Intraoperative

Myocardial Protection

PRESENTOR – Dr. Sameer goyal

MODERATOR – Dr. S.K. Mathur
Dr. R.K Dubey

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 Cardiac Physiology
 Myocardium requires continuous supply of o2.
 Ischemia occurs when demand > supply.
 Myocardial o2 supply depends on:

a) arterial o2 content

o2 content = (Hb) 1.34 (% saturation) + .003(Po2)

b) flow of oxygenated blood to myocardium i.e.

CBF.
 Blood flow to subendocardium occurs during
diastole. Most vulnerable to ischemia.
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 O2 delivery may be insufficient because of either:

a) ↓ in perfusion pressure ( systemic

hypotension, CAD )

b) ↑ in ventricular end diastolic pressure ( aortic

stenosis, VF, ventricular distension etc).

 Myocardial O2 consumption

1) normal beating heart = 8ml/ 100gms/ min

2) empty beating heart = 5.6ml/ 100gms/ min

3) arrested heart = 1.1ml/ 100gms/ min

4) cooling to 22C = .3ml/ 100gms/ min 3

 Events during CPB that may lead to
myocardial injury
 Aortic cross clamping,
 VF,
 Ventricular distension,
 Coronary embolism,
 Low perfusion pressure,
 Catecholamines,
 Reperfusion
4
 Mechanism of myocardial ischemic injury

 Depletion of high energy phosphates,

 Intracellular acidosis
 Alteration in Calcium homeostasis,
 O2 free redicals,
 Complement activation.

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 AORTIC CROSS CLAMP

 PROBLEMS WITH NORMOTHERMIC ISCHEMIC ARREST

• PERSISTENT ELECTRICAL AND MECHANICAL ACTIVITY

DURING MUCH OF THE ISCHEMIC PERIOD DEPLETES
HIGH ENERGY PHOSPHATE AND COMPROMISES POST-
REPAIR VENTRICULAR PERFORMANCE

• SAFE ISCHEMIC TIME INSUFFICIENT TO COMPLETE

MOST REPAIRS

• INTERMITTENT CROSS CLAMP WITH PERIODS OF

REPERFUSION DOES LITTLE TO IMPROVE OPERATING
CONDITIONS OR PREVENT MYOCARDIAL NECROSIS.

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 RAPID CESSATION OF ELECTRO-MECHANICAL
ACTIVITY FOLLOWING CROSS CLAMP DESIRABLE
BOTH FOR EXPOSURE AND MYOCARDIAL
PRESERVATION
 DIFFERENCES IN MYOCARDIAL VULNERABILITY
MAKE IT IMPOSSIBLE TO PREDICT A ‘SAFE’
PERIOD OF ISCHEMIA
 EXTENT OF NECROSIS IS DIRECTLY
PROPORTIONAL TO THE DURATION OF AORTIC
CROSS CLAMP
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 PATHOPHYSIOLOGY OF GLOBAL
MYOCARDIAL ISCHEMIA

 HIGH ENERGY PERSITENT HIGH ENERGY

PHOSPHATE
PRODUCTION PHOSPHATE UTILIZATION

DECREASED HIGH ENERGY

PHOSPHATE AVAILABILITY

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 DURING ISCHEMIA, THE MAIN SOURCES OF HIGH ENERGY
PHOSPHATE ARE CREATINE PHOSPHATE AND ANAEROBIC
PRODUCTION OF ATP

 ANAEROBIC PRODUCTION OF ATP IS SELF- LIMITED

BECAUSE OF ACCUMULATION OF METABOLITES SUCH AS
LACTATE, PYRUVATE AND PROTONS, WHICH EVENTUALLY
INHIBIT ESSENTIAL ENZYME SYSTEMS

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 CP AND ATP LEVELS DECLINE RAPIDLY FOLLOWING
GLOBAL ISCHEMIA BECAUSE OF PERSISTENT ENERGY
UTILIZATION FOR ELECTROMECHANICAL AND BASAL
METABOLIC ACTIVITY

