922 In children, therapeutic apheresis requires selected modifications given a child’s smaller size, blood volume, and developmental stage Often, RBC priming is used to prevent hemo dilution and hypov[.]
C Taylan and S M Sutherland 922 In children, therapeutic apheresis requires selected modifications given a child’s smaller size, blood volume, and developmental stage Often, RBC priming is used to prevent hemodilution and hypovolemia Although peripheral access may be used in older patients, the majority of pediatric patients require double lumen central venous catheters if the therapy will be needed for an extended period of time Often diversional activities appropriate for the child’s developmental age are provided to allay anxiety, divert attention, and elicit cooperation That said, if the infrastructure of an apheresis center is appropriately designed, a child’s size and clinical condition are not exclusionary criteria for apheresis This chapter will give an overview of therapeutic apheresis techniques in general and will describe some of the issues that are unique to the application of apheresis techniques in pediatrics Principles of Separation Apheresis involves the removal of whole blood from an individual and the subsequent separation of that blood into cellular elements and plasma; it is generally performed for the purpose of removing or exchanging one of these blood components There are two techniques which can be used to achieve this separation: mechanical centrifugation and membrane filtration During mechanical centrifugation, blood cells and components are separated based upon their density Centrifugal apheresis can target blood cells or plasma and is very efficient, achieving nearly 80% plasma extraction efficiency Notably, it requires relatively low blood flow rates and therefore can be performed using either peripheral or central venous access Additionally, centrifugation can utilize intermittent or continuous flow Intermittent flow centrifugation processes small volumes of blood in cycles (a cycle consists of blood being drawn, processed, and re-infused); continuous flow centrifugation simultaneously removes, processes, and re-infuses blood Intermittent flow techniques can be performed using a single venous access site; however, the procedure time is longer and larger extracor- poreal blood volumes are required; it is rarely used for therapeutic apheresis Continuous flow centrifugation is faster but requires two vascular access sites (or a dual lumen central catheter), one for withdrawal of blood and a second for its return Membrane filtration devices, on the other hand, selectively remove plasma along with high- molecular- weight proteins based upon differing membrane pore sizes (pore range 0.2–0.6 μm, Table 48.1) As a result, membrane filtration devices are capable of plasma removal and exchange but not cytapheresis Notably, these devices are less efficient with lower plasma extraction efficiency (about 30%), require higher blood flow rates which tends to necessitate central vascular access, and require continuous flow Regardless of the method of extraction, all apheresis systems have certain aspects in common First, all devices employ single-use, disposable, biocompatible plastic-ware to maintain sterility during the procedure Second, these devices all incorporate safety features such as air traps to prevent air embolism, filters to prevent reinfusion of aggregates, pressure monitors to ensure safe access and intra-device pressures, and appliances to infuse an anticoagulant to prevent clot formation in the extracorporeal circulation Finally, all automated separators have an obligate extracorporeal volume (ECV) which must be in the instrument’s tubing during the apheresis procedure The necessary ECV varies depending both on the type of device used and the type of procedure being performed The temporary loss of these volumes is usually well tolerated by adults, but volume and RBC balance must be taken into careful consideration when automated apheresis is performed in small children, Table 48.1 Size of cellular blood components Cell type Plasma Platelets Erythrocytes Lymphocytes Eosinophils Basophils Neutrophils Monocytes Diameter N/A 1–4 μm 6–8 μm 6–10 μm 9–15 μm 10–15 μm 12–15 μm 10–30 μm 48 Therapeutic Apheresis in Children especially if the ECV represents >10–15% of the patient’s total blood volume Pediatric-Specific Technical Considerations The use of apheresis in children is feasible regardless of the size of the patient, as long as adequate vascular access can be established However, apheresis procedures in young children must be customized to the situation and to the size of the patient because apheresis equipment and the software that controls it are, in general, designed for use in adults Vascular Access Although apheresis procedures can be performed using peripheral venous access, most pediatric patients will not have antecubital veins large enough to support adequate flows The access for drawing blood from the patient is of paramount importance as it must be capable of tolerating the pressures generated by the device; frequently, this necessitates placement of a 16 or 17-gauge steel needle (similar to those used to access arteriovenous fistulas) The return access can be a standard, plasticized peripheral intravenous line; however, it needs to be of larger bore as well (18 to 20-gauge) As a result, the vast majority of children who receive apheresis so via a double lumen central venous catheter, utilizing the same access for both draw and return In these situations, it is preferable to draw from the proximal port and reinfuse through the distal point to minimize recirculation; however, in practice the