Critical Care Combined
Conference
R4 李建霖 / VS 吳允升
2013/08/29
Patient Profile
•
•
•
•
•
•
Age: 52 y/o
Sex: female
Marital status: married
Occupation: housekeeper
Smoking: nil
Alcohol: nil
Family History
Brief History
2006/07
2006/08
• 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
Brief History
2006/08
• CV OPD medication:
– Viagra, Coumadin and Bosentan
2008/10
• UCG: ↑ pulmonary HTN
– TRPG: 98.4mmHg
2012/10
• Cardiac cath: MPA: 57mmHg
• Remodulin use
Present Illness
• Progressive dyspnea
2013/02/28 • 為恭 hospital:
2013/02/27
– Desaturation + hypotension  intubation
– VT  Cardioversion x 1
 ED of NTUH
– VT  Cardioversion x 2
 CCU admission
Treatment Course
2013/02/28
• Persistent hypoxia (SpO2~85%) under
FiO2 1.0
– UCG: LVEF: 78.3%, TRPG: 70.6mmHg
– Cashed epoprostenol + iNO
• VA ECMO
2013/03/04 • Central VA ECMO
2013/03/01
Central VA ECMO
Treatment Course
2013/02/28
• Persistent hypoxia (SpO2~85%) under
FiO2 1.0
– UCG: LVEF: 78.3%, TRPG: 70.6mmHg
– Cashed epoprostenol + iNO
• VA ECMO
2013/03/04 • Central VA ECMO
2013/03/01
– Improved daily activity under central VA
ECMO (吃飯，看電視…)
 Wait for lung transplantation
Treatment Course
• Bleeding tendency under ECMO use
• GI bleeding + wound bleeding 
massive blood transfusion
2013/06/01 • First donor: cross match positive
• Flow-PRA:
• Class I: 100%
• Class II: 99.78%
2013/02/28
Treatment Course
2013/06/26
• 2nd donor: still cross match positive
• Consult Dr.蔡孟昆 for positive flow PRA
• Desensitization protocol
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
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)
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
1:4 positive
> 1:8
positive
6/26
1:32 positive 1:32 positive
1:32 positive 1:32 positive
7/07
1:32 positive 1:32 positive
1:32 positive 1:32 positive
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
Panel Reactive Antibody
Class I (%)
Class II (%)
3/04
65.50
42.11
6/04
100
99.78
7/08
100
82.04
7/15
99.82
99.06
Discussion
Desensitization in
Lung Transplantation
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, solidphase immunoassays; vXM, virtual crossmatch; XM, crossmatch.
• The comparative sensitivities are LUM > ELISA/FC > CDC
Transplantation 2013;95: 19~47
Kidney International(2011) 79, 583 – 586.
Pretransplant Panel Reactive
Antibodies in Lung Transplantation
1987~2005 USA
10236 lung transplant
Ann Thorac Surg 2008; 85: 1919–24
Pretransplant Panel Reactive
Antibodies in Lung Transplantation
Ann Thorac Surg 2008; 85: 1919–24
Pretransplant Panel Reactive
Antibodies in Lung Transplantation
Ann Thorac Surg 2008; 85: 1919–24
Pretransplant Panel Reactive
Antibodies in Lung Transplantation
Ann Thorac Surg 2008; 85: 1919–24
Pretransplant Panel Reactive
Antibodies in Lung Transplantation
Ann Thorac Surg 2008; 85: 1919–24
Preexisting HLA Antibodies in Lung
Transplantation
Transplantation 2013;95: 19~47
Pretransplantation
Donor-Specific Antibodies
Transplantation 2013;95: 761~765
Desensitization Therapies
J Heart Lung Transplant 2010;29:914 –956
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
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
Plasmapheresis + IVIG
Therapeutic Apheresis (1997) 1(2):147-151
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):147-151
Peritransplant IVIG &
Extracorporeal Immunoadsorption
• January 1992 ~ July 2003
• Duke University Medical Center, Durham, NC,
USA
Human Immunology 66, 378 –386 (2005)
Peritransplant IVIG &
Extracorporeal Immunoadsorption
• An averaged median of 83.5 days
(3rd-party)
Human Immunology 66, 378 –386 (2005)
Peritransplant IVIG &
Extracorporeal Immunoadsorption
P = 0.32
(23)
(12)
(345)
Human Immunology 66, 378 –386 (2005)
P = 0.05
P = 0.03
Human Immunology 66, 378 –386 (2005)
Therapeutic apheresis in lung
transplantation in Jena
2008 ~ 2012
Atherosclerosis Supplements 14 (2013) 33-38
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
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
Donor-specific HLA Antibodies
Following Plasma Exchange Therapy
J. Clin. Apheresis 28:301–308, 2013
Donor-specific HLA Antibodies