 PROLONGED ISCHEMIA RESULTS IN SEVERE MYOCARDIAL

CONTRACTURE

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ENERGY UTILIZATION IS CLOSELY LINKED TO MOVEMENT OF
CALCIUM IONS

TRANSPORT OF CALCIUM INTO THE MYOCYTE

(CONSUMES LITTLE ENERGY)

RISE IN INTRACELLULAR CALCIUM TRIGGERS A

SERIES OF REGULATORY REACTIONS RESULTING
IN MYOCARDIAL CONTRACTION AND ENERGY
UTILIZATION

ENERGY DEPENDENT TRANSPORT OF

CALCIUM TO OUTSIDE THE CELL FOR
MYOCARDIAL RELAXATION

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 LOW PRODUCTION OF INCREASED
ATP DUE TO ANAEROBIC PRODUCTION AND
METABOLISM ACCUMULATION
OF H+ IONS AND
FREE FATTY ACIDS
INCREASED CYTOSOLIC
CONCENTRATION OF IONIZED
CALCIUM
RELEASE OF
INTRACELLULAR
FORMATION OF RIGOR
LIPOPROTEIN LIPASE
BONDS BETWEEN
CONTRACTILE
PROTEINS WITH
PERSISTENT ENERGY
UTILIZATION LOSS OF CELL
INTEGRITY AND
FUNCTION
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Consequences of ischemia and reperfusion injury

 Depends on length of ischemia,

temp. of myocardium,
 Myocardial stunning: represents viable
myocardium having systolic/diastolic dysfunction
in the presence of normal myocardial perfusion.

* complete functional recovery.

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 Hybernating myocardium: viable myocardium
that is chronically underperfused and has
downregulated its contractile functions.

* On reperfusion, returns to normal function.

 Myocardial necrosis : myocytes irreversibly
injured

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 Intervention before the onset of ischemia

A) Minimization of ongoing ischemia:

* by use of nitrates, anticoagulants, antiplatelet agents,

* insertion of IABP in the perioperative period,

* controlling HTN, tachycardia, pt. anxiety,

* use of supplemental O2.

B) Perioperative ß-blokade:

* unless contraindicated, ↓ cardiac related mortility.

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C) Rapid revascularization

D) Fibrillary arrest : creates a nearly motionless heart,

: either through electrical stimulation or

myocardial cooling.

1) Normothermic fibrillary arrest :

: by placing alternating current generator in contact

with ventricular myocardium.

: ventricle remain in fibrillation with little ventricular

motion.

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Disadv. :

1) energy consumption is high as myocardium is warm

and in a state of continuous contraction.

2) ↑ wall tension.

3) endocardial perfusion compromised due to aabsence

of diastole.
 Not recommended

2) Hypothermic fibrillary arrest : energy consumption is less

but not as low as complete arrest

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 Prevention of ventricular distention

 CAUSES INCREASED MYOCARDIAL WALL TENSION AND

MVO2
 REDUCES SUBENDOCARDIAL PERFUSION DUE TO
INCREASED INTRACAVITY PRESSURE
 POTENTIATED BY
• INADEQUATE VENOUS RETURN
• AORTIC INSUFFICIENCY
• VF
• INCREASED PV RETURN AND NONCORONARY
COLLATERAL FLOW IN THE QUIESCENT HEART
• POST-REPAIR CARDIAC FAILURE 18
 STRATEGIES TO PREVENT VENTRICULAR
DISTENSION

 OPTIMIZE VENOUS DRAINAGE

 OPTIMIZE CPB FLOW RATES
 VENT THE LEFT HEART
 EARLY DEFIBRILLATION
 EARLY CROSS CLAMPING IN AORTIC
INCOMPETENCE
 VASODILATORS MAY HELP SOMETIMES

