- Email: [email protected]
Central Venous Lines in Pediatric Oncology Patients: A Single Institution Experience, Including Risk Factors for Early Removal
, - ,
iÌÀ>Ê6iÕÃÊ iÃÊÊ*i`>ÌÀVÊ"V}ÞÊ*>ÌiÌÃ\Ê Ê-}iÊÃÌÌÕÌÊ Ý«iÀiVi]ÊVÕ`}Ê,ÃÊ >VÌÀÃÊvÀÊ >ÀÞÊ,iÛ> Amisha Shah, BA, MD. - Pennsylvania State University College of Medicine Class of 2010 Andrew Freiberg, BS, MD - Associate Professor, Penn State Hershey Children’s Hospital Erik B. Lehman, MS - Biostatistician, Department of Public Health Sciences, Penn State Hershey Medical Center
Abstract Aim/Purpose: To tabulate the types of lines used for childhood cancer at our institution and risk factors for early removal. Background/Introduction: Most children with cancer require central venous catheters for chemotherapy, support and monitoring, but infection, dysfunction (i.e. mechanical problems such as fracture and nonthrombotic obstruction) and thrombosis often necessitate unplanned removal. Timing and type of line chosen may determine central line longevity. Review of Relevant Literature: A literature search revealed that there are minimal and conflicting data in the realm of pediatric central lines and reasons for their removal, especially in the ALL population. Methods: We reviewed records of all children diagnosed with cancer at our institution from 2002 to 2003 to catalog types of lines and variables that impacted line survival. Results: 174 children were diagnosed with cancer in 2002-2003; 175 lines in 103 children total were used in the study117 were removed electively, 58 were removed non-electively. Several variables, including infection, predicted non-elective removal. External tunneled lines were associated with non-elective removal (OR: 11.9, p<0.01) and removal due to infection (OR: 10.41, p<0.01) more often than were tunneled ports. Patients with acute lymphoblastic leukemia (ALL) in which a tunneled port was placed at diagnosis were more likely to require non-elective removal than tunneled ports placed after induction chemotherapy (43% vs. 8%). While this difference did not reach significance due to low numbers of early placements, 43% of placements at diagnosis failed by 125 days, whereas 100% of lines placed late were still in place until 393 days and 72% were still in place up to 803 days. Conclusions: Early central line removal in pediatric oncology is determined by interdependent factors and prospective studies are needed to guide the timing and type of line for individual patients. However, early line placement for ALL may be associated with poor line survival.
Background hildren with cancer often receive treatment through central venous lines (CVLs). A central venous line facilitates access for blood draws and the administration of treatment via intravenous therapy, while also reducing the pain associated with these procedures (Callahan et al., 2004). CVLs are classified into two broad categories: external catheters (including peripherally inserted central catheters (PICCs) and tunneled external catheters), and tunneled totally-implant-
able devices (ports). PICCs are often used as more temporary forms of venous access. Each catheter can be implanted with a single or double lumen, depending on the needs and goals of access. The type of central line a patient receives depends on the patient’s age (size), diagnosis, and treatment plan, including intensity and duration of treatment. These lines are at risk for complications such as infection, dysfunction, and thrombosis, often necessitating unplanned removal or replacement (Barret et al., 2004; Male et al., 2003).
Correspondence concerning this article should be addressed to [email protected]. DOI: 10.2309/java.15-3-5
Review of Literature Few studies have evaluated the types of central line and their complications in relation to specific cancer diagnoses, as well as other factors that contribute to failed central lines (Male et
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al., 2003). This is especially true for patients with acute lymphoblastic leukemia (ALL), a cancer in which timing of line placement is controversial. ALL patients often receive central lines at diagnosis or upon recovery from induction chemotherapy. Studies that have reviewed timing of central line placement in ALL patients have shown conflicting results. Abbas et al. showed that line infections in ALL patients depend on patient age and treatment regimen, but not the timing of CVL placement, while McLean et al., in a much larger study showed that CVLs placed early in induction are associated with a greater risk of positive blood cultures. In contrast, another study showed that placing a CVL in ALL patients prior to beginning therapy was safe, and complications were more due to mechanical factors (Carr et al., 2006). Purpose, Definition of Terms This single-institution study was conducted to delineate the advantages and disadvantages of different types of central venous lines and the optimum timing and type of line placement in pediatric cancer patients. We believe that the survival of central lines is predictable based on patient factors such as the diagnosis and the timing of insertion and type of line chosen. Unfortunately, therapeutic and supportive care needs often dictate the timing and type of line placed, so modification is not always possible. We aim to determine the risk factors for the complications of central venous lines and the reasons for removal in children being treated for cancer and where modification is possible, to use recommendations based upon these data to improve the quality of care provided to our pediatric oncology patients. The current study focused particularly on CVL placement in ALL patients in hopes of evaluating preferred timing of definitive line placement. For the purpose of our study we divided patient diagnoses into four categories: acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia (AML), lymphoma (which included both Hodgkin’s and Non-Hodgkin’s Lymphoma), and solid tumors (including central nervous system tumors). In our study, we defined central line dysfunction as tip dislodgement, port displacement, fracture of the port, and malfunction which necessitated removal of a port. Methodology Hypothesis The review was conducted in hopes of delineating the advantages and disadvantages of different types of central venous lines including the timing and type of line placed in pediatric oncology patients. We hypothesize that the survival of central lines is predictable based on patient factors such as diagnosis, placement timing, and type of line chosen. Study Design/Variables: A retrospective chart review of all children diagnosed with cancer on the Pediatric Hematology/Oncology service during the years 2002 and 2003 was conducted compiling the following set of variables: • demographics of the patient (gender, age, DOB) • patient diagnosis
