PLEX.pptx

plasma exchange ICU
PLEX

1. Therapeutic plasma exchange in ICU PRESENTER: MAYANK SACHAN

2. Outline Introduction Mechanism of action Different types of apheresis Kinetic theory Technical considerations: Vascular access, Anticoagulation, Estimation of plasma volume, Replacement fluids Complications Monitoring Specific indications

3. History Apheresis : Derived from the Greek word “ aphaeresis ,” meaning “to separate,” “to take away by force,” or “to remove”

4. History First described: 1914 : vivi -diffusion: animal experiments First used:1952: hyperviscosity in multiple myeloma Automated cell separators: 1960s Goodpasture syndrome: 1975 : Lockwood et al SLE: 1976: Jones et al TTP: 1977: Bukowski et al

5. Terminology APHERESIS A procedure in which blood of the patient or donor is passed through a medical device which separates one or more components of blood and returns the remainder with or without extracorporeal treatment or replacement of the separated component.

6. Terminology Plasmapheresis: A procedure in which blood of the patient or the donor is passed through a medical device which separates plasma from other components of blood and the plasma is removed without the use of replacement solution. This procedure is used to collect plasma for blood components ( in blood bank). Therapeutic Plasma Exchange (TPE) and replaced with a replacement solution such as colloid solution (e.g., albumin and/or plasma) or a combination of crystalloid/colloid solution.

7. Mechanism of TPE Removal of a pathogenic substance from the plasma IgG in myasthenia gravis, IgM in Waldenström macroglobulinemia, or IgG and IgM isoagglutinins prior to ABO incompatible organ transplantation. Delivery of large amounts of deficient plasma components ADAMTS13 in thrombotic thrombocytopenic purpura (TTP).

8. 3. Other Effects on the Immune System: Mechanism of TPE Stimulates the proliferation of B cells and plasma cells, sensitizing them to immunosuppressants. Removal of inflammatory mediators (cytokines, complement) Correction of altered T-helper cell type ½ (Th1/Th2) ratio favoring Th1 predominance.

9. The substance targeted for removal must have a sufficiently long half-life The substance to be removed must be acutely toxic and/or resistant to conventional therapy Shou l d b e s u f f i ci e n tly la r g e, with a mole c ular weight greater than 15,000 daltons, Characteristic of Target to be removed

10. Apheresis methods Therapeutic apheresis can be performed using a variety of collection methods The two most common methods are: Centrifugation : Centrifuge devices are more common worldwide Separation based on specific gravity - uses peripheral or central line Membrane Filtration : Less common, but considered therapeutically equivalent to centrifugal apheresis Filtration or seiving technology- uses central line (similar to dialysis)

11. Centrifugation • A system draws whole blood from a donor patient, adds anticoagulant, separates the blood components based on specific gravity (density), collects or removes specific components and returns uncollected components back to the donor patient • Separates blood components • Can remove all blood components (cellular components and plasma)

12. Membrane Filtration / Plasmafiltration • Plasma is removed from the patient’s blood by filtration across a plasma filter membrane and replaced with fresh plasma or a protein solution post-filter • Blood components are separated based on molecular size using convection • Limited to removal of plasma ; no cellular components are removed

13. Membrane Membrane Filtration / Plasmafiltration

14. The ideal blood flow rate ( Q b ) is usually 100–150 mL/min When the blood flow rate is 100 mL /min, a plasma removal rate of 30–50 mL /min can be expected Average time required to perform a typical membrane filtration ( V e = 2,800 mL) is <2 hours (40 mL/min × 60 minutes = 2,400 mL/hr) Membrane Filtration / Plasmafiltration

15. Plasma removal efficacy (PRE) Fraction of plasma that passes through a device is removed per procedure. PRE is faster and higher in cTPE

16. Kinetic Model Pathological immunoglobulin A. Ongoing production in body D. Inhibit its prodution by chemotherapy C. Removal of Ig by PLEX B.Redistribution : From intravascular space to extravascular space & then return back to intravascular space as its concentration falls after removal by PLEX C +D > A+ B

17. The removal of different circulating macromolecules depends upon: Size and distribution between intra- and extravascular compartments Kinetic Model

18. Kinetic model Intensity and frequency of TPE sessions: The half-life and volume of distribution of the substances. For a substance that is neither rapidly synthesized nor redistributed and limited to the intravascular space, the first session of plasma exchange will remove 65–70% of the target substance The second session will remove an additional 23% and the third session only an additional 9% of the target substance. The net reduction will be affected by the redistribution from extravascular to intravascular compartments, production rate and by volumes of distribution Kinetic Model

