antonio maria calafiore choices and possibilities to optimise myocardial protection during ischemic...

Antonio Maria CALAFIORE

Choices and possibilities Choices and possibilities to optimise myocardialto optimise myocardial

protection during ischemicprotection during ischemicperiodsperiods

Technical successTechnical success and and avoidance of avoidance of intraoperative damageintraoperative damage are both the are both the

main targets of any cardiac operation. main targets of any cardiac operation. The early and late success of a cardiac The early and late success of a cardiac

procedure is related to how well the procedure is related to how well the surgeon corrected the mechanical surgeon corrected the mechanical

problem, and problem, and how carefully myocardial how carefully myocardial protection avoided secondary protection avoided secondary

dysfunctional effectsdysfunctional effects of aortic clamping of aortic clamping for technical repair.for technical repair.

Myocardial ischemiaMyocardial ischemia is characterized by is characterized by rapid rapid accumulation of protonsaccumulation of protons, ,

cessation of electron transportcessation of electron transport and and initiation of the inefficient process of initiation of the inefficient process of

anaerobic metabolismanaerobic metabolism..

Reperfusion injuryReperfusion injury is a major is a major complication characterized by complication characterized by

restoration of flow to a previously restoration of flow to a previously ischemic heart.ischemic heart.

Significant evidence now exists that the Significant evidence now exists that the primary mediators of reversible and primary mediators of reversible and

irreversible myocardial irreversible myocardial ischemia/reperfusion injury include ischemia/reperfusion injury include intracellular intracellular Ca++ overloadCa++ overload during during ischemia/reperfusion and ischemia/reperfusion and oxidative oxidative stressstress induced by reactive oxygen induced by reactive oxygen species generated at the onset of species generated at the onset of

reperfusion.reperfusion.

Ischemia/reperfusion injury

Intracellular Ca++ overloadIntracellular Ca++ overload at the onset at the onset of reperfusion is due to of reperfusion is due to restoration of restoration of intracellular pH via Na+/H+ exchangeintracellular pH via Na+/H+ exchange with consequent reversed Na+/Ca++ with consequent reversed Na+/Ca++

exchange. Reduction of free energy for exchange. Reduction of free energy for ATP hydrolysis causes reduced ATP hydrolysis causes reduced efficiency of pumps to maintain efficiency of pumps to maintain iinntracellular Ca++ homeostasis.tracellular Ca++ homeostasis.


Reactive oxygen speciesReactive oxygen species (ROS), (ROS), including superoxyde anion (Oincluding superoxyde anion (O22¯̄), ), hydrogen peroxide (Hhydrogen peroxide (H22OO22) and the ) and the

hydroxil radical (OH), are derivatives of hydroxil radical (OH), are derivatives of many biological systems and in high many biological systems and in high

concentration are associated with concentration are associated with oxidative stress and consequent oxidative stress and consequent

cardiovascular tissue injury.cardiovascular tissue injury.


Neutrophils activationNeutrophils activation and and nitroxidenitroxide ( (NONO)) are are involved in ROS production.involved in ROS production.NeutrophilsNeutrophils, activated , activated by inflammatory mediators, respond byby inflammatory mediators, respond by rolling, adhering and transmigrating rolling, adhering and transmigrating across the endothelial layer to reach theacross the endothelial layer to reach the extravascular interstitium. extravascular interstitium.


Neutrophils contain a potent arsenal Neutrophils contain a potent arsenal of proteolitic and cytotoxic of proteolitic and cytotoxic

substancessubstances. Activated neutrophils . Activated neutrophils release release hystotoxic enzymeshystotoxic enzymes such as such as

elastase, myeloperoxidase, elastase, myeloperoxidase, collagenase and others. They also collagenase and others. They also release cytokines and release cytokines and oxygen free oxygen free

radicalsradicals..


NONO can also interact with ROS to can also interact with ROS to generate various reactive nitrogen generate various reactive nitrogen

species and appears capable of both species and appears capable of both contributing and reducing injury.contributing and reducing injury.

In the absence of normal levels of its In the absence of normal levels of its cofactors, cofactors, nitric oxide sinthasenitric oxide sinthase itself itself

can generate superoxide anion.can generate superoxide anion.


