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EXTRACORPOREAL

CARDIOPULMONARY

RESUSCITATION

(ECPR)

THE MISSOURI PERFUSION SOCIETY 23rd Annual Scientific Meeting Embassy Suites Country Club Plaza

Kansas City, Missouri June 1 & 2, 2018

Gary Grist RN CCP Emeritus

No disclosures

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OBJECTIVES

◼ Describe the mechanisms of reperfusion injury and its relationship to shock and CPR patients.

◼ Explain the strategy to revive cardiac arrest patients with the heart/lung pump who are not responsive to CPR resuscitation.

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OXYGEN TOXICITY VS. REPERFUSION INJURY

◼ AOX = antioxidants

◼ ROS = reactive oxygen species

AOX active but too much O2

AOX inactive O2 low or normal

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ANTIOXIDANTS

◼ Catalase, Superoxide dismutase, Glutathione peroxidase, Glutathione, Vitamin C, Vitamin E, Beta carotene, Coenzyme Q10, etc.

◼ Protect against the damaging effects of oxygen

◼ pH sensitive: > 7.20

◼ Depleted antioxidants thought to contribute to aging

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COMPLICATIONS OF ECMO

➢ Brain damage➢ encephalopathy➢ coma➢ seizure➢ infarct➢ hemorrhage

➢ Cardiac failure➢ arrhythmia➢ ventricular failure➢ cardiac stun➢ stone heart➢ elevated cardiac enzymes

➢ Multiple organ failure➢ renal failure➢ pulmonary infiltrates/hemorrhage➢ elevated liver enzymes➢ elevated glucose➢ gut ulcer/slough➢ coagulopathy

➢ Systemic inflamatory response➢ Failure to improve

SYMPTOMS OF REPERFUSION INJURY

➢ Brain damage➢ encephalopathy➢ coma➢ seizure➢ infarct➢ hemorrhage

➢ Cardiac failure➢ arrhythmia➢ ventricular failure➢ cardiac stun➢ stone heart➢ elevated cardiac enzymes

➢ Multiple organ failure➢ renal failure➢ pulmonary infiltrates/hemorrhage➢ elevated liver enzymes➢ elevated glucose➢ gut ulcer/slough➢ coagulopathy

➢ Systemic inflamatory response➢ Failure to improve

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FOUR MECHANISMS OF REPERFUSION INJURY

◼ Oxidative stress √

◼ Calcium Stress √

◼ Neutrophil-Endothelium Interaction

◼ Apoptosis

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OXYGEN STRESS:MYOCYTE CELL DEATH BY ISCHEMIC ANOXIA &

SUBSEQUENT REPERFUSION

Becker LB, New concepts in reactive oxygen species and cardiovascular reperfusion physiology. Cardiovascular Research 61 (2004);461-470

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CALCIUM STRESS:EXCITABLE CELLS: CARDIAC MYOCYTES AND NEURONS

◼ Intracellular [iCa+2] = __1__ Extracellular [iCa+2] 10,000

◼ Upon reperfusion, influxing calcium causes a ‘mitochondrial permeability transition pore’ (MPTP)

◼ Cardiac injury• Arrhythmia• Cardiac Stun• Stone Heart• Fibrillation feedback phenomenon

◼ Increasing Joules needed for defibrillation

◼ Central nervous system injury• Hemorrhage• Infarction

◼ ECMO w/ right neck cannulation• Left side infarcts 61%

◼ exposed to immediate reperfusion from the ECMO pump

• Right side infarcts 11%◼ protected from immediate

reperfusion by R carotid ligation• Bilateral infarcts 28%

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NEUTROPHIL-ENDOTHELIUM INTERACTION

◼ Neutrophils activated by ischemia release cytotoxic granules and ROS, damaging capillaries.

◼ Damaged capillaries become a blood flow “obstacle course”.

