Heart Transplantation and Donor Heart Preservation Mohammed Quader MD November 20 2014 1.
-
Upload
norah-bennett -
Category
Documents
-
view
225 -
download
5
Transcript of Heart Transplantation and Donor Heart Preservation Mohammed Quader MD November 20 2014 1.
Heart Transplantation and Donor Heart Preservation
Mohammed Quader MDNovember 20 2014
1
Heart Failure
2
Heart Failure Hospitalizations
1.0 Million Hospitalizations a Year and Rising
0
100
200
300
400
500
600
700
79 80 85 90 95 00 06
Years
Dis
char
ges
in T
ho
usa
nd
s
Male Female
United States: 1979-2006 Source: NHLBI. Hospital Compare 2007-2010 3
HF an Epidemic
Prevalence- 5.7 MillionNew cases- 670,000/ yrMortality- 52,828/yrCost- $34 Billion
4
Heart Failure Outcomes – REMATCH Trial
P=0.0001
1yr = 52%
1yr = 28%
2yr = 29%
2yr = 13%
1yr =52%
1yr = 28%
2yr = 29%
2yr = 8%
P=0.0003
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
1.00
0 6 12 18 24 30 36 42 48Months Post Enrollment
Pe
rce
nt
Su
rviv
al
Survival1Yr- 25%2Yr- 8%
5
6
7
ADULT HEART TRANSPLANTATION Survival
0
20
40
60
80
100
0 1 2 3 4 5
Years
Su
rviv
al (
%)
ISHLT
75%85%
70%
8
Heart Transplantation is a“Gold Standard” Treatment for
Advanced Heart Failure
9
Richard Lower and Norman Shumway46th Annual Congress of American College of Surgeons 1960
10
Richard Lower and Norman Shumway – 2002Stamford CA
11
First Successful Human Heart Tx December 3, 1967
Christian Bernard 12
Conduct of Heart Transplantation
13
Donor Heart Procurement
14
15
16
17
18
Surgical Procedure
Bi-Atrial anastomosisBi-Caval anastomosis
19
Bi-atrial Anastomosis
20
21
22
23
Bi-Caval Anastomosis
24
25
26
Heart Transplantation is Limited by the Available Donor Hearts
27
Heart Transplantation Trends
• Donor Heart Preservation
19981999
20002001
20022003
20042005
20062007
20082009
20102011
20121000
1200
1400
1600
1800
2000
2200
2400
2600
2800
3000Hearts Transplanted in US
Year
Tota
l Num
ber 2055 – 2400/yr
28
SRTR HTx Data
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 370.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
Listed Patients for HTx- 3000
TransplantedDiedRemoved from list
Months
%
29
How to Increase the Number of HTx?
1. Increase awareness of organ donation
30
How to Increase the Number of HTx?
1. Increase awareness of organ donation2. Accept “extended criteria donors”
31
How to Increase the Number of HTx?
1. Increase awareness of organ donation2. Accept “extended criteria donors”3. Accept DCD heart donors
32
DCD – Donation after Circulatory Death
33
Deceased organ donors in the UK 2007-12
609 611 624 637 652 705
200288
335373
436
507
0
200
400
600
800
1000
1200
1400
2007-8 2008-9 2009-10 2010-11 2012-13 2012-13
Num
ber
DBD DCD
809
1212
49.7%
34
Uniform Determination of Death Act, 1980
• Irreversible cessation of circulatory and respiratory function - OR-
• Irreversible cessation of all functions of the entire brain, including the brain stem
35
Brain Death• Severe neurological
injury• Meets Brain death
criteria: -Clinical exam-Apnea test
DCD• Severe neurological
injury• Does not meet criteria
for brain death• Family has elected to
withdraw support
36
Process of Organ Procurement
• Donation After Brain Death DBD
• Patient is maintained on ventilator for organ recovery
• Organs dissected in-situ
• 3-4 hour surgery
37
Process of Organ Procurement
• Donation After Brain Death DBD
• Patient is maintained on ventilator for organ recovery
• Organs dissected insitu
• 3-4 hour surgery
• Donation After Cardiac Death
DCD• Patient is extubated in the
Operating Room or ICU
• Surgery begins 5-20 minutes after cessation of cardiac function and declaration by patient’s physician
• Rapid recovery with organs procured en bloc.