more patent lumen with superior flows is usually chosen for the draw access The length and gauge of the catheter will depend on the child’s physical size and vein quality; however, in all cases the wall of the catheter must be resilient enough to withstand the negative pressure generated during the apheresis procedure Although catheters designed for dialysis are commonly used for apheresis procedures, newer “power injectable” central lines such as the PowerHickman® (Bard, 923 Tempe, Arizona, United States) can be used as well These catheters are capable of tolerating the pressures generated by the apheresis devices but are smaller, more flexible, and allow greater customization of length For larger patients who are likely to require apheresis chronically, several companies make “power injectable” ports through which procedures can be performed Unfortunately, standard softer central venous catheters such as those commonly used in oncology patients and the intensive care unit are not suitable apheresis access Although they may be used for return of the blood, they are not stiff enough to be used for drawing of the blood into the device Table 48.2 provides general guidelines for apheresis access across weight categories It is worth noting that in situations where patients already have some type of extracorporeal circulation (i.e., extracorporeal membrane oxygenation, cardiopulmonary bypass, or continuous renal replacement therapy), most apheresis devices can be attached directly to these circulations without the need for alternate venous access Extracorporeal Volume and Blood Priming One of the most important considerations when adapting apheresis instruments designed for adults for use in children is the extracorporeal volume (ECV) of the device The actual ECV varies from approximately 200 to 400 mL depending on the device employed and the procedure performed Although adult-sized patients may tolerate the transient loss of such a volume, smaller pediatric patients almost certainly will not Generally speaking, if the ECV of the device exceeds 10–15% of the child’s blood volume, blood priming of the device should be employed Although the ECV for all apheresis devices/procedures is clearly defined, patients total blood volume must always be estimated Traditionally, pediatricians estimate total blood volume to be 65–85 mL/kg depending on age However, most apheresis devices contain more complex, empirically derived formulas for blood volume estimation that take into account gender, weight, C Taylan and S M Sutherland 924 Table 48.2 Weight-based apheresis line choices for children Catheter selection for all apheresis therapies based on patient weight and expected duration of therapy Expected usage ≤14 days Expected usage >14 days 50 kg 9.5 Fr (cuffed Power Hickman, Bard) 9.5 Fr (cuffed Power Hickman, Bard) 12 Fr Dual Lumen Apheresis Port (Vortex®, Powerflow®)c Two 8Fr single lumen Apheresis Ports (Vortex®, Powerflow®)d No cuffed, permanent solution available for children 50 kg These ports cannot be used earlier than 7–21 days after placement a b and height programed directly into the software [8] Often, the apheresis instrument is primed by filling all of the tubing with red blood cells at a predetermined hematocrit before starting; however, priming can also be accomplished by infusing red cells or fluids directly into the patient at the start of the procedure while the machine is filling with blood coming directly from the patient With proper planning, it is possible to perform an apheresis procedure in a small child with no change in the patient’s blood volume or red cell mass during the procedure The technical details of priming for pediatric apheresis procedures are discussed in detail elsewhere [9, 10] Anticoagulation Apheresis requires anticoagulation to prevent clotting in the device and extracorporeal circulation Most commonly, the anticoagulant employed is sodium citrate which prevents clotting through the chelation of calcium; the clot- ting cascade is highly dependent on calcium and lowering calcium levels prevents activation One substantial benefit of citrate anticoagulation is its regional nature; citrate allows anticoagulation of the circuit without exposing the patient to the bleeding risks of systemic anticoagulation On the other hand, citrate can lead to transient hypocalcemia The severity of this side effect depends primarily on the rate of infusion and the rate of hepatic citrate metabolism; smaller children and those with hepatic dysfunction are at the greatest risk for hypocalcemia The symptoms of hypocalcemia during apheresis can range from mild (perioral, hand, and foot tingling and paresthesias) to severe (tremors, muscle spasms, tetany, seizures, and arrhythmias) [11–14] Thus, patients undergoing apheresis using citrate anticoagulation should be monitored for early signs of citrate accumulation and hypocalcemia by focused symptom history or measurement of ionized calcium levels In small children or sedated/ unconscious patients who are incapable of verbalizing their symptoms frequent vital signs 48 Therapeutic Apheresis in Children monitoring is warranted along with serial calcium determination Mild symptoms (tingling) can be treated by reducing the citrate infusion rate, stopping the procedure temporarily, or administering oral calcium supplements Severe symptoms such as seizures, tetany, or EKG changes should be managed by terminating the procedure and administering calcium intravenously Heparin can also be used as the anticoagulant for apheresis procedures In this case, the patient typically receives a therapeutic dose of heparin during the procedure with resultant systemic and extracorporeal anticoagulation; these