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Pediatric Tandem Therapeutic Apheresis: A Multidisciplinary Approach

Sirignano, Rachel, M.*†; Meyer, Erin, K.‡§; Fasano, Ross; Paden, Matthew, L.*†

doi: 10.1097/MAT.0000000000000641
Renal/Extracorporeal Blood Treatment

The epidemiology, safety, and efficacy of pediatric multiple tandem extracorporeal therapies are not well understood. We conducted a retrospective chart review of therapeutic apheresis (TA) from January 1, 2012 to October 31, 2015. We collected procedural/clinical demographics, American Society for Apheresis (ASFA) indication, complications, and mortality. One hundred eighty tandem TA procedures were performed in 53 patients. Median age was 9 years (range: 2 months to 21 years) with a median weight of 28 kg (range: 6–170.3 kg) with nine patients weighing < 10 kg. Forty-five percent of patients were in tandem with continuous veno-venous hemofiltration (CVVH), 21% cardiopulmonary bypass (CPB), 4% extracorporeal membrane oxygenation (ECMO), and 11% had multiple extracorporeal therapies (CVVH and ECMO). Common indications were solid organ transplant (50% cardiac, 13% renal) and sepsis-induced thrombocytopenia-associated multiple organ failure (26%). Equipment (4%) and patient (4%) complications occurred, with rare failure (1%) and no procedure-related mortality. Tandem procedures are used in critically ill pediatric patients with higher morbidity and mortality (21%) than typical TA patients. The high percentage of patients outside of category I or II (83%) underscores the emerging nature of tandem extracorporeal therapies and need for further investigation.

From the *Department of Pediatrics, Critical Care Medicine, Emory University, Atlanta, Georgia

Children’s Healthcare of Atlanta, Atlanta, Georgia

Department of Pathology, Emory University, Atlanta, Georgia

§Department of Hematology/Oncology/BMT/Pathology, Nationwide Children’s Hospital, Columbus, Ohio.

Submitted for consideration January 2017; accepted for publication in revised form July 2017.

Disclosure: The authors have no conflicts of interest to report and did not receive any funding from external or internal sources.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML and PDF versions of this article on the journal’s Web site (

Correspondence: Rachel M. Sirignano, Department of Pediatrics, Division of Critical Care, Emory University, Children’s Healthcare of Atlanta, 1405 Clifton Road NE, Atlanta, GA 30322. Email:

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Therapeutic apheresis (TA) has a history of successful use in the pediatric population.1 , 2 As patient acuity has increased, there has been emerging use of multiple extracorporeal therapies used in tandem in pediatric critical care.3 Recent studies have described using therapeutic plasma exchange (TPE) in tandem with either continuous renal replacement therapies (CRRTs) or extracorporeal membrane oxygenation (ECMO) or combinations of all three therapies.4–9 Although the indications for multiple extracorporeal therapy use varies, common among the indications for these critically ill children are complications arising from transplantation and those with multiple organ failure.10 , 11

A paucity of clinical and procedural outcome data exists for pediatric patients supported with multiple extracorporeal therapies. Prior studies have investigated the impact of additional circuits on extracorporeal therapies and have identified common adverse effects of hypocalcemia, hypotension, and transfusion reactions.12–15 However, study limitations include small pediatric patient numbers, incomplete description of circuit connections, a limited description of anticoagulation required for all extracorporeal components, and very little information on how multiple independent teams (ECMO, dialysis, and apheresis) work together to provide these complex therapies. Studies have demonstrated that communication may be key to mitigating adverse reactions in simultaneous extracorporeal therapies.4

Historically, at our center, all TA was performed as a consultation from the requesting physician with the American Red Cross, who sent apheresis nurses with varying levels of pediatric experience to the bedside alone to perform these complex procedures. Recognizing that this was not optimal care, an Advanced Technology team was developed to provide for the apheresis needs of our patients. From a medical leadership standpoint, this team was made up from members of pathology, transfusion medicine, critical care medicine, cardiology, hematology, and nephrology. The procedures were performed by the members of our existing Advanced Technology team, who was currently providing both ECMO and CRRT services for the hospital and are staffed 24 hours a day in the hospital. Consensus guidelines for anticoagulation approach, indications for use, laboratory monitoring, and management of common complications were created and implemented through electronic medical records–based physician order sets beginning in January 2012. Our goal for this article is to describe the use of tandem extracorporeal procedures in a high-volume pediatric institution which uses a multidisciplinary approach to providing TA for these complex patients.

