Interventions for Occluded Central Venous Catheters: A Meta-analysis Ana Cristina Carvalho da Costa, RN, PhD,a Nayara Narley Pires Vieira, RN, MSc,a Christiane Inocêncio Vasques, RN, PhD,a Elaine Barros Ferreira, RN, PhD,a Eliete Neves Silva Guerra, DDS, PhD,b Paula Elaine Diniz dos Reis, RN, PhDa

CONTEXT: Thrombotic occlusion is 1 of the most frequent complications in catheters implanted in abstract children. OBJECTIVE: To identify the interventions used to treat thrombotic events in long-term central venous catheters in pediatric patients with cancer. DATA SOURCES: Electronic searches were performed in the Cumulative Index to Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, Latin American and Caribbean Health Sciences Literature, LIVIVO, PubMed, Scopus, Web of Science, Google Scholar, OpenGrey, and ProQuest databases. There were no restrictions on language or publication period. STUDY SELECTION: This systematic review was performed in 2 phases and included clinical trials and observational studies on drugs used to treat thrombotic catheter events in pediatric patients with cancer. The review was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis checklist, and the protocol was registered at PROSPERO (identifier CRD42018083555). DATA EXTRACTION: The authors evaluated the quality of included studies using the Methodological Index for Nonrandomized Studies and Grading of Recommendations Assessment, Development and Evaluation methods. The meta-analysis was performed by using Stata software. RESULTS: Ten studies were included. The drugs used to restore catheter function were alteplase, urokinase, and streptokinase. A meta-analysis of 6 studies revealed an overall restoration rate of 88% for alteplase. LIMITATIONS: Reference studies were excluded when it was not possible to reliably extract data that met the inclusion criteria of this review. Sampling issues (absence of randomization, blinding, or a control group) were the main methodologic concerns for the included articles. CONCLUSIONS: On the basis of the evidence obtained, thrombolysis is effective and potentially safe in this population.

aInterdisciplinary Research Laboratory Applied to Clinical Practice in Oncology and bLaboratory of Oral Histopathology, Faculty of Health Sciences, University of Brasília, Brasília, Brazil

Drs Costa and Ferreira conceptualized and designed the study, drafted the initial manuscript, and reviewed the manuscript; Ms Vieira and Dr Guerra designed the data collection instruments, collected data, conducted the initial analyses, and reviewed the manuscript; Drs Vasques and Reis conceptualized and designed the study, coordinated and supervised data collection and critically reviewed the manuscript for important intellectual content; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. This trial has been registered with PROSPERO (https://www.crd.york.ac.uk/prospero/) (identifier CRD42018083555). DOI: https://doi.org/10.1542/peds.2018-3789 Accepted for publication Sep 6, 2019

To cite: da Costa ACC, Vieira NNP, Vasques CI, et al. Interventions for Occluded Central Venous Catheters: A Meta-analysis. Pediatrics. 2019;144(6):e20183789

