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Therapeutic Apheresis

Therapeutic Apheresis. Inside the black box. Apheresis is a process by which blood being removed from a subject is continuously speparated into component parts, usually to allow a desired component(s) to be retained while the remainder is returned to the subject

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Therapeutic Apheresis

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  1. Therapeutic Apheresis Inside the black box

  2. Apheresis is a process by which blood being removed from a subject is continuously speparated into component parts, usually to allow a desired component(s) to be retained while the remainder is returned to the subject • Plasmapheresis from greek apairesos or Roman aphairesis meaning to take away by force

  3. History of Apheresis

  4. History • Earliest continuous flow centrifugation device was hand cranked cream separator in 1877 by Dr. Carl Gustav Patrik De Laval • Applications of flow centrifugation in: • Petroleum industry (separate impurities) • Nuclear fuels (separate uranium isotopes) • Waste management (separate solid and liquid wastes)

  5. History • Plasmapheresis (removal of plasma with return of RBC) first performed 1914 John Abel at Johns Hopkins University in a dog in context of artificial kidney research

  6. History • Developed manual plasmapheresis where blood drawn from donor (vein then kept open by IV saline) • Centrifuge blood in blood bank • RBC then reinfused with saline • Plasma stored for use • Major method of collecting source plasma from paid donors until early 1980’s

  7. History • 1959 Skoog and Adams used manual plasmapheresis in patient with Waldenstrom’s to reduce serum viscosity • Followed by use in treatment of Rh sensitized pregnant women to prevent hemolytic disease of newborn with variable outcomes

  8. History • Earliest work in early 1950’s by Dr. Edwin Cohn at Harvard • Devised fractionation scheme for plasma and important in providing albumin for WWII • Developed the Cohn centrifuge in response to need for cellular components that might be needed in event of nuclear war • Blood into conical centrifugal separation chamber

  9. History • 1962 IBM engineer son dx with CML • Together with Dr. Emil Freireich and IBM developed NCI-IBM (2990) at National Cancer Institute • Initially process 11L of blood from CML patients for leukopheresis • 1964 studies on CLL patient leukopheresis • 1969 1st automated plasma exchange procedures

  10. Principle of Operation

  11. Principle of Operation • Blood reaching equilibrium after application of centrifugal force: Plasma (1.025-1.029 specific gravity) Platelet (1.040) Mononuclear (lymph, mono, PBSC,blast) (1.070) Granulocyte (neut, baso, eos) (1.087) Neocyte RBC RBC (1.093-1.096)

  12. Principle of Operation • Intermittent flow • Blood processed in discrete batches • Separation until container filled with dense component (RBC) • Needs to empty before next batch • Continuous flow • All fractions can be removed in ongoing manner • Do not need to empty container until end of procedure

  13. Principle of Operation Gambro Spectra: • Continuous automated centrifugal separator

  14. Plasma collect bag Waste bag 272ml ECV 52ml RBC ECV Inlet Pump ACD pump Plasma pump Centrifuge channel

  15. Physiology of Apheresis

  16. Effectiveness of TPE depends on: • Volume of plasma removed relative to total plasma volume • Distribution of substance to be removed • Between intra and extravascular compartments • Speed at which the substance equilibrates between compartments • Rate at which substance is synthesized

  17. Mathematical models used to predict TPE outcome assume the intravascular plasma volume is a closed compartment • Also assumes that steady state between synthesis and catabolism is not altered during TPE

  18. The equation that describes the removal of a substance in PLEX is: Y = Y0e-x Y = final concentration Y0 = initial concentration e = base of natural logarithms (2.718…..) X = number of times patient’s total plasma volume is exchanged

  19. Assumes no equilibration with extravascular stores Assumes no further substance is produced Predicts 37% of substance remains at end of 1 plasma volume exchange 22% remaining after 1.5 PV exchange 14% remaining after 2.0 PV exchange

