A total of 100 catheters were included in the analysis. Results indicate this lower dose technique to be effective in restoring the patency of multilumen CVCs, but not as effective when clearing PICCs. No catheters were lost because of occlusion. In the past 20 years, vascular access devices (VADs) have become an integral part of almost all treatment protocols in patients who require either prolonged or intensive therapies. They are reliable tools for the administration of antitumoral or antimicrobial chemotherapy, blood products, catecholamines, or total parenteral nutrition. Central venous catheters (CVC) are associated with a variety of complications, including catheter infection, catheter malposition, pinch off syndrome, embolization, catheter fracture, and catheter occlusion, which compromise patient care progress and outcomes. 1-8 Catheter occlusion is the most common non-infectious complication associated with the use of short- and long-term VADs Several types of catheter obstructions exist: mechanical, physical and biological. Biological occlusion is the formation of fibrin clots in the catheter lumens, or tip, that can limit the life span of the VAD because of a range of dysfunctions, from complete obstruction of the line to frequent withdrawal occlusions. Biological occlusion also increases the risk of thrombosis and thromboembolism. Fibrin networks have also been related to a higher risk of catheter colonization and infection, as they act as a nidus for microorganisms. 9,14 Maria Eulàlia Juvé is a Clinical Research Nurse in the Nursing Education and Research Department at Bellvitge University Hospital in Barcelona, Spain. She is Master in Medical-Surgical Nursing (University of Barcelona). She also lectures undergraduate and postgraduate nursing students. Address correspondence to: Maria Eulàlia Juvé, Dirección de Enfermeria, Hospital Universitario de Bellvitge, Feixa Llarga s/n, L Hospitalet de Llobregat, Barcelona, Spain ( lalajuve@csub.scs.es or lalajuve@terra.es). Vol. 26, No. 4, July/August

2 Thrombotic and other occlusions of the catheter sometimes require VAD removal and replacement, affecting the patient s care and well-being. In the 1980s, the first research regarding the use of fibrinolytic agents such as streptokinase or urokinase in the treatment of CVC occlusions was published Today, many standardized protocols that are used to restore catheter patency when a catheter is biologically occluded include 5000 or 10,000 international units (IU) urokinase instillation boluses 5,9,10,12,17-20 or higher-dose infusions for specific patient populations. 21,22 Urokinase is considered cost-effective when compared with catheter replacement and when complications from this therapy occur at a reported rate of less than 10%, including allergic type reactions or microemboli. 9,10 This study aimed to test the efficacy of catheter salvage and its cost-effectiveness in the administration of 2000 IU dose urokinase instillation bolus in cancer patients with CVCs. DEFINITIONS Catheter occlusion is defined as the inability to draw blood from any of the lumens of the catheter or the inability to administer infusates through the catheter with normal infusion pressure because of mechanical, physical, or biological factors. Biological occlusion of the catheter includes the formation of an intraluminal thrombus, extraluminal fibrin sleeves, or mural thrombus. Thrombus formation may occur as a response to vascular injury secondary to catheter placement. Mechanical obstruction of the catheter occurs when the infusion equipment, the lumens, or the outer parts of the CVC are bent, preventing solutions from being administered or blood specimens from being obtained. Physical occlusion of the VAD is the consequence of drug precipitate of incompatible solutions or because of the formation of calcium-phosphorous complexes in total parenteral nutrition administration. Fibrin sleeves may develop as a result of the catheter s contact with blood. Fibrin can quickly clot around the catheter tip even though turbulence caused by the infusion would seem to prevent it. In withdrawal occlusion, fluids can be administered, but blood cannot be drawn because of a fibrin sleeve that is pulled over the tip when withdrawal is attempted. Low dose urokinase lock (LDUL) technique is the administration of 2000 international units of urokinase into the occluded lumen of the catheter. The urokinase is locked within the lumen for 15 minutes, and patency is tested through a 2 ml blood draw afterword. In LDUL technique, 100,000 IU of urokinase the mini- mum dose vial available in Spain were reconstituted with 10 ml of sodium chloride. OUTCOMES MEASURES The primary outcome of this study was catheter salvage, which was defined as complete viability and correct functioning