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 Myocardial Preconditioning

 DEFINED AS THE CONCEPT OF ENDOGENOUS ADAPTATION

TO SUBLETHAL GLOBAL ISCHEMIA RESULTING IN
PROTECTION AGAINST A LONGER LETHAL ISCHAEMIC
EPISODE

 HAS BEEN DEMONSTRATED EXPERIMENTALLY IN ANIMAL

HEARTS, AND ALSO IN CLINICAL CIRCUMSTANCES IN
HUMANS IN A FEW STUDIES

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 POSSIBLE MECHANISMS OF
PRECONDITIONING

 INITIALLY THOUGHT TO BE DUE MANIFESTATION OF INCREASED

COLLATERAL FLOW

 PRESENT RESEARCH HYPOYHETISES THE EFFECTS TO BE

MEDIATED BY ADENOSINE AND A SIGNAL TRANSDUCTION
PATHWAY INVOLVING G-PROTEINS, A PHOSPHOLIPASE AND
PROTEIN KINASE C (PKC)

 ANOTHER HYPOTHESIS INVOLVED ATP-DEPENDANT K+

CHANNELS

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 SHOWN TO HAVE MAXIMUM BENEFIT WHEN THE ISCHEMIC
PERIOD IS A SINGLE EPISODE OF 3 - 5 MINS, ABOUT 3 - 5 MINS
PRIOR TO THE PROLONGED ISCHEMIC PERIOD

 THE BENEFITS WEAR OFF BEYOND ABOUT 2 HOURS OF

PROLONGED ISCHEMIA

 BENEFITS SEEN MAXIMALLY WITH LIMITING INFARCT SIZE AND

ARRHYTHIAS AFTER THE ISCHEMIC PERIOD

 HAS NOT BEEN SHOWN TO HAVE SIGNIFICANT BENEFITS IN

DECREASING MYOCARDIAL STUNNING RELATED LOW CARDIAC
OUTPUT

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 Stimuli producing preconditioning response:

: ischemia,

: drugs ( bradykinin, phenylephrine,

endotoxin, adenosine)

: inhalational anaesthetic agents(

sevoflurane, desflurane, isoflurane).

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 Interventions during ischemia

A) Myocardial tempr.

1) Hypothermia: myocardial O2 consumption

↓ by 50% for every 10C ↓ in myocardial

tempr. Cooling produced through:

a) cold cardioplegia : given at 4C to 10C and

produce myocardial cooling to 15C to16C.

b) topical cooling : chilled saline or slush

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2) Warm cardioplegia : metabolic activity continues
but at a lesser degree because mechanical
activity of heart is abolished.

a) supplied continuously to avoid ischemic injury.

b) lower postop incidence of low output state.

c) use of blood cardioplegia which carry enough O2

to meet demands of warm myocardium.

d) may not provide adequte protection in presence

of severe CAD.

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3) Tepid cardioplegia :

: administerd at 29C,

: provide some benefits of warm cardiplegia

while minimizing effects of hypothermia on

myocardium.

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Purpose of cardioplegia
•   Objective is to stop the heart as quickly as
possible to enjoy the benefits of a quiet,
bloodless operative field while minimising
ischaemic injury to the heart

•   Cold chemical cardioplegia provides better

protection than cold ischaemic arrest

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 Hypothermia potentiates the protective effects of
chemical cardioplegia

•   Ideal cardioplegic solution should eliminate

external cardiac work by inducing diastolic arrest,
minimize myocardial oxygen requirements and
cause no myocardial damage itself

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Ions & Buffers

 •   The solution should be slightly hypertonic

(315-350 mOsm/l) to minimize myocardial

oedema

•     Cardioplegia solutions are buffered so as to

maintain an alkaline pH; as at 37°C the neutral

pH of water is 6.8, at 0°C it rises to 7.5,

therefore require to maintain an alkaline

solution if neutrality is maintained [ie a pH

of 6.8 while hypothermic is acidic which may

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cause ischaemic myocardial damage]
 Composition of Cardioplegia
Solutions
Two types:

1) Crystalloid cardioplegia :

: do not contain Hb,

: deliver dissolved O2 only,

: small amount of O2 is adequate at cold

tempr. But insufficient in warm myocardium.

