Acessibilidade / Reportar erro

Approach to thrombotic occlusion related to long-term catheters of hemodialysis patients: a narrative review

Abstract

Currently, permanent catheters (pCVC) are becoming an alternative vascular access for long-stay patients in whom arteriovenous access cannot be made. Occlusion is a commun mechanical complication related to pCVC, leading to inadequate dialysis dose and frequent changes of local catheter location, which can cause exclusion of vascular sites. The aim of this study was to perform a narrative review of treatment of pCVC thrombotic occlusion in HD patients. The treatment of CVCP thrombosis typically consists on the saline infusion or administration of thrombolytics such as tissue plasminogen activated, reteplase and urokinase. There are few studies on the use of alteplase in pCVC clogged in oncology area and in dialysis population, and they all report success with the use of thrombolytic therapy ranging from 80-95% of cases, using 1mg/ml. Due to the high cost of alteplase, studies have suggested that cryopreservation and fractionated alteplase dose have made its use financially viable.

Keywords:
catheter obstruction; central venous catheters; hemodialysis units, hospital; kidney failure, chronic

Resumo

Atualmente, cateteres venosos permanentes (CVCp) estão se tornando cada vez mais uma alternativa de acesso vascular de longa permanência para pacientes nos quais o acesso arteriovenoso não pode ser confeccionado, sendo a oclusão trombótica complicação mecânica comum. Essa complicação pode ocasionar mudanças frequentes dos locais de cateter, eliminando os sítios vasculares. Este estudo teve como objetivo realizar uma revisão narrativa do manejo da oclusão trombótica de CVCp na população em HD. O tratamento da trombose de CVC consiste em infusão de solução salina ou na administração de trombolíticos como plasminogênio tecidual ativado, reteplase ou uroquinase. Há poucos estudos sobre o uso de alteplase em CVCp obstruídos na população em diálise, e todos eles relatam sucesso entre 80 a 95% dos casos com uso de trombolítico na dose de 1 mg/ml. Por tratar-se de medicamento de custo elevado, estudos sugerem que a criopreservação e o fracionamento da alteplase tornam o uso financeiramente viável.

Palavras-chave:
cateteres venosos centrais; falência renal crônica; obstrução do cateter; unidades hospitalares de hemodiálise

An overview of chronic kidney disease

Chronic kidney disease (CKD) is a frequent condition characterized by progressive irreversible loss of renal function.11 Romão Jr JE. A Doença Renal Crônica: do Diagnóstico ao Tratamento. Prat Hosp 2007;52:183-7.,22 Romão Jr JE. Doença renal crônica: definição, epidemiologia e classificação. J Bras Nefrol 2004;26:1-3. CKD is a serious global public health issue. The disease is expected to cause significant increases in the number of kidney transplants and patients on dialysis. According to Lugon et al.,33 Lugon JR. Doença renal crônica no Brasil: um problema de saúde público. J Bras Nefrol 2009;31:2-5. the world is facing an epidemic of CKD, with patient numbers growing at a faster pace in developing nations.

The number of individuals with CKD in the United States has been estimated to grow from 470,000 in 2004 to over 2.2 million in 2030.44 Stevens LA, Stoycheff N, Levey AS. Staging and management of chronic kidney disease. In: Greenberg A, ed. Primer on Kidney Diseases (5th ed). Philadelphia: Saunders Elsevier; 2009. p.436-45. In Brazil, the 2004 Census of the Brazilian Society of Nephrology revealed that 59,153 individuals were on dialysis; in 2012, the number grew to 97,586, or 475 patients per million population.55 Sesso RCC, Lopes AA, Thomé FS, Lugon JR, Watanabe Y, Santos DR. Diálise crônica no Brasil - Relatório do Censo Brasileiro de Diálise, 2011. J Bras Nefrol 2012;34:272-7. DOI:http://dx.doi.org/10.5935/0101-2800.20120009
http://dx.doi.org/10.5935/0101-2800.2012...

Hypertension and diabetes mellitus are the most important factors associated with progression of CKD.11 Romão Jr JE. A Doença Renal Crônica: do Diagnóstico ao Tratamento. Prat Hosp 2007;52:183-7.,66 National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002;39:S1-266.

The Kidney Disease Outcomes Quality Initiative (KQOQI) Clinical Practice Guidelines published by the National Kidney Foundation categorizes CKD patients into five functional stages based on their glomerular filtration rates (GFR), as shown in Table 1.11 Romão Jr JE. A Doença Renal Crônica: do Diagnóstico ao Tratamento. Prat Hosp 2007;52:183-7.,77 Bastos MG, Kirsztajn GM. Chronic kidney disease: importance of early diagnosis, immediate referral and structured interdisciplinary approach to improve outcomes in patients not yet on dialysis. J Bras Nefrol 2011;33:93-108. PMID: 21541469

Table 1
Chronic kidney disease staging proposed by the KDOQI and updated by the National Collaborating Centre For Chronic Conditions 2013

Hemodialysis is the most widely used mode of therapy for patients with stage-5 CKD. The 2012 Census of the Brazilian Society of Nephrology reported that 97,586 patients were on dialysis in Brazil; 89.4% were treated with HD, 5.3% with continuous ambulatory peritoneal dialysis (CAPD), 4.9% with automated peritoneal dialysis (APD), and 0.4% with intermittent peritoneal dialysis (IPD).88 Censo Brasileiro de diálise 2012 [Acesso 3 Nov 2013]. Disponível em: http://www.sbn.org/pdf/socios2012.pdf
http://www.sbn.org/pdf/socios2012.pdf...

Central venous catheters used as hd access devices

The KDOQI99 Besarab A, Raja RM. Acesso vascular para hemodiálise. In: Daugirdas JT, Ing TS. Manual de diálise. 3a ed. Rio de Janeiro: Medsi; 2003. p.68-102.,1010 National Kidney Foudation. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for 2006 Updates: Hemodialysis Adeuqacy, Peritoneal Dialysis Adequacy, Vascular Access. Am J. Kidney Dis. 2006;48:S1-S322. defines optimal HD access as the one that offers adequate blood flow for the prescribed dialysis regimen, a long life, and low rates of mechanical and infectious complications. Autogenous arteriovenous fistulae (AVF) are the option that more closely meets the criteria above, as they provide the best five-year patency rates, lower rates of mechanical and infectious complications, and require fewer interventions than other HD access devices.