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• date of diagnosis • type of central line (Totally Implantable Device, external catheter, PICC line) • time of placement • time of removal (specifying if non-elective removal was necessary) • reason for removal (elective- end of therapy, new type line needed, expired vs. non-elective- infection, dysfunction, thrombosis) • number of lines used • resulting complications, if any Our institution is a full member of the Children’s Oncology Group (COG), therefore the majority of patients were treated according to current accepted COG protocols, including ALL. The study was approved by the Hershey Medical Center Institutional Review Board and determined to be exempt from informed consent. Data Analysis Data were assembled into Microsoft Excel spreadsheets so that calculations could determine the patients’ ages at diagnosis and central line insertion, and the time between diagnosis and line placement. We then compared the diagnosis to CVL type, diagnosis to the reason for removal, and CVL type to the reason for removal. PICC lines were considered temporary forms of central lines, but were also included in this analysis. Each line was then assessed to determine if its removal was “elective” or “non-elective”. Elective removal was defined as lines planned as temporary, lines removed because a new type of line was needed, or lines removed after the patient had completed therapy. Patients who had short term PICC lines removed in exchange for a long-term CVL were also considered to be elective removals. Non-elective removal was defined as lines that were removed due to complications such as infection, dysfunction, or thrombosis. Central lines in patients who expired during the course of therapy were considered in a separate category. Diagnoses were grouped into four categories: ALL, AML, lymphoma, and solid tumors. The category of solid tumors included Wilm’s tumor, sarcoma, brain tumor, neuroblastoma, and other solid tumors that are not as common in the pediatric population such as melanomas and testicular cancer. All analyses were carried out using SAS statistical software, version 9.1.3 (SAS Institute, Cary, NC). To determine what risk factors affect non-elective removal and removal due to infection and what risk factors influence line survival, the data were analyzed in three separate ways: using all lines for all patients, using the first permanent line for all patients, using the first permanent line for only acute lymphoblastic leukemia (ALL) patients. For the analyses of non-elective removal and removal due to infection using all lines for all patients, we applied a generalized estimating equations (GEE) analysis which is an extension of logistic regression that accounts for the correlation between observations on the same patient for a binary outcome. Odds ratios with 95% confidence limits were used to quantify the magnitude and direction of the differences in the rate of the outcomes between the groups of the independent
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variables. When analyzing these same outcomes using the first permanent line for all patients or using the first permanent line for only ALL patients, a standard logistic regression was utilized instead employing odds ratios (OR) with 95% confidence limits once again (Table 3). Exact logistic regression and odds ratios were substituted when cell counts were small. Using the first permanent line for all patients or the first permanent line for only ALL patients, a Kaplan-Meier survival analysis was used to determine what factors impact short line survival. Differences in line survival between the groups of independent variables were tested for significance using a Log Rank test for the equality of strata. Mean survival times were used to quantify line survival (Table 2). Kaplan-Meier curves were plotted to visualize the survival rates over time (Figures 1, 2, 3). A survival analysis could not be applied to all lines for all patients due to the correlation between the lines on the same patient. This characteristic of the data violates the assumption of independence of the observations which is necessary for survival analysis to be valid.
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Protection of human or animal subjects Our study design did not involve direct contact with human subjects. Since our study design was a retrospective chart review, data were collected directly from patient charts. Patient information was password-protected on a secure server. IRB approval was obtained and patient consent was not required.
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Results There were 174 children diagnosed with cancer in 20022003; 175 total central lines were used in 103 of these children. Seventy-one children in the study were excluded for various reasons. Of these, 58 patients were excluded because their therapy did not necessitate the placement of a central line, primarily in 28 patients with brain tumors. Other types of tumors in decreasing order of frequency that did not require central lines included sarcomas, neuroblastomas, nephroblastomas, and melanomas. Only twenty patients were excluded from the study because of incomplete line data for analysis, such as the type of line, date of diagnosis, date of placement, or date of removal was not found in the patient’s chart. If a patient received multiple lines, and one of the lines had incomplete data, the entire patient was removed from the study. Of the total 103 patients included in the study, 34 patients had ALL.