19. Vascular access Depends primarily on the method used: Centrifugal based TPE ( cTPE ) : Requires lower blood flow rates ( Qb ) (50–120 mL/min)  narrower catheters such as : peripheral 18-Gauge needle or central venous line Membrane based ( mTPE ) : Require higher Qb (150- 200 mL/min)  wider catheters : hemodialysis catheters

20. Estimation of plasma volume TBV (total blood volume) is 70ml/kg in males and 65ml/kg in females Estimated Plasma Volume (EPV) [ Kaplan formula ] = TBV X (100 – hct %) e.g. For 70 kg male with HCT 40% TBV = 70kg X 70ml/kg = 4900ml EPV = 4900 X (100- 40) = 2900ml PEX volume is 30–50 ml/kg body weight. Exchange volume: 1 - 1.5 times Of EPV (ASFA 2019) The process go on for about 2 hours

21. Replacement Fluids Cons: Hypo-oncotic, only ~1/3 stays intravascular, this may lead to intravascular fluid deficit, hypotension. Therefore usually used in combination with albumin: start procedure with NS replacement, then finish with albumin replacement Using crystalloids <30% of total will decrease risk of hypotension as well as total cost Lacks coagulation factors/ immunoglobulins Crystalloid (normal saline) Pros: Cheap, No infectious/allergic risks Readily available

22. Cons: Doe s no t r ep l a c e othe r p r o t ein f r a c tions, s u c h as coagulation factor Expensive Cause acidosis Albumin (5%) (Used for most indications of TPE) Pros: Colloid, iso -oncotic stays intravascular, No to very, very low allergic/ infectious risks Replacement Fluids

23. Plasma Pros Iso -oncotic Replaces coag factors, immunoglobulins and other plasma proteins Cons Infectious and allergic risks Additional citrate load, increases risk of hypocalcemia and alkalosis TRALI risks Needs to be ABO compatible Expensive Indications: Thrombotic thrombocytopenic purpura (TTP) to replace ADAMTS-13 Replacing coag factors in liver failure, or in patient undergoing repeated daily TPE procedures with albumin as replacement fluid Replacement Fluids

24. Cryo-poor plasma: By-product of cryoprecipitate production Similar to plasma, except only has about ½ of the vwF , fibrinogen of FFP, normal levels of most other plasma proteins Pros Same as plasma Theoretical: better for TTP due to less high MW- vWF ? (Not been confirmed by studies) Cons Same as plasma Regular plasma is still firstline therapy for TTP. Cryo-poor plasma is indicated for TTP refractory to TPE with plasma

25. Anticoagulation Citrate Acid Citrate Dextrose (ACD) Most commonly used anticoagulant for apheresis Citrate ion chelates free Ca++ ions and blocks calcium-dependent coagulation cascade Ensures that extracorporeal blood remains in a fluid state Pros: Ubiquitous compound found in all human cells, not “foreign” Metabolized by liver quickly to bicarbonate, little systemic effect Cons: Can cause transient systemic hypocalcemia (citrate toxicity), presenting with numbness, peri-oral tingling, tetany, cramping, EKG changes

26. Heparin Prevents clotting by potentiating antithrombin’s activity by 1000x Used alone or in combination with citrate Required/preferred by some instruments ( Liposorber LDL, photopheresis instruments membrane filtration) Degree of anticoagulation similar to DVT prophylaxis (plasma concentration 0.5 to 2.0 IU/ml) Pros: reduce citrate dose, avoid hypocalcemia , Short term systemic anticoagulation, Reverse overdose with protamine Con: Risk of inducing HIT Anticoagulation

27. Complications Related to Vascular Access -Hematoma -Pneumothorax - Local or systemic infection. -Catheter dysfunction

28. Related to the Procedure -Hypotension from externalization of blood in the extracorporeal circuit -Hypotension due to decreased intravascular oncotic pressure - Bleeding from reduction in plasma levels of coagulation factors Loss of cellular elements (platelets) Hypersensitivity reactions (ethylene oxide) Drugs removal: Hold drugs >1 hour prior to and during apheresis Complications

29. Related to Anticoagulation -Bleeding (especially with heparin) Hypocalcemic symptoms (with citrate) Metabolic alkalosis from citrate Complications

30. Related to Replacement Fluids -Hypotension (use of hypo-oncotic saline) -Anaphylaxis (FFP) Anaphylactoid associated with ACE inhibitors ACE inhibitors prevent metabolism of bradykinin generated during procedure -> anaphylactoid reactions Delay apheresis till 24-48h after last dose of ACE inhibitor Complications

