|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 23, No 13 (May 1), 2005: pp. 3024-3029 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.12.097 Central Venous Lines in Children With Lesser Risk Acute Lymphoblastic Leukemia: Optimal Type and Timing of PlacementFrom the Departments of Pediatrics and Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC Address reprint requests to Thomas W. McLean, MD, Department of Pediatrics, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157; e-mail: tmclean{at}wfubmc.edu
PURPOSE: In pediatric patients with acute lymphoblastic leukemia (ALL), the optimal time for central venous line (CVL) insertion and the optimal type of CVL (internal v external) is unclear. This study was undertaken to compare complication rates between early versus late line insertion, and between internal versus external lines in children with lesser risk ALL. PATIENTS AND METHODS: We performed a retrospective analysis of patients enrolled onto Pediatric Oncology Group (POG) protocol 9201. Data regarding demographics, CVL types and insertion dates, blood counts, and complications were reviewed through week 25 of therapy.
RESULTS: Of 697 patients enrolled onto POG protocol 9201, 362 patients had sufficient data for analysis. When compared to late line placement (> day 15 of induction), early CVL placement ( CONCLUSION: In pediatric patients with lesser risk ALL, internal lines (ports) should be the preferred CVL type due to a lower risk of infectious and thrombotic complications. In addition, CVLs placed early in induction are associated with a higher risk of positive blood culture than those placed later in induction.
Central venous lines (CVLs) are widely used in pediatric oncology, though the optimal timing for insertion and type of CVL in pediatric patients with acute lymphoblastic leukemia (ALL) are unknown. Within the pediatric ALL population, we have observed interinstitutional variation in the timing of CVL insertion. Although individual circumstances vary, some institutions insert the CVL at the beginning of remission induction therapy, while others delay CVL placement until the patient has entered remission (typically 4 weeks from initiation of therapy). Although children with ALL are often neutropenic at diagnosis, early placement is often performed because of the added convenience and comfort of having a CVL in place during remission induction. A number of studies have addressed CVL complications in oncology patients (pediatric and adult), but data are sparse regarding optimal timing of CVL placement in pediatric ALL patients.1–15 The present study was undertaken to address the issues of optimal timing and type of CVL placement, relative to risks such as infection and thrombosis, in pediatric patients with lesser risk ALL. We hypothesized that early CVL placement and external CVLs are associated with higher complication rates compared to late CVL placement and internal CVLs.
Patients The treatment protocol was opened June 8, 1992 as a pilot study to assess feasibility. A second pilot study and the phase III study (Pediatric Oncology Group [POG] protocol 9201) enrolled a total of 697 patients through November 15, 1999. Eligibility criteria included patients aged 1 to 10 years with B-precursor ALL with an initial peripheral WBC lower than 50,000/mm3 and no overt CNS disease. In addition, patients' leukemia cells must have had simultaneous trisomy of chromosomes 4 and 10 (or, if genetic testing was uninformative, a DNA index of > 1.16) along with the absence of poor-risk lesions [t(1;19), t(9;22), and 11q23 rearrangements]. POG Protocol 9201 was approved by the Wake Forest University School of Medicine institutional review board, and informed consent was obtained for all patients. Similarly, institutional review board approval and informed consent was obtained by the treating institution for each patient registered onto the study. In addition, the present study was approved by the ALL Committee Chair of the POG (B. Camitta, personal communication, 2001).
Therapy
Data Collection
Data Analysis
Patients Flow sheets for all 697 patients were reviewed in detail through week 25 of therapy. Toxicity reporting, including infections and thromboses, was required by each treating institution. Reporting data on the presence or absence of CVL, type of CVL, and date of CVL placement was not required, but many patients' flow sheets did contain these data. Only the patients whose flow sheets contained data from these items were included in this report. Of 697 protocol-registered patients, 362 patients (52%) had sufficient data available for analysis (Fig 1). Patient characteristics are listed in Table 1.
