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Journal of Clinical Oncology, Vol 24, No 28 (October 1), 2006: pp. 4575-4580 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.5343 Catheter-Related Deep Venous Thrombosis and Other Catheter Complications in Children With Cancer
From the University of Texas Southwestern Medical Center at Dallas, Division of Hematology-Oncology, Department of Pediatrics, and Children's Medical Center Dallas, Dallas, TX Address reprint requests to Janna M. Journeycake, MD, Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75390-9063; e-mail: Janna.Journeycake{at}childrens.com
PURPOSE: Asymptomatic deep vein thrombosis (DVT) is a complication of central venous catheter (CVC) use in children with cancer, but its clinical significance is not well defined. Children with CVCs commonly experience two other CVC-related complications: occlusion and infection. The aim of this study was to determine the frequency of these two complications and their association with DVT. PATIENTS AND METHODS: We conducted a retrospective cohort study of patients who were diagnosed with cancer. Data collected included number and type of catheter insertions, duration of use, reason for removal, associated catheter complications, and demographic information. RESULTS: Catheters were placed in 287 patients for a total of 128,403 days (mean, 290 ± 269 days/catheter). Of 21 patients (7%) diagnosed with CVC-related DVT, only five had specific signs or symptoms. Nineteen (90%) of these 21 children had prior history of catheter occlusion, and 10 of the 19 also experienced infection. Ten children (48%) were not identified as having DVT until they had had multiple catheters with recurrent complications. Odds of having DVT were higher in patients who had a single catheter complicated by repeated occlusions (odds ratio [OR], 3.7; P = .001) or infection (OR, 2.2; P = .016). Patients experiencing both infection and occlusion were at 6.4 times (P < .0001) higher risk of developing DVT. CONCLUSION: Children with CVC-related DVT frequently have recurrent catheter complications. Unrecognized thrombosis may therefore be clinically important. Prospective studies are needed to determine if identification and treatment of occult DVT will prevent additional CVC-related complications and prolong the duration of catheter use.
Tunneled central venous catheters (CVCs) inserted into the upper venous system are standard in the treatment of childhood cancer because they allow for consistent and rapid intravenous access for chemotherapy, antibiotics, and nutritional support. However, potentially serious and life-threatening complications of CVCs could lead to the inability to obtain blood for testing, delays in therapy, hospitalization, the need for catheter replacement, and possibly death. The most commonly encountered complications are catheter occlusion, infection, and deep venous thrombosis (DVT). Limited data exist regarding the incidence and clinical significance of CVC-related thrombosis in children with cancer, even though its prevalence is reported to be as high as 50%.1 The prevalence of this complication is also high in adults who have cancer (27% to 66%).2 Most affected patients do not have signs or symptoms of acute DVT, such as extremity or facial swelling, pain, or pulmonary embolism.1,2 The diagnosis is usually made radiographically in asymptomatic patients. However, we speculated that recurrent episodes of bacteremia or catheter occlusion could be clinical correlates of seemingly occult DVT. Therefore, we investigated the relationships among bacteremia, occlusion, and DVT in children with cancer and CVCs. We hypothesized that these complications would be more frequent in patients who had DVT confirmed by imaging study.
We conducted a retrospective cohort study of patients with cancer at Children's Medical Center Dallas (Dallas, TX) between January 1, 1999, and December 31, 2001, who had catheters inserted to facilitate therapy. Data collected from the patients' records included the number and types of catheters inserted, catheter location, duration of catheter use, episodes of catheter-related bacteremia or fungemia, episodes of catheter occlusion, patient age and sex, and type of cancer. We also reviewed pharmacy records and infection control reports to ensure data accuracy. The study was approved by the Institutional Review Board of the University of Texas Southwestern Medical Center at Dallas.
Definitions
Institutional Clinical Guidelines
Statistical Analysis
Study Population Four hundred sixty-nine children were diagnosed with cancer in our center during the 3-year study period. Of these, 287 (61%) had one or more temporary or tunneled CVCs. All patients had their first catheters placed within 30 days of the diagnosis of cancer.