◼ No reflow phenomenon caused by cellular aggregation in the damaged capillaries. Mura et al. Critical Care 2006 10:R130

http://www.benbest.com/cryonics/ischemia.html#reperfuse

Normal mouse lung Mouse lung after gastric ischemic/hypoxia reperfusion

http://www.thoracic.org/sections/clinical-information/critical-care/critical-care-research/animal-

models-of-acute-lung-injury.html

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ACCELERATED APOPTOSIS CAUSED BY REPERFUSION INJURY

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REPERFUSION INJURY POTENTIAL (RIP)Acronym for “Rest In Peace”

◼ RIP: the hidden risk of a lethal reperfusion injuryupon sudden reperfusion of ischemic tissues.

◼ Shock: inadequate blood flow = poor tissue oxygenation & CO2 removal

• Cardiogenic• Septic• Traumatic• Hypovolemic septic• Neurogenic

◼ Shock: a state of insufficient perfusion that holds the potential for reperfusion injury if normothermic oxygenation is suddenly restored.

◼ RIP markers to assess degree of shock:• Tissue anoxia = anion gap• Tissue CO2 retention = p[v-a]CO2

A cause of acute organ failure in transplants.

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FIRST ANION GAP IN PICU AFTER CPB: CORRELATION TO SURVIVAL

0

10

20

30

40

50

60

AG < 15mEq/L

AG 15-19mEq/L

AG 20-24mEq/L

AG =/> 25mEq/L

% Mortality

CMH survival to discharge vs. 1ST anion gap after CPB, p < 0.05

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VENOARTERIAL CO2 GRADIENTON ECMO VS. SURVIVAL

Lamia B, Minerva Anestesiol 2006

* CMH survival to discharge vs. average CO2 gradient on ECMO: n = 454, p < 0.05

~60% MORTALITY*

~30% MORTALITY*

~15% MORTALITY*

~100% MORTALITY*

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THE CO2 GRADIENT AND CORRECTED ANION GAP: MORTALITY IN CARDIAC AND RESPIRATORY

ECMO PATIENTS

0

10

20

30

40

50

60

70

80

90

100

< 15 15-19 20-24 >24

% CO2 GRADIENT MORTALITY

% AG MORTALITY

n = 360, p < 0.05

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244 RESPIRATORY & CARDIAC PATIENTS INSIDE THE LANE

SURVIVORS (n = 193, 95%) AND EXPIRED (n = 51, 63%)

0

5

10

15

20

25

30

35

40

0 5 10 15 20 25 30 35 40

1ST CO2 GRADIENT

1S

T C

OR

RE

CT

ED

AN

ION

GA

P

40 RESPIRATORY & CARDIAC PATIENTS OUTSIDE THE LANE

SURVIVORS (n = 10, 5%) AND EXPIRED (n = 30, 37%)

0

5

10

15

20

25

30

35

40

0 5 10 15 20 25 30 35 40

1ST CO2 GRADIENT1S

T C

OR

RE

CT

ED

AN

ION

GA

P

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REPERFUSION INJURY POTENTIAL (RIP) MAPPING:

BLOOD PRIMED, NORMOTHERIC ECMO PATIENTS(N = 284)

PATIENTS OUT

OF THE LANE

-

10

20

30

40

50

60

70

80

90

100

SURVIVED EXPIRED

PE

R C

EN

TA

GE

PATIENTS IN

THE LANE

-

10

20

30

40

50

60

70

80

90

100

SURVIVED EXPIRED

PE

R C

EN

TA

GE

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ECMO VS ECPRFOR ARREST PATIENTS

www.aic.cuhk.edu.hk/web8/toc.htm

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TERMINATING CPR◼ 1959

• Dr. Safar starts CPR

• 10 minute limit

◼ 1989• 30 years since CPR started

• Still a 10 minute limit

◼ 2005 AHA Guidelines for CPR• 46 years since CPR started

• No change in 10 minute limit◼ “For the newborn infant,

discontinuation of resuscitation can be justified after 10 minutes without signs of life despite continuous and adequate resuscitative efforts.”