38
Donation after Circulatory DeathChallenges Beyond Ethics
1. Warm ischemia = myocardial injury2. Recovery of function3. Preservation of function4. Metabolic/functional evaluation
39
Donation after Circulatory DeathChallenges
1. Warm ischemia- Limit myocardial injurya. Ischemic preconditioningb. Na/H+ pump blockersc. Membrane stabilizersd. Anticoagulantse. Selective organ perfusion
40
Donation after Circulatory DeathChallenges Beyond Ethics
1. Warm ischemia = myocardial injury2. Recovery of function3. Preservation of function4. Metabolic/functional evaluation
41
• Cardiac protection from brain injury-– Catecholamine surge– Loss of vasomotor tone– Hypothalamus-pituitary axis damage– Pituitary-adrenal axis damage
42
Cardiac Arrest Heart Donors
43
UNOS HTx Database 1994 to 2012N = 29,242
CPR + Group CPR – Group
1,396 27,846
4.7% 95.3%
44
Heart Donor CharacteristicsCPR + Group CPR - Group P Value
Age in yrs 25 28 < 0.0001Females 31% 27% 0.0027Cause of deathAnoxiaStrokeHead trauma
45%12%40%
13%23%60%
< 0.0001
45
Heart Recipient CharacteristicsCPR + Group CPR – Group P Value
Mean Age - yrs 41 45 < 0.0001
Females 31% 27% 0.001
Listing Status1A1B2
54%34%12%
47%34%18%
< 0.0001
46
Acuity of Illness in Recipients at TxCPR + Group CPR - Group P Value
Admitted to ICU 37% 33% 0.0008
Inotrope Support 48% 44% 0.0075
ECMO Support 3% 1.3% < 0.001
47
Heart Transplantation Outcomes
CPR + Group CPR - Group P Value
Primary Graft Failure 2.29% 2.63% 0.489
Survival at30 days1 year5 years
95%88%73%
95%88%74%
0.826
48
Recipient Survival
50%
60%
70%
80%
90%
100%
0 12 24 36 48 60
Months
Rec
ipie
nt
Su
rviv
al
CPR+ (n=1394) CPR- (n=27806)
p = 0.8267 by Wilcoxon
49
Survival by Duration of CPR
50%
60%
70%
80%
90%
100%
0 12 24 36 48 60Months
Gra
ft S
urv
ival
T1 (n=650) T2 (n=378) T3 (n=237)
p = 0.2165 by Wilcoxon
T1: 1 - 15 min.T2: 16 - 30 min.T3: > 30 min.
50
Can we recover myocardial function in a DCD donor?
51
• 57 F with ICH, GCS 3, but did not meet BD criteria• Consent and IRB approval• Ventilator support withdrawn• After asystole, 5min standoff time, then to OR• After 24min of warm ischemia, heart was exposed,
systemic heparin and CPB support • After 3 hrs of CPB support heart recovered function to
support the circulation and weaned off the CPB • On 5mic/k/m of DOPA, MAP 50s, CI of 2.4 L/m/mt2
Ali et al. JHLT 2009 52
Donation after Circulatory DeathChallenges
1. Warm ischemia = myocardial injury2. Recovery of function- IS POSSIBLE3. Preservation of function ex vivo4. Metabolic/functional evaluation
53
Back to the basicsof Myocardial Metabolism
54
Myocardial Perfusion and Oxygen ConsumptionBuckberg et al. ATS 1977
Fick principle and radio-labeled particles distribution • At working condition• At rest• Arrested state• At fibrillation• At hypothermia
55
Buckberg et al. ATS 1977
Myocardial Oxygen Consumption
56
Myocardial Oxygen Consumption
Buckberg et al. ATS 197757
Buckberg et al. ATS 1977
Myocardial Perfusion
58
Buckberg et al. ATS 1977
Myocardial Oxygen Delivery
59
Key Findings
• Myocardial oxygen uptake fell progressively as myocardial temperature was reduced under all conditions
• Fibrillating heart at normo-thermia consumes 80% more oxygen compared to beating heart
• Lowest oxygen requirements were always found in arrested hearts (80% less) compared to beating empty or fibrillating hearts at any temperature
Buckberg et al. ATS 1977 60
Key FindingsPerfusion Distribution
• Distribution of blood is even in a beating heart at all temperatures
• In arrested hearts the endocardial/epicardial ratio progressively shifted to epicardial side with decreasing temperatures beyond 220C
• Oxygen delivery diminishes with hypothermia
Buckberg et al. ATS 1977 61
Best Preservation Strategy for HeartBuckberg et al.
