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Critical Care Combined Conference R4 李建霖 / VS 吳允升 2013/08/29.

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Presentation on theme: "Critical Care Combined Conference R4 李建霖 / VS 吳允升 2013/08/29."— Presentation transcript:

1 Critical Care Combined Conference R4 李建霖 / VS 吳允升 2013/08/29

2 Patient Profile Age: 52 y/o Sex: female Marital status: married Occupation: housekeeper Smoking: nil Alcohol: nil

3 Family History

4 Brief History Dyspnea  馬偕 UCG: pulmonary HTN Refer to Dr. 曾春典 ’s OPD Cardiac cath: MPA: 50mmHg, PAWP: 10mmHg Chest CT: Compatible with primary pulmonary hypertension. No evidence of pulmonary embolism. NO, high flow O2 & Viagra test: only partial response 2006/ /08

5 Brief History CV OPD medication: – Viagra, Coumadin and Bosentan UCG: ↑ pulmonary HTN – TRPG: 98.4mmHg Cardiac cath: MPA: 57mmHg Remodulin use 2006/ / /10

6 Present Illness Progressive dyspnea 為恭 hospital: – Desaturation + hypotension  intubation – VT  Cardioversion x 1  ED of NTUH – VT  Cardioversion x 2  CCU admission 2013/02/ /02/28

7 Treatment Course Persistent hypoxia (SpO2~85%) under FiO2 1.0 – UCG: LVEF: 78.3%, TRPG: 70.6mmHg – Cashed epoprostenol + iNO VA ECMO Central VA ECMO 2013/02/ /03/ /03/04

8 Central VA ECMO

9 Treatment Course Persistent hypoxia (SpO2~85%) under FiO2 1.0 – UCG: LVEF: 78.3%, TRPG: 70.6mmHg – Cashed epoprostenol + iNO VA ECMO Central VA ECMO – Improved daily activity under central VA ECMO ( 吃飯,看電視 …)  Wait for lung transplantation 2013/02/ /03/ /03/04

10 Treatment Course Bleeding tendency under ECMO use GI bleeding + wound bleeding  massive blood transfusion First donor: cross match positive Flow-PRA: Class I: 100% Class II: 99.78% 2013/02/ /06/01

11 Treatment Course 2 nd donor: still cross match positive Consult Dr. 蔡孟昆 for positive flow PRA Desensitization protocol 2013/06/26

12 Desensitization Protocol Indication: 術前 PRA > 74%, Virtual cross match (+) OR: 術中 3 次的 plasma exchange – 1) 5% albumin BW x 80 x (1 – HCT%) ≈ total plasma volume (TPV) Albumin volume = TPV x 0.05 Albumin bottle = albumin volume / 10 – 2) 5% albumin – 3) FFP exchange

13 Desensitization Protocol ICU: – 當日 : Simulect 20mg in N/S 50mL run 30 mins – POD1: FFP exchange – POD2: FFP exchange – POD3: 75% FFP + 25% albumin – POD4: Simulect 20mg in N/S 50mL run 30 mins – POD5: 50% FFP + 50% albumin – POD6: IVIG (2g/kg, Total volume / 2~3 days / 24 hours)

14 Results of Cross Match 4°C T cell4°C B cell37°C T cell37°C B cell 6/011:8 positive1:4 positive > 1:8 positive 6/261:32 positive 7/071:32 positive

15 Desensitization 7/07 Plasma exchange x 3 during OP 7/08 Plasma exchange + Simulect 7/09 Plasma exchange 7/10 Plasma exchange 7/11 Simulect + IVIG (24-hour drip) 7/13 DFPP (2A) 7/14 IVIG 7/15 Rituximab

16 Panel Reactive Antibody Class I (%)Class II (%) 3/ / / /

17 Discussion Desensitization in Lung Transplantation

18 Seminars in Dialysis—Vol 25, No 2 (March–April) 2012, pp. 193–200

19 Impact of HLA Compatibility on Lung Transplant Survival Transplantation2010;90: 912–917

20 Impact of HLA Compatibility on Lung Transplant Survival Transplantation2010;90: 912–917

21 Impact of HLA Compatibility on Lung Transplant Survival Transplantation2010;90: 912–917

22 Methods for Antibody Screening Transplantation 2013;95: 19~47 AMR, antibody-mediated rejection; CDC, complement-dependent lymphocytotoxicity; ELISA, enzyme-linked immunosorbent assay; FC, flow cytometry; HAR, hyperacute rejection; SAB, single-antigen beads; SPI, solid- phase immunoassays; vXM, virtual crossmatch; XM, crossmatch. The comparative sensitivities are LUM > ELISA/FC > CDC