◼ 2008 Current PALS Recommendation• 49 years since CPR started

• 15-30 minute limit◼ Discontinue CPR efforts after 15

minutes for newborn in delivery room. All others, discontinue CPR efforts after 30 minutes.

www.castorcanada.com/chainofsurvival.htm

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IN-HOUSE PICU WITNESSED ARREST:DURATION OF CPR

*Morris et al. 2004 @ CHOP

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◼ How do we know that brain damage occurs after 10 minutes of cardiac arrest?• Answer: Because a few patients are revived after lengthy

CPR and have obvious brain damage.◼ Limits of resuscitation. I. Thanatophysiologic and therapeutic limits. Z

Gesamte Inn Med. 1981 May 15;36(10):305-10.

◼ Why should efforts cease after 30 minutes of CPR?• Answer: The current concept is that during CPR, poor blood

flow kills the brain cells. CNS survival after 30 minutes is unlikely.◼ AHA Circulation, 2005. 112(24 Suppl): p. IV1-203.◼ AHA Pediatrics, 2006. 117(5): p. e989-1004.

◼ New Concept: During CPR, brain cells do not die until the ROSC (or starting ECMO). Sudden tissue reperfusion with warm, oxygenated blood causes reperfusion injury that kills the brain.

• Idris AH et al. Crit Care Med 2005; 33(9):2043-8.• Becker, L.B.,Cardiovasc Res, 2004. 61(3): p. 461-70.

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REPERFUSION INJURY POTENTIAL MAP

0

5

10

15

20

25

30

35

40

0 5 10 15 20 25 30 35 40

1ST CO2 GRADIENT

1S

T C

OR

RE

CT

ED

AN

ION

GA

P

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RIP MAPPING THE CPR PATIENT

Blood gas values taken from CLINICAL APPLICATION OF BLOOD GASES, FOURTH ED. © 1989, SHAPIRO, HARRISON,

CASE & KOZLOWSKI-TEMPLIN, EDs., PP 337-338

BLOOD GAS TYPE

pH / pCO2 / pO2 / base

ABG 7.37 / 42 / 80 / -1

VBG 7.33 / 50 / 32 / -1

ABG 7.52 / 28 / 436 / -1

VBG 7.31 / 58 / 25 / -2

ABG 7.27 / 48 / 430 / -6

VBG 7.09 / 84 / 25 / -6

CPR 35 min 100% ABG 7.11 / 38 / 322 / -19

VBG 6.82 / 96 / 20 / -20

30%

CPR 5 min 100%

58

TIME FiO2 ∆ pCO2

CPR 15 min 100%

8

30

36

60 min prior

to arrest.

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ECMO VS ECPR

1. ECMO strategy:

maintain normal physiology

◼ Urgent

• Patient not coding

◼ Normothermia

◼ Blood Primed

• No hemodilution

◼ Normalized iCa+2

2. ECPR strategy:

thwart a lethal

physiology

◼ Emergent

• Patient coding

◼ Hypothermia

◼ Clear prime

• Intentional hemodilution

◼ Reduce iCa+2

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REPERFUSION STRATEGY

COMBATING RIP WITH ECPR:A TWO STEP PROCESS

1. STOP THE DYING (PREVENT REPERFUSION INJURY)

◼ Hypothermia

◼ Hemodilution

◼ Hypocalcemia

2. BRING BACK TO LIFE(REVERSE THE RIP)

◼ Normalize venous pCO2

◼ Normalize venous pH

◼ Normalize hematocrit

◼ Normalize calcium

◼ Rewarm

◼ Continue support

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HYPOTHERMIA PREVENTS REPERFUSION INJURY

◼ “Destructive processes following ischemia/reperfusion can be prevented or significantly mitigated by hypothermia” KH Polderman, Crit Care Med 2009 37:7(Suppl), S188

• VU University Medical Center is the university hospital affiliated with the Vrije Universiteit (literally: Free University) of Amsterdam, The Netherlands

◼ Protective effects of mild to moderate hypothermia

• Mitochondrial injury & dysfunction

• Cerebral metabolism

• Influx of calcium

• Cell membrane leakage

• Cell edema

• Intracellular acidosis

• Production of ROS

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◼ CPR + induced hypothermia is not a new idea

◼ 1964 Safar CPR poster

◼ Delaying hypothermia during CPR has deleterious effects

◼ Circulation, 2006. 113(23): p. 2690-6.