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2) Blood cardioplegia : produced by mixing blood to
crystalloid in adefinite ratio, with a final Hct. Of 16
to 20%.

•   improved oxygen carrying capacity and delivery

until electromechanical quiescence developed
 enhanced myocardial oxygen consumption
 preserved high-energy phosphate stores
 buffering changes in pH
 use of free radical scavengers (superoxide
dismutase, catalase, and glutathione)
 provide appropriate osmotic environment for
myocardial cells and lessen the myocardial oedema
  31
•   Most effective at 20°C, if too cold have increased
blood viscosity and reduced oxygen dissociation
from Hb

•   Clinically shows little/no benefit over crystalloid

cardioplegia

•   More complex & expensive than crystalloid

•   May show benefits for long ischaemic periods

and in poor ejection fraction patients

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 Cold Blood Cardioplegia
pitfalls
advantages  hypothermic inhibition of
 lowers myocardial
mitochondrial enzymes
oxygen demands  shifting oxyhaemoglobin
dissociation curve to left
 activating platelets,
leukocytes, complement
 impaired membrane
stabilization

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KCl
 Produce/maintain diastolic arrest

•   Usually 10 - 30 mEq/l

Histidine 
 Buffer

Mannitol

•    Contributes to a hypertonic cardioplegia

•    Also has free oxygen radical scavenging benefits

 
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Mg
•     Potentially can induce cardiac arrest by itself
•     Stabilises cell membranes
•     Blocks phosphorylase action of myosin thereby
preserving high energy substrates
•     Slow calcium channel blocker
 
Procaine
•     Is by itself a cardioplegic agent; blocks
permeability of cell membrane to sodium
during repolarisation
•     Slow calcium channel blocker
•     Also stabilises cell membrane
•    Prevents vasoconstriction due to the particle
contents of the IV solution thereby improving
distribution of cardioplegia in coronary artery
disease; coronary vasodilator 35

 
Calcium

•  Essential to myocardial contractility and to maintain normal

membrane functioning

•  But implicated in reperfusion injury [“calcium paradox”]

•  Therefore most institution include a small amount of

calcium in crystalloid cardioplegia (1mM/L)

•  Blood cardioplegia does not need any additional calcium

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Aspartate/Glutamate
 metabolic substrate

Glucose
 metabolic substrate

Blood
 O2 carrying capacity

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 Cardioplegic Route

 antegrade (aorta)
 retrograde (coronary sinus)

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 Antegrade Cardioplegia

Advantages pitfalls
 Produces prompt  poor distribution in
arrest coronary patients unless
delivered through the vein
grafts
 poor distribution in patients
with aortic regurgitation
 risk of ostial injury from
direct perfusion (during
AVR)
 interruption of procedure
during mitral surgery

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 Retrograde Cardioplegia

 perfusion pressure < 40 mmHg

prevent perivascular haemorrhage and

oedema!

 flow rate = 200mL/min

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 Retrograde Cardioplegia

advantages pitfalls
 distribution of CP to  shunting of CP into
regions supplied by ventricular cavities via
occluded or stenosed Thebesian channels
vessels  perfusion defects
 improved especially right ventricle
subendocardial CP and posterior septal
delivery regions
 flushing of air and/or (sonicated albumin
atheromatous debris studies)
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 Anterograde and retrograde cardioplegia often
are used together.
 Anterograde cardioplegia can be used to arrest
the myocardium with additional doses given
retrograde with venting of aortic root. This
maximise distribution of cardioplegia