Catheters
Thirty-one patients underwent at least one imaging study to evaluate the status of their catheters and/or associated vessels. The primary indications for radiographic examination were catheter dysfunction (n = 21), acute arm and neck pain and swelling (n = 4), or the desire of the pediatric surgeon to determine the best location for placement of another CVC after multiple catheters had been inserted into the patient (n = 6).
Catheter-Related Complications
Catheter Occlusion
Catheter Infection
DVT
Although there were no differences in the age, sex, or ethnicity of patients with or without thrombosis, children diagnosed with lymphoblastic leukemia/lymphoma (P < .001) were represented disproportionately among those identified with DVT. One of these children (patient 4) had DVT identified during induction chemotherapy, and two others (patients 10 and 12) were diagnosed during consolidation. Patients with T-cell disease were treated with regimens that included many weeks of asparaginase therapy. Table 3 compares the characteristics between patients with and without confirmed CVC-related DVT.
Patients who developed DVT had on average more catheters placed (2.7 ± 1.9) than those without DVT (1.5 ± 0.8; P = .006). Ten of the 21 children with DVT had had multiple catheters inserted before thrombosis was identified. DVT was sometimes noted at the site of a previous CVC in the upper venous system distant from the vessel in which the current catheter was placed, so the timing of the thrombotic events usually could not be determined.
Clinical Correlates of DVT
Nineteen of 21 patients with thrombosis (90%) experienced catheter occlusion on at least one occasion. Ten (47%) of these children also had CVC-related bacteremia before diagnosis of DVT. Thirty-three (12%) of the 266 patients not diagnosed as having CVC-related DVT had a history of both infectious and occlusive complications involving one or more catheters, but only one of these patients was screened with an imaging study. Having multiple episodes of occlusion and infection was associated with unrecognized DVT. Of the 16 patients with asymptomatic DVT, 14 (88%) had two or more catheter-related complications before identification of the thrombus. The OR for DVT in patients with repeated catheter occlusion was 3.0 (95% CI, 1.2 to 7.5; P = .016). The OR for DVT in patients with both infection and occlusion was 6.4 (95% CI, 2.5 to 15.9; P < .0001). Table 5 depicts the risk of being diagnosed with DVT when catheter complications involved any prior catheter.
The primary risk factor for DVT in children with cancer is having a CVC.4,5 Thrombosis frequently is triggered by damage to vascular endothelium from the insertion of the catheter or administration of chemotherapy,6 and further stimulated by inflammatory responses associated with infection and chronic illness. Tolar and Gould7 first suggested that various catheter complications were inter-related, and that catheter complications led to the development of venous thrombosis. Thirty percent of patients in their study who had catheter-related problems subsequently developed thrombosis. In our large study of children with cancer, we also observed a relationship between specific catheter complications and DVT. We report here a 39% incidence of catheter occlusion leading to dysfunction, which is consistent with published rates.3,8,9 The occlusion is often caused by a small clot within or surrounding the tip of the catheter lumen and managed by local instillation of a thrombolytic agent. Recombinant tPA, now the most common agent used to restore catheter patency, has been shown to be safe and effective.3,8,9 In our study population, tPA was successful 89% of the time. Possible reasons for failure of tPA include presence of a fibrin sheath extending over the tip of the catheter or a nonocclusive large vessel thrombus encasing the catheter tip.10,11 If such a thrombus is not identified, it potentially could be a nidus for bacterial infection. In addition, the thrombus could extend and lead to complete occlusion of catheter or possibly symptomatic DVT. The incidence of catheter-related infection has been well defined in previous reports,12-14 but only recently have studies