31. Drug removal by TPE Aminoglycosides can be best administered before the procedure to benefit from both a high peak with bactericidal effect and reduced toxicity related to a low trough level through extracorporeal removal. Beta-lactam plasma levels, on the other hand, should be maintained above the minimum inhibitory concentration which often requires a supplementary dose post-procedure. Monoclonal antibodies such as rituximab have a small volume of distribution and a long distribution half-life and therefore are significantly removed by TPE. Significant removal of enoxaparin, tacrolimus , and mycophenolic acid during TPE has been reported Most studies involved administering medications after TPE and scheduling the next TPE session 24–36 h later. Therapeutic drug monitoring

32. Monitoring The following tests must be performed before TPE: ABO Rh blood group and, if appropriate, an RBC antibody screen (in case plasma or RBC priming is needed); ionized calcium, magnesium, and potassium (which may be affected by citrate anticoagulation); coagulation tests (activated partial thromboplastin time, partial thromboplastin time, prothrombin time, and fibrinogen) circulating biomarkers such as troponin, brain natriuretic peptide, CRP, and LDH are no longer reliable for assessing the disease course

33. Indications for plasmapharesis Guidelines for therapeutic apheresis are published by the American Society for Apheresis (ASFA) ,2019.

34. ASFA Categories Category I Disorders for which apheresis is accepted as first-line therapy , either as a primary stand-alone treatment or in conjunction with other modes of treatment Category II Disorders for which apheresis is accepted as second-line therapy , either as a stand-alone treatment or in conjunction with other modes of treatment Category III Disorders for which the optimum role of apheresis is not established ; decision making should be individualized Category IV Disorders for which published evidence demonstrates or suggests apheresis to be ineffective or harmful ; Institutional Review Board approval is desirable if apheresis treatment is undertaken in these circumstances

35. AFSA Category Examples Category I • Guillain-Barre syndrome Myasthenia CRISIS • Thrombotic thrombocytopenia purpura (TTP) • Goodpasture syndrome : DAH, dialysis – independent NMDA Receptor antibody enecphelitis Acute liver failure Category II • Refractory thyroid storm Atypical HUS AIHA CIDP Lembert Eaton myasthenic syndrome

36. Category III • Heparin-induced thrombocytopenia and thrombosis • pancreatitis with severe hypertriglyceridemia Category IV • HELLP syndrome: antepartum • Amyotrophic lateral sclerosis Dermatomysitis / polymyositis AFSA Category Examples

37. PLEX in AIDP (GBS) Cochrane Database of Systematic Reviews 2017, Issue 2. Art. No.: CD001798.

38. PLEX in AIDP (GBS)

39. PLEX in AIDP (GBS)

40. PLEX in AIDP (GBS) Rationale: removal of Abs Replacement fluid: albumin / plasma Strategy: 1-1.5 TPV, 5-6 sessions Parameters to monitor: clinical response Comments: consider TPE if failed to respond to IVIg and/or impending repiratory failure. Donot use simultaneously with IVIg

41. Anti-GBM disease Lancet 1976 Apr 3;1(7962):711-5. Immunosuppression and plasma-exchange in the treatment of Goodpasture's syndrome. Lockwood CM , Rees AJ , Pearson TA , Evans DJ , Peters DK , Wilson CB . Abstract Seven patients with Goodpasture's syndrome induced by anti-glomerular-basement-membrane (anti-G.B.M.) antibody were treated by a regimen of intensive plasma-exchange, cytotoxic drugs, and steroids . In the three patients retaining some renal function at presentation, this regimen led to suppression and eventual termination of antibody synthesis with improvement in renal function. In four patients, all anuric at presentation, antibody to G.B.M. persisted with variable reduction in the circulating levels. No return of renal function occurred in this group, all of whom had extensive changes on renal biopsy. Pulmonary haemorrhage , life-threatening in one patient, was rapidly controlled in all five patients in whom it was a presenting feature. In addition to its effect on antibody levels, plasma-exchange, using volume-replacement with plasma-protein fraction (P.P.F.), resulted in substantial depletion of complement and fibrinogen, mediators possibly contributing to the antibody-induced injury.