1. Asystole/ arrested heart2. Hypothermia
62
Present PracticeDonor Heart Procurement and Transport
• Cardiac Arrest with high potassium solution• Storage in cold solution (40C) for
transportation
63
ADULT HEART TRANSPLANTS (2007-2012)Risk Factors For 1 Year Mortality
(N = 10,739)
60 90 120 150 180 210 240 270 300 330 3600.0
0.5
1.0
1.5
2.0
2.5
Ischemia time (minutes)
Haz
ard
Ratio
of 1
Yea
r Mor
talit
y p < 0.0001
201464
ADULT HEART TRANSPLANTS (2007-2012)Risk Factors For 1 Year Mortality
(N = 10,739)
60 90 120 150 180 210 240 270 300 330 3600.0
0.5
1.0
1.5
2.0
2.5
Ischemia time (minutes)
Haz
ard
Ratio
of 1
Yea
r Mor
talit
y p < 0.0001
201465
ADULT HEART TRANSPLANTS (2003-2008)Risk Factors For 5 Year Mortality
(N = 10,306)
60 120 180 240 300 3600.0
0.5
1.0
1.5
2.0
2.5
Ischemia time (minutes)
Haz
ard
Ratio
of 5
Yea
r Mor
talit
y p < 0.0001
2014 66
Myocardial Metabolism at 40C
Ozeki et al. Circulation Journal 2007; 153-159
67
Red – Cold Static, Black- Continuous Perfusion
Ozeki et al. Circulation Journal 2007; 153-15968
Cold Static PreservationMetabolic Markers of Injury
Ozeki et al. Circulation Journal 2007; 153-15969
Myocardial Metabolism
At 370 C - 100%At 40 C – 5%But not 0%
70
Donation after Circulatory DeathChallenges
1. Warm ischemia = myocardial injury2. Recovery of function3. Preservation of function- ex vivo4. Metabolic/functional evaluation
71
Ex-Vivo Perfusion for Preservation and Restoration of Function
1. Perfusate2. Perfusion apparatus
72
Ideal Perfusate
• Iso-osmotic• Oxygen delivery• Electrolyte balance• Supply substrate for metabolism• Maintain acid/base balance• Wash out lactate and other waste metabolites• Supply antioxidants and anti-inflammatory substrates• Allow for long transport time
73
Limitations of Blood as Perfusate
• Limited heart donor blood• Admixed with drugs and plegia solution• Hemolysis, particulate matter• No liver or kidney to filter metabolites
74
Perfusate Components
• Osmolarity – 300-400 mOsm/L Albumen Mannitol Raffinose
75
Perfusate Components
• Oxygen carrier-–RBC–Flurocarbon emulsions–PEG-bovine hemoglobin–Hemarena–Fetal hemoglobin–Dissolved O2
76
Perfusates Components
• Electrolytes- maintain asystole–potassium- 20-100mmol/L–Calcium- 0.05 – 5mmol/L–Na- 9-136mmol/L–Magnesium- 4- 13mmol/L–Lidocaine- membrane stabilizer both at
initial fibrillation and reperfusion
77
Perfusate Components
• Energy substrate–Glucose + insulin–Arginine, preferred at lower temps–Aspartate and glutamate–Short-chain FA
78
Perfusate Components
• Buffers–Bicarbonate–Phosphates–Histidine
79
Perfusate Components
• Vasodilators–Adenosine–Acetylcholine–5HTP–NO donors- nitroprusside, L-Arginine
80
Perfusate Components
• Oxygen radical scavengers–Glutathione
• Ideal temperature- around 200 C, lower temps shuns aerobic metabolism
• Perfusion pressure- 30-50mmHg
81
Preservation solutions- 167 types!