Arteriovenous (AV) grafts - a flexible curved or straight plastic tube indirectly connecting an artery and a vein in one of the patient's limbs - may also be used. However, an AV graft is approximately four times more expensive than an AVF, offers a shorter life than an AVF, and presents increased risk of infection, thrombosis, and stenosis.1111 Lugon JR, Strogoff JP, Warrak MEA. Hemodiálise. In: Riella MC. Princípios de nefrologia e distúrbios hidroeletrolíticos. 4a ed. Rio de Janeiro: Guanabara Koogan; 2003.

A double lumen catheter may be inserted into a central vein and used as a hemodialysis access device. When used for more than three weeks, non-tunneled, non-cuffed catheters, also known as short-term catheters, may yield high rates of infection. These catheters are best used in emergency dialysis patients or while the vascular access matures.1212 Kim SH, Song KI, Chang JW, Kim SB, Sung SA, Jo SK, et al. Prevention of uncuffed hemodialysis catheter-related bacteremia using an antibiotic lock technique: a prospective, randomized clinical trial. Kidney Int 2006;69:161-4. PMID: 16374438 DOI:http://dx.doi.org/10.1038/sj.ki.5000012
http://dx.doi.org/10.1038/sj.ki.5000012...
Catheters equipped with felt or Dacron cuffs reduce the incidence of infectious and mechanical complications and should be used whenever patients require long-term catheters.1111 Lugon JR, Strogoff JP, Warrak MEA. Hemodiálise. In: Riella MC. Princípios de nefrologia e distúrbios hidroeletrolíticos. 4a ed. Rio de Janeiro: Guanabara Koogan; 2003.

Long-term tunneled catheters allow for increased blood flow and provide for better dialysis dosage management. Once they are made of silicone or Carbothane, these catheters produce less bacterial adherence, lower rates of infection and central vessel stenosis when compared to short-term catheters.1212 Kim SH, Song KI, Chang JW, Kim SB, Sung SA, Jo SK, et al. Prevention of uncuffed hemodialysis catheter-related bacteremia using an antibiotic lock technique: a prospective, randomized clinical trial. Kidney Int 2006;69:161-4. PMID: 16374438 DOI:http://dx.doi.org/10.1038/sj.ki.5000012
http://dx.doi.org/10.1038/sj.ki.5000012...
,1313 III. NKF-K/DOQI Clinical Practice Guidelines for Vascular Access: update 2000. Am J Kidney Dis 2001;37:S137-81.

Although AV fistulae are clear favorites for patients on HD, AV grafts are disproportionately used in the United States and, in global terms, central venous catheters (CVC) are excessively relied on.1212 Kim SH, Song KI, Chang JW, Kim SB, Sung SA, Jo SK, et al. Prevention of uncuffed hemodialysis catheter-related bacteremia using an antibiotic lock technique: a prospective, randomized clinical trial. Kidney Int 2006;69:161-4. PMID: 16374438 DOI:http://dx.doi.org/10.1038/sj.ki.5000012
http://dx.doi.org/10.1038/sj.ki.5000012...
The KDOQI discourages the use of CVC in HD patients, suggesting that only 10% of the cases require this mode of access.55 Sesso RCC, Lopes AA, Thomé FS, Lugon JR, Watanabe Y, Santos DR. Diálise crônica no Brasil - Relatório do Censo Brasileiro de Diálise, 2011. J Bras Nefrol 2012;34:272-7. DOI:http://dx.doi.org/10.5935/0101-2800.20120009
http://dx.doi.org/10.5935/0101-2800.2012...
However, in the 1980s central venous catheters began to be used as permanent venous access devices for patients on HD. Consequently, the number of prevalent patients on HD equipped with CVC increased. In the United States, initiatives to reduce the use of AV grafts resulted in increased use of CVC. Today, more than 80% of incident patients on dialysis use CVC. According to the National Kidney Foundation, the share of prevalent patients on dialysis implanted with catheters grew from 19% to 27%.55 Sesso RCC, Lopes AA, Thomé FS, Lugon JR, Watanabe Y, Santos DR. Diálise crônica no Brasil - Relatório do Censo Brasileiro de Diálise, 2011. J Bras Nefrol 2012;34:272-7. DOI:http://dx.doi.org/10.5935/0101-2800.20120009
http://dx.doi.org/10.5935/0101-2800.2012...

In Brazil, 9.4% of the patients on HD in 2007 used CVC for access devices versus 11.4% in 2008.88 Censo Brasileiro de diálise 2012 [Acesso 3 Nov 2013]. Disponível em: http://www.sbn.org/pdf/socios2012.pdf
http://www.sbn.org/pdf/socios2012.pdf...
The 2011 Census of the Brazilian Society of Nephrology reported a prevalence of 14.2% in the use of CVC.55 Sesso RCC, Lopes AA, Thomé FS, Lugon JR, Watanabe Y, Santos DR. Diálise crônica no Brasil - Relatório do Censo Brasileiro de Diálise, 2011. J Bras Nefrol 2012;34:272-7. DOI:http://dx.doi.org/10.5935/0101-2800.20120009
http://dx.doi.org/10.5935/0101-2800.2012...
Rates of CVC use in Brazil are low and close to the levels recommended by the KDOQI. Nevertheless, a relatively small number of RRT centers (55% of 13 centers) responded the Census survey, and these rates may have been underestimated.55 Sesso RCC, Lopes AA, Thomé FS, Lugon JR, Watanabe Y, Santos DR. Diálise crônica no Brasil - Relatório do Censo Brasileiro de Diálise, 2011. J Bras Nefrol 2012;34:272-7. DOI:http://dx.doi.org/10.5935/0101-2800.20120009
http://dx.doi.org/10.5935/0101-2800.2012...
Additionally, non-tunneled catheters are predominantly used in Brazil for their lower cost and ease of insertion by a nephrologist. According to the KDOQI, short-term non-tunneled catheters should be used for no longer than seven days and reserved for emergency situations, hospitalized patients, and individuals with acute kidney injury. In chronic cases, these devices must be changed for long-term tunneled catheters, because even though they have higher rates of infection and dysfunction than native fistulae, these rates are still lower when compared to the rates associated with the use of temporary CVC.1313 III. NKF-K/DOQI Clinical Practice Guidelines for Vascular Access: update 2000. Am J Kidney Dis 2001;37:S137-81.,1414 O'Grady NP, Alexander M, Dellinger EP, Gerberding JL, Heard SO, Maki DG, et al. Guidelines for the prevention of intravascular catheter-related infections. Centers for Disease Control and Prevention. MMWR Recomm Rep 2002;51:1-29.