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Results for all lines in all patients Of the 103 patients who received at least 1 central line, the median was 1 (range 1-8, mean±SD 1.74±1.24). 34 patients with ALL had at least 1 central line during therapy (median 2, range 1-7, mean±SD 1.76±1.13). Table 1 shows the complete list of central lines by diagnosis, listing the reasons for removal. Out of the 175 lines in 103 patients used for analysis, 117 lines (in 93 patients) were removed electively and 58 (33%) of lines (in 33 patients) were removed non-electively. The total catheter days for the patients in our study was 57,083, so the number of non-elective removals was 1.02 per 1000 catheter days. A further breakdown of non-elective port removals was performed to determine characteristics predicting non-elective removal. ALL patients had significantly fewer non-elective removals than other diagnoses, and AML had significantly more
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non-elective removals when compared against the rest of the population as did solid tumors although not statistically significant. Our lymphoma patient population was too small for risk calculations. Likewise, external tunneled lines and PICC lines were removed non-electively significantly more often than ports and double-lumen more often than single-lumen catheters. Age was a minor factor predicting non-elective removal, with only the 10-15 age group showing a slight decreased risk of non-elective removal when compared with the <5 year old group. Having more than one central line during treatment, as would be expected, was associated with increased risk for nonelective removal. Since infection made up the majority of the reasons for nonelective removal, we conducted the same analysis for removals due to infection as we did for non-elective removals. As with non-elective removal overall, removal due to infection was significantly increased for AML, PICC and external tunneled lines, double lumen devices, and having more than one line during therapy. For ALL, removal due to infection was actually decreased for lines placed later, but the difference was not significant. Results for first permanent line for all patients Ninety six central lines were used in the survival analysis of the first permanent line; if the patient received a PICC line prior to the placement of a port or external tunneled line, then the first tunneled line was used in measuring survival. Of these patients, 32 patients had a diagnosis of ALL. Survival analyses were conducted independently based on age at diagnosis, age at insertion, diagnosis (Figure 1), and type of line, external tunneled or port (Figure 2), to determine line survival time (in days) for each type of line (Table 2). Without regard to reason for removal, age at insertion 5-10 years (mean=713.91 days, p=0.07) and ALL diagnosis (mean=891.42 days, p<0.01) were associated with longer line survival time. Tunneled ports had significantly longer survival than tunneled external lines (628.78 days vs. 165.56 days, p-value<0.01). In addition, having had a prior PICC was associated with significantly longer permanent line survival (827.38 days, p-value<0.01). As mentioned above, duration of line survival is associated with the diagnosis and planned therapy, so we used the rate of non-elective removal and removal due to infection as better measures of line success, i.e. elective removal of the line (Table 3). Age at diagnosis, diagnosis, and having had a prior PICC were not predictors of non-elective removal or removal due to infection (p-values>0.05), although solid tumors showed a higher rate of non-elective removal (OR: 2.92, p=0.08) and removal due to infection (OR: 3.7, p=0.07) compared to ALL. Only external tunneled lines were significantly associated with non-elective removal (OR: 11.9, p<0.01) and removal due to infection ( 10.41, p<0.01) compared to ports. Results for ALL by timing of insertion A separate survival analysis of the first permanent line for only ALL patients was conducted comparing the longevity of lines, based on timing of placement (<21 days or ≥21 days) relative to diagnosis (Figure 3). Based on our analysis, 43% of lines placed early (<21 days) for ALL treatment failed by 125
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days, whereas 100% of lines placed late (≥21 days) were still in place until 393 days, and more than 72% were still in place up to 803 days. Permanent lines placed at ≥21 days had a mean survival time of 1004.08 days vs. 614.86 days for lines placed at <21 days (p= 0.51). The survival curves clearly show the elective removal of lines grouped around 800 and 1200 days, corresponding to the scheduled end of chemotherapy for girls and boys respectively. In order to stratify our data further, a survival analysis of the first permanent line for ALL patients was created, excluding external lines and concentrating only on internal catheters (Tunneled ports). Again, lines placed at ≥21 days had longer mean survival time of 1023.79 days (p=0.72). Statistical significance was not reached due to the small number of lines (7) placed early. In all of our survival analyses, having a prior PICC line was associated with longer mean survival time although not statistically significant when limited to ALL patients or ALL patients with tunneled ports only. The results of our survival analysis for ALL patients by timing are furthermore consistent with the results of an analysis for non-elective removals and removals due to infection. From this analysis, we found that patients who had a line placed at <21 days had a higher rate of non-elective removals than patients who had a line placed at ≥21 days (43% vs. 8%). Despite the above results however, none of these comparisons reached statistical significance. Conclusions We reviewed the records of all children at a single institution diagnosed with cancer over a two-year period, with the goal of defining the types of central lines used in these patients. As such, our data represent our current clinical practice, specifically among our Pediatric Oncologists and Pediatric Surgeons in regard to the choice of central lines and timing of line placement. As there are no randomized controlled trials comparing line choice and timing of placement, clinical practice is mainly based on the collective experiences of the clinicians caring for these patients. Better guidance is needed. We did attempt to determine what