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 144, number 6, December 2019:e20183789 REVIEW ARTICLE Central venous catheters (CVCs) have thrombosis in children are different registered at the International been used for .3 decades in pediatric from those in adults.10 Despite this, Prospective Register of Systematic oncology. These devices are protocols for the administration of Reviews (PROSPERO) under considered appropriate in the care of thrombolytic agents for restoration of identifier CRD42018083555.13 children with cancer and are catheter function in children with commonly used for drug cancer are generally empirical and Eligibility Criteria administration, blood sampling, and are extrapolated from adult Inclusion Criteria 1–3 nutritional support. However, they guidelines; moreover, thrombolytic This review included articles about are also associated with a variety of therapies differ in the type of drug clinical trials or observational studies complications, including catheter used, dosing, and the duration of 4 5,10 involving pediatric patients with occlusion. treatment. cancer (children and adolescents CVC occlusion may be due to A systematic review to evaluate younger than 18 years) with partially thrombus formation or interventions to restore patency of or completely occluded long-term nonthrombotic causes, such as occluded CVCs has been previously CVCs (totally implanted catheters catheter malposition or intraluminal published.11 However, the authors of [TICs] and tunneled catheters [TCs]), drug precipitation. The most frequent this review examined a small number including all treated lumens and all causes of catheter dysfunction in of randomized clinical trials that types of cancer; in addition, this pediatric patients are wall thrombi, generally addressed the management review included articles about intraluminal and CVC tip thrombi, or of thrombotic occlusion, regardless of interventions to treat thrombotic thrombi caused by fibrin sheaths.5 the type of catheter or the patient age events by using pharmacologic and CVC occlusion may lead to inability to and clinical condition. In addition, nonpharmacologic substances. draw blood and/or infuse fluids.6 new technologies and studies have Restoration of catheter function was been developed since its publication, defined as the ability to instill 5 mL of CVC thrombotic occlusion is 1 of the and there is a need to update the saline solution and to aspirate 3 mL most frequent complications, findings. of blood in patients weighing $10 kg occurring in 20% to 40% of the or the ability to infuse 3 mL of saline 7 Although alteplase is the only drug catheters implanted in children. This solution and to aspirate 1 mL of blood approved by the US Food and Drug type of CVC occlusion can lead to in patients weighing ,10 kg.8 There Administration (FDA) for restoration infection, thromboembolism, catheter were no restrictions on language or of catheter function in the United dysfunction, or thrombus publication period. propagation, resulting in deep venous States, urokinase and streptokinase 3 thrombosis. are available in other countries and Exclusion Criteria continents for this purpose, despite Replacement or removal of an The studies were assessed in 2 established recommendations. Thus, occluded CVC in a child who is sick phases. In phase 1 (title and abstract the use of different types of may lead to discontinuation of review), the following exclusion thrombolytic agents for the treatment therapy, need for sedation or general criteria were applied: (1) studies with of CVC thrombotic occlusion around anesthesia, repeated surgical use of a short-term CVC, hemodialysis the world justifies the need for such interventions, and significant cost catheter, peripherally inserted central a systematic review and meta- increases associated with prolonged catheter, apheresis catheter, umbilical analysis. treatment and additional catheter, or arterial catheter or with procedures.8 The treatment of CVC In this systematic review, we aimed to use of different types of catheters in occlusion is less costly and faster than identify the interventions used to the same study; (2) studies in adults the surgical removal and replacement treat thrombotic events involving or in mixed populations in which it of the catheter, reducing the risk of long-term use of CVCs in pediatric was not possible to perform reliable adverse events (AEs) to the patient.9 patients with cancer. extraction of data referring to children with cancer; (3) studies in Fibrinolytic therapy has been used for which the authors evaluated .20 years in the treatment of CVC METHODS interventions to prevent thrombotic thrombotic occlusion. The fibrinolytic events; and (4) reviews of the system in children is a dynamic, age- Protocol and Registration literature, letters, case reports, or dependent system with unique This systematic review was protocols. characteristics that markedly performed according to the Preferred influence the response to Reporting Items for Systematic In phase 2 (full-text reading), the thrombolytic agents. In addition, the Reviews and Meta-Analysis following additional criteria were pathophysiological mechanisms of checklist.12 The protocol was applied: (5) studies in which authors