  20. Metabolic Characteristics of Plasma Proteins

  21. Normal Immunoglobulins One plasma volume exchange: • IgG drops to 34% of baseline • IgA drops to 39% of baseline • IgM drops to 31% of baseline • Varying reports as to time to recovery of Ig • Ranges from 3 days to 5 weeks to full recovery • Variation due to different methods of calculating recovery, some patients on immunosuppressive medications

  22. Paraproteins • Removal of paraproteins (ie myeloma) is 50% of predicted • Some cases can have greater removal than predicted (see last 2 reasons) • Due to: • Increase in plasma volume (up to 1.5x greater, especially if IgG >40g/L) • Some myeloma patients have higher proportion of IgG in intravascular space (56-85%) • As remove paraprotein in TPE, plasma volume progressively decreases

  23. Complement and Immune Complexes • C3 has equal distribution between intra/extravascular space • Decrease to 37% of baseline with 1 plasma volume exchange • Recovery to 90% at 24 hours and 100% at 48 hours • Similar results for circulating immune complexes

  24. Coagulant Proteins Fibrinogen: • Decrease to 25% of pretreatment with single exchange of 1 PV • Decrease to 10-30% of pretreatment with consecutive daily 1 PV exchange • recover to 100% of pretreatment levels by 2-3 days

  25. Coagulant Proteins Prothrombin: • Decreased to 30% of baseline Factor VII & factor VIII: • Decreased to 45-50% of baseline Factor IX: • Decreased to 60% of baseline Factor V, X, XI: • Decrease to 38% of baseline Antithrombin: • Activity to 40%, Ag to 70%

  26. Recovery to 85-100% of baseline within 24 hours • Elevation of PTT, PT, TT post exchange • PTT,TT returned to normal 4 hours post exchange • PT returned to normal 24 hours post exchange

  27. While decreases in coagulation proteins, large studies have not shown increased bleeding risks in patients undergoing repeat exchanges • Concern if preexisting hemostatic risk: • Currently bleeding, surgical procedure within last 24 hours, preexisting coagulopathy

  28. Electrolytes • Potassium decrease (minimal)(0.25meq/L with albumin and up to 0.7meq/L with FFP • No change in sodium and glucose • Bicarbonate decrease 6meq/L and chloride increase 4meq/L with albumin and this reverses with FFP (more citrate in FFP)

  29. Other plasma proteins and molecules • LDL cholesterol, ALP, ALT decrease to 37% after 1 PV exchange • AST, LDH,amylase, CK, ferritin, transferrin decrease to 47% after 1 PV exchange • ALT, AST, amylase 100% recovery in 48hrs • LDH, ALP,CK 60% recovery in 48hrs • LDL cholesterol 44% recovery in 48hrs

  30. CBC RBC: • Up to 12% decrease in Hb immediately after 1 PV exchange • Recovery to 100% within 24 hours • Felt to be due to expansion of plasma volume with albumin more than FFP WBC: • Some have shown increase in neutrophils (up to 2x109/L), while others have not

  31. CBC Platelets: • 15-50% reductions have been seen post 1PV exchange • With 5-10 repeated exchanges platelets may drop to 20-25% pretreatment levels • Recover to 70-85% by 24 hours and 100% by 72-96 hours • Platelets may fall by smaller amount if baseline platelets <150

  32. Removal of Autoantibodies • Monoclonal immunoglobulins • Paraproteins • Polyclonal autoantibodies • Antibodies in immune complexes

  33. IgG 45% intravascular • 1.25 plasma volume exchange removes 32% of total body IgG • Reequilibration between intra/extravascular compartments may be complete by 24 hours • To deplete total body IgG by 85% requires 5 exchanges of 1.25 plasma volumes on alternate day schedule • 21 day resynthesis half life

  34. IgM 75% intravascular • Faster rate of synthesis than IgG at 5-6 day resynthesis half life • To reduce to 85% requires 3-4 exchanges of 1.25 plasma volumes

  35. Hyperviscosity Syndrome • Concentration of paraprotein at which patients develop clinical hyperviscosity is variable • For IgM, reduction of serum viscosity may occur with removal of 0.5 plasma volume