factors are associated with central line complications. Some of these factors (e.g. age, diagnosis, and therapy) cannot be modified while others such as the timing of placement and the type of line chosen could in theory be changed if clearly identified risks could be determined. Thirty three percent of the central lines in 33 of our patients were removed non-electively. This compares favorably with a similar population of patients of whom 40% experienced premature line removal due to a variety of causes, mostly infection (Abbas et al., 2003). Excluding “accidental” removals however, 27% of the patients in that study actually required premature removal. We found no instances of accidental removal among our patients. The above study also refers to a combined analysis of 8 other studies with an infection rate of 2.17 per 1000 catheter days. In another study (Wagner et al., 2004), of 21 patients with sickle cell disease, out of 30 devices there were 18 device infections (60%) involving 15 venous ports and three tunneled catheters, with 1.5 infections per 1,000 catheter days. Our patients experienced 58 non-elective removals due to all
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causes, out of 57,083 catheter days, for a rate of only 1.02, but our analysis did not include the total number of infections, just those requiring removal. One population for which our data might affect clinical practice is acute lymphoblastic leukemia. These patients require reliable access from the beginning of induction, and central access for most of their therapy. A central line placed soon after diagnosis would be ideal, but there is a belief among many clinicians that central lines placed during induction are at high risk for complications, so should be delayed until marrow recovery after the end of this first month of therapy. Is the risk really increased, or is there a subset of patients for which the risk is especially high or low so that a clear decision can be made to place the line immediately or should be delayed? Unfortunately the ALL population in our sample was too small, particularly the number of patients having early line placement, even in our nonrandomized retrospective sample to answer this question. We did find that central lines in ALL patients that last the first 200 days (i.e. for the initial more intensive chemotherapy cycles) are likely to last until the end of treatment. Limitations Due to the nature of our study design, data analysis for line survival was complicated due to the fact that many patients received more than one central line. In order to assess the longevity of each line, survival analyses in Figures 1, 2, and 3 were conducted on only the first permanent line. A major problem in interpreting our data is the interdependence of the risk factors. For example, all AML patients in our population get external lines, and the majority gets double lumen catheters. So although our data show that AML increases the risk of non-elective removal, so do external lines and multiple lumens. This population is clearly at increased risk for complications such as thrombosis and infection necessitating non-elective removal, but which of these factors, in addition to the relatively intensive chemotherapy and consequent prolonged myelosuppression and immunosuppression children with AML receive, contributes most to this risk cannot be determined from our retrospective data. Recommendations for Practice Since central lines are a risky but necessary aspect of supportive care for seriously ill patients, institutions need to track their experience with these lines. Besides defining our current practice, our study is important because it quantifies the risk of specific catheter complications and the overall rate of non-elective removal for specific categories of patients. We would be interested in comparing these rates to the experience at other institutions to
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determine goals for best practice in this high risk population. For ALL in particular, we are currently comparing line survival for early vs. late placement for a larger group of patients. Overall, this descriptive single institution study was conducted in hopes of identifying parameters that influence line survival in pediatric cancer patients. Line infections and other forms of non-elective removal pose a threat to the delivery of therapy these patients receive and may contribute to therapy failure and adverse outcomes. We believe that the results of this study will help us improve our ability to deliver care and manage and monitor pediatric cancer patients. References Abbas, A.A.H., Fryer, C.J.H., Paltiel, C., et al (2003). Factors influencing central line infections in children with acute lymphoblastic leukemia: results of a single institution study, Pediatric Blood Cancer, 42, 325-331. Barret, M., Imeson, J., Leese, D., et al (2004). Factors influencing early failure of central venous catheters in children with cancer, Journal of Pediatric Surgery, 39, 1520-1523. Callahan, C., & De La Cruz, H. (2004). Central line placement for the pediatric oncology patient: a model of advanced practice nurse collaboration. Journal of Pediatric Oncology Nursing, 21, 16-21. Carr, E., Jayabose, S., Stringel, G., et al. (2006). The safety of central line placement prior to treatment of pediatric acute lymphoblastic leukemmia. Pediatric Blood Cancer, 47, 886-888. Grady, N.P., Alexaner, M., Dellinger, P., et al. (2002). Guidelines for the prevention of intravascular catheter-related infections. Pediatrics, 10, 1-24. Hanley, C., Nagel, K., Odame, I., et al. (2003). Immediate versus delayed access of implantable venous access devises: does the timing and access make a difference to the frequency of complications? Journal of Pediatric Hematology Oncology, 25, 613-615. Male, C., Chait, P., Andrew, M., et al. (2003). Central venous line-related thrombosis in children: association with central venous line location and insertion technique. Blood, 101, 4273-4278. McLean, T.W., Fisher, C.J., Snively, B.M., & Chauvenet, A.R. (2005). Central venous lines in children with lesser risk acute lymphoblastic leukemia: optimal type and timing of placement. Journal of Clinical Oncology, 23, 3025-3029. Wagner, S.C., Eschelman, D.J., Gonsalves, C.F., et al. (2004). Infectious complications of implantable venous access devices in patients with sickle cell disease. Journal of Vascular Interventional Radiology, 15, 375-378.