Downloaded from www.aappublications.org/news by guest on September 28, 2021 2 COSTA et al did not investigate treatment of attained. When consensus was not bias, items were scored as 0 (not catheter occlusion, (6) duplicated reached, a third author (C.I.V.) was reported), 1 (reported but data, (7) studies in which authors did included for a final decision. inadequate), or 2 (reported and not include patients with cancer, and adequate). The ideal overall score (8) studies with incomplete data on Data Extraction and Synthesis was 16 for noncomparative studies the treated population or catheter Two reviewers independently and 24 for comparative studies. type used. collected data from the selected Disagreements between both studies. A third reviewer assessed the reviewers were resolved by a third Search Methods accuracy of the information collected. reviewer. We developed search strategies for For all included studies, the following A summary of the overall strength of each of the following databases: characteristics were recorded: study evidence available was performed Cumulative Index to Nursing and characteristics (author, year, country by using the Grading of Allied Health Literature (CINAHL), of publication, and study design), Recommendations Assessment, Cochrane Central Register of sample characteristics (size, catheter Development and Evaluation Controlled Trials (CENTRAL), Latin type, and number of occluded CVCs), (GRADE) method.16 A summary of American and Caribbean Health intervention characteristics (drug findings table was produced by Sciences Literature (LILACS), LIVIVO, type, doses, infusion time, and follow- using GRADEpro software PubMed, Scopus, and Web of Science. up time), outcome characteristics (McMaster University, Hamilton, fi Agrayliteraturesearchwas (ef cacy [restoration of catheter Canada). performed by using Google Scholar, patency] and safety), and the main OpenGrey, and ProQuest Theses and conclusion. If the required data were Dissertations. The ending search date not complete or the data presented RESULTS could not be extrapolated, attempts was February 16, 2018, across all Study Selection databases. Hand searching of the were made by e-mail to contact the reference lists of included studies was authors to retrieve missing In phase 1, 3601 articles were found also performed. In addition, e-mails information. across the 7 databases. After duplicates were removed, 26 of the were sent to experts to inquire about fi The ef cacy outcome was expressed 2936 studies were selected for additional studies relevant to the as the percentage of catheter function review. phase 2. A gray literature search restored from the total sample of was used to identify 242 articles, Appropriate truncation and word included studies. but none met the inclusion criteria. combinations were selected and After heterogeneity between the The reference lists of included adapted for each database search studies was assessed, a meta-analysis studies were screened, and 23 (Supplemental Tables 3 through 12). was performed for the data by using articles were included. After 3 All references were managed by using Stata software version 14 (Stata Corp, consecutive attempts in a period of reference manager software College Station, TX). Heterogeneity 1month,wedidnotobtainanswers (EndNote X7; Thomson Reuters, New was calculated by using I2, following from the experts, and articles were York), and duplicates were removed. the appropriate Cochrane not included through this type of guidelines.14 A value .50% was search. Subsequently, 49 articles Search Outcomes considered an indicator of substantial were obtained for full-text reading, The selection was completed in 2 heterogeneity among studies, and 39 articles were excluded phases. In phase 1, 2 reviewers enabling the use of a random-effects (Supplemental Table 13). Therefore, (A.C.C.d.C. and N.N.P.V.) independently model. When I2 was ,50%, a fixed- only 10 studies fulfilled the reviewed the titles and abstracts of all effects model was used. The eligibility criteria and were included citations identified from databases. significance level was set at 5%. in the qualitative synthesis. Of these, Articles that did not appear to meet 6 matched the criteria used for the the inclusion criteria were discarded. Quality Appraisal meta-analysis. A flow diagram of the In phase 2, the same reviewers applied Risk of bias of selected studies was process of identification, inclusion, the inclusion criteria to the full text of evaluated by using the and exclusion of studies is shown in the articles. The reference lists of Methodological Index for Fig 1. selected studies were critically Nonrandomized Studies (MINORS)15 assessed by both examiners. Any for nonrandomized clinical trials and Study Characteristics disagreement in phase 1 or 2 was observational studies. Two reviewers Of the 10 selected studies, 6 were resolved by discussion until an independently assessed the quality of clinical trials8,17–21;of4 agreement between the 2 authors was each study. For judgment of risk of observational studies, 3 were