Complications related to central venous catheters used as hd access devices

Permanent venous catheters (PVCs) are being developed as an alternative to long-term vascular access devices for patients in whom an arteriovenous access can not be made, such as obese individuals, children, and patients with multiple prior vascular access devices without a viable site for the implantation of a new device.99 Besarab A, Raja RM. Acesso vascular para hemodiálise. In: Daugirdas JT, Ing TS. Manual de diálise. 3a ed. Rio de Janeiro: Medsi; 2003. p.68-102.,1515 Lok CE, Mokrzycki MH. Prevention and management of catheter-related infection in hemodialysis patients. Kidney Int 2011;79:587-98. PMID: 21178979 DOI:http://dx.doi.org/10.1038/ki.2010.471
http://dx.doi.org/10.1038/ki.2010.471...
,1616 Timoney JP, Malkin MG, Leone DM, Groeger JS, Heaney ML, Keefe DL, et al. Safe and cost effective use of alteplase for the clearance of occluded central venous access devices. J Clin Oncol 2002;20:1918-22. DOI: http://dx.doi.org/10.1200/JCO.2002.07.131
http://dx.doi.org/10.1200/JCO.2002.07.13...

However, mechanical and infectious complications have been reported in individuals offered permanent venous catheters, with significant impact on patient morbidity and mortality and sizable increases in the expenses incurred in the treatment of these complications, including hospitalization, medication - namely thrombolytic agents and antibiotics - and the implantation of additional catheters.1717 Chan MR, Yevzlin AS. Tunneled dialysis catheters: recent trends and future directions. Adv Chronic Kidney Dis 2009;16:386-95. DOI: http://dx.doi.org/10.1053/j.ackd.2009.06.006
http://dx.doi.org/10.1053/j.ackd.2009.06...

According to the United States Renal Data System (USRD), infection is second only to cardiovascular disease in the list of leading causes of death of patients on dialysis, despite the progress seen in preventive care and the development of novel antimicrobial drugs. The reported death rate of patients with stage-5 CKD in the United States is 176/1000 patient-years, with bloodstream infections accounting for close to 26/1000 patient-years.1818 Cheung AK, Sarnak MJ, Yan G, Berkoben M, Heyka R, Kaufman A, et al. Cardiac diseases in maintenance hemodialysis patients: results of the HEMO Study. Kidney Int 2004;65:2380-9. DOI:http://dx.doi.org/10.1111/j.1523-1755.2004.00657.x
http://dx.doi.org/10.1111/j.1523-1755.20...

19 Katneni R, Hedayati SS. Central venous catheter-related bacteremia in chronic hemodialysis patients: epidemiology and evidence-based management. Nat Clin Pract Nephrol 2007;3:256-66. DOI: http://dx.doi.org/10.1038/ncpneph0447
http://dx.doi.org/10.1038/ncpneph0447...
-2020 Jaber BL. Bacterial infections in hemodialysis patients: pathogenesis and prevention. Kidney Int 2005;67:2508-19. PMID: 15882306 DOI: http://dx.doi.org/10.1111/j.1523-1755.2005.00364.x
http://dx.doi.org/10.1111/j.1523-1755.20...
Seventy-five percent of the infection-related deaths are caused by sepsis.1919 Katneni R, Hedayati SS. Central venous catheter-related bacteremia in chronic hemodialysis patients: epidemiology and evidence-based management. Nat Clin Pract Nephrol 2007;3:256-66. DOI: http://dx.doi.org/10.1038/ncpneph0447
http://dx.doi.org/10.1038/ncpneph0447...
The incidence of catheter-related bacteremia ranges from 4.1 cases per 1,000 patient-days to as many as 19.8 cases per 1000 patient-days.2121 Biernat JC, dos Santos F, dos Santos AMG, Raubach AA, Souza M, Demin MSS, et al. Contaminação de Lúmen de Cateter de Hemodiálise: prevenção e tratamento com M-EDTA. J Bras Nefrol 2008;30:105-12. A trial carried out in two centers recently published by our group showed that the prevalence of bloodstream infections (BI) in patients managed with prophylactic antibiotic lock therapy (ALT) was statistically lower than the prevalence observed in patients given heparin to seal the PVC (0.57 x 1.74 events per 1000 catheter-days, p = 0.005); the individuals given prophylactic ALT had longer BI-free survival (log-rank = 17.62, p < 0.0001) and had the catheter implanted for more days (171 days (79-256) vs. 203 days (111.5 to 326), p = 0.015).2222 Silva TN, de Marchi D, Mendes ML, Barretti P, Ponce D. Approach to prophylactic measures for central venous catheter-related infections in hemodialysis: a critical review. Hemodial Int 2014;18:15-23. DOI: http://dx.doi.org/10.1111/hdi.12071
http://dx.doi.org/10.1111/hdi.12071...

The most common mechanical complications related to permanent venous catheters are occlusions and blood flow reductions, which may negatively impact the dosing of dialysis and lead to frequent catheter changes, thus exhausting possible sites for catheterization.1616 Timoney JP, Malkin MG, Leone DM, Groeger JS, Heaney ML, Keefe DL, et al. Safe and cost effective use of alteplase for the clearance of occluded central venous access devices. J Clin Oncol 2002;20:1918-22. DOI: http://dx.doi.org/10.1200/JCO.2002.07.131
http://dx.doi.org/10.1200/JCO.2002.07.13...