23 Kidney International(2011) 79, 583 – 586.

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25 Pretransplant Panel Reactive Antibodies in Lung Transplantation Ann Thorac Surg 2008; 85: 1919– ~2005 USA lung transplant

26 Pretransplant Panel Reactive Antibodies in Lung Transplantation Ann Thorac Surg 2008; 85: 1919–24

27 Pretransplant Panel Reactive Antibodies in Lung Transplantation Ann Thorac Surg 2008; 85: 1919–24

28 Pretransplant Panel Reactive Antibodies in Lung Transplantation Ann Thorac Surg 2008; 85: 1919–24

29 Pretransplant Panel Reactive Antibodies in Lung Transplantation Ann Thorac Surg 2008; 85: 1919–24

30 Preexisting HLA Antibodies in Lung Transplantation Transplantation 2013;95: 19~47

31 Pretransplantation Donor-Specific Antibodies Transplantation 2013;95: 761~765

32 Desensitization Therapies J Heart Lung Transplant 2010;29:914 –956

33 Plasma Exchange in Desensitization A single exchange of 1.0 PV removes ~63% of all solutes in the plasma – An exchange of 1.5 PV removes ~78% In case of slowly forming antibodies, 5 separate treatments during a 7- to 10-day period will be required to remove 90% of the patients’ initial total-body burden Transfus Med Hemother 2012;39:234–240

34 Plasma Exchange in Desensitization TPE should be repeated daily for a minimum of 3 days – 5–7 days – Until the circulating antibodies are reduced to very low titer The effect appears to be long lasting – No return of DSA observed in patients followed for an average of 13 months Transfus Med Hemother 2012;39:234–240

35 Plasmapheresis + IVIG Therapeutic Apheresis (1997) 1(2):

36 Plasmapheresis + IVIG Plasmapheresis was begun as soon as possible after notification that a suitable organ was available and accepted – 1 session, 1.5 plasma volume – 5% albumin + 4U FFP Immediately after plasmapheresis  20 g of 5% IVIG Therapeutic Apheresis (1997) 1(2):

37 Peritransplant IVIG & Extracorporeal Immunoadsorption January 1992 ~ July 2003 Duke University Medical Center, Durham, NC, USA Human Immunology 66, 378 –386 (2005)

38 Peritransplant IVIG & Extracorporeal Immunoadsorption An averaged median of 83.5 days Human Immunology 66, 378 –386 (2005) (3 rd -party)

39 Peritransplant IVIG & Extracorporeal Immunoadsorption Human Immunology 66, 378 –386 (2005) P = 0.32 (12) (23) (345)

40 P = 0.03 P = 0.05 Human Immunology 66, 378 –386 (2005)

41 Therapeutic apheresis in lung transplantation in Jena Atherosclerosis Supplements 14 (2013) ~ 2012

42 Therapeutic apheresis in lung transplantation in Jena 3 consecutive days – When necessary, every second or third day after that until graft functionality was established or the graft was lost Average 1.3 times the plasma volume Replacement fluid: – Early postoperative phase: therapeutic plasma – Later: 1:1 mix of Octaplas LG and 5% human albumin Atherosclerosis Supplements 14 (2013) 33-38

43 Mycophenolate Mofetil (target level: 1.5~3 ug/ml), FK 506 (target level: 8~10 ug/ml) and Prednisolone

44 Donor-specific HLA Antibodies Following Plasma Exchange Therapy A cycle of TPE: daily for 5 days using 1.5-volume exchanges Replacement fluid: 5% albumin – Risk of bleeding: FFP J. Clin. Apheresis 28:301–308, 2013 St. Louis Children’s Hospital from 2007 to 2010

45 Donor-specific HLA Antibodies Following Plasma Exchange Therapy J. Clin. Apheresis 28:301–308, 2013

46 Donor-specific HLA Antibodies Following Plasma Exchange Therapy J. Clin. Apheresis 28:301–308, 2013 P = 0.02 P = 0.58

47 Therapeutic strategies antibody- mediated rejection

48 Guidelines for Heart Transplant A PRA10% indicates significant allosensitization Desensitization therapy should be considered when the calculated PRA is considered by the individual transplant center to be high enough to significantly decrease the likelihood for a compatible donor match or to decrease the likelihood of donor heart rejection where unavoidable mismatches occur – Average threshold PRA level for initiation of treatment: 35% (range 10 –100%) Choices to consider as desensitization therapies include IV immunoglobulin (Ig) infusion, plasmapheresis, either alone or combined, rituximab, and in very selected cases, splenectomy J Heart Lung Transplant 2009;28:213–25 J Heart Lung Transplant 2010;29:914 –956