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 144, number 6, December 2019 3 based on evaluation of patient partial or total occlusion was blood and the inability to infuse 5 mL charts,22–24 and 1 was a prospective evaluated in 6 studies (60%). of saline through the catheter.26 cohort study.25 CVC sample sizes ranged from 417 to 1608 among a total Partial occlusion was defined as the The drugs used for restoration of of 447 long-term CVCs studied in 747 inability to withdraw 3 mL of blood, catheter patency were – patients. Among the long-term CVCs with a retained ability to infuse 5 mL alteplase8,17,19,22 24 (n = 6), used, 218 (48.3%) were TCs and 233 of saline through the catheter. urokinase18,20,21 (n = 3), and (51.7%) were TICs. Partial occlusion Complete occlusion was defined as streptokinase25 (n = 1). In all trials, was evaluated in 4 studies (40%), and the inability to withdraw 3 mL of investigators evaluated the efficacy of

FIGURE 1 Flow diagram of literature search and selection criteria. Adapted from Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097.PICC, peripherally inserted central catheter.

Downloaded from www.aappublications.org/news by guest on September 28, 2021 4 COSTA et al drugs without using a control group. infusion, achieving a success rate of effects model was chosen for the In only 1 study20 was the same drug 91.7%. The catheters used in this statistical analysis. After (urokinase) used in 3 different groups study had already undergone consideration of the alteplase with 2 infusion regimens. unsuccessful thrombolysis with intervention, the results revealed an consecutive urokinase boluses at overall CVC function restoration rate The aim of the studies was to 5000 and 10 000 IU. of 88% (total sample = 322 catheters) evaluate the efficacy and safety of the (Fig 2). drugs in restoring catheter patency Molinari et al20 used urokinase in 3 by using different doses and different different doses and in 2 infusion Risk of Bias of Individual Studies infusion times. The restoration rate protocols. Partially occluded CVCs ranged from 50%25 to 97.5%,19 and were divided into 2 groups: 1 by Three studies17,19,21 were classified the administration time ranged from using urokinase bolus administration as having a high risk of bias because 30 minutes8,20,22,23 to 48 hours.18 The of 5000 IU and another by using they scored #8 points (50% of the authors of 2 studies reported AEs urokinase bolus administration of total score), and 3 other studies8,20,25 related to alteplase, including sepsis,8 25 000 IU. Fully occluded CVCs, or were classified as having a low risk of catheter rupture,22 and blood those refractory to the previously bias because they scored between 13 dyscrasia (characterized as an described treatments, received low- and 18 points. The other 4 studies abnormality of either prothrombin or dose systemic urokinase at a dose of were classified as having an unclear partial thromboplastin time, or of 1000 IU/kg per hour in a prolonged risk of bias because they scored – fibrinogen, with increased bleeding infusion that varied from 1 to 3 hours between 9 and 11 points.18,22 24 More events within 48 hours).22 There because low-dose systemic urokinase information about the MINORS15 were no AEs reported in the other could be administered up to 4 times. scores is provided in Fig 3. articles. The descriptive Restoration rates in these 3 groups characteristics of the included articles were 89.4%, 97%, and 77.8%, Risk of Bias Within Studies are summarized in Table 1. respectively. Although the studies had different 21 designs, the main methodologic Results of Individual Studies The Winthrop and Wesson study problem concerned the sample. In 17 had the earliest publication date, and The Atkinson et al study included the authors used a urokinase dose of most of the studies, including the the smallest number of catheters, and 5000 IU, achieving a success rate of clinical trials, convenience samples alteplase was used at the standard 2- 66.7%. Tobiansky et al25 alone used were used, without randomization of mg dose, achieving a success rate of streptokinase for CVC thrombolysis, participants and without use of 75%. It should be noted that the CVC in a dose of 5000 IU, and showed the a control group. used had already been treated with lowest rate of restoration among the fi a urokinase bolus (10 000 IU) included studies (50%). Con dence in Cumulative Evidence without success. The Blaney et al8 Using the GRADE summary of study included the largest number of Synthesis of Results findings table, we found that the catheters, with the same 2-mg dose of Six of the 10 studies included were quality of evidence ranged from very alteplase, and achieved a restoration used in the meta-analysis. One low to low. This variation was directly rate of 83.1%. study25 was excluded as unique in related to the risk of bias as well as to Chesler and Feusner22 achieved using streptokinase, and another20 heterogeneity among the studies a high success rate (88.1%) despite was excluded because the catheters (Table 2). using a minimum dose of alteplase were treated with multiples doses of (0.5 mg). Fisher et al23 also used urokinase, making it impossible to a lower dose of alteplase (1 mg) but identify the dose received through DISCUSSION achieved an even higher rate of each catheter. In addition, 2 Thrombotic events are increasingly restoration (92.8%). Iqbal et al19 studies18,21 were excluded because common and cause significant used alteplase doses between 0.5 and the authors addressed the use of problems in children with cancer and 1 mg, depending on patient weight, urokinase in totally different doses those requiring a CVC. Despite this, and had the highest success rate and infusion regimens, with guidelines for the management of among the included studies (97.5%). considerable heterogeneity among long-term CVC occlusion are Peng et al24 used alteplase in doses them, not allowing for a reliable unavailable for the pediatric ranging from 0.5 to 2 mg, achieving comparison. Because the population. However, thrombolytic a restoration rate of 75.8%. Bagnall heterogeneity among the studies was agents with established roles in the et al18 used urokinase at a dose of significant (59.22%; confidence management of thrombotic CVC 200 IU/kg per hour in a prolonged interval 1.41–83.65), the random- complications are adopted as the first

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 144, number 6, December 2019 5 6 TABLE 1 Summary of Descriptive Characteristics of Included Studies (n = 10) Study Characteristics Sample Characteristics Intervention Characteristics Outcome Characteristics Main Conclusion Author, Year; Study Design Sample Catheter Type Drug Type (Dose) Infusion Follow-up Efficacy Safety Country Size, n (n) Time, h Time (No. LT-CVCs occluded) Bagnall Quasi-randomized 58 (12) TIC (2) and TC Urokinase continuous 24 and 48 — Catheter patency was Prothrombin time, partial Low-dose urokinase may be et al,18 study (10); did not infusion (200 IU/kg documented when blood thromboplastin time, fibrin safe and effective for 1989; clear after 2 per lumen per h); up return was established degradation products, and clearing of occluded CVCs Downloaded from United boluses of to 2 infusions and a dye study revealed fibrinogen were determined in infants and children. States urokinase patency; overall before urokinase infusion, at (5000 IU/mL restoration of catheter mid infusion, and after and 10 000 IU/ function = 91.7% (11 of infusion. Bleeding 2 mL) 12 CVCs) complications were not observed during therapy, www.aappublications.org/news and no febrile reactions occurred. Molinari Quasi-randomized 84 (84) TC (84) IL-UK (5000 IU/mL or 0.5 (IL-UK) 20 d Overall restoration of Incidence of complications was A dose of 5000 IU of IL-UK was et al,20 study 25 000 IU/mL) in and 3 catheter function: IL-UK prospectively evaluated; no as effective as 25 000 IU to 2004; Italy bolus; low-dose S-UK (S-UK) (5000 IU/mL) = 89.4% (42 episode of bleeding was resolve withdrawal (1000 IU/kg per h); of 47 CVCs); IL-UK (25 000 reported occlusion in partially up to 4 infusions IU/mL) = 97% (33 of 34 implanted CVCs; systemic CVCs) (P = .393); S-UK = treatment with urokinase 77.8% (7 of 9 CVCs) may rescue a significant proportion of CVCs

