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

Correspondência para: Marcela Lara Mendes. Faculdade de Medicina de Botucatu Hospital das Clínicas de Botucatu. Rua Chico Padre, no 36 Jd D. Nicota, Botucatu, Brasil. CEP: 18611-310. E-mail: mazinha26@yahoo.com.br Abordagem da oclusão trombótica dos cateteres de longa permanência dos pacientes em hemodiálise: uma revisão narrativa Approach to thrombotic occlusion related to long-term catheters of hemodialysis patients: a narrative review

and patients on dialysis.According to Lugon et al., 3 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. 4n 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. 5ypertension and diabetes mellitus are the most important factors associated with progression of CKD. 1,6he 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. 1,7emodialysis 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). 8

centrAl venous cAtheters used As hd Access devices
The KDOQI 9,10 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. 11 double lumen catheter may be inserted into a central vein and used as a hemodialysis access device.When used for more than three weeks, nontunneled, non-cuffed catheters, also known as shortterm catheters, may yield high rates of infection.These catheters are best used in emergency dialysis patients or while the vascular access matures. 12atheters equipped with felt or Dacron cuffs reduce the incidence of infectious and mechanical complications and should be used whenever patients require longterm catheters. 11ong-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. 12,13lthough 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. 12The KDOQI discourages the use of CVC in HD patients, suggesting that only 10% of the cases require this mode of access. 5However, 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%. 5 In Brazil, 9.4% of the patients on HD in 2007 used CVC for access devices versus 11.4% in 2008. 8The 2011 Census of the Brazilian Society of Nephrology reported a prevalence of 14.2% in the use of CVC. 5 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. 5dditionally, 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. 13,14

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. 9,15,16owever, 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. 17ccording 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.9][20] Seventy-five percent of the infection-related deaths are caused by sepsis. 19he 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. 21A 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). 22he 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. 16e 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. 13 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. 16hrombosis is the most frequent cause of occlusion in HD patients.Deitcher et al. 22 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. 23ibrin 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. 24The fibrin sheath attracts platelets and coagulation factors and promotes the adhesion of white blood cells. 25Figure 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. 22,26ew 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. 25ossible consequences of thrombotic occlusion are CVC-related infection, pulmonary embolism, and post-thrombotic syndrome. 27

treAting thrombotic occlusions of longterm 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. 16nfusion of saline solution may be the most costeffective 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. 13If a first infusion fails to remove the obstruction, patients should be further studied with the aid of X-ray imaging.
Timoney et al. 16 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 °C 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.

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.
Timoney et al. 16 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. 22 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. 23aire et al. 30 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. 29Multicenter trial COOL found that alteplase was as effective in children or adults, with 83% to 87% of the occlusions resolved. 28ark et al. 31 included 570 permanent venous catheters in a prospective study with patients on HD and analyzed the use of alteplase in reestablishing  32 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. 33 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 study 34 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. 35 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. 36 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.

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, 2009.29

tAble 2
MAin chARActeRistics oF Recent studies on the tReAtMent oF thRoMbotic occlusion