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Materials and Methods

This study was reviewed by Children’s Healthcare of Atlanta institutional review board. It was approved with waiver for health insurance portability and accountability act (HIPAA) authorization and written consent because of the deidentified nature of the retrospective data (number 15–160).

A retrospective chart review was performed for patients receiving multiple extracorporeal therapies in tandem with TA from January 1, 2012 to October 31, 2015. The tandem extracorporeal therapies evaluated included cardiopulmonary bypass (CPB), both veno-arterial and veno-venous ECMO and CRRT in the form of continuous veno-venous hemofiltration (CVVH). The following data were collected from the electronic medical record review: patient demographics, admitting diagnosis, American Society for Apheresis (ASFA) indication for TA, procedure location, any information regarding procedure-related complications and failures, procedure-related mortality, and case mortality. Patient demographics included weight and age. Therapeutic apheresis indications for the time period under review were determined in reference to the ASFA sixth special issue (SI).16 Procedure-related complications were defined as any clinical issue that occurred to the patient as a direct result of the TA within a 24 hour period. Hypocalcemia was defined by low serum ionized calcium (< 4.4 mg/dl) associated with symptoms. Hypotension was defined by blood pressure > 2 standard deviations below average for patient age. Procedure failure was defined as the inability to complete the TA procedure. Procedure-related death was defined as patient death as a direct result of the TA within a 24 hour period. Case mortality was defined as patient death before discharge home. Multitandem procedures were defined as more than two extracorporeal procedures performed simultaneously (e.g., CRRT, ECMO, and TPE). All procedures were performed in the 182 intensive care unit (ICU) beds and operating rooms at Children’s Healthcare of Atlanta, which is composed of two stand-alone children’s hospitals that serve as quaternary referral, level 1 trauma, transplant, and ECMO centers for the state of Georgia. The variety of locations seen in this study was because of the severely ill nature of the patient cohort. The apheresis machine and team was mobilized and brought to the location where the patient required the therapy, as opposed to transferring the patient to a central apheresis unit.

The decision to perform TA was made by consulting the apheresis physician on-call, who primarily relied on the ASFA guidelines. In clinical situations that were not described in the ASFA guidelines, or had limited or no pediatric evidence, collaboration between members of the Advanced Technology team occurred to adjudicate whether the procedure should be performed, and whether so, what the clinical treatment plan would be. The recommendations of the Advanced Technology team was documented in the electronic medical record. In this cohort, all patients already had existing vascular access for other extracorporeal procedures, and they were being performed by one of the Advanced Technology specialists. The Advanced Technology specialists are pediatric intensive care nurses or respiratory therapists who have received formal training, assessment, and mentoring at Children’s Healthcare of Atlanta on the management of extracorporeal circuits and the common procedures associated with them (ECMO, CRRT, apheresis procedures). The course and training requirements have been in place for 25 years at this hospital and have evolved over time to meet training, trainee, regulatory, and patient needs. In addition to that training, with the introduction of a new device (the Spectra Optia; CaridianBCT, Lakewood, CO), the Advanced Technology specialists were trained onsite by CaridianBCT. Apheresis was performed using one of two systems: Spectra Optia (CaridianBCT), or COBE Spectra (CaridianBCT).