49 Desensitization Protocol in NTUH Indication: 術前 PRA > 74%, Virtual cross match (+) OR: 術中 3 次的 plasma exchange – 1) 5% albumin BW x 80 x (1 – HCT%) ≈ total plasma volume (TPV) Albumin volume = TPV x 0.05 Albumin bottle = albumin volume / 10 – 2) 5% albumin – 3) FFP exchange

50 Desensitization Protocol in NTUH ICU: – 當日 : Simulect 20mg in N/S 50mL run 30 mins – POD1: FFP exchange – POD2: FFP exchange – POD3: 75% FFP + 25% albumin – POD4: Simulect 20mg in N/S 50mL run 30 mins – POD5: 50% FFP + 50% albumin – POD6: IVIG (2g/kg, Total volume / 2~3 days / 24 hours)

51 58008C 血漿置換術(支付點數 2475 點) Plasma exchange :限下列病患實施  SLE , CNS involvement  Myasthenia gravis crisis  Macroglobulinaemia  RPGN  Goodpasture's disease  Multiple myeloma  Guillain-Barre syndrome  Thrombocytopenic purpura  Multiple sclerosis and neuromyelitis optica  其他經專案向保險人申請同意實施者 58016C 二重過濾血漿置換療法(支付點數 2475 點) Double filtration plasmapheresis :施行本項之適應症請依支付標 準 58008C 「血漿置換術」之規定辦理。 全民健保醫療費用支付查詢網站 : 51

52 52 Membrane apheresis (MCS+) KM8800 Centrifugal Device KPS8800HF400

53 53 Transfus Apher Sci Apr;32(2): J Clin Apher. 2010;25(5):240-9

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56 AdvantagesDisadvantages Membrane apheresis Fast and efficient plasmapheresis No citrate requirements Can be adapted for cascade filtration Removal of substances limited by sieving coefficient of membrane Unable to perform cytapheresis Requires high blood flows, central venous access Requires heparin anticoagulation, limiting use in bleeding disorders Centrifugal devices Capable of performing cytapheresis No heparin requirement More efficient removal of all plasma components Expensive Requires citrate anticoagulation Loss of platelets Brenner: Brenner and Rector's The Kidney, 8th ed 56

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59 Portion of Plasma Volume a Exchanged (V e /V p ) Volume Exchanged (V e, mL ) Immunoglobulin or Other Substance Removed (MRR, %) 0.51, , , , , ,40095 a Plasma volume = 2,800 mL in a 70-kg patient, assuming hematocrit = 45%. V e, volume of plasma exchanged; V p, estimated plasma volume; MRR, macromolecule reduction ratio. Handbook of Dialysis 59

60 60 D-9 D-7 D-5 D-3 D-1 OP day D1 D3 D5 2 PV TPE (OR) 1.5 PV DFPP 1.5 PV DFPP 1.5 PV DFPP 1.5 PV DFPP 1.5 PV DFPP 1.5 PV DFPP 1.5 PV DFPP 1.5 PV DFPP TIW 1.5 PV DFPP Solumedrol 500mg IVIg 15g (heart lung machine) Bortezomib (Velcade) IV slow push IVIg 30g slowing infusion Solumedrol 500mg + Rituximab (Mabthera) IV drip RATG + FK506 IVIg IVIg IVIg IVIg IVIg Initial Ab X(1-78%) 5 = initial amount residual Ab X(1-86%) Experience from a heart transplantation case at NTUH

61 61 J Clin Apheresis 2010;25:83-177

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63 Traffic Accident 8/148/158/168/238/319/59/69/1 LM dissection s/p POBAS Cardiac echo: LVEF 19% VV-ECMO Transfer to NTUH Cardiac cath: No ISRS Desaturation PCWP 40 mmHg Dilate LV LV Drain 9/1510/5 LV Assist Device Remove VV-ECMO 10/20 Extubation

64 10/25 檢查項目數值 標準值說明 37 ℃ B cell1:32 PositiveNegative 37 ℃ T cell1:32 PositiveNegative 4 ℃ B cell1:32 PositiveNegative 4 ℃ T cell1:32 PositiveNegative Donor: 楊 XX 11/3 檢查項目數值 標準值說明 37 ℃ B cell1:32 PositiveNegative 37 ℃ T cell1:32 PositiveNegative 4 ℃ B cell1:32 PositiveNegative 4 ℃ T cell1:32 PositiveNegative Donor: 鄭 XX Panel reactive antibody: Anti-HLA class I: 61% Anti-HLA class II: 72%