2010
iÌÀ>Ê6iÕÃÊ iÃÊÊ*i`>ÌÀVÊ"V}ÞÊ*>ÌiÌÃ\Ê Ê-}iÊÃÌÌÕÌÊ Ý«iÀiVi]ÊVÕ`}Ê,ÃÊ >VÌÀÃÊvÀÊ >ÀÞÊ,iÛ> Amisha Shah, BA, MD. - Pennsylvania State University College of Medicine Class of 2010 Andrew Freiberg, BS, MD - Associate Professor, Penn State Hershey Children’s Hospital Erik B. Lehman, MS - Biostatistician, Department of Public Health Sciences, Penn State Hershey Medical Center
Abstract Aim/Purpose: To tabulate the types of lines used for childhood cancer at our institution and risk factors for early removal. Background/Introduction: Most children with cancer require central venous catheters for chemotherapy, support and monitoring, but infection, dysfunction (i.e. mechanical problems such as fracture and nonthrombotic obstruction) and thrombosis often necessitate unplanned removal. Timing and type of line chosen may determine central line longevity. Review of Relevant Literature: A literature search revealed that there are minimal and conflicting data in the realm of pediatric central lines and reasons for their removal, especially in the ALL population. Methods: We reviewed records of all children diagnosed with cancer at our institution from 2002 to 2003 to catalog types of lines and variables that impacted line survival. Results: 174 children were diagnosed with cancer in 2002-2003; 175 lines in 103 children total were used in the study117 were removed electively, 58 were removed non-electively. Several variables, including infection, predicted non-elective removal. External tunneled lines were associated with non-elective removal (OR: 11.9, p<0.01) and removal due to infection (OR: 10.41, p<0.01) more often than were tunneled ports. Patients with acute lymphoblastic leukemia (ALL) in which a tunneled port was placed at diagnosis were more likely to require non-elective removal than tunneled ports placed after induction chemotherapy (43% vs. 8%). While this difference did not reach significance due to low numbers of early placements, 43% of placements at diagnosis failed by 125 days, whereas 100% of lines placed late were still in place until 393 days and 72% were still in place up to 803 days. Conclusions: Early central line removal in pediatric oncology is determined by interdependent factors and prospective studies are needed to guide the timing and type of line for individual patients. However, early line placement for ALL may be associated with poor line survival.
Background hildren with cancer often receive treatment through central venous lines (CVLs). A central venous line facilitates access for blood draws and the administration of treatment via intravenous therapy, while also reducing the pain associated with these procedures (Callahan et al., 2004). CVLs are classified into two broad categories: external catheters (including peripherally inserted central catheters (PICCs) and tunneled external catheters), and tunneled totally-implant-
able devices (ports). PICCs are often used as more temporary forms of venous access. Each catheter can be implanted with a single or double lumen, depending on the needs and goals of access. The type of central line a patient receives depends on the patient’s age (size), diagnosis, and treatment plan, including intensity and duration of treatment. These lines are at risk for complications such as infection, dysfunction, and thrombosis, often necessitating unplanned removal or replacement (Barret et al., 2004; Male et al., 2003).
Correspondence concerning this article should be addressed to [email protected]. DOI: 10.2309/java.15-3-5
Review of Literature Few studies have evaluated the types of central line and their complications in relation to specific cancer diagnoses, as well as other factors that contribute to failed central lines (Male et
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al., 2003). This is especially true for patients with acute lymphoblastic leukemia (ALL), a cancer in which timing of line placement is controversial. ALL patients often receive central lines at diagnosis or upon recovery from induction chemotherapy. Studies that have reviewed timing of central line placement in ALL patients have shown conflicting results. Abbas et al. showed that line infections in ALL patients depend on patient age and treatment regimen, but not the timing of CVL placement, while McLean et al., in a much larger study showed that CVLs placed early in induction are associated with a greater risk of positive blood cultures. In contrast, another study showed that placing a CVL in ALL patients prior to beginning therapy was safe, and complications were more due to mechanical factors (Carr et al., 2006). Purpose, Definition of Terms This single-institution study was conducted to delineate the advantages and disadvantages of different types of central venous lines and the optimum timing and type of line placement in pediatric cancer patients. We believe that the survival of central lines is predictable based on patient factors such as the diagnosis and the timing of insertion and type of line chosen. Unfortunately, therapeutic and supportive care needs often dictate the timing and type of line placed, so modification is not always possible. We aim to determine the risk factors for the complications of central venous lines and the reasons for removal in children being treated for cancer and where modification is possible, to use recommendations based upon these data to improve the quality of care provided to our pediatric oncology patients. The current study focused particularly on CVL placement in ALL patients in hopes of evaluating preferred timing of definitive line placement. For the purpose of our study we divided patient diagnoses into four categories: acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia (AML), lymphoma (which included both Hodgkin’s and Non-Hodgkin’s Lymphoma), and solid tumors (including central nervous system tumors). In our study, we defined central line dysfunction as tip dislodgement, port displacement, fracture of the port, and malfunction which necessitated removal of a port. Methodology Hypothesis The review was conducted in hopes of delineating the advantages and disadvantages of different types of central venous lines including the timing and type of line placed in pediatric oncology patients. We hypothesize that the survival of central lines is predictable based on patient factors such as diagnosis, placement timing, and type of line chosen. Study Design/Variables: A retrospective chart review of all children diagnosed with cancer on the Pediatric Hematology/Oncology service during the years 2002 and 2003 was conducted compiling the following set of variables: • demographics of the patient (gender, age, DOB) • patient diagnosis