byguest on September28, 2021 refractory to IL-UK or those that are apparently completely occluded. Winthrop Quasi-randomized 14 (21) TC (21) Urokinase (5000 IU/2 2 — Restoration of catheter No cases of bleeding or allergic Urokinase can be used safely et al,21 study mL) function = 66.7% (14 of reactions and effectively to restore 1984; 21 CVCs) catheter patency in Canada pediatric patients. Atkinson Quasi-randomized 25 (4) TIC (1) and TC Alteplase (2 mg/2 mL); 4 — Overall restoration of Coagulation parameters were Alteplase may be a safe and et al,17 study (3); remained up to 2 doses catheter function = 75% monitored before and effective thrombolytic 1990; occluded (3 of 4 CVCs) immediately after alteplase agent in the treatment of United after an administration. No occluded CVCs. States initial bolus coagulation abnormalities of 10 000 IU of or bleeding complications urokinase were noted in this group. Blaney et al,8 Open-label, quasi- 310 (160) TIC (160) Alteplase (2 mg/2 mL 0.5, 2, 2.5, 48 h Restored function was Safety was measured by the Administration of alteplase is 2006; randomized for wt $ 30 kg or and 4 defined as the ability to incidence of ICH, safe and effective for United study 110% of the withdraw 3 mL of blood documented by computed restoration of CVC function States estimated internal and infuse 5 mL of tomography or MRI during in pediatric patients. volume of CVC for normal saline solution in the treatment period and OT tal et COSTA wt , 30 kg [not to patients weighing within 48 h after the $10 kg or the ability to completion of treatment EITISVlm 4,nme ,Dcme 2019 December 6, number 144, Volume PEDIATRICS TABLE 1 Continued Study Characteristics Sample Characteristics Intervention Characteristics Outcome Characteristics Main Conclusion Author, Year; Study Design Sample Catheter Type Drug Type (Dose) Infusion Follow-up Efficacy Safety Country Size, n (n) Time, h Time (No. LT-CVCs occluded) exceed 2 mL]); up to withdraw 1 mL of blood with alteplase. Serious AEs 2 doses and infuse 3 mL of included major hemorrhage normal saline solution in (defined as severe blood Downloaded from patients weighing ,10 loss [.5 mL/kg] or blood kg; restoration of loss resulting in hypotension catheter function was as or requiring transfusion), follows: at 0.5 h = 55.6% thrombosis, embolic events (89 of 160 CVCs), at 2 h = (defined as any serious 75.6% (121 of 160 CVCs), embolic event, including www.aappublications.org/news after second dose (2.5 h) pulmonary or arterial events = 79.4% (127 of 160 [eg, stroke, peripheral or CVCs), and after second major organ] or cholesterol dose (4 h) = 83.1% (133 plaque), sepsis, catheter- of 160 CVCs) related complications, or any other serious adverse event. In total, 9 serious AEs were reported in 8 patients, 2 of which were assessed by the investigator as related to

byguest on September28, 2021 alteplase administration (1 case of sepsis and 1 case of a ruptured catheter lumen). No patients experienced ICH. Chesler and Retrospective 42 (42) TC (40) and TIC Alteplase (0.5 mg/1 0.5 and 1 30 d Patency of the device was Minimal adverse reactions to Alteplase at a dose of 0.5 mg, Feusner,22 observational (2) mL); up to 2 doses then tested by the ability alteplase were observed; no unadjusted for CVC 2002; study (review of to instill and withdraw allergic events, no volume, is safe and United patient medical 5 mL of normal saline subsequent abnormalities of effective in small children States records and from the line; overall either prothrombin or with cancer. pharmacy restoration of catheter partial thromboplastin records) function = 88.1% (37 of times or of fibrinogen, and 42 CVCs) no increased bleeding events within 48 h, except in 1 patient. Fisher Retrospective 22 (14) TC (9) and TIC Alteplase (1 mg/1 mL); 0.5–3 24 h Restoration of catheter Incidence of bleeding or Alteplase was safe and et al,23 observational (5) up to 2 doses function after 1 or 2 infection 24 h after an effective in restoring 2004; study (review of doses = 92.8% (13 of 14 alteplase dose was obtained patency of occluded CVCs United patient medical CVCs) from patient medical in infants and children. States records) records. No AEs were noted after alteplase was received. 7 8 TABLE 1 Continued Study Characteristics Sample Characteristics Intervention Characteristics Outcome Characteristics Main Conclusion Author, Year; Study Design Sample Catheter Type Drug Type (Dose) Infusion Follow-up Efficacy Safety Country Size, n (n) Time, h Time (No. LT-CVCs occluded) Iqbal et al,19 Quasi-randomized 40 (40) TC (3) and TIC Alteplase (1 mg/mL for 1–2 — Restoration of catheter In the dose used, the sample Cryopreserved alteplase 2002; study (37) wt . 10 kg and function after 1 or 2 did not experience any appears to be safe and Saudi 0.5 mg/0.5 mL for doses = 97.5% (39 of 40 adverse effects. effective in the dose used Downloaded from Arabia wt , 10 kg); up to 2 CVCs) (1 mg/1 mL) to restore doses patency in occluded CVADs in pediatric patients with cancer. Peng et al,24 Retrospective 89 (62) TC (36) and TIC Alteplase (0.5 mg/2 mL, ,2, 2–4, 48 h Efficacy was defined as The safety outcomes measured Alteplase is safe and effective 2011; observational (26) 0.5 mg/2 mL, 2 mg/2 and .4 restoration of CVAD were major bleeding and in treatment of CVC www.aappublications.org/news Australia study (review of mL, or 2 mg/3 mL, patency after aspiration any AE attributed to the occlusion but is less patient charts) according to the of tPA; restoration of TC administration of tPA within effective in implantable clinical practice function after first dose 48 h of administration. There ports. Treatment of guideline); up to 2 = 80.6% (29 of 36 CVCs); were no cases of ICH, occluded CVCs can extend doses restoration of TC function embolic events, or deaths the catheter life by months after second dose = within 48 h of treatment to years, preventing costly 88.9% (32 of 36 CVCs); attributable to the and traumatic catheter restoration of TIC instillation of alteplase. replacement procedures. function after first dose = 46.2% (12 of 26 CVCs);

