The Use of Fluid Boluses to Safely Perform Extracorporeal Photopheresis (ECP) in Low-Weight Children: A Novel Procedure

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1 Journal of Clinical Apheresis 25:63 69 (2010) The Use of Fluid Boluses to Safely Perform Extracorporeal Photopheresis (ECP) in Low-Weight Children: A Novel Procedure Jennifer Schneiderman,* David A. Jacobsohn, Jennifer Collins, Kimberly Thormann, and Morris Kletzel Division of Hematology/Oncology/Stem Cell Transplantation, The Children s Memorial Hospital, Feinberg School of Medicine, Northwestern University, Chicago, Illinois Apheresis procedures in small children are technically challenging and require special planning with attention to extracorporeal volume. Discontinuous procedures such as extracorporeal photopheresis (ECP) require additional consideration. Alternative methods to perform ECP have been utilized in small children that require manipulation of mononuclear cells outside the standard closed-loop system. We present a safe and feasible alternative to the procedure for children who weigh less than 40 Kg, while maintaining a closed loop, sterile system utilizing the UVAR XTS device. A retrospective chart review was performed analyzing the use of fluid boluses (normal saline in those between 20 and 40 Kg, 5% albumin in those under 20 Kg) before ECP. Eleven patients underwent 334 ECP procedures for acute and chronic graft-versus-host disease (n 5 9), and for prevention of graft-versus-host disease (n 5 2). Volumes of fluid boluses were calculated based on the expected extracorporeal volume during the first draw cycle. Treatments consisted of at least three draw cycles using the 125 ml bowl. The median weight was 28.5 Kg (range 19 to 39); nine of 11 required red cell transfusions to maintain adequate hematocrit. Complications attributed to ECP included tachycardia, dizziness, nausea, and hypotension; these occurred either in combination or isolation in 31% of the procedures and resolved following additional fluid boluses. Only three (0.8%) required early photoactivation due to these complications. The median time to completion of treatment was 2 h and 58 min (range 1:30 to 5:03). ECP is well tolerated in low-weight pediatric patients if hematocrit and hydration are carefully maintained. J. Clin. Apheresis 25:63 69, VC 2010 Wiley-Liss, Inc. Key words: extracorporeal photopheresis; pediatrics; graft-versus-host disease; hematopoietic stem cell transplantation INTRODUCTION Performing apheresis procedures in children can be technically difficult due to significant differences from adults in size and blood volume. Apheresis machines are primarily designed for use in adult patients; therefore their use in children requires thoughtful attention to placement of an appropriate central line, fluid status, and safe modification of the procedure [1]. This is particularly true for extracorporeal photopheresis (ECP), which is a discontinuous procedure in which a set volume of blood is removed from the patient without simultaneous replacement of fluid. To perform ECP in a closed, sterile system, the Therakos UVAR XTS machine must be used, which is approved by the Federal Drug Administration (FDA) in patients weighing 40 kilograms (Kg) or more. This weight limitation excludes a significant population of children who may benefit from this therapy. Here we describe a modification of the procedure, which has allowed patients weighing as little as 15 Kg to undergo and benefit from ECP. VC 2010 Wiley-Liss, Inc. BACKGROUND Extracorporeal photopheresis (ECP) is an apheresis procedure, in which peripheral blood mononuclear cells are separated from blood, treated with 8-methoxypsoralen (8-MOP) exposed to UV-A light, and reinfused into the patient. Approved by the FDA in 1988 for the treatment of cutaneous T-cell lymphoma (CTCL), ECP is categorized by the American Society for Apheresis (ASFA) as either primary, first-line adjunctive or supportive therapy for CTCL, prevention and treatment of rejection in the setting of cardiac transplant, and acute *Correspondence to: Dr. Jennifer Schnesiderman, Northwestern University Feinberg School of Medicine, The Children s Memorial Hospital, Division of Hematology/Oncology/Stem Cell Transplantation, 2300 Children s Plaza, Box #30, Chicago, IL 60614, USA. jschneiderman@childrensmemorial.org Received 27 August 2009; Revision 30 December 2009; Accepted 3 February 2010 Published online 18 March 2010 in Wiley InterScience ( DOI: /jca.20231