Of the 362 eligible patients, all achieved remission after 4 weeks of induction chemotherapy. One hundred eighty-two patients (50%) had a documented fever during the first 25 weeks of therapy. During this time period, 22 patients (6%) had a documented thrombosis associated with their CVL. Fifty patients (14%) had their CVL removed. Sixty patients (17%) had a positive blood culture, and 85 patients (23%) had a documented infection of any type (including positive blood cultures). All positive blood cultures were bacterial in etiology except in two patients who had fungal isolates: one of those two patients had an external CVL placed early, and the other had a port placed early. Two hundred eighty-five patients had data on both CVL type and timing of CVL placement. The majority of patients (53%) had an internal line (port) placed early. The primary outcomes assessed for this study were positive blood culture, CVL-associated thrombus, and CVL removal for any reason. There were no deaths associated with CVL placements or CVL complications.
Internal Versus External CVLs
Timing of CVL Placement Of the 362 patients, 339 patients had sufficient data regarding timing of CVL placement. Of these 339 patients, 234 patients (69%) had a CVL placed early, (defined as on or before day 15 of induction therapy; range, day –3 to day 15); 105 patients (31%) had CVLs placed late (defined as day 16 or later of therapy; range, day 16 to day 133). By multivariate analysis, when compared to late line placement, early CVL placement was associated with an increased risk of having a positive blood culture (odds ratio, 2.2; 95% CI, 1.0 to 5.0; P = .05), even when adjusted for age, sex, race, institution, and type of CVL (internal v external; Table 2). Early CVL placement was not independently associated with thrombosis or CVL removal. The association of a positive culture with early CVL placement was also independent of ANC at the time of CVL placement (data not shown).
ANC
This study defines the independent contribution of CVL type to the risk of infectious and thrombotic complications among a large group of pediatric patients with lesser risk ALL, all of whom received essentially identical treatment. We found that, when compared with external CVLs, internal CVLs had a lower rate of infection, thrombosis, and need for removal. This finding was independent of the timing of CVL placement (early v late) and ANC at the time of CVL placement. We also found that CVLs placed later in induction therapy (on or after day 16 of induction) were associated with a lower rate of positive blood culture than those placed early (day –3 to day 15). The literature comparing CVL type (internal v external) and the risk of infection is controversial,1,15–19 but most institutions currently favor ports over external CVLs. In our study, 17% of assessable patients had external CVLs placed. Our results support a lower rate of infection for internal CVLs. Although the exact reasons are unknown, infection risk is likely related to several characteristics of external CVLs: a permanent breach in the skin integrity, increased manipulation (both intentional and unintentional), and the practice of more frequent flushing. The issues of perioperative antibiotic prophylaxis14 and antibiotic-impregnated catheters20–22 have been raised but not well studied in this population. Other strategies to prevent CVL complications have recently been reviewed,23 as have conditions associated with CVL infection.24 Our data are in agreement with the findings of Ingram et al18 that external CVLs have more occlusion or thrombosis than internal CVLs. In that study, catheter diameter was suggested as one possibility for the observed difference between external and internal CVLs. Like infection risk, the amount of manipulation required of external CVLs may be a contributing factor to thrombosis risk. A recent study showed that CVL thrombosis risk is influenced by location of the CVL and insertion technique,6 neither of which were assessed in our study. The overall risk of thrombosis in children with ALL is exacerbated by L-asparaginase therapy.25 L-asparaginase therapy would explain any increased risk of thrombosis for CVLs placed early, but it would not explain the increased risk for external CVLs compared to internal CVLs. While CVL-related thrombosis has been well documented in children,12 primary thrombotic prophylaxis is not current standard practice in children with ALL, because no controlled trial has been published documenting safety and efficacy. Evidence indicates that neutropenia is an independent risk factor for infection related to CVLs, and for sepsis of unknown origin.14,26 Shaul et al14 indicate that neutropenia and the failure to administer prophylactic antibiotics are risk factors for the development of early CVL infection in pediatric patients. To avoid early infection and