patients should be considered at risk for bleeding during and immediately after the procedure For patients at greater bleeding risk it is safest to monitor the degree of heparinization during the procedure and adjust the infusion rate accordingly In pediatric apheresis, it is particularly important to pay attention to the rate at which the anticoagulant is administered to the patient Since the anticoagulant is added to the blood drawn from the patient in a constant ratio of volume of anticoagulant per volume of blood, the rate of blood draw determines the dose of anticoagulant that the patient ultimately receives Apheresis procedures in children are often performed at relatively higher flow rates than adults (relative to weight) Thus, the dose anticoagulant (citrate or heparin) will be higher in a child than in an adult on a per kilogram basis Specific anti-coagulation protocols will vary between institutions and are dependent on the device being used For many devices, the anticoagulant dose is expressed as a ratio relative to the blood flow rate For example, the default blood flow to anticoagulant ratio for plasma exchange at our institution is 10:1, meaning that for every 10 mL of blood that passes through the device, 1 mL of anticoagulant (ACD-A) is added; typical ratios for ACD-A are between 8:1 and 15:1 where higher ratios provide less aggressive anticoagulation We typically use heparin only to provide photopheresis, primarily due to device specifications In this scenario, depending on the patient’s platelet count, 7500–10,000 units of heparin is added to 500 mL of normal saline and anticoagulation is provided at a ratio of 8:1 925 to 12:1 It is important to note that these ranges are merely guidelines and that it is important that anticoagulation is tailored to the individual Volumetric Control The rates at which blood is drawn, processed, and returned during an apheresis procedure are determined by computerized algorithms that control the peristaltic pumps that move the blood through the tubing While it is beyond the scope of this chapter to discuss these algorithms in detail, a few general points are worth noting First, within certain limits, the patient’s net balance of volume and the net balance of red cell mass can be manipulated independently during an apheresis procedure This means, for example, that it is possible to administer a red cell transfusion during plasmapheresis with no net increase in the patient’s intravascular volume, a maneuver that can be very advantageous for a patient with anemia and oliguric kidney failure Second, it is possible to perform a plasmapheresis procedure that results in a net removal of plasma volume from the patient, or in a net fluid gain It is important to note, however, that while these manipulations are feasible, using apheresis procedures as a method of volumetric control is not ideal; patients who need true ultrafiltration will be better served by some form of renal replacement therapy However, subtle manipulations in volume can be helpful for patients who are exquisitely volume sensitive Apheresis Treatment Modalities and Procedures Historically, there have been four primary therapeutic apheresis procedures: plasmapheresis, erythrocytapheresis, leukapheresis, and plateletpheresis All four can be performed safely and effectively in pediatric patients with various modifications This section will discuss these four primary procedures as well as several more specialized techniques C Taylan and S M Sutherland 926 Plasmapheresis transmitted infectious disease, blood product allergic reactions, or transfusion-associated Plasmapheresis involves separation and removal lung injury (TRALI) [15] However, removal of of plasma from the cellular components of blood plasma and replacement with 5% albumin leads During the procedure, a patient’s plasma is col- to depletion of important plasma proteins (i.e., lected and discarded into a waste bag while the non-pathologic immunoglobulins and coagucells themselves are mixed with a replacement lation cascade components) As an example, fluid and returned to the patient Therapeutic as shown in Fig. 48.1, plasmapheresis of one plasma exchange is generally employed in two plasma volume without concomitant replacesituations The first would be a scenario where a ment with a plasma product will reduce the levpatient’s plasma compartment contained a non- els of coagulation proteins by about 60–65% physiologic or undesirable protein or substance This may be associated with a fibrinogen level An example of this is Goodpasture’s disease; below 100 mg/dL and prolongation of the proin this case, the pathogenesis of the patient’s thrombin time (PT) and partial thromboplastin disease is the presence of circulating antibod- time (PTT); however, it is not usually associated ies against the glomerular basement membrane with clinical bleeding Generally speaking, if the The antibodies are contained within the plasma rate of hepatic regeneration of these coagulation component and are removed along with the factors is normal, performing plasmapheresis on plasma Normovolemia is restored by replacing an alternate day schedule tends not to require the discarded plasma with an equal volume of exogenous replacement with FFP. However, if an osmotically equivalent fluid Options primar- daily plasmapheresis is required or the patient ily include donated fresh frozen plasma (FFP) has synthetic hepatic dysfunction, a concomior 5% albumin Often, 5% albumin is used in tant coagulopathy, or significant bleeding risk, isolation as it allows the procedure to be per- at least a portion of the replacement fluids must formed with minimal concern for transfusion- be comprised of