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REPERFUSION AFTER GLOBAL MYOCARDIAL
ISCHEMIA

 POST ISCHEMIA, THE MYOCARDIUM IS COMPOSED OF A

HETEROGENOUS POPULATION OF CELLS

• IRREVERSIBLE DAMAGED

• MINIMALLY DAMAGED

• STUNNED MYOCARDIAL CELLS

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 POOR MYOCARDIAL PROTECTION BEFORE AND DURING
CROSS CLAMP
• LARGE MASS OF IRREVERSIBLY DAMAGED CELLS
LEADING USUALLY TO PATIENT DEATH

 OPTIMAL PROTECTION
• VIABLE MYOCARDIUM AND SURVIVAL WITH MINIMUM
INTERVENTIONS

 SUBOPTIMAL PROTECTION
• POPULATION OF STUNNED CELLS WHOSE FATE
DEPENDS ON REPERFUSION MANAGEMENT
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ABNORMALITIES ENCOUNTERED DURING REPERFUSION

STRUCTURAL ELECTRICAL
MYOCARDIAL OEDEMA HETEROGENOUS ACTIVITY

PLATELET DEPOSITION INCREASED AUTOMATICITY

VASCULAR INJURY
VASCULAR COMPRESSION
BIOCHEMICAL
ACIDOSIS
DECREASED OXYGEN
UTILIZATION

MECHANICAL DECREASED H-E-P

PRODUCTION
IMPAIRED SYSTOLIC
INCREASED
AND DIASTOLIC
CATACHOLAMINES
FUNCTION
INCREASED CELLULAR
CALCIUM
INCREASED FREE
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RADICALS
 THE RESPONSE OF MYOCARDIAL CELLS TO
UNCONTROLLED REPERFUSION DEPENDS IN LARGE PART
ON THE TIME-RELATED POINT ALONG THE PATHWAY TO
CELL DEATH THAT HAS BEEN REACHED DURING THE
PERIOD OF ISCHEMIA

 THE CRITICAL POINT AT WHICH THE ‘EXPLOSIVE

CELLULAR RESPONSE’ TO UNCONTROLLED PERFUSION IS
SEEN CANNOT BE DEFINED

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 MYOCARDIAL RESPONSE TO REPERFUSION
 MYOCARDIAL STUNNING
 REPERFUSION ARRHYTHMIAS
• VENTRICULAR TACHYCARDIA
• VENTRICULAR FIBRILLATION
 STONE HEART
• HARD AND FIBRILLATING HEART
• MAY INVOLVE ONLY SOME REGIONS OF THE HEART,
TYPICALLY THE BASILAR PORTION OF THE LEFT
VENTRICLE AND THE SUBENDOCARDIUM
• INDICATES USUALLY THAT THE HEART HAS REACHED
THE POINT OF ‘NO-RETURN’, THOUGH NOT
NECESSARILY SO. 47
 ENDOTHELIAL CELL DAMAGE DUE TO
REPERFUSION

 SWELLING OF ENDOTHELIAL CELLS, AGGREGATION OF

NEUTROPHILS AND PLATELET PLUGS CAUSE
MICROVASCULAR OBSTRUCTION
 ADDITIONALLY, MYOCARDIAL OEDEMA CAN ALSO
COMPRESS THE MICROVASCULATURE LEADING TO
INHOMOGENEOUS REPERFUSION, OR SOMETIMES, THE
‘NO-REFLOW’ PHENOMENON

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 MOLECULAR BASIS OF REPERFUSION
RESPONSE
 INFLUX OF CALCIUM INTO MYOCYTES, ESPECIALLY
ACCUMULATION IN MITOCHONDRIA
 RELEASE OF COMPLEMENT FRAGMENTS SUCH AS C5a FROM
ISCHEMIC MYOCARDIUM

