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, http://links.lww.com/ASAIO/A1]).
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, http://links.lww.com/ASAIO/A179]).
Descriptive statistical analysis (Microsoft Excel 2010, Redmond, WA) were performed to describe the patient demographics and complication rates.
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).
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.
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%).
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.
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.
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, http://links.lww.com/ASAIO/A1).
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.
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.
Valuable assistance was provided by cardiac anesthesiologist, Dr. Nina Guzzetta (Emory University).
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