of all catheter lumens, either to obtain blood or to administer infusates after LDUL technique was used to clear a biological occlusion. Study Design, Setting, and Population In this retrospective study, we retrieved general and occlusion data from two previous catheter-related events studies: Carratalà et al 23 and Juvé ME, Rubio D, Farrero S, et al (unpublished data, 1992) in adult patients with hematologic malignancies at Bellvitge University Hospital, a 900-bed referral institution, in Barcelona, Spain. The 1992 observational and prospective study aimed to describe catheter-related events in hematology patients in our center. Results from this study were not published but used to set catheter care policies in the setting. The second group of data was obtained from a clinical trial control group examining the prevention of CVC-related infections in neutropenic patients. 23 Occlusion data, although collected, were used in that trial only for infection-related purposes or considerations. At the time these studies were performed, all patients were at least age 16. Participants gave their consent and the studies were approved by the Nursing Department and the Ethics Committee. Patients had a double-lumen or triple-lumen nontunneled polyurethane CVC (Arrow International, Inc., Reading, Pa) or a 14-gauge, single-lumen peripherally inserted central catheter (PICC) (Drum, Abbot Laboratories, Sligo, Ireland). Patients receiving total parenteral nutrition therapy were excluded. Using maximal barrier precautions, physicians inserted the CVCs into the subclavian or the jugular vein and PICCs were inserted into the cephalic or the basilic vein by a registered nurse. Ward nurses performed all catheter maintenance care. (In Spain, ward nurses are always registered nurses with 3 years of university nursing studies. Some registered nurses have higher university degrees such as a Master s in Medical-Surgical Nursing.) Skin care included gently scrubbing with 4% chlorhexidine gluconate soap for at least 30 seconds, rinsing with saline solution, and drying with a sterile gauze. The catheter insertion site was also protected with 1 ml of 1% chlorhexidine pomade and a gauze dressing. Catheter hubs were externally disinfected and protected with this 246 Journal of Infusion Nursing

3 same technique (soap, rinse, dry, and dress). Catheter lumen care included assessment for occlusion by withdrawing 2 ml of blood, flushing the lumen with 10 ml of 0.9% sodium chloride, and connecting it to the infusate, or locking it with 1.6 ml of 1% sodium heparin. catheter could not be cleared after three attempts, the lumen was externally locked with the clamp, the line protected, and the results reported to the physician for further assessment through radiological or other diagnostic techniques. Catheter Patency Restoration When a catheter obstruction was identified, the nurse first ruled out mechanical occlusion. Then, using a soft push-pull technique, the lumen was flushed with 0.9% sodium chloride. If blood was drawn, a bolus of 10 ml of 0.9% sodium chloride was administered and the lumen was connected to the infusate or locked as needed. If blood could not be drawn, the LDUL technique was used. Next, 0.2 ml from this solution (equivalent to 2000 IU) was instilled into the occluded lumen. The syringe was left connected to create a closed system, and the patient was asked to remain as still as possible while the catheter area was protected with a sterile drape. After 10 to 15 minutes, an attempt to draw blood was performed. If catheter patency was restored, the lumen was flushed with saline and connected to the infusate or locked. If not, the procedure was repeated. If the RESULTS Data from 100 patients were obtained (43 in the first group and 57 in the second). As shown in Table 1, the baseline characteristics of patients in each group were similar, and no significant differences were found related to age, sex, and underlying disease, except for a higher percentage of acute myeloblastic leukemia patients in the second group. In the first group, the type of catheter used was either PICC or CVC; only CVCs were used in the second group. The highest percentage of catheter used in each group was double lumen CVC. Those catheters remained in place for a similar mean duration. There was a total of 11 clotted catheters in the first group; 6 occurred in the second group (Tables 2 and 3). No catheters were lost because of occlusion. Mechanical occlusion was observed only twice in a patient with a TABLE 1 Baseline Characteristics of Patients and Catheters Characteristic Group 1 Group 2 Sex, n(%) of patients Male 26 (60.50) 39 (68.4) Female 17 (39.5) 18 (31.6) Age, y Mean Median Underlying disease, n (%) of patients Acute myeloblastic leukemia 15 (34.9) 37 (64.9) Chronic myelogenous leukemia 6 (14.0) 6 (10.5) Acute lymphoblastic leukemia 7 (16.2) 8 (14.0) Non-Hodgkin lymphoma 5 (11.6) 4 (7.0) Hodgkin s disease 4 (9.3) 2 (3.5) Multiple myeloma 6 (14.0) Type of catheter, n(%) of patients PICC 18 (41.9) CVC double lumen 25 (58.1) 35 (61.4) CVC triple lumen 22 (38.6) Duration of catheterization, days PICC mean 12.5 CVC (double/triple lumen) mean PICC, peripherally inserted central catheter; CVC, central venous catheter. Vol. 26, No. 4, July/August