42. Design: Retrospective review of patients treated for confirmed anti-GBM antibody disease over 25 years. Setting: A tertiary referral center in the United Kingdom. Patients: 71 treated patients with anti-GBM antibody disease. Intervention: All patients received plasma exchange, prednisolone , and cyclophosphamide . Measurements: Patient and renal survival, renal histology, and antibody levels. Anti-GBM disease

43. Renal function at entry and patient/renal survival Levy et al. Ann Intern Med . 134:1033-1042; 2001 . Anti-GBM disease

44. Patient and renal survival at 5 years *Patient survival at 5 years was calculated only for patients with at least 5 years of follow-up. † Renal survival at 5 years was calculated only for patients surviving at 5 years. Levy et al. Ann Intern Med . 134:1033-1042; 2001 . Anti-GBM disease

45. Patients with the Goodpasture syndrome and severe renal failure should be considered for urgent immunosuppression therapy, including plasma exchange, to maximize the chance of renal recovery. Patients needing immediate dialysis are less likely to recover. Anti-GBM disease

46. Anti-GBM disease (Goodpasture syndrome) Rationale : removal of pathologic autoantibodies Replacement fluid : albumin ; plasma if bleeding Strategy : 1-1.5 TPV daily or alternate days over 10-20 days until disease control Parameters to monitor: renal function, clinical response Comments : presence or absence of antibody should not guide decisions to initiate or end TPE

47. High-volume plasma exchange in patients with acute liver failure: An open randomised controlled trial Intervention 1.5 l of plasma exchanged per hour Fresh Frozen Plasma only exchange The total volume exchanged was ~15% of body weight or about 6-10L per day on 3 consecutive days RRT continued Sites Copenhagen (Rigshospitalet) Helsinki (Liver Transplantation Unit) London (Kings College Hospital) Planned Recruitment 3 years ; took 11! Larsen et al, J Hepatol Jan 2016; 64 (1) 69 – 78

48. High-volume plasma exchange in patients with acute liver failure: An open randomised controlled trial

49. Effects: INR, Bilirubin, ALT, Ammonia : reduced significantly after plasma exchange No change in plasma lactates levels Less number of patients required RRT (47 vs 68%) Significant less Angiopoietin 2 levels Insignificant increase in incidence of pancreatitis Larsen et al, J Hepatol Jan 2016; 64 (1) 69 – 78

50. Acute liver failure Rationale: removal of albumin-bound and water-soluble toxins Replacement of plasma proteins including clotting factors Immunomodulation Reduction of proinflammatory response Replacement fluid: plasma Strategy: High-volume TPE if possible (target 8–12 L); otherwise, 1–1.5 TPV daily until clinical improvement or transplantation Parameter to monitor: clinical response Comments : Always consider TTP in the differential in specific scenarios (e.g., pregnancy and acute liver failure) Supportive care may improve nontransplant outcome Support care may stabilize while awaiting liver transplant

51. Thrombotic thrombocytopenic purpura

52. Blood. 50: 413-417; 1977. Thrombotic thrombocytopenic purpura

53. Thrombotic thrombocytopenic purpura

54. TTP Rationale : administration of ADAMTS13 protease and removal of anti-ADAMTS13 autoantibodies Replacement fluid : plasma Strategy: Daily until platelet count > 150 × 10.9/L, LDH approaching normal and resolution of non-fixed neurologic symptoms then Continue for 2 more sessions then stop Parameteers to monitor: Platelet count, LDH, ADAMTS13 activity Comments: R ecovery of ADAMTS13 activity to > 10% within 7 days is associated with clinical response

55. Myasthenic crisis Rationale: Removal of autoantibodies and immunomodulation Replacement fluid: albumin Strategy: 1–1.5 TPV; 3–6 sessions over 10–14 days, until disease control Parameter to monitor: clinical response Comments: More effective if initiated during myasthenic crisis, especially with bulbar or severe generalized response; more effective than IVIG in patients with MuSK -Ab

56. NMDA Antibody encephalitis Rationale: Removal of antibodies (including anti-neuronal autoantibodies) Replacement fluid : albumin Strategy : 1–1.5 TPV; 5–12 sessions over 1–3 weeks until clinical response Parameter to monitor: clinical response Comments: Check for ovarian tumors and other tumors (germ cell tumors , carcinoma, teratoma, lymphoma)

57. Emerging ICU Indications: This classical blood purification concept may apply to systemic inflammatory syndromes encountered in a wide variety of critical con- ditions , but timing and anti-/pro-inflammatory balance may be pivotal in determining benefit versus potential detriment. Furthermore, TPE removes damage-associated molecular patterns (DAMPs) that are released by injured cells and may trigger and perpetuate multiorgan dysfunction. Pts. with Rapidly progressing sepsis with MODS, sepsis, hemophagocytic lymphohistiocytosis , chimeric antigen receptor T-cell-associated cytokine release syndrome, severe pancreatitis, and severe burns may benefit with in future with modified version of this modality.