Myocardial Protection

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"MYOCARDIAL PROTECTION"
Refers to strategies and methodologies
used either to attenuate or to prevent
postischemic myocardial dysfunction that
occurs during and after heart surgery.


Pre-CPB hemodynamic stability
Cardioplegic techniques
Success & adequacy of surgical repair
Separation from CPB
Hemodynamic stability in early postop.
Preexisting systemic & myocardial disease
Multiple factors:
PREOPERATIVE FACTORS
INTRAOPERATIVE FACTORS
POSTOPERATIVE FACTORS

Preoperative factors
Adult Vs pediatric
CAD Vs Valv HD
Preop hemodyn stability
Ischemia/ infarction
Arrhythmias, hypotension

Intraoperative factors
Anaesthetic
Hypovolemia
LV dysfn
Arrhythmias, tachy, HT
Inadeq ventilation
Direct manipulation
MIDCAB, OPCAB

Postoperative factors:
Adequate ventilation
Avoid vent distension
Avoid vasospasm
Maintain hemodynamics
Control bleeding
Maintain CBF


15-20 mins following
normothermic ischemia:

Total diastolic arrest from cell membrane
depolarisation
Myocardial contracture stone heart
Vacuolization of SR, mitochondria
Release of lysosomal enzymes
Uncoupling of oxidation and respiration
Sequester calcium/expel hydrogen
Depletion of ATP < 50% of
Normal Level-
irreversible lethal cell injury
glycolysis is blocked
increasing cellular acidity
protein denaturation
structural, enzymatic, nuclear
changes



Hibernating myocardium
Moderate and persistent reduction in
myocardial blood flow cause diminished
regional contraction (non-contractile)

Metabolic processes remain intact (viable)

Decrease in the magnitude of the pulse of
calcium involved in the excitation-contraction
process
(inadequate calcium levels in the cytsol during
each heart beat)


Stunned myocardium
Severe reduction in myocardial blood flow

Function of the myocardium remains
impaired (stunned) for a certain period
despite reestablishment of flow

But full recovery is expected
Process occurs over a period of 1-2 weeks

Contractile proteins recover if the myocyte is
reperfused before irreversible damage
Myocardial injury..factors
Ischemia
Ventricular distension
Tachycardia
Hypertension / hypotension
Fall in DPTI:TTI ratio
Ventricular hypertrophy
Reperfusion
Pharmacological measures
Hypothermia and potassium infusions
the cornerstone of myocardial protection
during on-pump heart surgery,

Many other cardioprotective techniques
and methodologies available.

The ideal cardioprotective technique,
solution, and/or method of administration
has yet to be found.
Myocardial O
2
demand:
75%
50%
10%
Non cardioplegic techniques
INTERMITTENT AoXCl + VF +
MODERATE HYPOTHERMIC
PERFUSION (30C TO 32C)
Quiet field (during ventricular fibrillation)
Avoids the profound metabolic changes that occur
with more prolonged periods of ischemia.
Duration of fibrillation till completion of distals
Heart defib, proximals using an aortic partial clamp

In 1992, Bonchek et al- 3000 pts of CABG
Elective operative mortality of rate 0.5%, an
urgent mortality rate of 1.7%, and an
emergency rate of 2.3%.
Inotropic support was needed in only 6.6%
1% required IABP.

In 2002, Raco et al-
800 pts CABG
Mortality- 0.6%, 3.1%, 5.6% in elective,
urgent, emergent groups.

Intermittent AoXCl is a safe technique both
in elective and nonelective pts when
performed by an exp surgeon.

SYSTEMIC HYPOTHERMIA AND
ELECTIVE FIBRILLATORY ARREST
Systemic hypothermia (25-28C)
Elective fibrillatory arrest
Maintenance of perf pres bet 80-100 mmHg
Surgical field may be obscured by blood
during revascularization

In 1984, Atkins et al reported a low
incidence of perioperative infarction
(1.8 %) and a low hospital mortality
rate (0.4%) in 500 consecutive
patients using this technique.