Previous research has described the practical aspects of placing multiple extracorporeal devices together.17 This was referenced in making standardized connections for common clinical situations requiring simultaneous extracorporeal therapies (Figure 1). The circuits were set up in a fashion best suited for ease of flow and decreased disturbances depending on which extracorporeal therapy was being performed. For patients receiving multitandem procedures, a CVVH filter was already placed in parallel to the ECMO circuit (Figure 2). The apheresis machine was then placed in series to the CRRT and parallel to ECMO pump, with counter-current flows to mitigate pressure limitations for both pumps. Pressures were device and patient size specific with flows of each device ranging from 50 to 150 ml/min for CVVH, 250 to 5000 ml/min for ECMO/CPB, and 30 to 70 ml/min for TA.

Figure 1

Figure 1

Figure 2

Figure 2

Standardized TPE order sets were collaboratively developed for institutional physicians ordering therapies. Patients < 15 kg received a blood prime of less than 14 day old blood, irradiated for immunosuppressed patients. The prime volume was calculated to be total volume of 250 ml made up of packed red blood cells and 0.9% normal saline to equal hematocrit (Hct) of 40%. Initial treatment for plasma exchange was as directed by the appropriate ASFA guideline and usually was either total plasma volume (TPV) or 1.5 TPV. Total blood volume (TBV) for the patient was estimated as TBV = 75 ml × weight (kg) for non-neonatal patients and 90 ml × weight (kg) for neonates. In addition to the patient’s native blood volume, we also added the total volume of the additional extracorporeal circuits being used (e.g., ECMO circuit, CVVH circuit) to the patient’s TBV. Adjustment for patient’s Hct was then used to calculate the TPV = TBV × (1 − Hct). Total number of days, and timing of subsequent days of exchange was based off the ASFA guidelines dependent on the indication for TPE or whether ASFA guidance was lacking, were decided by consensus as above.16

Anticoagulation therapies used depends on the tandem extracorporeal treatment being performed. Patients on ECMO or undergoing CPB were anticoagulated using a continuous heparin infusion. Patients on ECMO were managed per institutional protocol to maintain iStat Kaolin activated clotting time (ACT) (Abbott Laboratories, Abbott Park, IL) ranges between 160 and 190 seconds or antifactor Xa levels between 0.3 and 0.7 (unit/ml). Patients undergoing CPB were given 500 unit/kg heparin to maintain iStat Kaolin ACT > 480 seconds. In these patients, no additional anticoagulant was used for the apheresis circuit. However, the Spectra Optia requires an anticoagulant prescribed to function. Normal saline was used instead of anticoagulant citrate dextrose (ACD-A) and run at a 50:1 ratio to allow the Optia to perform its therapy. Patients receiving CVVH were anticoagulated with ACD-A for regional anticoagulation of the circuits. Strict guidelines were in place to decrease the risk of occurrence for hypocalcemia.12 , 14 Calcium chloride (CaCl) infusions were calculated as milligrams of CaCl (not elemental calcium), and weight based at 20 mg/kg and dissolved in 100 ml of 0.9% normal saline solution. Calcium gluconate infusions were calculated as 50 mg/kg and dissolved in 100 ml of 0.9% normal saline solution. An infusion of one of these calcium solutions was run throughout the plasmapheresis procedure at a rate of 25 ml/hr. Point-of-care ionized calcium levels were checked using iStat to maintain ionized calcium at an optimum range of 1–1.4 mg/dl in the postfilter circuit and 4.4–5.2 mg/dl in the patient via titration of the calcium infusions (Supplement 1 contains the clinical protocol [see Supplemental Digital Content 1,]).

Protocols for the TA also had other embedded orders to minimize other common adverse events.12 Automated best practice advisories were in place in the electronic medical record to alert providers of any patient receiving angiotensin-converting enzymes inhibitors as part of their medical management, and it was recommended to hold the medication for 24 hours before performing TA to decrease hypotensive events. Orders were placed for the patient to remain in bed at least 30 minutes post procedure to reduce the risk of procedure-related syncope. Automatic orders for heparin locks were placed to decrease risk of clot and malfunction of any lumens being accessed only intermittently for apheresis procedures. Also, anaphylaxis kits were ordered to bedside during apheresis procedures because of the risk for transfusion reactions to occur (Supplement 2 contains TPE physician order sets [see Supplemental Digital Content 2,]).