started to focus on exploring the possible correlation of catheter-related bacteremia with local thrombosis involving either the catheter tip or the major vein in which the catheter had been placed. A study of 72 autopsies demonstrated an association between thrombosis and infection in that all seven episodes of catheter-related sepsis occurred among the 31 individuals who also had DVT at the catheter site, suggesting that an infected thrombus played a role in the septic event.15 Several other studies have demonstrated that a decreased rate of catheter tip and large vessel thrombosis as well as infection resulted from regularly flushing catheters with thrombolytic agents or by using catheters bonded with heparin.12,16-18 A recent report from the Children's Oncology Group found that urokinase flushes every 2 weeks extended the interval before a first occlusive event and reduced the overall catheter complication rate.18 In children with external catheters, the rate of infection was also reduced.18 Therefore, if local thrombin generation could be prevented, infections might be prevented as well. A recent report of 105 adolescent and adult patients with hematologic malignancy suggested that those who had catheter infection were at increased risk of developing symptomatic DVT (relative risk, 17.6; 95% CI, 4.1 to 74.1).19 Although the authors concluded that infection was likely to precede symptomatic DVT, radiographic imaging was not performed in this study unless there was a suggestion of thrombosis. Thus, it is plausible that occult DVT actually antedated and contributed to the infections. Finally, a recent report described 43 adult leukemia patients who had nontunneled jugular CVCs and were screened with ultrasonography every 4 days. Thirteen patients (30%) developed local thrombosis, and four of them also had bacteremia.20 Interestingly, two of the four patients had thrombosis identified 1 day before signs and symptoms of infection, indicating that DVT preceded and may have contributed to the development of bacteremia. These reports suggest that the presence of DVT may increase the risk of bacteremia. If CVC-related DVT were the initial complication, its identification and treatment could be critical in the prevention of subsequent catheter-related infection and the possible need for CVC removal. This retrospective study is limited because routine screening for asymptomatic DVT was not performed. Although nearly every patient with more than one occlusive episode had imaging to assess the catheter function, 33 patients with multiple occlusions and/or infections were not screened. Therefore, we have likely underestimated the rate of asymptomatic catheter-related DVT. However, we have defined here a strong association between DVT confirmed by imaging studies and other troublesome catheter complications. The DVT risk seems to be highest in patients who had a history of multiple catheters with complications, a single catheter associated with infection, or repeated episodes of occlusion. Conversely, it seems to be uncommon for a patient without any catheter complications to develop DVT. Although most patients with catheter-related thrombosis have none of the commonly expected signs and symptoms, our results suggest that these thrombi may not be truly clinically silent. In our cohort, many patients with CVC-related DVT had already had their catheters replaced because of infection or occlusive complications. In theory, DVT may have contributed to the recurrence of complications or the need for replacement. Had thrombosis been identified earlier, therapeutic anticoagulation might have prevented the need for additional catheters, minimized interruptions in therapy, and decreased episodes of serious infection. We believe that prospective studies are necessary to define further the scope of asymptomatic CVC-related DVT, possibly followed by a randomized clinical trial to study the risks and benefits of anticoagulation in this patient population.
The authors indicated no potential conflicts of interest.
We thank Naveed Ahmad, MD, Matthew Porteus, MD, PhD, Patrick Leavey, MD, and Charles Quinn, MD, for the valuable assistance with data analysis and review of the manuscript.
