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Critical Care Combined Conference

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Presentation on theme: "Critical Care Combined Conference"— 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 2006/07 2006/08

5 Brief History CV OPD medication: UCG: ↑ pulmonary HTN
Viagra, Coumadin and Bosentan UCG: ↑ pulmonary HTN TRPG: 98.4mmHg Cardiac cath: MPA: 57mmHg Remodulin use 2006/08 2008/10 2012/10

6 Present Illness Progressive dyspnea 為恭 hospital:  ED of NTUH
Desaturation + hypotension  intubation VT  Cardioversion x 1  ED of NTUH VT  Cardioversion x 2  CCU admission 2013/02/27 2013/02/28

7 Treatment Course Persistent hypoxia (SpO2~85%) under FiO2 1.0 VA ECMO
UCG: LVEF: 78.3%, TRPG: 70.6mmHg Cashed epoprostenol + iNO VA ECMO Central VA ECMO 2013/02/28 2013/03/01 2013/03/04

8 Central VA ECMO

9 Treatment Course Persistent hypoxia (SpO2~85%) under FiO2 1.0 VA ECMO
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 2013/02/28 2013/03/01 2013/03/04

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% 2013/02/28 2013/06/01

11 Treatment Course 2nd 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 cell 4°C B cell 37°C T cell 37°C B cell
6/01 1:8 positive 1:4 positive > 1:8 positive 6/26 1:32 positive 7/07

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 (%) 3/04 65.50 42.11 6/04 100 99.78 7/08 82.04 7/15 99.82 99.06

17 Desensitization in Lung Transplantation
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
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 Transplantation 2013;95: 19~47

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

24

25 Pretransplant Panel Reactive Antibodies in Lung Transplantation
1987~2005 USA 10236 lung transplant 1987~2005 USA 12751 lung transplant Ann Thorac Surg 2008; 85: 1919–24

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

31 Pretransplantation Donor-Specific Antibodies

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 (3rd-party) Human Immunology 66, 378 –386 (2005)

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

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

41 Therapeutic apheresis in lung transplantation in Jena
2008 ~ 2012 Atherosclerosis Supplements 14 (2013) 33-38

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
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
St. Louis Children’s Hospital from 2007 to 2010 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

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

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 健保給付之適應症 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:

52 Devices for plasma exchnage in NTUH
Centrifugal Device Membrane apheresis (MCS+) KM8800 KPS8800 HF400

53 Centrifugal seperation of plasma
Transfus Apher Sci Apr;32(2):209-20 J Clin Apher. 2010;25(5):240-9

54

55

56 Comparison between these methods
Advantages Disadvantages 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

57

58

59 Target volume Portion of Plasma Volumea Exchanged (Ve/Vp)
Volume Exchanged (Ve, mL) Immunoglobulin or Other Substance Removed (MRR, %) 0.5 1,400 39 1.0 2,800 63 1.5 4,200 78 2.0 5,600 86 2.5 7,000 92 3.0 8,400 95 aPlasma volume = 2,800 mL in a 70-kg patient, assuming hematocrit = 45%. Ve, volume of plasma exchanged; Vp, estimated plasma volume; MRR, macromolecule reduction ratio. Handbook of Dialysis

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

61 ASFA guidelines for AMR of cardiac allografts
J Clin Apheresis 2010;25:83-177

62

63 LM dissection s/p POBAS
Traffic Accident Transfer to NTUH Desaturation PCWP 40 mmHg Dilate LV Cardiac echo: LVEF 19% Extubation 8/14 8/15 8/16 8/23 8/31 9/1 9/5 9/6 9/15 10/5 10/20 VV-ECMO LV Drain LV Assist Device LM dissection s/p POBAS Cardiac cath: No ISRS Remove VV-ECMO

64 Transplantation 10/25 11/3 Panel reactive antibody:
檢查項目 數值   標準值 說明   37℃ B cell 1:32 Positive Negative T cell   4℃ Donor:楊XX 11/3 檢查項目 數值   標準值 說明   37℃ B cell 1:32 Positive Negative T cell   4℃ Donor:鄭XX Panel reactive antibody: Anti-HLA class I: 61% Anti-HLA class II: 72%

65 Double Filtration Plasmapheresis
Rituximab (Mabthera) mg Bortezomib (Velcade) mg Solu-Medrol mg Intravenous immunoglobulin gm R-anti-thymocyte globulin mg Plasma Exchange Hypotension, Bradycardia 11/3 11/4 11/8 11/6 11/10 11/12 Double Filtration Plasmapheresis 3L/session, 1.2x plasma volume total 5 course Donor 11/12 檢查項目 數值   標準值 說明   37℃ B cell 1:8 Positive Negative T cell 1:2 Positive   4℃ 1:4 Positive Donor:侍XX

66 Massive bloody pleural effusion
Isoproterenol Millisrol Dopamine Primacor (Milrinone) Bosmin 3000 Graft failure ? 2500 2000 CO: 2.23 CI: 1500 1000 CVVH 500 11/11 11/12 11/13 11/14 11/15 11/16 11/17 11/18 11/19 Massive bloody pleural effusion PT PTT sec 26.6 39.1 Transplant DFPP DFPP IVIG IVIG Solu-Medrol FK506 Cellcept

67 Sensitization Definition Antibody
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 Prevent rejection Recipient Desensitization Humoral Response
Cellular Response Donor selection Recipient Desensitization Immunosuppressive agents

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

75 Proposed protocol for desensitization
Solumedrol 500mg IVIG 15g (heart lung machine) Bortezomib (Velcade) IV slow push IVIG 30g slowing infusion Solumedrol 500mg + Rituximab (Mabthera) IV drip RATG + FK506 D D D D D-1 OP day D D D5 TIW 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 1.5 PV DFPP 2 PV TPE (OR) 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 Clin Transplantation 2000;14:162-6
N Engl J Med 1998;339:

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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