Descriptive statistical analysis (Microsoft Excel 2010, Redmond, WA) were performed to describe the patient demographics and complication rates.

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During this time period, 180 TA procedures were performed in 53 patients in tandem with another extracorporeal therapy. Table 1 describes the age and weight demographics of the cohort. All but three of the TA procedures were TPE, with the remainder leukocytapheresis. The median age was 9 years 3 months old, with patients ranging from infant to adult, 3 years 2 months old to 15 years 9 months old (25–75% interquartile range). The median weight of cases was 28 kg with the majority between 14 and 58.6 kg (25–75% interquartile range).

Table 1

Table 1

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Therapeutic apheresis was done in tandem with various extracorporeal therapies. Table 1 indicates the number of procedures, number of patients, and percentage of total patients based on the type of extracorporeal therapy. A single procedure was transitioned from CPB to ECMO after failure to wean off bypass. The multitandem procedures describe patients receiving TPE, CVVH, and ECMO simultaneously.

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Indication for TA procedures is presented in Table 2. As defined by the ASFA (6th SI) which was the standard at the time these procedures were performed, category I indications are for disorders where apheresis is first-line therapy either alone or in conjunction with other treatments.16 Category III indications include disorders for which the optimum role of apheresis therapy is not established and decision-making should be individualized. No procedures were performed under category II, category IV, or uncategorized. Re-review of the indications using the current ASFA (seventh SI), added category II indications, being defined as second-line therapy either in conjunction with or as stand-alone treatment.18 The vast majority of these procedures were conducted for patients requiring solid organ transplant (51% cardiac, 13% renal) and sepsis-induced thrombocytopenia-associated multiple organ failure (TAMOF) (26%).

Table 2

Table 2

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Complications and Outcomes

Of the 180 procedures, eight (4%) experienced equipment-related complications, and an additional eight (4%) experienced patient complications. Equipment-related complications included air-in-line (1), clot (4), and pump malfunction (3). Patient-related complications included hypocalcemia (1), seizure (1), hypotension (2), hemorrhagic stroke (2), and cardiac arrest (2). Table 3 details the source of equipment and patient-related complications. Pump malfunction was because of the inability to achieve adequate ECMO blood flow in two cases. The primer was unable to increase the speed, and a cephalad-directed internal jugular cannula was added to help achieve prescribed flow. The two patients who sustained a cardiac arrest were both orthotopic heart transplant (OHT) patients. The first patient, who underwent a new OHT, had ventricular fibrillation during anesthetic induction, was emergently placed on CPB via the femoral vessels, and TPE was able to be completed after the patient was stabilized. The second patient was on CVVH from chronic renal failure and was receiving TPE for antibody-mediated transplant rejection. He developed ventricular tachycardia requiring chest compressions during TPE. Plasmapheresis was paused until after stabilization of patient, but ultimately this was the one of two procedures which were unable to be completed. Total procedure failure rate was 1%. There were no procedure-related mortalities.

Table 3

Table 3

Although not procedure related, 21% (11 total patients: three < 10 kg, two between 10 and 20 kg, and six >20 kg) did not survive to discharge home because of their underlying disease processes. Table 4 details the underlying illness, size of the patient, and cause of death. Many patients (six) died in the middle of their prescribed TA and were unable to complete the total prescribed number of TA.

Table 4

Table 4

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Therapeutic plasma exchange is used in a variety of clinical conditions. The clinical conditions requiring TPE in a pediatric population vary from current guidelines, and patterns of use are inconsistent across institutions.18–20 The peer-reviewed published evidence to support TA in pediatric patients are limited to either case series, poor-quality cohort studies, case-control studies, single-case reports, surveys, or expert opinion without explicit critical appraisal of the literature.21 In a field marked by inherent baseline variation, it is difficult to determine therapeutic efficacy in even more vulnerable populations such as critically ill children. The addition of multiple extracorporeal circuits in these patients increases logistical complexity in an attempt to maintain the highest level of safety.