FFP. Often, institutions will Fraction of plasma exchanged (%) 100 90 80 70 60 50 40 30 20 10 0 0.5 1.5 2.5 Plasma volumes exhanges performed Fig 48.1 Relationship between TPE volume exchanges and plasma turnover As larger fractions of plasma are exchanged, each successive increase becomes less efficient This is due to the fact that the process is provided continuously; the patient’s plasma becomes mixed with the donor plasma during the course of the therapy A single-volume exchange replaces approximately 65% of the patient’s plasma, a 1.5x volume exchange replaces approximately 75% of a patient’s plasma, and a double- volume exchange replaces approximately 85% of a patient’s plasma The diminishing returns suggest that exchanges larger than 2x volume are unlikely to provide significant incremental effect 48 Therapeutic Apheresis in Children set a pre-therapy fibrinogen threshold of 150– 180 mg/dL and patients due to undergo plasmapheresis who have fibrinogen levels lower than this threshold will receive FFP as part of the replacement fluid; while some situations may require 100% of the replacement fluid to be FFP, often a mixture of 50% FFP and 50% 5% albumin will suffice The second scenario where plasmapheresis is employed is in the setting of a blood protein or component deficiency The best example of this is likely thrombotic thrombocytopenic purpura (TTP) In this case, the goal is not only removal of a pathologic substance but also the replacement of an absent physiologic one In these situations, the replacement fluid must consist entirely of FFP. Although some patients with mild deficiencies may respond to plasma infusion alone, the vast majority require a large enough plasma volume to restore normal protein levels that plasma exchange is necessary to prevent massive volume overload A very important aspect of plasma exchange is the concept of efficiency and dose As plasma is removed from the patient, the replacement fluid or fluids of choice must be given concurrently to maintain intravascular volume and oncotic pressure As a result of this, the replacement fluids become admixed with the patient’s plasma, thereby diluting it Subsequently, a portion of the plasma removed throughout the procedure is technically the replacement fluid itself At the beginning of a treatment, the majority of the removed fluid is the patient’s plasma, whereas at the end of the plasmapheresis, much of what is removed is actually replacement fluid The relationship between the amount of plasma removed (expressed as multiples of the patient’s plasma volume) and the fraction of the original plasma remaining is given in Fig. 48.1 A plasmapheresis procedure that exchanges a volume equal to the patient’s plasma volume (single-volume exchange) will achieve about 63% removal of the original plasma, with 37% remaining in the patient, as shown in the figure Removal of twice the patient’s plasma volume (double-volume exchange) will remove 86% of the original plasma From the figure, it is apparent that the additional benefit of prolonging a 927 plasmapheresis past two volumes is marginal Finally, the overall efficiency of a single plasmapheresis procedure, or of a series of treatments, is also affected by the distribution between intraand extravascular compartments of the targeted substance and on other metabolic characteristics such as rate of synthesis and degradation [16] Figure 48.2 illustrates two commonly utilized regimens, daily single-volume exchanges (Fig. 48.2a) and alternate- day 1.5x volume exchanges (Fig. 48.2b) Each regimen is capable of achieving similar effective clearance albeit over shorter and longer timeframes, respectively While alternate- day regimens are associated with greater inter-treatment rebound and longer effective clearance times, they also allow the body to re-accumulate physiologic components of hematologic homeostasis (i.e., clotting factors) The use of single-, 1.5x, or double-volume exchanges as well as delivery of the therapy on a daily or alternate day schedule depends on the manner in which these aspects are prioritized Erythrocytapheresis Erythrocytapheresis involves separation of RBCs from the plasma and other cellular components The RBCs are discarded and the volume replaced with an equal volume of replacement fluid or donor RBCs When the patient’s RBCs are replaced with donated RBCs, the procedure is commonly referred to as an automated exchange transfusion This technique is most often employed in hemoglobinopathies; however, it has also been used to manage diseases caused by intra-erythrocytic parasites such as babesiosis and malaria [17] In children and adults, however, the primary applications of erythrocytapheresis are in sickle cell disease In patients with sickle cell disease, automated exchange transfusion can be used urgently to manage acute chest syndrome and/or cerebrovascular events On a non-urgent basis, it can be used pre-operatively, during pregnancy, and in lieu of manual transfusion therapy The apheresis machines can be programmed to achieve a desired post-procedure hemoglobin S level which can lead to more effective and effi- ... undesirable protein or substance This may be associated with a fibrinogen level An example of this is Goodpasture’s disease; below 100 mg/dL and prolongation of the proin this case, the pathogenesis... through the tubing While it is beyond the scope of this chapter to discuss these algorithms in detail, a few general points are worth noting First, within certain limits, the patient’s net balance... setting of a blood protein or component deficiency The best example of this is likely thrombotic thrombocytopenic purpura (TTP) In this case, the goal is not only removal of a pathologic substance