CONTINOUS CORONARY
PERFUSION
Continous blood perfusion of empty beating heart
Aortic root/ ostial infusion
Used in OPCAB
Unsafe for open heart
Continous retro + AoXCl- open heart

CARDIOPLEGIC
TECHNIQUES
Cardioplegic solutions
Crystalloid cardioplegia
Blood cardioplegia
Cardioplegic principles
Immediate arrest..rapid infusion for 2mins
Hypothermia
Substratesglucose/aa/adenosine
Maintain pH..bicarb/ THAM/ blood
Free radical damage
mannitol/deferoxamine/LDBC/allopurinol
Edema ..mannitol/glucose/albumin
Cardioplegic delivery
Antegrade route
Advantage: immediate cardioplegia
Problems:
Impaired perfusion beyond obstruction
AVI..also in mitral surgery as aortic
root distorted on atrial retraction
Hypertrophied heart



Retrograde route
Advantage:
Better septal cooling
Cardioplegic solution perfuse beyond stenosis
Problems:
RV not adequately protected
Risk of coronary sinus perforation / myocardial
hemorrage / edema
Infusion pressure kept < 50mmHg
Antegrade + retrograde
More prompt arrest
Better disribution of solution
Hypothermia
Basal metabolism
in the absence of myocardial
contraction, the myocyte still
requires oxygen for basic house
keeping functions

This basal cost can be further
reduced with hypothermia





Hypothermia
Oxygen Demand reduction

Normothermic Arrest (37
o
C) 1mL/100g/min 90%
Hypothermic Arrest (22
o
C) 0.30 mL/100g/min 97%
Hypothermic Arrest (10
o
C) 0.14 mL/100g/min ~ 97%





Hypothermia
Decreased metabolic rate
Ischemia: intracellular pH ..
nonionised : ionised substrate ratio
NI substrate escapeout of cell.
Hypothermia NI:I ratio
Semiliquid to semisolid memebrane..
calcium influx.
glutamate release in brain ca sequest.
Hypothermia
Total extracorporeal circulation
Surface cooling
Surface cooling with partial CPB
Deep hypothermic total circulatory arrest
Low-flow, profoundly hypothermic
perfusion

All cooling for 30mins before starting CPB
Problems of hypothermia
DHCA can cause seizures, stroke, change
in mental status and muscle tone, post
pump choreoathetosis.
Neocortex, hippocampus, striatum
Loss of cerebral autoregulation<15C
Coagulopathy,acidosis,enzyme dysfunction
Along with alkalosis, shift Bohrs oxy-
dissociation curve to left.

In a multicenter trial- continuous warm
blood cardioplegia Vs intermittent cold blood
cardioplegia.
Similar myocardial preservation (mortality,
postoperative incidence of myocardial
infarction, need for intraaortic balloon
counterpulsation).

Rewarming
<10-12C gradient between venous blood and
water temperature.also between arterial blood
entering and core temperature.
CPB withdrawn when bladder temp is 37C
Prevent hyperthermia
Esophageal/PAC temp not reliable
Alpha stat method to correct pH. probably
better neuro. outcome in profound hypothermia
Reperfusion
Cell damage following ischaemia
is biphasic;
injury being initiated during
ischaemia
exacerbated during reperfusion

Components:
Intracell Ca2+ overload during isch & reper
Oxidative stress induced by reactive oxygen
species (ROS)
Ischemia endogenous antioxidant defense
Loss of cell memb integrity

conjugated dienes are chemical
signatures of oxygen free-radical lipid
peroxidation
Romaschin AD, Rebeyka I, Wilson GJ, et al.
J Mol Cell Cardiol 1987;19:289-293
free radicals are generated within 10
seconds of reperfusion after ischaemia
Zweier JL, Flaherty JT, Weisfeldt ML.
Proc Natl Acad Sci USA 1987;84:1404-1408


Reduce reperfusion injury
Reduce ionic calcium conc. in reperfusate
1.0 meq/Lchelate with CPD
pH of 7.6-7.8
Reperfusate pressure 50 mm Hg &
osmolality of 350 mOsm..reduce edema
Maintaining potassium arrest
Infusing at 37C
Calcium regulation
Hallmark of reperfusion is Ca uptake
Post ischemic failure of normal
sequestration by SR / contractile app.
Calcium phosphate crystal deposition
in mitochondrial matrix
Damage to respiratory chain and
failure of ATP production
Other measures:
Antioxidants- Vit E, glutathione
OFR scavengers-SOD, catalase,
peroxidase, allopurinol, mannitol,
CoQ10, deferoxamine mesylate
WBC filters

BLOOD CP LEUCOCYTE FILTRATION
Myocardial ischemia and reperfusion- activation
of neutrophils
Benefit of filtration in:
1. patients undergoing emergency CABG
2. prolonged crossclamping,
3. depressed ejection fraction,
4. heart transplantation.