The KDOQI defines access dysfunction as the inability to achieve blood flow rates (Qb) of 300 ml/min or less within the first 60 minutes of HD.1313 III. NKF-K/DOQI Clinical Practice Guidelines for Vascular Access: update 2000. Am J Kidney Dis 2001;37:S137-81.

Occlusion may be partial or complete, and has been defined as the difficulty infusing fluids into or removing fluids from the catheter. Occlusion may occur as a consequence of a number of factors, such as obstruction secondary to the formation of a fibrin sheath or thrombi, mechanical occlusion due to poorly positioned or twisted catheters, and occlusion by drugs.1616 Timoney JP, Malkin MG, Leone DM, Groeger JS, Heaney ML, Keefe DL, et al. Safe and cost effective use of alteplase for the clearance of occluded central venous access devices. J Clin Oncol 2002;20:1918-22. DOI: http://dx.doi.org/10.1200/JCO.2002.07.131
http://dx.doi.org/10.1200/JCO.2002.07.13...

Thrombosis is the most frequent cause of occlusion in HD patients. Deitcher et al.2222 Silva TN, de Marchi D, Mendes ML, Barretti P, Ponce D. Approach to prophylactic measures for central venous catheter-related infections in hemodialysis: a critical review. Hemodial Int 2014;18:15-23. DOI: http://dx.doi.org/10.1111/hdi.12071
http://dx.doi.org/10.1111/hdi.12071...
estimated that thrombosis accounts for 25% of the cases of CVC occlusion and recommended the use of anteroposterior chest X-ray images to eliminate occurrences of CVC poor positioning.2323 Schon D, Whittman D. Managing the complications of long-term tunneled dialysis catheters. Semin Dial 2003;16:314-22. DOI: http://dx.doi.org/10.1046/j.1525-139X.2003.16060.x
http://dx.doi.org/10.1046/j.1525-139X.20...

Fibrin adhesion compromises the long-term patency of catheters. The sheath, initially composed of fibrinogen, albumin, lipoprotein, and coagulation factors, begins to form 24 hours after the implantation of the CVC.2424 Beathard GA. Catheter thrombosis. Semin Dial 2001;14:441-5. DOI:http://dx.doi.org/10.1046/j.1525-139x.2001.00109.x
http://dx.doi.org/10.1046/j.1525-139x.20...
The fibrin sheath attracts platelets and coagulation factors and promotes the adhesion of white blood cells.2525 Deitcher SR, Fesen MR, Kiproff PM, Hill PA, Li X, McCluskey ER.; Cardiovascular Thrombolytic to Open Occluded Lines-2 Investigators. Safety and efficacy of alteplase for restoring function in occluded central venous catheters: results of the cardiovascular thrombolytic to open occluded lines trial. J Clin Oncol 2002;20:317-24. DOI: http://dx.doi.org/10.1200/JCO.20.1.317
http://dx.doi.org/10.1200/JCO.20.1.317...
Figure 1 illustrates the thrombotic occlusion formation process. Over the course of weeks and months, collagen adheres to the smooth muscle cells of the venous wall and migrates toward the tip of the catheter. The rate of occurrence of these processes varies among patients, depending on their inherited and acquired traits. When coagulation overwhelms the endogenous fibrinolytic system, thrombi may accumulate in the catheter. Catheter-associated thrombosis may be categorized as extrinsic, when the thrombi are located externally to the catheter, or intrinsic, when the thrombi are in the lumen of the catheter or along its surface.2222 Silva TN, de Marchi D, Mendes ML, Barretti P, Ponce D. Approach to prophylactic measures for central venous catheter-related infections in hemodialysis: a critical review. Hemodial Int 2014;18:15-23. DOI: http://dx.doi.org/10.1111/hdi.12071
http://dx.doi.org/10.1111/hdi.12071...
,2626 Liangos O, Gul A, Madias NE, Jaber BL. Long-term management of the tunneled venous catheter. Semin Dial 2006;19:158-64. DOI: http://dx.doi.org/10.1111/j.1525-139X.2006.00143.x
http://dx.doi.org/10.1111/j.1525-139X.20...

Figure 1
Thrombotic occlusion types - Lancet, 2009.

Few studies have described the risk factors associated with thrombotic occlusion of the catheter, and none have looked into this issue in populations on dialysis. Volume depletion, hypotension, hypercoagulability, vascular wall trauma, poor catheter tip positioning, drug infusion, and parenteral nutrition rank among risk factors.2525 Deitcher SR, Fesen MR, Kiproff PM, Hill PA, Li X, McCluskey ER.; Cardiovascular Thrombolytic to Open Occluded Lines-2 Investigators. Safety and efficacy of alteplase for restoring function in occluded central venous catheters: results of the cardiovascular thrombolytic to open occluded lines trial. J Clin Oncol 2002;20:317-24. DOI: http://dx.doi.org/10.1200/JCO.20.1.317
http://dx.doi.org/10.1200/JCO.20.1.317...
Possible consequences of thrombotic occlusion are CVC-related infection, pulmonary embolism, and post-thrombotic syndrome.2727 Besarab A, Pandey R. Catheter management in hemodialysis patients: delivering adequate flow. Clin J Am Soc Nephrol 2011;6:227-34. DOI: http://dx.doi.org/10.2215/CJN.04840610
http://dx.doi.org/10.2215/CJN.04840610...

Treating thrombotic occlusions of long-term catheters used in hemodialysis patients

The treatment of CVC thrombosis usually involves the infusion of 0.9% sodium chloride or thrombolytic agents such as tissue plasminogen activator, reteplase or urokinase.1616 Timoney JP, Malkin MG, Leone DM, Groeger JS, Heaney ML, Keefe DL, et al. Safe and cost effective use of alteplase for the clearance of occluded central venous access devices. J Clin Oncol 2002;20:1918-22. DOI: http://dx.doi.org/10.1200/JCO.2002.07.131
http://dx.doi.org/10.1200/JCO.2002.07.13...