byguest on September28, 2021 restoration of TIC function after second dose = 57.7% (15 of 26 CVCs); overall restoration of catheter function = 75.8% (47 of 62 CVCs) Tobiansky Observational 63 (8) TC and TIC (8) Streptokinase (5000 IU/ 6 Until Restoration of catheter Not evaluated In this study, streptokinase et al,25 study, cohort mL) catheter function = 50% (4 of 8 was used only in patients 1997; study was CVCs) with cancer and was Australia removed successful half of the time. or until After successful treatment patient of occlusion, the lines death lasted for a median of 136 d (range 43–261). CVAD, central venous access device; ICH, intracranial hemorrhage; IL-UK, intraluminal urokinase; LT-CVC, long-term central venous catheter; S-UK, systemic urokinase; tPA, tissue plasminogen activator; —, not reported. OT tal et COSTA FIGURE 2 Meta-analysis of restoration of catheter function with alteplase (sample = 322). Results are from the random-effects model meta-analysis. ES, effect size. approach to restore catheter fibrin, low immunogenicity, and short CVC function in children, regardless patency.5 systemic half-life (5 minutes). This of age, weight, or type of protease converts plasminogen to catheter used. In this systematic review, we plasmin when in contact with investigated the available evidence fibrinous material, promoting The alteplase dose for restoration of for the interventions used in the thrombolysis.27 catheter patency depends on patient treatment of thrombotic events in weight and the filling volume of the long-term CVCs in pediatric patients The use of alteplase in the restoration occluded lumen. The FDA,28,29 the with cancer. Among interventions of catheter function was approved in manufacturer,30 and the American used to restore catheter function, September 2001 by the FDA after 2 College of Chest Physicians31 alteplase was the most frequent, clinical trials,28,29 but the population recommended administration of up to followed by urokinase. No used in these studies consisted 2 doses of 2 mg (2 mL) for patients nonpharmacologic intervention was predominantly of adult patients, weighing $30 kg and up to 2 doses of identified. prompting the need for a phase IV 1 mg/1 mL for patients weighing ,30 Alteplase is a recombinant tissue study to clarify the safety and efficacy kg; the dose should be up to 110% of plasminogen activator and is of the drug in the general pediatric the volume of the occluded catheter, considered the first option in the population. The results of this not exceeding 2 mL. However, in this noninvasive treatment of CVC research8 corroborated the results of systematic review, large dose thrombotic occlusion. The benefitof previous studies regarding the safety variations were observed, ranging alteplase is its high specificity for and efficacy of alteplase in restoring from 0.5 mg/0.5 mL to 2 mg/3 mL,

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 144, number 6, December 2019 9 alteplase remain within the catheter biofilm, making alteplase a vehicle for for 30 minutes and that if function is bacterial dissemination when infused not restored within that time, into the catheter.33 90 minutes be added for a total time Although variations in doses and of 120 minutes for the first dose. If infusion times were found, the the CVC remains occluded, a second authors of the studies considered intraluminal dose should be alteplase to be safe and effective in administered for an equal period of restoration of CVC patency. However, time, extending the infusion time to one should always consider the risk 240 minutes.32 With some slight of bleeding associated with variations, in this review, most thrombolytic therapy, especially when studies in which alteplase was used the drug is used in children younger followed the recommended than 2 years and those weighing treatment times. ,10 kg because there are few studies in this population. The risk of Alteplase was generally well tolerated catheter thrombosis and associated in clinical trials in pediatric complications was significantly populations, with a reported low higher in young children and those incidence of AEs such as sepsis, minor with low weight. Higher risk was bleeding (gastrointestinal bleeding, associated with the relatively greater hematomas), fever, and venous size of the catheter compared with FIGURE 3 thrombosis.32 The studies included in that of the small vessel lumen, Methodologic appraisal of selected studies this review reported AEs considered based on MINORS. reduced plasma levels of plasminogen serious and related to the drug, and antithrombin III, and low including 1 case of sepsis and 1 case catheter flow when compared with with different dose standardizations of catheter rupture. Particular that in older children.26 In addition, in relation to the child’s weight, attention should be paid to sepsis there was a risk of systemic infusion differing from the recommendations because a positive correlation was of alteplase because of reduced described previously. observed between the use of alteplase priming of pediatric catheters. for treatment of occluded catheters There are some differences in the and the development of CVC- Until 1999, urokinase was used literature related to the drug infusion associated bloodstream infection. worldwide in pediatric centers for time; however, the FDA and the This correlation probably reflects the treatment of CVC occlusion. However, manufacturer recommend that potential of the thrombus to contain in January 1999, the FDA withdrew