possible premature CVL removal, the authors recommend that placement of permanent CVLs be postponed until the ANC is higher than 1,000/mm3. Perioperative antibiotic administration is also recommended.14 Our data support neutropenia as a contributing factor to the risk of CVL removal, though it is difficult to determine an independent effect of ANC because the patients' ANC generally improved during induction. To our knowledge only one previous study19 has assessed the timing of CVL placement as a risk factor in a similar population. In that study, "early" was defined as during the first 3 weeks of induction therapy, and was not found to be a risk factor for infection. However, the study reported an unusually high rate of infections, was relatively small (n = 148), and was from a single institution.19 For some patients, for example, those with difficult intravenous access, the benefits of inserting a port early in induction therapy may outweigh the risks. The benefits of early CVL placement include reduced pain of phlebotomy and reliable access for medication administration (including at least one vesicant, vincristine) during the first 4 weeks of therapy. Certainly, the risks and benefits for individual patients must be considered. In general, however, the results of our study show that external CVLs and early placement of CVLs are associated with a higher risk of complications compared with internal CVLs and late placement of CVLs. This study is limited by its retrospective nature and the fact that it did not include all patients on POG protocol 9201. Some patients had missing data regarding CVL type and timing of placement. Thus, it is possible that a selection bias exists in these data, with patients who had complications more likely to have data than those who did not have complications. It is also possible that thrombolytic agents such as urokinase or alteplase (t-PA) were used in some patients but not recorded on the data flow sheets. Thus, the rate of thrombosis may be underestimated in this study. Data regarding the complications were recorded only through week 25 of therapy. However, it is our opinion that CVL complications beyond week 25 are unlikely to be related to the timing of insertion. This theory is supported by the rare occurrence of CVL complications at week 25 in our patients. Patients who had their CVLs placed early obviously had a longer time period to develop complications, and our results suggest that this extra time (during induction therapy) is the high-risk period. Therefore, we believe that CVLs placed early are at higher risk of complication due to the additional CVL exposure time during the first weeks of therapy. Although it could be argued that the distinction between early and late placement (day 15 of induction) is arbitrary, this cutoff was chosen based on the bimodal distribution of the data. Because it is generally hoped that a CVL will last throughout treatment (130 weeks in POG 9201), the results of this study should be considered when scheduling CVL placement in this patient population. Another limitation of this study is that only lesser risk ALL patients were included. As remission rates are similar for standard and even high-risk ALL patients, it is possible that these results may be applicable to other pediatric patients with ALL. It should be emphasized, however, that patients receiving more intensive therapy were not included in this study. In summary, these data show that for pediatric patients with lesser risk ALL, CVLs placed early and external CVLs are associated with higher complication rates. We recommend that internal CVLs (ports) should be the line of choice. To minimize infectious and thrombotic complications, consideration should be given to delaying port placement until the end of remission induction therapy. Prospective studies are needed to further clarify optimal timing for CVL placement in these and other ALL patients.
The authors indicated no potential conflicts of interest.
Presented in part at the 15th Annual Meeting of the American Society of Pediatric Hematology/Oncology and Pediatric Academic Society, Baltimore, MD, May 2-5, 2002. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Wiener ES, McGuire P, Stolar CJ, et al: The CCSG prospective study of venous access devices: An analysis of insertions and causes for removal. J Pediatr Surg 27:155–163, 1992[CrossRef][Medline] 2. Johnson EM, Saltzman DA, Suh G, et al: Complications and risks of central venous catheter placement in children. Surgery 124:911–916, 1998[Medline] 3. van Hoff J, Berg AT, Seashore JH: The effect of right atrial catheters on infectious complications of chemotherapy in children. J Clin Oncol 8:1255–1262, 1990[Abstract]