Infusion of saline solution may be the most cost-effective treatment for CVC obstruction, but it is not a safe option for the patient, as thrombi may become loose with manipulation of the occluded CVC. According to the KDOQI, urokinase is the drug of choice for the treatment of malfunctioning CVC, as it resolves 70-90% of the cases of obstruction.1313 III. NKF-K/DOQI Clinical Practice Guidelines for Vascular Access: update 2000. Am J Kidney Dis 2001;37:S137-81. If a first infusion fails to remove the obstruction, patients should be further studied with the aid of X-ray imaging.

Timoney et al.1616 Timoney JP, Malkin MG, Leone DM, Groeger JS, Heaney ML, Keefe DL, et al. Safe and cost effective use of alteplase for the clearance of occluded central venous access devices. J Clin Oncol 2002;20:1918-22. DOI: http://dx.doi.org/10.1200/JCO.2002.07.131
http://dx.doi.org/10.1200/JCO.2002.07.13...
described alteplase, a recombinant protein with a low incidence of allergic reactions (0.02%), as a safe alternative to urokinase. The authors showed that vials with 50 mg of alteplase may be aseptically reconstituted into 50 ml of sterile water and then divided into portions of 2.5 ml and stored in labeled vials at -20 ºC for up to 30 days. Administration is safe, with no reported cases of bacterial or fungal vial contamination after the storage period. This may be a safe, effective, and cost-effective alternative to urokinase for patients with occluded central venous lines.

Alteplase, reteplase, and urokinase catalyze the conversion of the plasminogen bound to the clot into plasmin, thus initiating fibrinolysis,2727 Besarab A, Pandey R. Catheter management in hemodialysis patients: delivering adequate flow. Clin J Am Soc Nephrol 2011;6:227-34. DOI: http://dx.doi.org/10.2215/CJN.04840610
http://dx.doi.org/10.2215/CJN.04840610...

28 Ponec D, Irwin D, Haire WD, Hill PA, Li X, McCluskey ER; COOL Investigators. Recombinant tissue plasminogen activator (alteplase) for restoration of flow in occluded central venous access devices: a double-blind placebo-controlled trial--the Cardiovascular Thrombolytic to Open Occluded Lines (COOL) efficacy trial. J Vasc Interv Radiol 2001;12:951-5. DOI:http://dx.doi.org/10.1016/S1051-0443(07)61575-9
http://dx.doi.org/10.1016/S1051-0443(07)...
-2929 Baskin JL, Pui CH, Reiss U, Wilimas JA, Metzger ML, Ribeiro RC, et al. Management of occlusion and thrombosis associated with long-term indwelling central venous catheters. Lancet 2009;374:159-69. DOI: http://dx.doi.org/10.1016/S0140-6736(09)60220-8
http://dx.doi.org/10.1016/S0140-6736(09)...
as shown in the diagram below (Figure 2).

Figure 2
The mechanism of action of the tissue plasminogen activator. The tissue plasminogen activator converts plasminogen into plasmin, which then cleaves fibrin into fibrin degradation products to dissolve the thrombus. Adapted from Baskin et al., Lancet, 2009.2929 Baskin JL, Pui CH, Reiss U, Wilimas JA, Metzger ML, Ribeiro RC, et al. Management of occlusion and thrombosis associated with long-term indwelling central venous catheters. Lancet 2009;374:159-69. DOI: http://dx.doi.org/10.1016/S0140-6736(09)60220-8
http://dx.doi.org/10.1016/S0140-6736(09)...

Clinical trials and systematic reviews on the treatment of thrombotic occlusions

The few studies carried out on the use of alteplase to treat obstructed long-term catheters in cancer and dialysis populations have reported success rates ranging between 80% and 95%, as shown in Table 2.

Table 2
Main characteristics of recent studies on the treatment of thrombotic occlusion

Timoney et al.1616 Timoney JP, Malkin MG, Leone DM, Groeger JS, Heaney ML, Keefe DL, et al. Safe and cost effective use of alteplase for the clearance of occluded central venous access devices. J Clin Oncol 2002;20:1918-22. DOI: http://dx.doi.org/10.1200/JCO.2002.07.131
http://dx.doi.org/10.1200/JCO.2002.07.13...
reported a success rate of 81% when alteplase at 1 mg/ml was infused for 45 minutes in the lumen of 168 catheters of patients on chemotherapy. No adverse events were described.

In another study, Deitcher et al.2222 Silva TN, de Marchi D, Mendes ML, Barretti P, Ponce D. Approach to prophylactic measures for central venous catheter-related infections in hemodialysis: a critical review. Hemodial Int 2014;18:15-23. DOI: http://dx.doi.org/10.1111/hdi.12071
http://dx.doi.org/10.1111/hdi.12071...
reported success rates ranging from 52% to 78% when 2 mg of alteplase were infused for 30 to 120 minutes in the lumen of nonfunctioning permanent venous catheters of patients on chemotherapy. The catheters still obstructed were infused a second time with 2 mg of alteplase for 30 to 120 minutes, and success rates increased to 83% to 87%. Thus, the procedure using up to two infusions of 2 mg of alteplase is safe and effective to restore flow in obstructed PVCs.2323 Schon D, Whittman D. Managing the complications of long-term tunneled dialysis catheters. Semin Dial 2003;16:314-22. DOI: http://dx.doi.org/10.1046/j.1525-139X.2003.16060.x
http://dx.doi.org/10.1046/j.1525-139X.20...