2 64 Schneiderman et al. and chronic graft-versus-host disease (GVHD) [2 6]. ECP has also been studied in the setting of autoimmune diseases such as scleroderma, other solid organ transplantation (lung and kidney) and in the treatment of Crohn s disease with varying efficacy. Although ECP s exact mechanism of action has not been defined, a shift from an inflammatory state (TH1) to that of tolerance (TH2) has been proposed. A typical treatment involves the isolation and treatment of approximately mononuclear cells. On photoactivation, 8-MOP conjugates with and forms covalent bonds with DNA, which leads to the formation of both monofunctional (addition to a single strand of DNA) and bifunctional adducts (crosslinking of psoralen to both strands of DNA), leading to apoptosis of all mononuclear cells. Over the subsequent 24 to 48 h, the majority of treated cells undergoes programmed cell death, or apoptosis and are engulfed by antigen presenting cells such as dendritic cells (DC s), processed, and are presented in the context of HLA antigen class I and II [7,8]. This process has been shown to reduce the production of inflammatory cytokines (IL-2, TNF-a, and IFN-g) while increasing production of anti-inflammatory cytokines (TGF-b). Moreover, increases in regulatory T-cells (CD4/CD251) have been documented in both the cardiac transplant and GVHD literature, suggesting that these cells play a central role in the mechanism of action [9,10]. Graft-versus-host disease is a multisystem, potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). Many studies have been carried out in both adults and children in acute and chronic GVHD; it is also being studied in the context of GVHD prevention [11 25]. ECP has been shown to be effective therapy for acute and chronic GVHD, and has allowed doses of other immune suppressive medications to be tapered and ultimately discontinued [11,13,15]. ECP is performed using a disposable tubing kit from the manufacturer. The device draws blood through the tubing and separates it by centrifugation to collect the buffy coat. The buffy coat is pooled in a sterile bag; the other blood components are then returned to the patient. This process is repeated five additional times, to total six cycles. The estimated extracorporeal volume is based on hematocrit and varies by cycle number; we refer to a graph that is distributed by the manufacturer. Due to its discontinuous flow system, the FDA approved procedure developed by Therakos (Exton, PA) applies to patients weighing more than 40 Kg, thus excluding a cohort of pediatric patients who may otherwise benefit from the procedure. To provide this procedure for our younger and smaller patients with acute and chronic GVHD while maintaining a sterile, closed-loop procedure, we have developed expertise in the use of the Therakos device in children weighing as little as 15 Kg using fluid boluses before and subsequently as needed throughout the procedure. MATERIALS AND METHODS Study Design and Data Collection A retrospective study of patients with acute and chronic GVHD weighing less than 40 Kg who were treated with ECP in the Apheresis Unit at Children s Memorial Hospital between June 2003 and November 2008 was performed. All parents signed an IRB approved consent form before transplant allowing for collection of clinical data from our database; patients between the ages of 12 and 18 years signed IRB approved assent forms. Parents and patients (when appropriate) were informed about the XTS device and the potential risks related to extracorporeal volume. Information extracted from the charts and blood bank records included: demographic data, ECP indication, patient weight, and hematocrit on the day of each procedure, number of red blood cell transfusions during the time period in which ECP was performed, central line type and size, adverse reactions, maximum draw and return flow rates, number of cycles performed, and length of the procedure. All procedures were performed using the UVAR XTS device with the 125 ml bowl. Patients were evaluated before the procedure by the apheresis staff. Vital signs, height, and weight were assessed before starting the treatment daily; children were assessed for intercurrent illness and fluid status. Fluid Management Calculation of fluid bolus. The first low-weight patient treated with ECP (26 Kg) was managed with a continuous infusion of isotonic IV fluid during the procedure. The majority of the subsequent patients weighing less than 40 Kg received an IV (IV) normal saline bolus before the procedure. The patient s total blood volume (TBV) is calculated by multiplying the weight in kilograms by 75 ml/kg. The Extracorporeal Blood Volume Management figure provided by Therakos is referenced to estimate the volume of blood that will be removed (extracorporeal volume, ECV) from the child during the first cycle; that value is recorded on the ECP worksheet for that day. Fifteen percent of the estimated TBV is subtracted from the ECV; the difference is given as normal saline immediately before starting the first draw cycle. For example, in a child weighing 25 Kg, the estimated TBV is 75 ml/kg, or 1,875 ml. If this patient has a hematocrit of 36%, the ECV can be estimated at 350 ml, which is higher than 15% of the TBV (280 ml). Thus, the bolus is calculated as 350 ml minus 280 ml, or 70 ml. In patients weighing less than 20 Kg, this bolus is given as 5% albumin. The bolus volume given should