4. Cairo MS, Spooner S, Sowden L, et al: Long-term use of indwelling multipurpose silastic catheters in pediatric cancer patients treated with aggressive chemotherapy. J Clin Oncol 4:784–788, 1986 5. Rackoff WR, Ge J, Sather HN, et al: Central venous catheter use and the risk of infection in children with acute lymphoblastic leukemia: A report from the Children's Cancer Group. J Pediatr Hematol Oncol 21:260–267, 1999[CrossRef][Medline]
6. Male C, Chait P, Andrew M, et al: Central venous line-related thrombosis in children: Association with central venous line location and insertion technique. Blood 101:4273–4278, 2003 7. Dawson S, Pai MK, Smith S, et al: Right atrial catheters in children with cancer: A decade of experience in the use of tunnelled, exteriorized devices at a single institution. Am J Pediatr Hematol Oncol 13:126–129, 1991[Medline] 8. Kappers-Klunne MC, Degener JE, Stijnen T, et al: Complications from long-term indwelling central venous catheters in hematologic patients with special reference to infection. Cancer 64:1747–1752, 1989[CrossRef][Medline] 9. Abrahm JL, Mullen JL: A prospective study of prolonged central venous access in leukemia. JAMA 248:2868–2873, 1982[Abstract] 10. Reilly JJ Jr, Steed DL, Ritter PS: Indwelling venous access catheters in patients with acute leukemia. Cancer 53:219–223, 1984[CrossRef][Medline] 11. Gorelick MH, Owen WC, Seibel NL, et al: Lack of association between neutropenia and the incidence of bacteremia associated with indwelling central venous catheters in febrile pediatric cancer patients. Pediatr Infect Dis J 10:506–510, 1991[Medline] 12. 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] 13. Landoy Z, Rotstein C, Lucey J, et al: Hickman-Broviac catheter use in cancer patients. J Surg Oncol 26:215–218, 1984[Medline] 14. Shaul DB, Scheer B, Rokhsar S, et al: Risk factors for early infection of central venous catheters in pediatric patients. J Am Coll Surg 186:654–658, 1998[CrossRef][Medline] 15. 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[Abstract] 16. Mueller BU, Skelton J, Callender DP, et al: A prospective randomized trial comparing the infectious and noninfectious complications of an externalized catheter versus a subcutaneously implanted device in cancer patients. J Clin Oncol 10:1943–1948, 1992[Abstract] 17. Decker MD, Edwards KM: Central venous catheter infections. Pediatr Clin North Am 35:579–612, 1988[Medline] 18. Ingram J, Weitzman S, Greenberg ML, et al: Complications of indwelling venous access lines in the pediatric hematology patient: A prospective comparison of external venous catheters and subcutaneous ports. Am J Pediatr Hematol Oncol 13:130–136, 1991[Medline] 19. Abbas AA, Fryer CJ, Paltiel C, et al: Factors influencing central line infections in children with acute lymphoblastic leukemia: Results of a single institutional study. Pediatr Blood Cancer 42:325–331, 2004[CrossRef][Medline]
20. Raad I, Darouiche R, Dupuis J, et al: Central venous catheters coated with minocycline and rifampin for the prevention of catheter-related colonization and bloodstream infections: A randomized, double-blind trial—The Texas Medical Center Catheter Study Group. Ann Intern Med 127:267–274, 1997
21. Maki DG, Stolz SM, Wheeler S, et al: Prevention of central venous catheter-related bloodstream infection by use of an antiseptic-impregnated catheter: A randomized, controlled trial. Ann Intern Med 127:257–266, 1997
22. 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
23. McGee DC, Gould MK: Preventing complications of central venous catheterization. N Engl J Med 348:1123–1133, 2003 24. Castagnola E, Molinari AC, Fratino G, et al: Conditions associated with infections of indwelling central venous catheters in cancer patients: A summary. Br J Haematol 121:233–239, 2003[CrossRef][Medline] 25. Mitchell LG, Andrew M, Hanna K, et al: A prospective cohort study determining the prevalence of thrombotic events in children with acute lymphoblastic leukemia and a central venous line who are treated with L-asparaginase: Results of the Prophylactic Antithrombin Replacement in Kids with Acute Lymphoblastic Leukemia Treated with Asparaginase (PARKAA) Study. Cancer 97:508–516, 2003[CrossRef][Medline] 26. Howell PB, Walters PE, Donowitz GR, et al: Risk factors for infection of adult patients with cancer who have tunnelled central venous catheters. Cancer 75:1367–1375, 1995[CrossRef][Medline] Submitted December 16, 2003; accepted November 30, 2004. This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
day 15 of induction) was associated with an increased risk of having a positive blood culture (odds ratio, 2.2; 95% CI, 1.0 to 5.0; P = .05). When compared with internal CVLs ("ports"), external CVLs were associated with a positive blood culture (odds ratio, 3.1; 95% CI, 1.3 to 7.5; P = .01), thrombosis (odds ratio, 3.9; 95% CI, 1.5 to 10.3; P = .006), and CVL removal (odds ratio, 5.6; 95% CI, 2.7 to 11.6; P < .001). 
1 of 3 outcomes: positive blood culture, central line clot, and central venous line (CVL) removal.