Haire et al.3030 Haire WD, Atkinson JB, Stephens LC, Kotulak GD. Urokinase versus recombinant tissue plasminogen activator in thrombosed central venous catheters: a double-blinded, randomized trial. Thromb Haemost 1994;72:543-7. PMID: 7878629 showed that 2 mg of alteplase cleared thrombotic occlusions more effectively (74%) than 5000 IU of urokinase (17%) infused for 120 minutes in the catheters of chemotherapy patients (p = 0.03). Ninety percent of the catheters requiring a second infusion of alteplase were successfully unclogged. The safety and efficacy of alteplase were also shown in pediatric patients on chemotherapy, with a reported success rate of 85% and no cases of bleeding.2929 Baskin JL, Pui CH, Reiss U, Wilimas JA, Metzger ML, Ribeiro RC, et al. Management of occlusion and thrombosis associated with long-term indwelling central venous catheters. Lancet 2009;374:159-69. DOI: http://dx.doi.org/10.1016/S0140-6736(09)60220-8
http://dx.doi.org/10.1016/S0140-6736(09)...
Multicenter trial COOL found that alteplase was as effective in children or adults, with 83% to 87% of the occlusions resolved.2828 Ponec D, Irwin D, Haire WD, Hill PA, Li X, McCluskey ER; COOL Investigators. Recombinant tissue plasminogen activator (alteplase) for restoration of flow in occluded central venous access devices: a double-blind placebo-controlled trial--the Cardiovascular Thrombolytic to Open Occluded Lines (COOL) efficacy trial. J Vasc Interv Radiol 2001;12:951-5. DOI:http://dx.doi.org/10.1016/S1051-0443(07)61575-9
http://dx.doi.org/10.1016/S1051-0443(07)...

Mark et al.3131 Little MA, Walshe JJ. A longitudinal study of the repeated use of alteplase as therapy for tunneled hemodialysis catheter dysfunction. Am J Kidney Dis 2002;39:86-91. DOI:http://dx.doi.org/10.1053/ajkd.2002.29885
http://dx.doi.org/10.1053/ajkd.2002.2988...
included 570 permanent venous catheters in a prospective study with patients on HD and analyzed the use of alteplase in reestablishing blood flow rates from poor (< 200 ml/min) to adequate levels over a period of two and a half years. The authors described a mean PVC survival of 10.2 months and found that thrombosis was the most common cause for catheter removal (36.3%). Alteplase was used in 2.77% of the dialysis sessions with a mean time between interventions of 27 days.

Vercaigne et al.3232 Vercaigne LM, Zacharias J, Bernstein KN. Alteplase for blood flow restoration in hemodialysis catheters: a multicenter, randomized, prospective study comparing "dwell" versus "push" administration. Clin Nephrol 2012;78:287-96. PMID: 22541682 DOI:http://dx.doi.org/10.5414/CN107351
http://dx.doi.org/10.5414/CN107351...
looked into 82 occluded PVCs of HD patients treated with alteplase (group 1) or alteplase followed by saline solution (group 2), and reported success rates of 65% and 82%, respectively. The authors did not find statistically significant differences between the groups (p = 0.84) and considered the alteplase infusion protocol followed by saline solution to be effective, safe, and convenient.

In a systematic review, Hilleman et al.3333 Hilleman D, Campbell J. Efficacy, safety, and cost of thrombolytic agents for the management of dysfunctional hemodialysis catheters: a systematic review. Pharmacotherapy 2011;31:1031-40. DOI: http://dx.doi.org/10.1592/phco.31.10.1031
http://dx.doi.org/10.1592/phco.31.10.103...
analyzed the literature on the efficacy, safety, and cost-effectiveness of thrombolytic therapy for dysfunctional HD permanent venous catheters. In the 18 studies meeting the inclusion criteria, higher success rates were found for reteplase (88%), followed by alteplase (81%), and tenecteplase (41%). The authors concluded that reteplase should be the thrombolytic agent of choice in the treatment of occluded CVC in centers with large numbers of patients on HD. However, this drug is not available in Brazil.

Another study3434 Mendes ML, Castro JH, Silva TN, Barretti P, Ponce D. Effective use of alteplase for occluded tunneled venous catheter in hemodialysis patients. Artif Organs 2014;38:399-403. recently published by our group analyzed 152 PVCs implanted in 102 patients on HD and found that 147 of 179 episodes of obstruction (82.8%) were successfully resolved with a single infusion of alteplase (1 mg/ml), 27 (15.1%) after a second infusion, and five (2.8%) remained occluded. The residence time of the thrombolytic agent in the catheter was 40 minutes. In this study, 98% of the PVCs were successfully unclogged. There was a downward trend in the efficiency of alteplase removing occlusions of PVCs in the subclavian versus the jugular vein. Cryopreservation of alteplase also proved safe and effective.

Shen et al.3535 Shen V, Li X, Murdock M, Resnansky L, McCluskey ER, Semba CP; COOL Investigators. Recombinant tissue plasminogen activator (alteplase) for restoration of function to occluded central venous catheters in pediatric patients. J Pediatr Hematol Oncol 2003;25:38-45. PMID:12544772 DOI: http://dx.doi.org/10.1097/00043426-200301000-00009
http://dx.doi.org/10.1097/00043426-20030...
enrolled 995 pediatric and adult patients with implanted PVCs in a multicenter trial and reported a success rate of 87% in the removal of occlusions. The catheters were infused with the thrombolytic agent for 30 to 120 minutes. In 70 patients (57%), blood flow was reestablished with a single 30-minute infusion of alteplase. Success was not correlated with patient age, gender, body weight, type of CVC, or time with the catheter. There were no deaths or severe adverse events such as bleeding or embolism attributable to the treatment.

In addition to occlusion removal, another important factor to be considered is the restoration of blood flow with the use of a thrombolytic agent. Adequate blood flow rates are extremely important for patients on dialysis, so that the target Kt/V and prescribed fluid removal levels are attained. In the literature, occlusion removal is considered successful when blood flow rates are restored to levels greater than 250 ml/min. In a small randomized trial, Zacharias et al.3636 Zacharias JM, Weatherston CP, Spewak CR, Vercaigne LM. Alteplase versus urokinase for occluded hemodialysis catheters. Ann Pharmacother 2003;37:27-33. DOI:http://dx.doi.org/10.1345/aph.1C105
http://dx.doi.org/10.1345/aph.1C105...
compared the efficacy of alteplase versus urokinase in reestablishing proper blood flow rates (> 200 ml/min) in partially and totally occluded venous catheters implanted in 30 patients on HD. The success rates observed in partially occluded PVCs were similar for both groups (87.8% vs. 75%, p = 0.205). However, the success rate in clearing totally occluded catheters was significantly higher when alteplase was used (88.2% vs. 42.8%, p = 0.018).