At least 90% of leucocytes must be
removed to attenuate reperfusion injury
markedly.
Leucocyte depletion should be maintained
for 510 min after the start of initial
reperfusion prior to aortic clamp release.
Filters remove more than 90% of WBCs
CONTROLLED REPERFUSION

Reduce reperfusion inj after ac coro occlusion.
AoXCl release- blood CP given at 50 ml/min per graft
with a perfusion pressure 50 mmHg for 20 min into
the grafts only.
Cannulation of a side branch of the vein graft.
Multicenter trial, the results were evaluated in 156 pts
with acute coronary occlusion- reduced overall
mortality from 8.7% to 3.9%.

Complications of
protective strategies
RV dysfunction..rewarming / poor
distributiontopical cooling
Coronary ostial stenosis..soft tipped
cannula/leakage around cannula
Endothelial damage to vein graft from
hyperkalemic crystalloid cardioplegic
Coronary sinus injury
Infusion pressure <50mmHg through sinus
Energy depleted heart
Cardiogenic shock/ unstable angina
Preop stabilisation with IABP /
pharmacological support / MechVent
Prompt amino acid enriched warm
blood cardioplegia
Followed by cold cardioplegia
Both antegrade + retrograde flow

PROTECTION STRATEGIES
UNDER INVESTIGATION
Ischemic preconditioning
Brief episode of ischemia slows the rate of
ATP depletion during subsequent ischemic
episodes.
(1) slowing of ATP depletion, or
(2) limitation of catabolite accumulation
during the terminal episode of ischemia.
Depletion of ATP could be slowed by a
reduction in energy demand during
ischemia, or by an increase in the net
availability of high-energy phosphates.
Brief periods of ischemia are known to cause
prolonged contractile dysfunction, the so called
"stunned myocardium."
preconditioning could effectively stun the
myocardium .reduce ATP utilization during
the early phase of ischemia.
Intermittent ischemia results in degradation of
larger molecules breakdown products, lactate,
H', NH3, inorganic phosphate, etc., are then
washed out upon reperfusion.limit catabolite
accumulation during the occlusion.
Alternatively, a reduced energy demand might
drive anaerobic glycolysis to a lesser extent.
Enzyme xanthine oxidase contributes to myocardial cell
death by generating superoxide anions

Preconditioning: adenine nucleotide content of the
myocardium. limit hypoxanthine accumulation and
superoxide production.

Myocardial lipid peroxidation, estimated as MDA
formation, is common during intermittent ischemia-
reperfusion.

Huizer et al measured urate production by human
hearts with CADnet production of urate increased in
ischemia.

A reduction in catabolite accumulation
could limit the osmotic load that occurs
during ischemia.
Another possibility is that preconditioning
could limit accumulation of chemotactic
factors that attract neutrophils to
ischemic/reperfused tissue.
Preconditioning can only delay cell death
ineff if sustained ischemic insult > 3 hrs
Preconditioning failed to protect the mid
and subepicardial myocardium
Second phase of protection req 24 hours to
appear & sustained for up to 72 hours.
Second window of protection (SWOP), late
phase preconditioning, or delayed precond.
Unlike classical preconditioning, which
protects only against infarction, the late
phase protects against both infarction and
myocardial stunning

adenosine subtype 1 (A1) receptor
ischemic stimulus
G protein and protein kinase C (PKC).
ATPregulated potassium channel (KATP).
protective effect
IP involves a complex cascade of intracellular events
amplified
effector
?
Anesthetic preconditioning
A safer and simpler alternative to IP is
pharmacologic intervention by inhalation
anesthetics
APC shares the same mechanism of action as
IP
The effect of inhalation anesthetics was
present 30 minutes after discontinuation
window of protection;
During this time, which can last for 1 to 2
hours, there is an acute memory phase of
preconditioning.
Anesthetic preconditioning
Isoflurane was administered in the
precardiopulmonary bypass (CPB) period
The higher cardiac index in the isoflurane
group was associated with a lesser degree
of ST segment changes than in the control
group.
There was no significant difference between
the 2 groups in the incidence of reperfusion
arrhythmias
Dogs were randomly assigned to receive 2 ml drug vehicle (50% polyethylene
glycol in ethyl alcohol; control experiments) or glyburide (0.05 mg/kg sup -1
administered intravenously) in the presence or absence of 1 MAC (end-tidal)
isoflurane in four experimental groups
Sevoflurane decreases the inflammatory
response after CPB, as measured by the
release of IL-6, CD11b/CD18, and TNF-.