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• date of diagnosis • type of central line (Totally Implantable Device, external catheter, PICC line) • time of placement • time of removal (specifying if non-elective removal was necessary) • reason for removal (elective- end of therapy, new type line needed, expired vs. non-elective- infection, dysfunction, thrombosis) • number of lines used • resulting complications, if any Our institution is a full member of the Children’s Oncology Group (COG), therefore the majority of patients were treated according to current accepted COG protocols, including ALL. The study was approved by the Hershey Medical Center Institutional Review Board and determined to be exempt from informed consent. Data Analysis Data were assembled into Microsoft Excel spreadsheets so that calculations could determine the patients’ ages at diagnosis and central line insertion, and the time between diagnosis and line placement. We then compared the diagnosis to CVL type, diagnosis to the reason for removal, and CVL type to the reason for removal. PICC lines were considered temporary forms of central lines, but were also included in this analysis. Each line was then assessed to determine if its removal was “elective” or “non-elective”. Elective removal was defined as lines planned as temporary, lines removed because a new type of line was needed, or lines removed after the patient had completed therapy. Patients who had short term PICC lines removed in exchange for a long-term CVL were also considered to be elective removals. Non-elective removal was defined as lines that were removed due to complications such as infection, dysfunction, or thrombosis. Central lines in patients who expired during the course of therapy were considered in a separate category. Diagnoses were grouped into four categories: ALL, AML, lymphoma, and solid tumors. The category of solid tumors included Wilm’s tumor, sarcoma, brain tumor, neuroblastoma, and other solid tumors that are not as common in the pediatric population such as melanomas and testicular cancer. All analyses were carried out using SAS statistical software, version 9.1.3 (SAS Institute, Cary, NC). To determine what risk factors affect non-elective removal and removal due to infection and what risk factors influence line survival, the data were analyzed in three separate ways: using all lines for all patients, using the first permanent line for all patients, using the first permanent line for only acute lymphoblastic leukemia (ALL) patients. For the analyses of non-elective removal and removal due to infection using all lines for all patients, we applied a generalized estimating equations (GEE) analysis which is an extension of logistic regression that accounts for the correlation between observations on the same patient for a binary outcome. Odds ratios with 95% confidence limits were used to quantify the magnitude and direction of the differences in the rate of the outcomes between the groups of the independent
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variables. When analyzing these same outcomes using the first permanent line for all patients or using the first permanent line for only ALL patients, a standard logistic regression was utilized instead employing odds ratios (OR) with 95% confidence limits once again (Table 3). Exact logistic regression and odds ratios were substituted when cell counts were small. Using the first permanent line for all patients or the first permanent line for only ALL patients, a Kaplan-Meier survival analysis was used to determine what factors impact short line survival. Differences in line survival between the groups of independent variables were tested for significance using a Log Rank test for the equality of strata. Mean survival times were used to quantify line survival (Table 2). Kaplan-Meier curves were plotted to visualize the survival rates over time (Figures 1, 2, 3). A survival analysis could not be applied to all lines for all patients due to the correlation between the lines on the same patient. This characteristic of the data violates the assumption of independence of the observations which is necessary for survival analysis to be valid.
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Protection of human or animal subjects Our study design did not involve direct contact with human subjects. Since our study design was a retrospective chart review, data were collected directly from patient charts. Patient information was password-protected on a secure server. IRB approval was obtained and patient consent was not required.
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Results There were 174 children diagnosed with cancer in 20022003; 175 total central lines were used in 103 of these children. Seventy-one children in the study were excluded for various reasons. Of these, 58 patients were excluded because their therapy did not necessitate the placement of a central line, primarily in 28 patients with brain tumors. Other types of tumors in decreasing order of frequency that did not require central lines included sarcomas, neuroblastomas, nephroblastomas, and melanomas. Only twenty patients were excluded from the study because of incomplete line data for analysis, such as the type of line, date of diagnosis, date of placement, or date of removal was not found in the patient’s chart. If a patient received multiple lines, and one of the lines had incomplete data, the entire patient was removed from the study. Of the total 103 patients included in the study, 34 patients had ALL.