3 ECP in Low-Weight Children is Safe and Feasible 65 not exceed 10 ml/kg. If the graph indicates that greater than 15% of the TBV will be removed in the first cycle, only three cycles will be planned. Boluses may be repeated as necessary in response to subjective feelings of restlessness, nausea, or dizziness, or objective observations of the staff such as tachycardia. For the purpose of nursing documentation, tachycardia, and hypotension were defined as a 20% increase or decrease from baseline, respectively. A complete treatment consists of three cycles in children weighing less than 40 Kg, although some patients tolerated four to five cycles per treatment day. Circuit Preparation The following equipment and supplies are gathered before all procedures: UVAR XTS Disposable Kit with the 125 ml bowl, 8-methoxypsoralen (UVADEX or 8- MOP, single use vial), two bags of 500 ml 0.9% normal saline (NS), 500 ml 0.9% NS with 10,000 U of heparin (or 500 ml 0.9% NS with 5,000 U of heparin for patients with platelet count <50,000), and EKG leads. Additional supplies are necessary for patients weighing less than 20 Kg, including hemostats, 250 ml 5% albumin with vented straight tubing, two stopcocks (for patients under 20 Kg), and one 30 ml syringe. The machine is primed in the usual manner with 0.9% NS and heparin solution. After priming is complete, the machine is programmed using the Set-up button for number of cycles, saline bolus amount, flow-rates and anticoagulant (AC) ratios. The normal saline bolus is calculated as previously discussed and entered (field allows values between 50 and 150 ml). For those under 20 Kg, the stopcocks are placed in series at the end of the access line, ensuring sterile technique. The primed albumin solution is attached to the first, and the empty 30 ml syringe is attached to the second. The albumin bolus is drawn up in the syringe and administered as a slow push before starting the first cycle. Subsequent fluid boluses may be given throughout the procedure depending on the patient s tolerance. Red Blood Cell Transfusions In general, patients weighing between 25 and 40 Kg were maintained at a hematocrit greater than or equal to 30%, while those weighing less than 25 Kg were transfused to keep the hematocrit greater than 35%. Other factors such as hydration status and blood pressure helped determine if a transfusion would be necessary if the complete blood count (CBC) results were borderline. Depending on parent and patient preference, the transfusion was given the day of or the day before the procedure. Central Line Selection As is the case with other apheresis procedures, the placement of an adequately sized, functional line is essential for successful completion of the procedure. This can be, especially challenging in the pediatric population. ECP has been successfully performed in our patients when lines with an internal diameter of at least 1.3 mm. Examples include the 5 French power peripherally placed central catheter (PICC), 10 French single lumen tunneled Hickman catheter, and 9.6 French vortex port (accessed with a 16 gauge noncoring straight, high flow needle). In addition, for patients who undergo ECP less frequently and opt not have a permanent central line, a 5 French Yueh catheter can be placed peripherally guided by ultrasound and removed after completion of the procedure. The Yueh catheter can be maintained overnight for a second day of ECP with standard heparin lock. Trouble Shooting Performing a discontinuous apheresis procedure in small children requires close observation by experienced nursing staff and early intervention for signs and symptoms of hypovolemia. There are many variables that are considered in assessing a patient s fluid status before starting the procedure. Baseline hydration is assessed in reviewing the interval history with the family (vomiting or diarrhea, recent oral intake), baseline vital signs, weight, and serum sodium. Patients chronically taking antihypertensive medications are asked to hold the dose on the morning of the procedure. As a general rule, patients receive a bolus of either normal saline (25 to 40 Kg) or 5% albumin (<25 Kg) just before initiation of the procedure as calculated above. Children are monitored expectantly for signs and symptoms of hypovolemia, including tachycardia, agitation and anxiety, nausea and vomiting, and hypotension with the goal of recognizing and intervening promptly. If the patient is sitting up, he/she is asked to lie down. If this maneuver does not alleviate symptoms, the patient may receive an additional fluid bolus of either normal saline or 5% albumin, using the same calculation. There are technical timing considerations related to the machine that should be considered when deciding about a second fluid bolus. For example, if the patient is due to receive blood back and he/she is stable, the bolus may be given in the form of the planned blood return. However, if the device is in the draw cycle, it can be paused to administer fluid. RESULTS Between June 2003 and November 2008, we have performed 334 ECP treatments in 11 patients for treatment of acute or chronic graft-versus-host disease (n 5