TABLE 2 GRADE’s Summary of Findings Table Certainty Assessment Certainty No. Studies Study Design Risk of Inconsistency Indirectness Imprecision Other Bias Considerations Restoration of catheter function with thrombolytic therapy 9 Clinical trials and Seriousa Seriousb Not serious Seriousc None ⨁◯◯◯very observational studies low Restoration of catheter function with alteplase 6 Clinical trials and Seriousa Seriousd Not serious Not serious None ⨁⨁◯◯low observational studies Restoration of catheter function with urokinase 2 Clinical trials and Seriousa Seriouse Not serious Not serious None ⨁⨁◯◯low observational studies Question: What is the efficacy of interventions used to treat thrombotic catheter occlusion in pediatric patients with cancer? a All included studies are nonrandomized with the absence of blinding and a control group. b I2 = 62.86%. c Use of different doses and different infusion times. d I2 = 59.86%. e I2 = 61.32%.

Downloaded from www.aappublications.org/news by guest on September 28, 2021 10 COSTA et al urokinase from the market because of studies included in this review. In a meta-analysis, alteplase appeared to suspected transmission of infectious addition, no drug-related AEs were be superior to other interventions. agents associated with its use.34 reported in the studies. Urokinase is a type of plasminogen Because of high heterogeneity in the activator that also converts Studies conducted in the 1990s doses of the thrombolytics studied, plasminogen to plasmin and has revealed that some catheters might the duration of infusion of these a half-life of ∼12 minutes. Although have undergone multiple treatments drugs should be considered in clinical urokinase derived from human cells with urokinase. This partial treatment practice because a shorter infusion was withdrawn from the market in of occlusion might have led to time optimizes the use of medical the late 1990s, this form is still inadequate lysis of the thrombus and resources and avoids delays in available for use in Europe, having formation of a nidus for infection, treatment, increased costs, and been replaced by the recombinant thus increasing the risk of CVC- associated complications. form derived from nonhuman cells in associated bloodstream infection and Moreover, the safety factor is North America on the basis of FDA associated complications.34 Infectious 10 fundamental, especially in the recommendations. complications related to the use of pediatric population. Although the urokinase were not reported in the Studies have reported the use of authors of the studies included in this studies in this systematic review. urokinase in different doses, both for review considered thrombolytic therapy as safe for restoration of CVC intraluminal bolus administration and Streptokinase, a thrombolytic agent patency, more vigilance and follow-up for extended systemic infusion, with produced by b-hemolytic group C 5 protocols should be instituted when varying infusion times. The Italian streptococci, is a single-chain these drugs are used in children. The Association of Pediatric Hematology polypeptide that reacts with lack of well-established clinical and Oncology recommends use of circulating plasminogen, converting it protocols, the use of varied urokinase for treatment of CVC to plasmin and forming concentrations of drugs (often with occlusion at a bolus dose of 5000 IU/ streptokinase-plasmin complexes. mL, with an infusion time of 15 to no adequate correlation with child The streptokinase-plasmin complex 60 minutes (recommendation IIB). In weight or occluded CVC intraluminal has increased thrombolytic activity the case of persistent CVC occlusion volume), and the paucity of studies in compared with that of plasmin that is resistant to intraluminal more vulnerable pediatric because it is not inactivated by a - thrombolysis, and in the absence of 2 populations (low weight and young) antiplasmin and a -macroglobulin. catheter-related thrombosis, systemic 2 induces an increased risk of AEs Streptokinase has a half-life of 18 to urokinase infusion is indicated at (especially hemorrhagic events) 30 minutes, with an associated lytic 1000 IU/kg per hour for 3 hours, and associated with therapy. effect ranging from 82 to may be repeated for a maximum of 184 minutes.10 Streptokinase was Another important factor to be taken 12 hours, or at a dose of 200 IU/kg widely used in the 1970s and 1980s; into account in the use of per hour for up to 24 hours however, it induced the formation of thrombolytics in clinical practice is (recommendation IIB).5 In most of antibodies, which led to resistance to cost-effectiveness. Despite the the studies in this systematic review, treatment, as well as allergic efficacy and safety demonstrated in doses were used in accordance with reactions, such as fever, hypotension, this population, the cost of drugs may the literature. urticaria, and bronchospasm, after be an impediment to their use in A study34 conducted in several repeated infusions.10 Thus, some centers. In the case of alteplase, pediatric oncology and hematology streptokinase is not considered to be despite the high cost, 1 study35 centers revealed a low incidence of a good alternative for treatment of revealed that its use in clearing long- complications with use of urokinase CVC occlusion because of FDA term CVCs was significantly less (9%). Allergic reactions, fever and warnings about the serious risk of costly than catheter removal and tremors, generation of microemboli, anaphylaxis and the possibility of replacement. This study revealed the and minor hemorrhagic events were death.26 cost/benefit in the use of alteplase reported. According to the not only in reducing hospitalization manufacturer, urokinase is A qualitative data analysis revealed time but also in reducing the use of contraindicated in patients with that similar restoration rates were other services, such as radiology, central nervous system neoplasms observed between studies in which laboratory, and nursing care, and because of the risk of intracranial alteplase and urokinase were used, material resources in general. In the bleeding.34 However, no reports of with a marked decrease in efficacy case of urokinase, the authors of 1 this restriction of use or of severe with use of streptokinase. However, study36 showed that its use in the bleeding events were found in the when the data were evaluated in pediatric population was cost-