The few studies in which alteplase was used to remove CVC occlusions reported positive results and described extended life for the catheters implanted in patients on hemodialysis and chemotherapy. Alteplase can also be cryopreserved and fractioned, making it a more cost-effective thrombolytic agent. However, more and larger studies are needed to compare the efficacy, safety, and cost-effectiveness of different thrombolytic agents in the management of hemodialysis CVC mechanical dysfunctions and identify the factors associated with thrombotic occlusion.

REFERÊNCIAS

  • 1
    Romão Jr JE. A Doença Renal Crônica: do Diagnóstico ao Tratamento. Prat Hosp 2007;52:183-7.
  • 2
    Romão Jr JE. Doença renal crônica: definição, epidemiologia e classificação. J Bras Nefrol 2004;26:1-3.
  • 3
    Lugon JR. Doença renal crônica no Brasil: um problema de saúde público. J Bras Nefrol 2009;31:2-5.
  • 4
    Stevens LA, Stoycheff N, Levey AS. Staging and management of chronic kidney disease. In: Greenberg A, ed. Primer on Kidney Diseases (5th ed). Philadelphia: Saunders Elsevier; 2009. p.436-45.
  • 5
    Sesso RCC, Lopes AA, Thomé FS, Lugon JR, Watanabe Y, Santos DR. Diálise crônica no Brasil - Relatório do Censo Brasileiro de Diálise, 2011. J Bras Nefrol 2012;34:272-7. DOI:http://dx.doi.org/10.5935/0101-2800.20120009
    » http://dx.doi.org/10.5935/0101-2800.20120009
  • 6
    National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002;39:S1-266.
  • 7
    Bastos MG, Kirsztajn GM. Chronic kidney disease: importance of early diagnosis, immediate referral and structured interdisciplinary approach to improve outcomes in patients not yet on dialysis. J Bras Nefrol 2011;33:93-108. PMID: 21541469
  • 8
    Censo Brasileiro de diálise 2012 [Acesso 3 Nov 2013]. Disponível em: http://www.sbn.org/pdf/socios2012.pdf
    » http://www.sbn.org/pdf/socios2012.pdf
  • 9
    Besarab A, Raja RM. Acesso vascular para hemodiálise. In: Daugirdas JT, Ing TS. Manual de diálise. 3a ed. Rio de Janeiro: Medsi; 2003. p.68-102.
  • 10
    National Kidney Foudation. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for 2006 Updates: Hemodialysis Adeuqacy, Peritoneal Dialysis Adequacy, Vascular Access. Am J. Kidney Dis. 2006;48:S1-S322.
  • 11
    Lugon JR, Strogoff JP, Warrak MEA. Hemodiálise. In: Riella MC. Princípios de nefrologia e distúrbios hidroeletrolíticos. 4a ed. Rio de Janeiro: Guanabara Koogan; 2003.
  • 12
    Kim SH, Song KI, Chang JW, Kim SB, Sung SA, Jo SK, et al. Prevention of uncuffed hemodialysis catheter-related bacteremia using an antibiotic lock technique: a prospective, randomized clinical trial. Kidney Int 2006;69:161-4. PMID: 16374438 DOI:http://dx.doi.org/10.1038/sj.ki.5000012
    » http://dx.doi.org/10.1038/sj.ki.5000012
  • 13
    III. NKF-K/DOQI Clinical Practice Guidelines for Vascular Access: update 2000. Am J Kidney Dis 2001;37:S137-81.
  • 14
    O'Grady NP, Alexander M, Dellinger EP, Gerberding JL, Heard SO, Maki DG, et al. Guidelines for the prevention of intravascular catheter-related infections. Centers for Disease Control and Prevention. MMWR Recomm Rep 2002;51:1-29.
  • 15
    Lok CE, Mokrzycki MH. Prevention and management of catheter-related infection in hemodialysis patients. Kidney Int 2011;79:587-98. PMID: 21178979 DOI:http://dx.doi.org/10.1038/ki.2010.471
    » http://dx.doi.org/10.1038/ki.2010.471
  • 16
    Timoney JP, Malkin MG, Leone DM, Groeger JS, Heaney ML, Keefe DL, et al. Safe and cost effective use of alteplase for the clearance of occluded central venous access devices. J Clin Oncol 2002;20:1918-22. DOI: http://dx.doi.org/10.1200/JCO.2002.07.131
    » http://dx.doi.org/10.1200/JCO.2002.07.131
  • 17
    Chan MR, Yevzlin AS. Tunneled dialysis catheters: recent trends and future directions. Adv Chronic Kidney Dis 2009;16:386-95. DOI: http://dx.doi.org/10.1053/j.ackd.2009.06.006
    » http://dx.doi.org/10.1053/j.ackd.2009.06.006
  • 18
    Cheung AK, Sarnak MJ, Yan G, Berkoben M, Heyka R, Kaufman A, et al. Cardiac diseases in maintenance hemodialysis patients: results of the HEMO Study. Kidney Int 2004;65:2380-9. DOI:http://dx.doi.org/10.1111/j.1523-1755.2004.00657.x
    » http://dx.doi.org/10.1111/j.1523-1755.2004.00657.x
  • 19
    Katneni R, Hedayati SS. Central venous catheter-related bacteremia in chronic hemodialysis patients: epidemiology and evidence-based management. Nat Clin Pract Nephrol 2007;3:256-66. DOI: http://dx.doi.org/10.1038/ncpneph0447
    » http://dx.doi.org/10.1038/ncpneph0447
  • 20
    Jaber BL. Bacterial infections in hemodialysis patients: pathogenesis and prevention. Kidney Int 2005;67:2508-19. PMID: 15882306 DOI: http://dx.doi.org/10.1111/j.1523-1755.2005.00364.x
    » http://dx.doi.org/10.1111/j.1523-1755.2005.00364.x
  • 21