Total intravenous anesthesia was provided
for both study and control groups by
infusion of propofol,fentanyl, and
midazolam. Sevoflurane 2% was added to
the cardioplegia solution in the experimental
group.

Myocardial function after CPB, as assessed
by RWMA and LVSVI, was also improved
1. Normothermic global ischemia lasting 15 min
significantly augmented the adhesion of PMNs to the
coronary endothelium.
2. This effect could be completely blocked by halothane,
isoflurane, or sevoflurane continuously administered
before and during ischemia and reperfusion at 1 and 2
MAC each.
3. Isoflurane given under control conditions without
ischemia had no effect on basal PMN adhesion.
4. Administration of sevoflurane just at the onset of
reperfusion was as effective as continuous application.
5. Suppression of the postischemic-enhanced PMN
adhesion by the volatile anesthetics was independent of
their vasodilating potency.
6. The volatile anesthetics did not influence the severity of
ischemic challenge, as judged by myocardial lactate
release.
Adenosine
Coronary vasodilatation
Immediate arrest
Ischemic preconditioning
Retards ischemia-induced ATP deple, delays onset of
ischemic contracture, atten myo stun, infarct size
lipid peroxidation, SOD, catalase, glutathione
peroxidase, glutath reductase.

Sodium/Hydrogen
Exchange Inhibition
Amiloride, cariporide, eniporide, zoniporide
Ejection fraction was greater, the resolution of
regional left ventricular wall motion
abnormalities tended to occur earlier, and the
cumulative release of CK-MB was less.

opioids
Hibernating animals use only '10% of their
normal, active energy expenditure.
Hibernation is a process mediated by cyclical
variation in endogenous opiate compounds.
-opiate receptor in particular is responsible.
Hibernation reversed by opiate antagonists.
Biological mechanism duplicated in humans,
thereby inducing a profound state of energy
conservation.
Drugs with -opiate activity confer myocardial
protection, which is additive to cardioplegia.
MYOCARD PROTECTION- OPCAB

Short-acting beta blocker esmolol
Cariporide and aprotinin- associated
with a marked attenuation of stunning.

Conclusion:
Ideal solution, technique, or delivery
method has yet to be identified
Complexity of ischemia/reperfusion injury,
Ideal protection is no longer limited to OT
Need to develop new therapeutic strategies
to protect the heart

Thank you
Dr. Narender to continue.
THANK YOU!
Pediatric CPB
Immature handling of calcium
Immature myocardium can use carbo/
aa/ketones/MCFA/LCFA.
Hypoglycemia / hemodilution
Resistant to ischemia :
1. increased gycolytic cabability
2. decreased 5nucleotidase..increased ATP
SUPPLY. DEMAND


100





0

.. .LA or PA wedge
Ao
TTI
DPTI
Buckberg 1972
DPTI: diastolic pressure time index
TTI: tension time index
Protection strategies
Design of cardioplegic solution
Temperature
Electromechanical work state
pH
Metabolic substrates/additives
Protection techniques
Systemic hypothermia with VF
Ischemic arrest with hypothermia
Continuous coronary perfusion
Chemical cardioplegia
Coming off bypass
Problems:
Systemic rewarming and aortic
unclampingtachy/fever/ increased SVR /
rise in circulating catecholamines
More compliant heart..greater LVED
Acute withdrawal of CCB/BB
Coronary vasospasm
Elevated O
2
req. of recovering myocardium

Solutions:
Reinstitute bypass in ventricular distension
Optimise hemodynamic parameters
High dose ionotropes better avoided
Adequate preload
Afterload reduction or IABP
Bleeding corrected
Failure to achieve separation.IABP/LVAD

Cessation of Myocardial
Blood Flow
mitochondria

cellular pO
2
< 5mmHg
within seconds

oxidative
phosporilation stops


cytosol
anaerobic glycolysis
glycogen
glucose-6-phosphate
pyruvate
lactate
cellular acidosis
depletion of ATP