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TRANSCRIPT
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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