  36. Drug Removal • Can remove: • ASA, tobramycin, dilantin, vancomycin, propranolol • May reduce plasma levels of enzymes that metabolize drugs • May reduce plasma levels of proteins that bind and transport drugs • Depends on distribution of drug between intra/extravascular space, half life of drug in circulation, timing of administration of drug, protein bound status, not lipid or tissue bound • 1% of prednisone removed • IVIG mainly removed as remains intravascularly • Ideally give medications after exchange

  37. TBV calculations • Calculate TBV by Nadler’s formula • For male: (0.006012xht3) / (14.6xwt) + 604 = TBV(ml) • For female: (0.005835xht3) / (15xwt) +183 = TBV (ml) • Will overestimate obese patient blood volume and underestimate muscular patient blood volume

  38. TBV calculations • Other methods: • Gilcher’s Rule of 5’s:

  39. Extracorporeal blood volume limited to 15% of TBV • To limit hypovolemia • Can prime with RBC if extracorporeal RBC volume is more than 15% of RBC volume • Intraprocedure hematocrit: (RCV-extracorporeal RCV)/TBV x100 • If this is <24%, the PLEX may not be tolerated • Acute onset anemia less tolerated on exchange

  40. Replacement Fluid • Need replacement fluid to exert oncotic pressure to replace removed plasma • 5% albumin exerts oncotic pressure resulting in slight reequilibration of fluid into intravascular space at end of PLEX • FFP • Pentastarch

  41. Volume Replacement • Up to 2/3 of anticoagulant volume may be retained in removed plasma • Don’t have to replace this whole volume • Hypovolemic exchanges • Potential for hypotension even if volume overloaded at start of exchange • PLEX modulates intravascular volume only • Unlike hemoperfusion or hemodialysis

  42. Anticoagulant • Citrate • Chelates calcium and block calcium dependent clotting factor reactions • Ensures extracorporeal blood remains in fluid state • Minimize activation of platelets and clotting factors

  43. Anticoagulant • 40% plasma calcium bound to albumin • 47% free plasma calcium • Target of chelation by citrate • Will decrease with little decrease in total calcium • 13% complexed to citrate/phosphate/lactate • Ionized calcium decrease 0.1mmol/L for each 0.5-0.6 nmol/L rise in plasma citrate

  44. Anticoagulant • Dilution, redistribution, removal, metabolism and excretion of infused citrate are factors protecting against severe hypocalcemia • Much of infused citrate is discarded with separated plasma • Usually 23-33% reduction in ionized calcium • Most rapid decrease in 1st 15 mins • Serum citrate levels return to normal 4 hours post exchange

  45. Anticoagulant • Citrate infusions 65-95mg/kg/hour are safe • >100mg/kg/hr lead to increased side effects • Hypomagnesemia can worsen symptoms • Duration of procedure increases risk of symptoms • 5% albumin can bind ionized calcium and contribute (more than FFP which contains citrate)

  46. Anticoagulant Variables affecting symptoms: • Absolute amount of calcium • Rate of decrease • Serum pH • Decrease in Mg, K, Na • sedatives

  47. Anticoagulant • Oral, acral paresthesia • Nausea and vomiting • Lightheadedness • Shivering, twitching, tremors • Worsening of myasthenia gravis during exchange • Muscle cramping • Tetany • QT prolongation • May cause metabolic alkalosis if renal disease and using FFP

  48. Vascular Access • Blood flow rates for adults ~60-150 ml/min • For small children may be down to 10ml/min • Flow rate depends on: • Vascular access • Ability to tolerate citrate (related to TBV)

  49. Vascular Access • Peripheral veins when possible • Draw site: • 16-18 G steel needle allows flows up to 120ml/min • Antecubital fossa • Medial cubital, cephalic, basilic • Disorders of autonomic nervous system have poor vascular tone, peripheral neuropathies; may be unable to maintain good flow rates

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