4 TABLE 2 Outcomes for Patients With Central Venous Catheters Outcome CVC Patients Group 1 CVC Patients Group 2 Clotted CVC, n (%) of patients 4 (16.0) 6 (9.5) Occluded CVC episodes 11 6 Episodes/patient (mean) CVC occlusion episodes requiring LDUL 4 (36.3) 2 (33.3) Time for deocclusion (min) Mean Number of LDUL instillations/episodes Catheter salvage 4 (100%) 6 (100%) CVC, central venous catheters; LDUL, low-dose urokinase lock. CVC and once in three different PICC patients, all of whom were in group 1. These mechanical occlusions were easily resolved by repositioning the lumens, tubes, or the dressing. No physical obstructions were reported in either group. When the mean of episodes were compared (Table 2), biological obstruction had a higher incidence in the first CVC patient group (2.7 versus 1). None of these catheters had previous mechanical obstruction, and no physical or withdrawal occlusions were reported. At the time of the biological occlusion episodes, one of the CVCs in Group 1 showed redness at the insertion site, but no other sign of complication occurred. A swab was obtained for a culture, which showed negative results for infection. The percentage of biological occlusions requiring LDUL technique was 36.3% in the first group and 33.3% in the second. Mean time for deocclusion was no more than 15 minutes. All CVCs requiring LDUL technique could be deoccluded with one 2000 IU urokinase dose. Biological obstruction was detected in 6 (33.3%) PICC patients, who developed 14 occlusion episodes TABLE 3 Outcomes for Patients With PICCs Outcomes Patients With PICCs Clotted PICC, n(%) of patients 6 (33.3) Occluded PICC episodes 14 Mean 4.2 PICC occlusion episodes requiring 5 (35.7) LDU (%) Time for deocclusion, min Mean 35 Number of LDUL instillations 1.0 Instillations/episode, mean 1.8 Catheter salvage 6 (100%) PICC, peripherally inserted central catheter; LDU, low-dose urokinase; LDUL, low-dose urokinase lock. (13 pure biological and one withdrawal occlusion) with a median incidence of four biological occlusions per PICC. One of these patients had a previous mechanical obstruction episode. In all PICC biological obstruction episodes, 9 (64.3%) were resolved using a flush of 0.9% sodium chloride. To restore patency in the remaining five (35.7%), LDUL technique was used. Only one PICC could be deoccluded using 2000 IU of urokinase. The other 4 needed an extra 2000 IU dose and an extra 15 minutes of lock time before patency was restored (Table 3). At the time of the PICC biological obstruction episodes, none presented signs of other catheter-related complications. DISCUSSION Although occlusion accounts for less than 25% of all VAD dysfunctions, 9 it is among the most frequent complications of VADs in the hospital setting. It can seriously alter catheter life span, impeding a patient s treatment and positive outcomes. Results in both of our study groups for multilumen CVCs are consistent with this incidence data. We have not been able to find specific data on the incidence of PICC occlusion for in-hospital patients, which is slightly higher compared with multilumen CVCs. In one study 24 on home infusion care, the authors describe a mean incidence of 30% for occluded PICCs. Although differences exist between these healthcare settings, our PICC occlusion results are consistent with them. All occluded catheters were salvaged, but not all biological occlusions detected required LDUL technique. No adverse event related to LDUL technique was identified. From our results, the use of urokinase to clear catheters would be indicated in about 35% of all biological occlusion episodes. The available data suggest 248 Journal of Infusion Nursing