2010
Results for all lines in all patients Of the 103 patients who received at least 1 central line, the median was 1 (range 1-8, mean±SD 1.74±1.24). 34 patients with ALL had at least 1 central line during therapy (median 2, range 1-7, mean±SD 1.76±1.13). Table 1 shows the complete list of central lines by diagnosis, listing the reasons for removal. Out of the 175 lines in 103 patients used for analysis, 117 lines (in 93 patients) were removed electively and 58 (33%) of lines (in 33 patients) were removed non-electively. The total catheter days for the patients in our study was 57,083, so the number of non-elective removals was 1.02 per 1000 catheter days. A further breakdown of non-elective port removals was performed to determine characteristics predicting non-elective removal. ALL patients had significantly fewer non-elective removals than other diagnoses, and AML had significantly more
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non-elective removals when compared against the rest of the population as did solid tumors although not statistically significant. Our lymphoma patient population was too small for risk calculations. Likewise, external tunneled lines and PICC lines were removed non-electively significantly more often than ports and double-lumen more often than single-lumen catheters. Age was a minor factor predicting non-elective removal, with only the 10-15 age group showing a slight decreased risk of non-elective removal when compared with the <5 year old group. Having more than one central line during treatment, as would be expected, was associated with increased risk for nonelective removal. Since infection made up the majority of the reasons for nonelective removal, we conducted the same analysis for removals due to infection as we did for non-elective removals. As with non-elective removal overall, removal due to infection was significantly increased for AML, PICC and external tunneled lines, double lumen devices, and having more than one line during therapy. For ALL, removal due to infection was actually decreased for lines placed later, but the difference was not significant. Results for first permanent line for all patients Ninety six central lines were used in the survival analysis of the first permanent line; if the patient received a PICC line prior to the placement of a port or external tunneled line, then the first tunneled line was used in measuring survival. Of these patients, 32 patients had a diagnosis of ALL. Survival analyses were conducted independently based on age at diagnosis, age at insertion, diagnosis (Figure 1), and type of line, external tunneled or port (Figure 2), to determine line survival time (in days) for each type of line (Table 2). Without regard to reason for removal, age at insertion 5-10 years (mean=713.91 days, p=0.07) and ALL diagnosis (mean=891.42 days, p<0.01) were associated with longer line survival time. Tunneled ports had significantly longer survival than tunneled external lines (628.78 days vs. 165.56 days, p-value<0.01). In addition, having had a prior PICC was associated with significantly longer permanent line survival (827.38 days, p-value<0.01). As mentioned above, duration of line survival is associated with the diagnosis and planned therapy, so we used the rate of non-elective removal and removal due to infection as better measures of line success, i.e. elective removal of the line (Table 3). Age at diagnosis, diagnosis, and having had a prior PICC were not predictors of non-elective removal or removal due to infection (p-values>0.05), although solid tumors showed a higher rate of non-elective removal (OR: 2.92, p=0.08) and removal due to infection (OR: 3.7, p=0.07) compared to ALL. Only external tunneled lines were significantly associated with non-elective removal (OR: 11.9, p<0.01) and removal due to infection ( 10.41, p<0.01) compared to ports. Results for ALL by timing of insertion A separate survival analysis of the first permanent line for only ALL patients was conducted comparing the longevity of lines, based on timing of placement (<21 days or ≥21 days) relative to diagnosis (Figure 3). Based on our analysis, 43% of lines placed early (<21 days) for ALL treatment failed by 125
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days, whereas 100% of lines placed late (≥21 days) were still in place until 393 days, and more than 72% were still in place up to 803 days. Permanent lines placed at ≥21 days had a mean survival time of 1004.08 days vs. 614.86 days for lines placed at <21 days (p= 0.51). The survival curves clearly show the elective removal of lines grouped around 800 and 1200 days, corresponding to the scheduled end of chemotherapy for girls and boys respectively. In order to stratify our data further, a survival analysis of the first permanent line for ALL patients was created, excluding external lines and concentrating only on internal catheters (Tunneled ports). Again, lines placed at ≥21 days had longer mean survival time of 1023.79 days (p=0.72). Statistical significance was not reached due to the small number of lines (7) placed early. In all of our survival analyses, having a prior PICC line was associated with longer mean survival time although not statistically significant when limited to ALL patients or ALL patients with tunneled ports only. The results of our survival analysis for ALL patients by timing are furthermore consistent with the results of an analysis for non-elective removals and removals due to infection. From this analysis, we found that patients who had a line placed at <21 days had a higher rate of non-elective removals than patients who had a line placed at ≥21 days (43% vs. 8%). Despite the above results however, none of these comparisons reached statistical significance. Conclusions We reviewed the records of all children at a single institution diagnosed with cancer over a two-year period, with the goal of defining the types of central lines used in these patients. As such, our data represent our current clinical practice, specifically among our Pediatric Oncologists and Pediatric Surgeons in regard to the choice of central lines and timing of line placement. As there are no randomized controlled trials comparing line choice and timing of placement, clinical practice is mainly based on the collective experiences of the clinicians caring for these patients. Better guidance is needed. We did attempt to determine what factors are associated with central line