• CHEMOTACTIC FOR NEUTROPHILS, WHICH

 PLUG MYOCARDIAL CAPILLARIES
 RELEASE LARGE AMOUNT OF OXYGEN DERIVED FREE
RADICALS
 RELEASE ARACHIDONIC ACID METABOLITES WHICH
CAUSE ENDOTHELIAL INJURY, PLATELET AGGREGATION
AND VASOCONSTRICTION
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 Free-radical Reperfusion Injury

 characterised by abnormal myocardial oxidative

metabolism

 mediated by the interaction of cyto-toxic oxygen free

radicals, endothelial factors, and neutrophils

 oxidising sarcolemmal phospholipids, and disrupting

membrane integrity (lipid peroxidation)

 delayed myocardial metabolic recovery

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 Therapies
 Physiological

• superoxide dismutase

• catalase

• nitric oxide

 Pharmacological

• mannitol

• allopurinol

• antioxidants
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 CONTROLLED REPERFUSION

 MINIMIZES THE PERSISTENCE OF MYOCARDIAL STUNNING

INTO THE POST-CPB PERIOD

 PROVIDES FOR OPTIMAL RECOVERY OF FUNCTION OF

REVERSIBLY DAMAGED MYOCARDIUM

 RESUSCITATES MYOCYTES THAT WOULD OTHERWISE

HAVE UNDERGONE NECROSIS

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 CONTROLLED REPERFUSION CONSISTS OF THE
FOLLOWING:

 MAINTINING ELECTROMECHANICAL QUIESCENCE DURING THE

FIRST 3 – 5 MINS. OF REPERFUSION
• PERMITS MORE RAPID REPLETION OF MYOCARDIAL ENERGY
CHARGE
• MINIMIZES REGIONAL HETEROGENECITY OF FLOW
• MINIMIZES MYOCARDIAL ENERGY EXPENDITURE TILL
RECOVERY HAS BEEN ESTABLISHED
• MINIMIZES INTRACELLULAR ACCUMULATION OF CALCIUM

 LARGE BUFFERING CAPACITY OF REPERFUSATE TO COMBAT

ACCUMULATED ACIDOSIS
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 MINIMIZING DAMAGE BY OXYGEN-DERIVED FREE RADICALS

 MAINTAINING LOW CALCIUM IN THE INITIAL PERFUSATE TO

PREVENT INTRACELLULAR ACCUMULATION OF CALCIUM

 SUBTRATE ENHANCEMENT OF THE REPERFUSATE FOR

REPLETION OF ENERGY CHARGE

 MAINTAINING LOW PERFUSION PRESSURES AROUND 30 –

40 mmHg DURING THE FIRST COUPLE OF MINUTES OF
REPERFUSION TO MINIMIZE ENDOTHELIAL CELL DAMAGE
AND SWELLING
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 SUGGESTED STRATEGIES FOR CONTROLLED
REPERFUSION
 USING BLOOD AS THE REPERFUSATE INSTEAD OF
CRYSTALLOID

• RBCs CONTAIN ABUNDANT FREE RADICAL SCAVENGERS

• BUFFERING CAPACITY OF BLOOD PROTEINS

 SUBSTRATE ENHANCEMENT s/a GLUTAMATE OR L-ASPARTATE

 BUFFERING AGENTS SUCH AS HYDROXYMETHYAL

AMINOMETHANE AND HISTIDINE

 LOW CALCIUM CONTENT 55

 ENOUGH POTASSIUM CONTENT TO MAINTAIN
ELECTROMECHANICAL QUIESCENCE, USUALLY 10 – 20
mEq/L

 OPTIMUM PERFUSION PRESSURE OF THE REPERFUSATE

 MAINTAINING TEMPERATURE OF REPERFUSATE BETWEEN

35 – 37 DEG. CENT.

 CONTINUING CONTROLLED REPERFUSION TILL THE HEART

IS BEATING FORCEFULLY, PREFERABLY IN SINUS RHYTHM

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Thank you!

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