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 144, number 6, December 2019 11 effective, finding a high success rate for use in the preparation of robust drugs are used in children, in restoration of CVC patency (98%), drug protocols, including especially in more vulnerable with the estimated cost for catheter concentration and infusion time, to populations (low weight and very replacement .20 times greater than standardize and guide clinical young). The impact of our results that for use of the drug. practice for restoration of catheter may affect catheter management, As a methodologic limitation of this function. safety, and quality of life in pediatric patients with cancer. review, we highlight the exclusion of The authors of only 2 studies8,22 reference studies with representative reported AEs related to thrombolytic samples and the use of other therapy; this is an important item to thrombolytics not described here that consider in designing future studies. ABBREVIATIONS met the main outcome of this review AE: adverse event (restoration of CVC function). CONCLUSIONS CENTRAL: Central Register of However, some of these studies had Controlled Trials a mixed population, and others had In view of the evidence obtained, the CINAHL: Cumulative Index to different types of catheters, and it most common interventions used for Nursing and Allied was not possible to reliably extract treatment of thrombotic catheter Health Literature the necessary data for the analysis; occlusion in pediatric patients with CVC: central venous catheter even after attempting to contact the cancer were alteplase and urokinase. FDA: US Food and Drug authors by e-mail, it was not possible The studies included in this Administration to aggregate this data for the review. systematic review revealed that GRADE: Grading of Recommendations thrombolysis is effective and All included studies had a risk of bias Assessment Development potentially safe in this population, related to the study population and and Evaluation with slight superiority of alteplase the high heterogeneity between the LILACS: Latin American and when compared with other doses used and infusion times; Caribbean Health interventions. moreover, the quality of the evidence Sciences Literature generated was not substantial. Although thrombolytic therapy is MINORS: Methodological Index for Although the evidence that was found considered safe for restoration of Nonrandomized Studies tends to reiterate the success of patency in occludedcatheters,more TC: tunneled catheter thrombolytic therapy in the pediatric vigilance and follow-up protocols TIC: totally implanted catheter population, there are insufficient data should be instituted when these

Address correspondence to Ana Cristina Carvalho da Costa, RN, PhD, Interdisciplinary Research Laboratory Applied to Clinical Practice in Oncology, Faculty of Health Sciences, University of Brasília, Rua 36 Norte, 3350, bloco D, apartamento 102 Águas Claras, Brasília-DF 71919-180, Brazil. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2019 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: No external funding. POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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Downloaded from www.aappublications.org/news by guest on September 28, 2021 14 COSTA et al Interventions for Occluded Central Venous Catheters: A Meta-analysis Ana Cristina Carvalho da Costa, Nayara Narley Pires Vieira, Christiane Inocêncio Vasques, Elaine Barros Ferreira, Eliete Neves Silva Guerra and Paula Elaine Diniz dos Reis Pediatrics 2019;144; DOI: 10.1542/peds.2018-3789 originally published online November 22, 2019;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/144/6/e20183789 References This article cites 31 articles, 4 of which you can access for free at: http://pediatrics.aappublications.org/content/144/6/e20183789#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Hematology/Oncology http://www.aappublications.org/cgi/collection/hematology:oncology _sub Pharmacology http://www.aappublications.org/cgi/collection/pharmacology_sub Therapeutics http://www.aappublications.org/cgi/collection/therapeutics_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 28, 2021 Interventions for Occluded Central Venous Catheters: A Meta-analysis Ana Cristina Carvalho da Costa, Nayara Narley Pires Vieira, Christiane Inocêncio Vasques, Elaine Barros Ferreira, Eliete Neves Silva Guerra and Paula Elaine Diniz dos Reis Pediatrics 2019;144; DOI: 10.1542/peds.2018-3789 originally published online November 22, 2019;

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