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CPR COOLING VS. ECPR COOLING

◼ CPR COOLING

• Blood flow ~ 40%

• Cooling protects against ‘too little’ O2 deliverycausing tissue anoxia

• Depth of cooling limited to >32C due to cardiac inhibition upon ROSC

◼ ECPR COOLING

• Blood flow ~ 100%

• Cooling protects against ‘too much’ O2 deliverycausing reperfusion injury

• Depth of cooling not limited by the need for cardiac recovery

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ECPR COOLING

◼ Cool ‘perfusate’ rapidly removes CO2 from tissues

◼ CO2 is more soluble at temperatures below 37C

◼ Metabolic rate reduced by hypothermia◼ CO2 production reduced

◼ O2 need reduced

◼ Neutrophil inflammatory response reduced

◼ Apoptosis slowed

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HEMODILUTION: ECPR CLEAR PRIME

◼ Hemodilution reduces oxygen delivery to tissues.

◼ Allows high blood flow without excessive O2 delivery to facilitate CO2 removal.

◼ Counters ‘no reflow’ phenomenon by making blood ‘thinner’.

◼ http://www.thoracic.org/sections/clinical-information/critical-care/critical-care-research/animal-models-of-acute-lung-injury.html

Normal mouse lungMouse lung after gastric ischemic/hypoxia reperfusion

www.benbest.com/cryonics/ischemia.html

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HYPOCALCEMIA: ECPR CALCIUM FREE PRIME

◼ Calcium free prime reduces intracellular migration to combat cardiac & CNS damage.

◼ Calcium stress is more lethal than oxygen stress.

Wang et al. Journal of Cerebral Blood Flow & Metabolism (2002) 22, 206–214; doi:10.1097/00004647-200202000-00008

Neuronal Cell Culture:

Survival After 12 Hours Oxygen-Glucose Deprivation

Dantrolene blocks ryanodine receptor sites which prevents intracellular Ca+2 fluxes and stops the formation of the MPTP.

Dantrolene reduces neuronal cell death from hypoxic/ischemia.

Muehlschlegel S, Sims JR. Dantrolene: mechanisms of neuroprotection and possible clinical applications in the neurointensive care unit. Neurocrit Care 2009;10:103-15.

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DATE TIME

TOTAL

TIME

MIN.

TEMPBLOOD

GASpH pCO2 pO2 Base HCT iCa COMMENT

1st day ~ 10:30 0 37 35

PT. CODES IN CATH LAB.

TRANSPORTED TO OR DURING

CPR FOR EMERGENT

ECPS/CPB.

11:10 40 37 ABG 7.01 72 43 -15.1Corrected Anion Gap = 16

mEq/L

11:51 81 37 VBG 6.90 113 18 -11 22 1.11 ON ECPS/CPB, LIMA >LCA REPAIR

11:59 89 33 VBG 6.98 63 23 -15.9 25 0.98

12:09 99 30 VBG 7.13 44 36 -13.8 26 1.04

12:20 110 24 VBG 7.22 35 48 -12.4 25 1.02

12:39 129 26 VBG 7.33 31 64 -8.9 24 1.00

13:02 152 26 VBG 7.32 28 67 -11.5 29 0.98

13:29 179 26 VBG 7.39 26 61 -9.8 31 0.79

13:42 192 25 VBG 7.42 23 113 -9.4 31 0.88

13:54 204 25 VBG 7.49 23 115 -6.3 31 0.88

14:12 222 31 VBG 7.4 27 46 -8.1 29 1.59

14:23 233 37 VBG 7.38 36 39 -4 32 1.32

14:38 248 37 VBG 7.37 36 36 -4.1 32 1.29

15:24 294 37 OFF ECPS/CPB, ON ECMO

22:00

2nd day

3rd day

SEDATION STOPPED. PT. AWAKES NERUOLOGICALLY INTACT.