4 66 Schneiderman et al. TABLE I. Patient Characteristics Patient # Reason for ECP Weight at ECP start (Kg) ECV/TBV X 100 at ECP start Initial fluid bolus (first procedure) (ml) a Fluid balance (first procedure) (ml) Line type Total # ECP Total # transfusions 1 cgvhd % 399 DL Vaxcel, 5Fr Yuey cgvhd % Fr Hickman, 5 Fr Yuey cgvhd % b 320 DL Vaxcel Prophylaxis Study % Fr Hickman cgvhd % None Fr Power PICC cgvhd % None Fr Power PICC Grade IV agvhd % Fr Power PICC cgvhd % ml 5 Fr Yuey cgvhd % Fr Power PICC Grade IV agvhd % Fr Power PICC Prophylaxis Study % Fr Power PICC 15 5 a Procedures performed with continuous IVF. b Had received PRBC prior to procedure. 9) or prevention of GVHD (n 5 2) in children weighing less than 40 Kg (median 28.5 Kg, range 19 to 39 Kg) (Table I). One patient (patient # 5) had significant weight fluctuation during the time of ECP due to concurrent steroid therapy; days of ECP treatment when the weight exceeded 40 Kg have been excluded from this analysis. All but two required red cell transfusions at some point during their therapy to safely perform the procedure (median 5, range 0 to 14). Transfusions were performed either the day before or day of ECP; no patients experienced immediate adverse effects of transfusion, including fluid overload, fever, rash, or chills. Two patients were treated as inpatients with Grade IV agvhd of the skin, liver, and gastrointestinal tract, thus requiring multiple platelet and PRBC transfusions not necessarily related to ECP (patients # 7, 10). Complications considered directly attributed to ECP included the following: tachycardia, hypotension, headache, dizziness, nausea, and vomiting; these occurred either in isolation or combination 31% of procedure days overall. Symptoms were noted to resolve following administration of either normal saline or 5% albumin boluses. One patient (#6) was managed without additional fluid boluses due to baseline hypertension related to steroid therapy. Other patients required at least one additional fluid bolus on a median of 27% of treatment days (range 0 to 71%). Only three (0.8%) procedures were terminated early due to these symptoms in the entire cohort; one patient presented dehydrated and did not tolerate the first draw cycle. This patient expired several days later because of Grade IV agvhd and had not undergone subsequent ECP treatments. In the other two patients, early photoactivation was performed after the second cycle and the cells were subsequently returned to the patients. One of the two patients who required early photoactivation had received IV contrast for a routine CT scan just before ECP and was found to develop rash, throat swelling, and agitation, which were attributed to a new allergy to the contrast material. The other had no intercurrent illness or complications contributing to the poor tolerance of the procedure. As both children have undergone subsequent ECP procedures without similar problems. Three of eleven patients required a change of the central line due to infection; the remaining eight had the same line throughout the time of ECP treatments. Six patients had 4 or 5 French Power PICCs, two had 10 or 12 French Hickman catheters, two had Vaxcel ports, and one was maintained exclusively with temporary 4 or 5 French Yuey catheters. Two additional patients switched to temporary Yuey catheters as their treatments became less frequent. Yuey catheters were placed on the morning of ECP by Interventional Radiology with ultrasound guidance; sedation was not required. There were 44 episodes of Occlusion Alarms charted for the entire cohort (13%). The majority of episodes were successfully treated with normal saline flushes or TPA; two lines (Power PICCs) had to be changed over a guide wire by Interventional Radiology before the successful completion of three cycles of ECP, while three patients required early photoactivation after the first buffy coat cycle due to line malfunction. Maximum draw flow rates ranged from 10 to 31 ml/min (median 17 ml/min), and maximum return flow rates ranged from 15 to 90 ml/min (median 43 ml/min). Eighty-eight percent of treatments consisted of three cycles of ECP as planned. Two patients were able to tolerate four or five cycles per treatment (21 treatments total). The median time to complete all ECP treatments was 2 h and 58 min (range 1:30 to 5:03). DISCUSSION When compared to adults, pediatric apheresis practices are complicated by the need to modify procedures to perform them safely, taking into account the child s small size. This is particularly pertinent when consider-