1. Intracellular- UW solution2. Extracellular- Celsor solution3. St. Thomas Solution4. HTK- histidine-tryptophan and keto-
gluteraldehyde
• < 2% comparison data from clinical studies• Clinical outcomes- similar
82
Available Perfusion Systems
• Organ Transport Systems Inc. Frisco TX• Organ Recovery Systems Inc. Chicago IL• Transmedics Inc. Andover MA
83
Organ Transport System-Lifecradle
84
Organ Recovery SystemHeart Transporter™, a portable perfusion pump equipped with temperature and perfusion pressure controls, as well as a bubble oxygenator
Ozeki et al. Circulation Journal 2007; 153-15985
Transmedics Inc.
86
Donor Heart Preservation
87
Transmedics Organ Care System• Miniature pump• Perfusate- blood mixed with
electrolytes, radical scavengers, antibiotics, Catecholamines, substrate and insulin, substrate
• Steroids, adenosine• No-touch monitoring and
manipulation of– coronary flow-
650-850ml/min– Perfusion pressure- 65mmHg– metabolic clearing
• Limited functional evaluation
88
Lactate levels
• End lactate levels correlated with organ preservation
• >5mmol/dL organ damage is to be expected
89
PROTECT I Trial2007
• Prospective Multicenter European trial to evaluate the safety and performance of organ care system for heart transplants
• 25 hearts• Graft survival at 30d
90
PROTECT I Trial2007
• 25pts• 20 HTx• 5 hearts not used
– 3, high lactates, low coronary flows– 2, technical reasons
• 30 day survival 95%• Feasibility and improvements
91
92
Donation after Circulatory DeathChallenges
1. Warm ischemia = myocardial injury2. Recovery of function3. Preservation of function4. Metabolic/Functional evaluation
93
Functional Evaluation
Working vs. Non-Working Conditions
94
Ex vivo Functional Assessment at VCUMangino et al. 2013
95
Non-Working Conditions• Pressures and flows
– Coronary resistance– Coronary flow
• Biochemical– Lactic acid production– Troponin release– Oxygen consumption
• Imaging– ECHO Cardiography– Nuclear imaging– MRI– Coronary angiography
• Histology
96
97Ghodsizad et al. HSF 2012
Coronary Angiography ex vivo
98Ghodsizad et al. HSF 2012
Donation after Circulatory DeathChallenges
1. Warm ischemia = myocardial injury2. Recovery of function3. Preservation of function4. Metabolic/Functional evaluation
99
Donation after Circulatory DeathChallenges
1. Warm ischemia = myocardial injury2. Recovery of function3. Preservation of function4. Metabolic/Functional evaluation
100
First Successful DCD Human Heart Tx December 3, 1967
Christian Bernard 101
After 53 years of first DCD HTx
Three Pediatric DCD HTx2009
102
103
What Does This Mean to a Patient Awaiting HTx
104
Clinical Impact of DCD HTx
• 4000 HTx each year• 15% increase in HTx• 600 more lives saved/year
105
Present and Future Possibilities
• Pulmonary edema• Pulmonary vascular
resistance manipulation• Surfactant delivery• Pulmonary emboli• Pneumonia• Cytokine inhibitors• Stem cell transfer• Molecular and gene
therapy• Immune modulation- nano
technology106
Marcelo Cypela and Shaf Keshavjee
Thank You
107