    Biernat JC, dos Santos F, dos Santos AMG, Raubach AA, Souza M, Demin MSS, et al. Contaminação de Lúmen de Cateter de Hemodiálise: prevenção e tratamento com M-EDTA. J Bras Nefrol 2008;30:105-12.
  • 22
    Silva TN, de Marchi D, Mendes ML, Barretti P, Ponce D. Approach to prophylactic measures for central venous catheter-related infections in hemodialysis: a critical review. Hemodial Int 2014;18:15-23. DOI: http://dx.doi.org/10.1111/hdi.12071
    » http://dx.doi.org/10.1111/hdi.12071
  • 23
    Schon D, Whittman D. Managing the complications of long-term tunneled dialysis catheters. Semin Dial 2003;16:314-22. DOI: http://dx.doi.org/10.1046/j.1525-139X.2003.16060.x
    » http://dx.doi.org/10.1046/j.1525-139X.2003.16060.x
  • 24
    Beathard GA. Catheter thrombosis. Semin Dial 2001;14:441-5. DOI:http://dx.doi.org/10.1046/j.1525-139x.2001.00109.x
    » http://dx.doi.org/10.1046/j.1525-139x.2001.00109.x
  • 25
    Deitcher SR, Fesen MR, Kiproff PM, Hill PA, Li X, McCluskey ER.; Cardiovascular Thrombolytic to Open Occluded Lines-2 Investigators. Safety and efficacy of alteplase for restoring function in occluded central venous catheters: results of the cardiovascular thrombolytic to open occluded lines trial. J Clin Oncol 2002;20:317-24. DOI: http://dx.doi.org/10.1200/JCO.20.1.317
    » http://dx.doi.org/10.1200/JCO.20.1.317
  • 26
    Liangos O, Gul A, Madias NE, Jaber BL. Long-term management of the tunneled venous catheter. Semin Dial 2006;19:158-64. DOI: http://dx.doi.org/10.1111/j.1525-139X.2006.00143.x
    » http://dx.doi.org/10.1111/j.1525-139X.2006.00143.x
  • 27
    Besarab A, Pandey R. Catheter management in hemodialysis patients: delivering adequate flow. Clin J Am Soc Nephrol 2011;6:227-34. DOI: http://dx.doi.org/10.2215/CJN.04840610
    » http://dx.doi.org/10.2215/CJN.04840610
  • 28
    Ponec D, Irwin D, Haire WD, Hill PA, Li X, McCluskey ER; COOL Investigators. Recombinant tissue plasminogen activator (alteplase) for restoration of flow in occluded central venous access devices: a double-blind placebo-controlled trial--the Cardiovascular Thrombolytic to Open Occluded Lines (COOL) efficacy trial. J Vasc Interv Radiol 2001;12:951-5. DOI:http://dx.doi.org/10.1016/S1051-0443(07)61575-9
    » http://dx.doi.org/10.1016/S1051-0443(07)61575-9
  • 29
    Baskin JL, Pui CH, Reiss U, Wilimas JA, Metzger ML, Ribeiro RC, et al. Management of occlusion and thrombosis associated with long-term indwelling central venous catheters. Lancet 2009;374:159-69. DOI: http://dx.doi.org/10.1016/S0140-6736(09)60220-8
    » http://dx.doi.org/10.1016/S0140-6736(09)60220-8
  • 30
    Haire WD, Atkinson JB, Stephens LC, Kotulak GD. Urokinase versus recombinant tissue plasminogen activator in thrombosed central venous catheters: a double-blinded, randomized trial. Thromb Haemost 1994;72:543-7. PMID: 7878629
  • 31
    Little MA, Walshe JJ. A longitudinal study of the repeated use of alteplase as therapy for tunneled hemodialysis catheter dysfunction. Am J Kidney Dis 2002;39:86-91. DOI:http://dx.doi.org/10.1053/ajkd.2002.29885
    » http://dx.doi.org/10.1053/ajkd.2002.29885
  • 32
    Vercaigne LM, Zacharias J, Bernstein KN. Alteplase for blood flow restoration in hemodialysis catheters: a multicenter, randomized, prospective study comparing "dwell" versus "push" administration. Clin Nephrol 2012;78:287-96. PMID: 22541682 DOI:http://dx.doi.org/10.5414/CN107351
    » http://dx.doi.org/10.5414/CN107351
  • 33
    Hilleman D, Campbell J. Efficacy, safety, and cost of thrombolytic agents for the management of dysfunctional hemodialysis catheters: a systematic review. Pharmacotherapy 2011;31:1031-40. DOI: http://dx.doi.org/10.1592/phco.31.10.1031
    » http://dx.doi.org/10.1592/phco.31.10.1031
  • 34
    Mendes ML, Castro JH, Silva TN, Barretti P, Ponce D. Effective use of alteplase for occluded tunneled venous catheter in hemodialysis patients. Artif Organs 2014;38:399-403.
  • 35
    Shen V, Li X, Murdock M, Resnansky L, McCluskey ER, Semba CP; COOL Investigators. Recombinant tissue plasminogen activator (alteplase) for restoration of function to occluded central venous catheters in pediatric patients. J Pediatr Hematol Oncol 2003;25:38-45. PMID:12544772 DOI: http://dx.doi.org/10.1097/00043426-200301000-00009
    » http://dx.doi.org/10.1097/00043426-200301000-00009
  • 36
    Zacharias JM, Weatherston CP, Spewak CR, Vercaigne LM. Alteplase versus urokinase for occluded hemodialysis catheters. Ann Pharmacother 2003;37:27-33. DOI:http://dx.doi.org/10.1345/aph.1C105
    » http://dx.doi.org/10.1345/aph.1C105

Publication Dates

  • Publication in this collection
    Apr-Jun 2015

History

  • Received
    07 Aug 2014
  • Accepted
    07 Nov 2014
Sociedade Brasileira de Nefrologia Rua Machado Bittencourt, 205 - 5ºandar - conj. 53 - Vila Clementino - CEP:04044-000 - São Paulo SP, Telefones: (11) 5579-1242/5579-6937, Fax (11) 5573-6000 - São Paulo - SP - Brazil
E-mail: bjnephrology@gmail.com