Following Plasma Exchange Therapy
P = 0.02
P = 0.58
J. Clin. Apheresis 28:301–308, 2013
Therapeutic strategies antibodymediated rejection
Guidelines for Heart Transplant
• A PRA 10% 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
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
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)
•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: http://www.nhi.gov.tw/query/query2_list.aspx
51
Centrifugal Device
(MCS+)
Membrane apheresis
KM8800
52
KPS8800
HF400
Transfus Apher Sci. 2005 Apr;32(2):209-20
J Clin Apher. 2010;25(5):240-9
53
Membrane
apheresis
Advantages
Disadvantages
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 Capable of performing
cytapheresis
devices
Expensive
Requires citrate anticoagulation
No heparin requirement Loss of platelets
More efficient removal
of all plasma components
Brenner: Brenner and Rector's The Kidney, 8th ed
56
Portion of Plasma Volume
Volumea
Exchanged
Exchanged (Ve/Vp) (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
59
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
TIW
D-9
D-7
D-5
D-3
D-1 OP day D1
D3
D5
1.5 PV 1.5 PV 1.5 PV 1.5 PV 1.5 PV 1.5 PV 2 PV 1.5 PV 1.5 PV 1.5 PV
DFPP DFPP DFPP DFPP DFPP
DFPP TPE DFPP DFPP DFPP
IVIg IVIg IVIg
IVIg IVIg
(OR)
Initial Ab X(1-78%)5
=0.0005 initial amount
residual Ab X(1-86%)
60
J Clin Apheresis 2010;25:83-177
61
Traffic
Accident
Transfer
to NTUH
Cardiac echo:
LVEF 19%
8/14 8/15 8/16
8/23
VV-ECMO
LM dissection
s/p POBAS
Desaturation
PCWP 40 mmHg
Dilate LV
8/31 9/1
9/5 9/6
Extubation
9/15
LV Drain
Cardiac cath:
No ISRS
10/5
LV Assist Device
Remove
VV-ECMO
10/20
10/25
檢查項目
數值
37℃
B cell
1:32 Positive Negative
37℃
T cell
1:32 Positive Negative
4℃
B cell
1:32 Positive Negative
4℃
T cell
1:32 Positive Negative
Donor:楊XX
數值
1:32 Positive
1:32 Positive
1:32 Positive
說明
37℃
37℃
4℃
檢查項目
B cell
T cell
B cell
4℃
T cell
1:32 Positive Negative
11/3
Panel reactive antibody:
Anti-HLA class I: 61%
Anti-HLA class II: 72%
標準值
標準值
Negative
Negative
Negative
說明
Donor:鄭XX
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
11/3
11/4
11/6
11/8
11/10
11/12
Donor
11/12
檢查項目
數值
標準值
37℃
B cell
1:8 Positive Negative
4℃
T cell
1:2 Positive Negative
說明
Double Filtration Plasmapheresis
37℃ T cell
1:2 Positive Negative
3L/session, 1.2x plasma volume
4℃
B cell
1:4 Positive Negative
total 5 course
Donor:侍XX
Isoproterenol
Millisrol
Dopamine
Primacor (Milrinone)
Bosmin
3000
Graft failure ?
2500
CO: 2.23
CI: 1.48
2000
1500
1000
CVVH
500
11/11
11/12
Transplant
11/13
11/14
DFPP
11/15
11/16
Massive bloody
pleural effusion
DFPP
IVIG
11/17
IVIG
Solu-Medrol
FK506
Cellcept
11/18
11/19
PT
PTT
sec
sec
26.6
39.1
• 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: 1218-24
Prevent rejection
Humoral Response
Donor selection
Recipient
Desensitization
Cellular Response
Immunosuppressive
agents
Human Immunology 2005;66:334-42
Examples of desensitization
J Heart Lung Transplant 2009;28:213-25
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
HLA class I
HLA class II
Clin Transplant
2006;20:476-84
Clin Transplant
2006: 20: 476–484
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;31:177-83 J
Heart Lung Transplant 2008;27:1036-9
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. 2010 Oct 25
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
TIW
D-9
D-7
D-5
D-3
D-1 OP day D1
D3
D5
1.5 PV 1.5 PV 1.5 PV 1.5 PV 1.5 PV 1.5 PV 2 PV 1.5 PV 1.5 PV 1.5 PV
DFPP DFPP DFPP DFPP DFPP
DFPP TPE DFPP DFPP DFPP
(OR)
IVIG IVIG IVIG IVIG IVIG
Initial Ab X(1-78%)5
=0.0005 initial amount
residual Ab X(1-86%)
Extracorporeal photopheresis
T-cell
B-Cell
Primary prophylaxis
N Engl J Med 1998;339:1744-51
Clin Transplantation 2000;14:162-6
Secondary prophylaxis
J Heart Lung Transplant 2006;25:283-8
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 Tcell antigens
– may cause a systemic cytotoxic CD8+ T-lymphocyte–
mediated immune response to the processed apoptotic Tcell antigens
– induce antigen-specific regulatory T cells, which may lead
to suppression of allograft rejection or GVHD
Thank You!