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

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Donor Heart Procurement

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15

16

17

18

Surgical Procedure

Bi-Atrial anastomosisBi-Caval anastomosis

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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

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How to Increase the Number of HTx?

1. Increase awareness of organ donation2. Accept “extended criteria donors”

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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%

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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

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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

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Donation after Circulatory DeathChallenges Beyond Ethics

1. Warm ischemia = myocardial injury2. Recovery of function3. Preservation of function4. Metabolic/functional evaluation

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• Cardiac protection from brain injury-– Catecholamine surge– Loss of vasomotor tone– Hypothalamus-pituitary axis damage– Pituitary-adrenal axis damage

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Cardiac Arrest Heart Donors

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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

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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

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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.

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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

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Back to the basicsof Myocardial Metabolism

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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

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Buckberg et al. ATS 1977

Myocardial Oxygen Consumption

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Myocardial Oxygen Consumption

Buckberg et al. ATS 197757

Buckberg et al. ATS 1977

Myocardial Perfusion

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Buckberg et al. ATS 1977

Myocardial Oxygen Delivery

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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

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Present PracticeDonor Heart Procurement and Transport

• Cardiac Arrest with high potassium solution• Storage in cold solution (40C) for

transportation

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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

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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%

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Donation after Circulatory DeathChallenges

1. Warm ischemia = myocardial injury2. Recovery of function3. Preservation of function- ex vivo4. Metabolic/functional evaluation

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Ex-Vivo Perfusion for Preservation and Restoration of Function

1. Perfusate2. Perfusion apparatus

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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

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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

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Perfusate Components

• Osmolarity – 300-400 mOsm/L Albumen Mannitol Raffinose

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Perfusate Components

• Oxygen carrier-–RBC–Flurocarbon emulsions–PEG-bovine hemoglobin–Hemarena–Fetal hemoglobin–Dissolved O2

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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

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Perfusate Components

• Energy substrate–Glucose + insulin–Arginine, preferred at lower temps–Aspartate and glutamate–Short-chain FA

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Perfusate Components

• Buffers–Bicarbonate–Phosphates–Histidine

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Perfusate Components

• Vasodilators–Adenosine–Acetylcholine–5HTP–NO donors- nitroprusside, L-Arginine

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Perfusate Components

• Oxygen radical scavengers–Glutathione

• Ideal temperature- around 200 C, lower temps shuns aerobic metabolism

• Perfusion pressure- 30-50mmHg

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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

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Available Perfusion Systems

• Organ Transport Systems Inc. Frisco TX• Organ Recovery Systems Inc. Chicago IL• Transmedics Inc. Andover MA

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Organ Transport System-Lifecradle

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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.

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Donor Heart Preservation

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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

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Lactate levels

• End lactate levels correlated with organ preservation

• >5mmol/dL organ damage is to be expected

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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

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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