Common minor adverse events noted for TA alone include hypotension and hypocalcemia. Studies have demonstrated that using a continuous infusion of calcium gluconate can decrease these adverse events from 35 % to 8.6 % in an adult population.14 In a pediatric population, these complications can be even higher, with up to 55% of procedures having an adverse event, which is why it is recommended that TPE be performed in a specialized pediatric center.15 Our low number (1.7%) of minor adverse events for tandem procedures may be related to use of standardized guidelines and institutional based protocols to mitigate citrate lock and use slow increase of flows upon initiation of TA (see Supplement 1, Supplemental Digital Content 1,

The burden of complications caused by both a pediatric population and equipment-related issues increase when performing TA in a critically ill cohort receiving other extracorporeal therapies. Our data demonstrated severe adverse patient events including seizure, hemorrhagic stroke, and cardiac arrest in 2.8% of our population and case mortality of 21%. Mortality data for those receiving ECMO in the pediatric population ranges anywhere from 25% to 66% across the international registry of ECMO support.22 Severe adverse events, including stroke, can occur in up to 12% of pediatric ECMO populations.23 Although these severe events are more common than in TA alone, they are comparable or lower than seen in ECMO populations.22 , 23

Another critically ill population which has used extracorporeal support techniques is for treatment of TAMOF.3 , 24 Twenty-six percent of patients required assistance because of acute kidney failure, cardiac dysfunction, and respiratory failure of TAMOF patients. Our 21% case mortality was lower than the 52.8% shown for pediatric populations receiving tandem ECMO and TPE.4 A case series showed two of three patients who suffered strokes while having multitandem procedures for their multiorgan failure.6 When assessing data from such a critically ill population, one must look at goal survival and mitigating morbidity and mortality because of the procedures themselves. Our data showed no mortality because of procedures. The two patients who sustained cardiac arrest were resuscitated and went on to receive their OHTs.

Another common need for multiple extracorporeal therapies pertains to solid organ transplant: heart and kidney. More than half of our patients (64%) required desensitization before transplantation or antibody-mediated rejection after transplantation. Although a significant degree of investigation has occurred in this area resulting in a change of category III indications to category II indications for cardiac transplant desensitization under the seventh SI guidelines (Table 2), 43% of patients still maintained category III indications. The recent publication of evidence for successful use of TA in cardiac transplantation allowed that indication to change to a category II indication and is a step in the correct direction, and additional such effort must be applied to these other populations. Specifically, more investigation is necessary in the use of tandem procedures population such as TAMOF and liver failure that have been successfully treated in specialized care centers but lack comprehensive guidelines.

Our institution is a quaternary center and is able to give a large volume of data for analysis in the solid organ transplant and TAMOF populations. But a single pediatric specific institution using rigorous guidelines may have inherent bias when analyzing the data. A multicenter analysis may better help with extrapolating results to other institutions. There is inherent bias in a retrospective review. Causality may not be assigned when using retrospective data to review extracorporeal therapies and morbidity or mortality. A prospective approach would be necessary to definitively define the role of extracorporeal therapies on morbidity and mortality in this vulnerable population. The data analysis was lacking in objective risk stratification which may help in assessing such a heterogeneous group of patients. But existing scoring systems (pediatric risk of mortality (PRISM) III, pediatric logistic organ dysfunction (PELOD)) include components which are inherently altered or invalid in patients receiving these therapies and are validated solely for use upon admission into the ICU.

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Tandem procedures are used in critically ill pediatric patients, and morbidity/mortality is higher than typical TA patients. Although new work released in the apheresis literature (ASFA seventh SI) has focused the importance of these procedures in solid organ transplants, our data have the majority of procedures outside of category I or II. This underscores the emerging nature of tandem extracorporeal therapies in the critically ill pediatric population and need for further investigation, especially in patients with multiorgan failure.

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Valuable assistance was provided by cardiac anesthesiologist, Dr. Nina Guzzetta (Emory University).

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extracorporeal membrane oxygenation; apheresis; pediatrics; tandem; continuous renal replacement therapy

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