complications. Some of these factors (e.g. age, diagnosis, and therapy) cannot be modified while others such as the timing of placement and the type of line chosen could in theory be changed if clearly identified risks could be determined. Thirty three percent of the central lines in 33 of our patients were removed non-electively. This compares favorably with a similar population of patients of whom 40% experienced premature line removal due to a variety of causes, mostly infection (Abbas et al., 2003). Excluding “accidental” removals however, 27% of the patients in that study actually required premature removal. We found no instances of accidental removal among our patients. The above study also refers to a combined analysis of 8 other studies with an infection rate of 2.17 per 1000 catheter days. In another study (Wagner et al., 2004), of 21 patients with sickle cell disease, out of 30 devices there were 18 device infections (60%) involving 15 venous ports and three tunneled catheters, with 1.5 infections per 1,000 catheter days. Our patients experienced 58 non-elective removals due to all
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causes, out of 57,083 catheter days, for a rate of only 1.02, but our analysis did not include the total number of infections, just those requiring removal. One population for which our data might affect clinical practice is acute lymphoblastic leukemia. These patients require reliable access from the beginning of induction, and central access for most of their therapy. A central line placed soon after diagnosis would be ideal, but there is a belief among many clinicians that central lines placed during induction are at high risk for complications, so should be delayed until marrow recovery after the end of this first month of therapy. Is the risk really increased, or is there a subset of patients for which the risk is especially high or low so that a clear decision can be made to place the line immediately or should be delayed? Unfortunately the ALL population in our sample was too small, particularly the number of patients having early line placement, even in our nonrandomized retrospective sample to answer this question. We did find that central lines in ALL patients that last the first 200 days (i.e. for the initial more intensive chemotherapy cycles) are likely to last until the end of treatment. Limitations Due to the nature of our study design, data analysis for line survival was complicated due to the fact that many patients received more than one central line. In order to assess the longevity of each line, survival analyses in Figures 1, 2, and 3 were conducted on only the first permanent line. A major problem in interpreting our data is the interdependence of the risk factors. For example, all AML patients in our population get external lines, and the majority gets double lumen catheters. So although our data show that AML increases the risk of non-elective removal, so do external lines and multiple lumens. This population is clearly at increased risk for complications such as thrombosis and infection necessitating non-elective removal, but which of these factors, in addition to the relatively intensive chemotherapy and consequent prolonged myelosuppression and immunosuppression children with AML receive, contributes most to this risk cannot be determined from our retrospective data. Recommendations for Practice Since central lines are a risky but necessary aspect of supportive care for seriously ill patients, institutions need to track their experience with these lines. Besides defining our current practice, our study is important because it quantifies the risk of specific catheter complications and the overall rate of non-elective removal for specific categories of patients. We would be interested in comparing these rates to the experience at other institutions to
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determine goals for best practice in this high risk population. For ALL in particular, we are currently comparing line survival for early vs. late placement for a larger group of patients. Overall, this descriptive single institution study was conducted in hopes of identifying parameters that influence line survival in pediatric cancer patients. Line infections and other forms of non-elective removal pose a threat to the delivery of therapy these patients receive and may contribute to therapy failure and adverse outcomes. We believe that the results of this study will help us improve our ability to deliver care and manage and monitor pediatric cancer patients. References Abbas, A.A.H., Fryer, C.J.H., Paltiel, C., et al (2003). Factors influencing central line infections in children with acute lymphoblastic leukemia: results of a single institution study, Pediatric Blood Cancer, 42, 325-331. Barret, M., Imeson, J., Leese, D., et al (2004). Factors influencing early failure of central venous catheters in children with cancer, Journal of Pediatric Surgery, 39, 1520-1523. Callahan, C., & De La Cruz, H. (2004). Central line placement for the pediatric oncology patient: a model of advanced practice nurse collaboration. Journal of Pediatric Oncology Nursing, 21, 16-21. Carr, E., Jayabose, S., Stringel, G., et al. (2006). The safety of central line placement prior to treatment of pediatric acute lymphoblastic leukemmia. Pediatric Blood Cancer, 47, 886-888. Grady, N.P., Alexaner, M., Dellinger, P., et al. (2002). Guidelines for the prevention of intravascular catheter-related infections. Pediatrics, 10, 1-24. Hanley, C., Nagel, K., Odame, I., et al. (2003). Immediate versus delayed access of implantable venous access devises: does the timing and access make a difference to the frequency of complications? Journal of Pediatric Hematology Oncology, 25, 613-615. Male, C., Chait, P., Andrew, M., et al. (2003). Central venous line-related thrombosis in children: association with central venous line location and insertion technique. Blood, 101, 4273-4278. McLean, T.W., Fisher, C.J., Snively, B.M., & Chauvenet, A.R. (2005). Central venous lines in children with lesser risk acute lymphoblastic leukemia: optimal type and timing of placement. Journal of Clinical Oncology, 23, 3025-3029. Wagner, S.C., Eschelman, D.J., Gonsalves, C.F., et al. (2004). Infectious complications of implantable venous access devices in patients with sickle cell disease. Journal of Vascular Interventional Radiology, 15, 375-378.
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