5 that LDUL technique can be effective in treating all CVC biological occlusion episodes, with a mean time for deocclusion of 15 minutes. But LDUL technique has not been effective in treating biological occlusion episodes in PICCs, probably because of differences in size (PICCs used are 71 cm long) and features between PICCs and CVCs studied. But with the data obtained in our study, we cannot determine whether urokinase dose, time needed for deocclusion, or frequency is the most important factor to consider. Timoney et al 25 found a trend in decreased efficacy in clearing PICCs with alteplase when compared with other VADs, but they concluded that these results were not statistically significant. We recommend further studies on the use of LDUL technique because While very low dose urokinase seems contrary to that used commonly in clinical practice, it has some pharmacological basis. In vitro, 40%- 80% clot lysis occurs with urokinase, at human plasma concentrations of just 100 units/ml. (...) In vitro, significant lysis of clot volumes from 1.5 to 8.4 ml would be expected at urokinase doses of less than 1000 units. 26(p126) This recommendation should be carefully considered for cost-effectiveness and dose security, especially in pediatric and neonatal patients, and because of the lowered chances of related adverse events. It should also be noted that more than one type of 27, 28 urokinase has been identified. That which is obtained from male human urine contains high molecular weight urokinase (HMW, Uk II; 54,000 daltons) and the one obtained from post-mortem neonates kidney cell cultures contains mainly lower molecular weight urokinase (LMW, Uk I; 33,000 daltons). It is believed, though not clearly defined, that to lyse the same fibrin sheath, a double dose of LMW urokinase is needed, compared with HMW urokinase. 27 But urokinase products, at least in the European market, are heterogeneous, presenting variable proportions of HMW and LMW. 28 Commercially available urokinase in the United States is also composed of both HMW and LMW forms. 29 Contradictory data on the availability of urokinase in the United States have been found in the latest health science literature. 12,25,30 Concern about the use of urokinase comes from the warning in 1999 by the US Food and Drug Administration (FDA) about the potential risk of viral infection as a result of using Abbokinase (Abbot Co., Chicago, Ill). Although no cases of infectious disease could be attributed to the use of this product, the FDA recommended that Abbokinase be reserved for only special situations, after other alternatives have been considered in situations where use of the drug may be critical to the care of a patient. 31 Alteplase seems to be the main drug used in the United States to treat catheter occlusion, but according to the latest news, urokinase is back on the US market. Abbot Laboratories received approval from the FDA in October 2002 to reintroduce the product in the healthcare community. 32 Urokinase used in our study was male urine-derived, HMW form (Urokinase Roger, Laboratorios Roger; Barcelona, Spain; currently Urokinase Vedim, UCB Pharma-Vedim Pharma, Barcelona, Spain). In our case, the urokinase was not kidney cell harvested. To our knowledge, manufacturers storage and handling processes differ from those identified by the FDA inspectors in the 1999 Abbokinase case, warranting the standards of best practice of Drug Manufacturing Practice in our country. 33,34 Cost Considerations In an era of increasing healthcare costs, LDUL technique could contribute to reduced drug-related expenses. In Spain, only 100,000 and 250,000 IU urokinase vials are produced; no 5,000 IU vial is approved. In addition, the manufacturer of urokinase recommends that the agent be used within 48 hours of reconstitution. 33,34 Given the commercially available vial sizes in our country, adherence to this recommendation results in a significant waste of the drug and an increase of the cost of treating this VAD complication. Although it is still more cost-effective than replacing the catheter (Table 4) 35, it would be desirable for manufacturers to produce prefilled LDUL syringes for catheter clearance. Several investigators have demonstrated the stability of reconstituted thrombolytics after cryopreservation. 25,36-38 Rhoney DH et al conclude that urokinase 5000 IU/mL did not show any appreciable changes in activity when reconstituted with sterile water for injection or 0.9% sodium chloride and frozen at 20 C or 70 C for up to six months. 36(p2050) Gale et al also supports this method of preservation: by taking small aliquots of the solution and freezing them, the vial can be used for multiple doses at a cost of less than $5.00 per dose. 37(p299) Making aliquots of LDU in the hospital pharmacy would be an optimal solution for urokinase cost containment. Clearly, the small the sample size in this study limits its power so larger studies are necessary. Obtaining a larger number of cases would entail acquisition of data over longer periods of time or from multiple centers. Another important limitation of our study is that we cannot show results from catheter-related bacteriemia or catheter contamination secondary to deocclusion because, although contamination and infection were controlled in both groups, they were not studied in relation to occlusion. Although new trends on catheter clearance with other thrombolytics (alteplase, reteplase) are being published in the healthcare literature because of 25, the Vol. 26, No. 4, July/August