Supported by National Institutes of Health Institutional National Research Service Award T32 CA09640, Wipe Out Kids Cancer, Children's Cancer Fund, and Children Helping Children Research Fund. Presented in part at the 44th Annual Meeting of the American Society of Hematology, Philadelphia, PA, December 6-10, 2002. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Glaser DW, Medeiros D, Rollins N, et al: Catheter-related thrombosis in children with cancer. J Pediatr 138:255-259, 2001[CrossRef][Medline] 2. Verso M, Agnelli G: Venous thromboembolism associated with long-term use of central venous catheters in cancer patients. J Clin Oncol 21:3665-3675, 2003 3. Deitcher SR, Fesen MR, Kiproff PM, et al: 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 20:317-324, 2002 4. Massicotte MP, Dix D, Monagle P, et al: Central venous catheter related thrombosis in children: Analysis of the Canadian registry of venous thromboembolic complications. J Pediatr 133:770-776, 1998[CrossRef][Medline] 5. Nowak-Gottl U, Kosch A, Schlegel N: Thromboembolism in newborns, infants and children. Thromb Haemost 86:464-474, 2001[Medline] 6. Yee AYY, Levine MN: The thrombophilic state induced by therapeutic agents in the cancer patient. Semin Thromb Hemost 25:137-145, 1999[Medline] 7. Tolar B, Gould JR: The timing and sequence of multiple device-related complications in patients with long-term indwelling Groshong catheters. Cancer 78:1308-1312, 1996[CrossRef][Medline] 8. Wang M, Hays T, Balasa V, et al: Low-dose tissue plasminogen activator thrombolysis in children. J Pediatr Hematol Oncol 25:379-386, 2003[CrossRef][Medline] 9. Shen V, Li X, Murdock M, et al: Recombinant tissue plasminogen activator (alteplase) for restoration of function to occluded central venous catheters in pediatric patients. J Pediatr Hematol Oncol 25:38-45, 2003[CrossRef][Medline] 10. Journeycake JM, Buchanan GR: Thrombotic complications of central venous catheters in children. Curr Opin Hematol 10:369-374, 2003[CrossRef][Medline] 11. Xiang DZ, Verbeken EK, Van Lommel ATL, et al: Sleeve-related thrombosis: A new form of catheter-related thrombosis. Thromb Res 104:7-14, 2001[CrossRef][Medline] 12. Hanna H, Benjamin R, Chatzinikolaou I, et al: Long-term silicone central venous catheters impregnated with minocycline and rifampin decrease rates of catheter-related bloodstream infection in cancer patients: A prospective randomized clinical trial. J Clin Oncol 22:3163-3171, 2004 13. Cesaro S, Corro R, Pelosin A, et al: A prospective survey on incidence and outcome of Broviac/Hickman catheter-related complications in pediatric patients affected by hematological and oncological diseases. Ann Hematol 83:183-188, 2004[CrossRef][Medline] 14. Wurzel CL, Halom K, Feldman JG, et al: Infection rates of Broviac-Hickman catheters and implantable venous devices. Am J Dis Child 142:536-540, 1988 15. Raad II, Luna M, Khalil SA, et al: The relationship between the thrombotic and infectious complications of central venous catheters. JAMA 271:1014-1016, 1994 16. Henrickson KJ, Axtell RA, Hoover SM, et al: Prevention of central venous catheter-related infections and thrombotic events in immunocompromised children by the use of vancomycin/ciprofloxacin/heparin flush solution: Randomized, multicenter, double-blind trial. J Clin Oncol 18:1269-1278, 2000 17. Pierce CM, Wade A, Mok Q: Heparin-bonded central venous lines reduce thrombotic and infective complications in critically ill children. Intensive Care Med 26:967-972, 2000[CrossRef][Medline] 18. Dillon PW, Jones GR, Bagnall-Reeb HA, et al: Prophylactic urokinase in the management of long-term venous access devices in children: A Children's Oncology Group Study. J Clin Oncol 22:2718-2723, 2004 19. van Rooden CJ, Schippers EF, Barge RMY, et al: Infectious complications of central venous catheters increase the risk of catheter-related thrombosis in hematology patients: A prospective study. J Clin Oncol 23:2655-2660, 2005 20. Lordick F, Hentrich M, Decker T, et al: Ultrasound screening for internal jugular vein thrombosis aids the detection of central venous catheter-related infections in patients with haemato-oncological diseases: A prospective observational study. Br J Haematol 120:1073-1078, 2003[CrossRef][Medline] Submitted December 29, 2005; accepted July 27, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
= .05. 