TRANSPORTED ON ECMO TO ARKANSAS/TEXAS FOR HEART & KIDNEY TX. SURVIVES NEURLOGICALLY

INTACT.

11 Y/O UNDERGOING ABLATION IN CATH LAB. LMCA OCCLUSION.

HIGHEST LACTIC ACID = 13 mmol/L

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TIME

TOTAL

TIME

MIN

TEMP pH pCO2 pO2 BASE HCT iCaANION

GAP

LACTIC

ACIDCOMMENT

0845 0

DESATURATED, NO

END TIDAL CO2, CPR

STARTED

0850 5 37 ABG 6.95 90 11 -15 22 1.25 CPR

0855 10 37 ABG 6.89 90 17 -18 40 1.24 CPR

0912 27 37 ABG 6.93 67 63 -19 38 1.22 CPR

0929 44 37 ABG 6.72 131 14 -21 35 1.12 CPR

0930 45STARTED ON ECPR

PUMP, COOLING

0934 49 25 VBG 6.77 106 57 -18 16 0.74 ON ECPR PUMP

0957 72 32 VBG 7.16 32 38 -16 19 0.98 ON ECPR PUMP

1033 108 32 VBG 7.02 52 59 -17 28 1.09 ON ECPR PUMP

1120 155TRANSFER TO ECMO

PUMP

1215 210 32 ABG 7.45 23 58 -6 ON ECMO PUMP

1215 210 32 VBG 7.42 29 34 -4 39 1.34 19 10 ON ECMO PUMP

S/P NW1 POD 15, FUNDOPLICATION, EMERGENT ECPR, WT = 3.8 KG

1 MIN OF CPR IN A SHUNTED PATIENT = 2 MIN OF CPR IN A PATIENT WITH NORMAL CARDIAC ANATOMY

SUCCESSFULLY WEANED FROM ECMO AFTER 122 HOURS, LARGE IVH BUT NO INFARCTIONS

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TIMECOUNT

DOWNTEMP pH pCO2 pO2 BASE

CO2

GRADHCT iCa

ANION

GAP

LACTIC

ACIDCOMMENT

1432 -380 37 OFF CPB

ABG 7.38 45 <33 0.7

VBG 7.35 52 <33 2

ABG 7.35 48 <33 -0.2

VBG 7.29 61 <33 0.4

ABG 7.36 37 <33 -4.2

VBG 7.27 56 <33 -2.2

ABG 7.31 21 38 -14.7

VBG 7.01 74 <33 -14.4

2016 -36 37 MINI CODE

2052 0 37 CODE CALLED, CPR STARTED

2125 33 28 VBG 7.05 46 71 -17 STARTED ON ECPR PUMP, COOLING

2141 49 30 VBG 7.14 55 61 -9.7 ON ECPR PUMP

2214 82 32 VBG 7.2 36 43 -13.4 ON ECPR PUMP

ABG 7.2 30 84 -14.8

VBG 7.24 30 54 -14.7

2334 TRANSFER TO ECMO PUMP

ABG 7.22 35 98 -14.9 ON ECMO PUMP

VBG 7.23 36 44 -15.6 ON ECMO PUMP

ABG 7.38 36 221 -3.6 ON ECMO PUMP

VBG 7.39 40 40 -0.8 ON ECMO PUMP

6 HRS S/P NW1, EMERGENT ECPR, WT = 2.6 KG

SUCCESSFULLY WEANED FROM ECMO AFTER 135 HOURS

~ 1 HR POSTOP3.7131.4150371650

191750 37

-242

32

16 21.1

1 1.0439

32

1.44 14.219

195

4625 32

0005

1030

~ 2 HR POSTOP

53

1442 35

~ 4 HR POSTOP1940 37

-182

-72

13

1.42 14-370 LAST BLOOD GASES IN OR737

ON ECPR PUMP02230 100

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Lancet 2008;372(9638):554-561

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THE END