5 ECP in Low-Weight Children is Safe and Feasible 67 TABLE II. Literature Review Reference # Patients Machine prime COBE vs UVAR/XTS Red cell transfusions Halle [27] 8 N COBE Mean 9% (0 36%) of procedures Salvaneschi [30] 23 N COBE agvhd 7/9 patients, cgvhd 1/14 patients Kanold [31] 102 N COBE (n 5 69), UVAR (n 5 33) Increased with agvhd Messina [29] 77 N COBE in all but 1 clinical site Hgb < 12 (if < 15 Kg), all patients with agvhd Calore [32] 15 Y COBE Hgb < 12 (if < 15 Kg) Kanold [28] 27 N COBE agvhd 16%, cgvhd 7%, < 25 Kg 16%, > 25 Kg 8% Berger [34] 25 N COBE < 40 Kg Hgb < 9 Duzovali [36] 7 Y, < 40 Kg XTS Hgb < 9 Landolfo [35] 8 Y, < 20 Kg COBE Not reported Linenberger [37] 7 Y, < 25 Kg COBE/XTS XTS also primed Our Patients 11 N XTS Median of 5 transfusions per patient, range 0 14 ing ECP due to the procedure s discontinuous nature, extracorporeal volume, line size, and transfusion requirements. Historically, there have been variations of the cell collection process used in low weight patients, most notably the two-step process initially reported by Andreu et al. in 1994 [26]. Mononuclear cells were collected by processing two blood volumes using the Cobe Spectra. 8-MOP was subsequently added to the product, which was then transferred to a UV-permeable bag and exposed to UV light (2 J/cm 2 as with the UVAR XTS device). Finally, the cells were returned to the patient. Since that time, several groups have successfully utilized this procedure in low-weight patients [16,27 35]. Duzovali and Chan [36] reported data on 133 procedures performed on seven patients with steroid resistant cgvhd using the UVAR-XTS device. In patients weighing less than 40 Kg, the machine was primed with PRBC, and patients were maintained at a hemoglobin of at least 9 g/dl. Linenberger et al. [37] reported a novel process utilized in seven patients weighing between 11 and 38 Kg, in which mononuclear cells were collected on the Cobe Spectra, photoactivated in the UVAR XTS device, and returned to the patient. This was well tolerated, but required priming both the Cobe and XTS devices with packed red cell units, thereby increasing exposure to blood products. The main drawback to performing two-step procedures is that the sterile, closed-loop system of the device is disrupted, increasing the risk for introduction of infectious agents (Table II). The majority of patients in our cohort required transfusion of packed red blood cells (PRBC) to maintain an adequate hematocrit for tolerance of ECV. The number of PRBC transfusions required compares favorably with other published reports. Not surprisingly, patients with higher weight required fewer transfusions; the patient who required the highest number of transfusions (14) weighed between 22 and 28 Kg and was treated with ECP for the longest period of time (113 treatments over four years). In accordance with other groups, we observed that patients with acute GVHD required more PRBC than those with chronic GVHD [28 30]. Transfusion practices vary among groups; some prime the COBE machine in addition to maintaining a minimum hemoglobin (target range reported 9 to 12 g/dl), further increasing blood product exposure. An additional issue to consider in comparing treatment with the UVAR XTS closed-loop system and the COBE method is that of product cell yield. Perseghin et al. [38] reported superior mononuclear cell (MNC) collection (p < 0.5) and less platelet contamination with the COBE software version 6 compared to version 4.6. Data were collected from 109 patients with GVHD treated using version 4.6 and 58 with version 6. Although the authors observed that patients treated with version 6 (and therefore with higher treated MNC) appeared to have a faster clinical response, the study was not randomized or powered to make this distinction. Schooneman [39] reported that collection on the COBE was superior to that on the UVAR XTS device, likely due to the smaller blood volume processed. However, clinical data comparing the two methods with respect to the number of MNC s treated and clinical outcome has never been presented and may not be of consequence to the patient. While the exact mechanism of action of extracorporeal photopheresis has not been specifically elucidated, it does appear to treat acute and chronic GVHD through the modulation of cytokine milieu and allow for tapering of other immune suppressive medications such as steroids [9,11,13,15,22,23]. This is significant, as up to 15% of adults and children continue to require therapy 7 years following the diagnosis of GVHD, leaving them at significant risk for infection and organ dysfunction [40]. Flowers et al. [41] recently published results from the first randomized study comparing the response of skin disease in adults with steroid resistant cgvhd treated with standard therapy or standard therapy plus ECP. A statistically significant portion of the patients treated with standard therapy plus ECP had at least 50% reduction in steroid dose with at least 25%

6 68 Schneiderman et al. improvement in skin score. This could prove to be the single most important achievement of ECP, as steroids, calcineurin inhibitors, and monoclonal antibodies have not provided adequate control of GVHD while they cause potentially significant toxicity and susceptibility to bacterial, fungal, and viral infections. Extracorporeal photopheresis, therefore, is a procedure that should be considered in pediatric patients for treatment of acute and chronic GVHD, and can be provided in a safe manner even in small children. We have safely performed ECP using the UVAR XTS machine in children weighing as little as 19 Kg using normal saline or 5% albumin boluses before initiation of the procedure, and are comfortable considering patients weighing over 15 Kg for therapy. 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