6 TABLE 4 Estimated Cost Comparison: Catheter Replacement Versus Urokinase Clearing VAD Replacement Estimated Cost Urokinase Use Estimated Cost PICC (Drum Abbot Co.) $12.00 CVC (Arrow Int. Inc.) $ Drugs/supplies* $25.00 Urokinase vial $45.00 Nurse time $30.00 $60.00 Physician time (CVC) $ X-ray $30.00 VAD, vascular access device; PICC, peripherally inserted central catheter; CVC, central venous catheter. US dollars have been ranked equally with Euros. These costs are calculated in the context of the Spanish Public Healthcare System, so they should not be misunderstood as universal. *Costs source: Hospital Pharmacy and Materials and supplies office. Bellvitge University Hospital Financial Department. Nurse s salary per hour: $15.00 (Bellvitge University Hospital Financial Department). skepticism about the reintroduction of Abbokinase into the US market, for years this has been an important area of study Clinical success rates of both drugs are similar, 48, 49 although some authors consider alteplase able to restore catheter function more reliably than urokinase. 45 Conclusion Advantages offered by LDUL technique include less time (median dwell time equals 15 minutes versus 45 minutes with alteplase), a lower dose, and a lower incidence of complications, but additional clinical trials are surely needed. Direct nursing time for LDUL technique is 15 to 20 minutes. Replacing a catheter involves nursing time for catheter withdrawal and physician and nursing time for placing a new one (Table 4). When considering these factors in addition to costs, supplies, medication, and X-rays, the option to deocclude VADs with urokinase continues to be more cost-effective. Failure to recognize early signs and symptoms of catheter complications, or to initiate nursing interventions, could compromise outcomes, expose the patient to a life-threatening situation, and put the nurse at risk for a malpractice lawsuit. Pending large-scale studies with newer IV devices, the use of LDUL technique (2000 IU HMW urine-derived urokinase) for CVCs while using the 5000 IU HMW urokinase dose for PICC occlusion seems to be a reasonable goal for infusion nurses. R E F E R E N C E S 1. O Grady NP, Alexander M, Patchen Dellinger E, et al. Draft guidelines for the prevention of intravascular catheter-related infections. CDC HICPAC August Available at: gov. Accessed November 20, Raad II, Bodey GP. Infectious complications of indwelling vascular catheters. Clin Infect Dis. 1992;15: Maki DG, Ringer M, Alvarado CJ. Prospective, randomised trial of povidone-iodine, alcohol and chlorehexidine for prevention of infection associated with central venous and arterial catheters. Lancet. 1991;338: Ray CE, Jr. Infection control principles and practices in the care and management of central venous devices. J Intraven Nurs. June 1999;22(supp): S18-S Wickham R, Purl S, Welker D. Long-term central venous catheters: issues for care. Semin Oncol Nurs. 1992;8(2): Evans Orr M. Issues in the management of percutaneous central venous catheters. Single and multiple lumens. Nurs Clin North Am. 1993;28(4): Nace CS, Ingle RJ. Central venous catheter pinch-off and fracture: a review of two under-recognized complications. Oncol Nurs Forum. 1993;20(8): Andris DA, Krzywda EA. Catheter pinch-off syndrome: recognition and management. J Intraven Nurs. 1997;20: Seery Cunningham R, Bonam-Crawford D. The role of fibrinolytic agents in the management of thrombotic complications associated with vascular access devices. Nurs Clin North Am. 1993;28(4): Kellerman S, Chan J, Jarvis W. Use of urokinase in pediatric hematology/oncology patients. Am J Infect Control. 1998;26(5): Krzywda EA. Predisposing factors, prevention and management of central venous catheter occlusions. J Intraven Nurs. June 1999;22(supp):S11-S Hadaway LC. Major thrombotic and nonthrombotic complications. Loss of patency. J Intraven Nurs. 1998;21(supp):S143-S Andris DA, Krzywda EA. Central venous catheters occlusion: successful management strategies. Medsurg Nurs. 1999;8(4): Stokes DC, Rao BN, Mirro J, et al. Early detection and simplified management of obstructed Hickman and Broviac catheters. J Pediatr Surg. 1989;24: Hurtubise MR, Bottino JC, Lawson M, et al. Restoring patency of occluded central venous catheters. Arch Surg. 1980;115: Lawson M, Bottino JC, Hurtubise MR, et al. The use of urokinase to restore the patency of occluded central venous catheters. Am J Intraven Ther & Clin Nutr. 1982;Oct: Journal of Infusion Nursing

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Alteplase versus urokinase in restoring blood flow in hemodialysis-catheter thrombosis. Am J Health Syst Phar. 2002;59: Vol. 26, No. 4, July/August