65 11/311/411/811/611/1011/12 Double Filtration Plasmapheresis 3L/session, 1.2x plasma volume total 5 course Rituximab (Mabthera) 200 mg Bortezomib (Velcade) 3.5 mg Solu-Medrol 1000 mg Intravenous immunoglobulin 45 gm R-anti-thymocyte globulin 25 mg Plasma Exchange Hypotension, Bradycardia Donor 11/12 檢查項目數值 標準值說明 37 ℃ B cell1:8 PositiveNegative 37 ℃ T cell1:2 PositiveNegative 4 ℃ B cell1:4 PositiveNegative 4 ℃ T cell1:2 PositiveNegative Donor: 侍 XX

66 /1111/1211/1311/1411/1511/1611/1711/1811/19 CVVH Transplant Millisrol Dopamine Primacor (Milrinone) Bosmin Isoproterenol DFPP CO: 2.23 CI: 1.48 Graft failure ? IVIG FK506 Cellcept Solu-Medrol Massive bloody pleural effusion PTPTT sec

67 Definition Exposure of the immune system to antigen (transplant organ) sufficient to generate an immune response Antibody – ABO – Anti-HLA – Non-HLA Blood transfusions Pregnancy Previous organ transplant Placement of a ventricular device Approximate 30% incidence of antibody production (PRA > 10%) after LVAD placement J Heart Lung Transplant 2002; 21:

68 Humoral ResponseCellular Response Immunosuppressive agents Donor selection Recipient Desensitization Prevent rejection

69 Human Immunology 2005;66:334-42

70 Examples of desensitization J Heart Lung Transplant 2009;28:213-25

71 Pre-heart transplant plasmaheresis for sensitized patients (high PRA) 1.5 plasma volume plasmapheresis + 20g 5% IVIG, then heart transplant 1.5 plasma volume plasmapheresis qod (followed by 20g 5% IVIG )X 5 sessions. Then a single plasmaphereis with IVIG at the time of surgery J Heart Lung Transplant 1999;18:701 Clin Transplant 2006;20:476-84

72 HLA class IHLA class II Clin Transplant 2006: 20: 476–484 Clin Transplant 2006;20:476-84

73 On-pump TPE for XM heart transplant High blood flow and thus increased pheresis rate to shorten treatment time than standard setting of TPE/DFPP 3 plasma volume within 60-90min Especially need to watch out [Ca] J Extra Corpor Technol 1999;31: J Heart Lung Transplant 2008;27:1036-9

74 Comparative long-term outcome 523 heart transplant, 95 PRA>10%, 21/95 desensitization, 74 untreated Survival: no significant difference Rejection: significant decrease in desensitized patients Clin Transplant Oct 25 1-year rejection-free survival5-year patient survival (Treated with PP+IVIG+Rituximab)

75 Proposed protocol for desensitization D-9 D-7 D-5 D-3 D-1 OP day D1 D3 D5 2 PV TPE (OR) 1.5 PV DFPP 1.5 PV DFPP 1.5 PV DFPP 1.5 PV DFPP 1.5 PV DFPP 1.5 PV DFPP 1.5 PV DFPP 1.5 PV DFPP TIW 1.5 PV DFPP Solumedrol 500mg IVIG 15g (heart lung machine) Bortezomib (Velcade) IV slow push IVIG 30g slowing infusion Solumedrol 500mg + Rituximab (Mabthera) IV drip RATG + FK506 IVIG IVIG IVIG IVIG IVIG Initial Ab X(1-78%) 5 = initial amount residual Ab X(1-86%)

76 Extracorporeal photopheresis T-cell B-Cell

77 Primary prophylaxis N Engl J Med 1998;339: Clin Transplantation 2000;14:162-6

78 Secondary prophylaxis J Heart Lung Transplant 2006;25:283-8

79 Extracorporeal photopheresis (ECP) Leukapheresis-based immunomodulatory therapy. Mechanism: – causes apoptosis of the treated and abnormal T cells – induces monocytes to differentiate into dendritic cells capable of phagocytosing and processing the apoptotic T- cell antigens – may cause a systemic cytotoxic CD8 + T-lymphocyte– mediated immune response to the processed apoptotic T- cell antigens – induce antigen-specific regulatory T cells, which may lead to suppression of allograft rejection or GVHD

80

81 Thank You!


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