Regardless of which stage is being Regardless of which stage is being addressed, addressed, current cardioprotection current cardioprotection

strategies strategies are designed to reduce are designed to reduce cellular and subcelluar ROS formation cellular and subcelluar ROS formation

and oxidative stress, and to prevent and oxidative stress, and to prevent intracellular Ca++ overload.intracellular Ca++ overload.


Cardiac arrestCardiac arrest during cardiac surgery during cardiac surgery in a flaccid diastolic state (with in a flaccid diastolic state (with reduction in myocardial oxygen reduction in myocardial oxygen

consumption as important consumption as important consequence) can be achieved by consequence) can be achieved by

targeting various points in the targeting various points in the excitation-contraction coupling excitation-contraction coupling

pathwaypathway. .

Cardioplegia

The agents used for this purpose The agents used for this purpose induce either a induce either a depolarized arrest depolarized arrest

(the membrane potential is (the membrane potential is higher than –80mV)higher than –80mV) or or a a

polarized or hyperpolarized polarized or hyperpolarized arrest arrest (the membrane potential is (the membrane potential is maintained at –80mV or at lower maintained at –80mV or at lower

levels).levels).

Cardioplegia

Cardioplegia

The most commonly used method The most commonly used method for inducing rapid diastolic arrest for inducing rapid diastolic arrest

is is moderate elevation of the moderate elevation of the extracellular [K+] (15 to 40 extracellular [K+] (15 to 40

mmol/L)mmol/L). As [K+] increases, the . As [K+] increases, the resting Em becomes resting Em becomes

progressively more depolarized. progressively more depolarized.

Depolarized cardiac arrest

As Em depolarizes to around –65 As Em depolarizes to around –65 mV ([K+] around 10 mmol/L), mV ([K+] around 10 mmol/L), the the

voltage-dependent fast Na+ voltage-dependent fast Na+ channel is inactivatedchannel is inactivated, ,

preventing the rapid Na+-induced preventing the rapid Na+-induced spike of the action potential and spike of the action potential and arresting the heart in diastole.arresting the heart in diastole.


With further increase of [K+] (around With further increase of [K+] (around 30 mmol/L), resting Em becomes 30 mmol/L), resting Em becomes –40 mV with consequent activation –40 mV with consequent activation of the slow Ca++ channel and Ca++ of the slow Ca++ channel and Ca++ overload. overload. The beneficial effects of The beneficial effects of increasing [K+] is then limited to a increasing [K+] is then limited to a

narrow windownarrow window. .


ThThee increase increase of of intracellular [Ca++]intracellular [Ca++] willwill caus causee contracture even in the contracture even in the

arrested conditionsarrested conditions and and will will contributcontributee to Ca++ overload and to Ca++ overload and

reperfusion injury. reperfusion injury. Energy-Energy-dependent transmembrane pumps dependent transmembrane pumps

remain activeremain active in an attempt to in an attempt to correct thcorrect thisis abnormal ionic gradient, abnormal ionic gradient,

further further depleting critical energy depleting critical energy supplies.supplies.


High concentration of High concentration of extracellular Mg++extracellular Mg++ can arrest alone the heart, possibly by can arrest alone the heart, possibly by

displacing Ca++ displacing Ca++ from the rapid from the rapid exchangeable sarcolemmal binding exchangeable sarcolemmal binding

sites involved in the excitation-sites involved in the excitation-contraction coupling. As concentrations contraction coupling. As concentrations

required are too high, required are too high, it is used it is used normally as an effective additive normally as an effective additive

protective agentprotective agent..


An alternative to An alternative to

depolarization is to maintain depolarization is to maintain

polarization of the Em close polarization of the Em close

to the resting Emto the resting Em. .

Polarized cardiac arrest

It can be obtainedIt can be obtained through different mechanisms.through different mechanisms.

@ @ blockage of Na+ channelsblockage of Na+ channels (procaine, (procaine, lidocaine), preventing the rapid, Na+ lidocaine), preventing the rapid, Na+ induced depolarization of the action induced depolarization of the action

potentialpotential@ @ opening of ATP-sensitive K+ channelsopening of ATP-sensitive K+ channels, ,

causing Em to be shifted towards the causing Em to be shifted towards the K+ equilibrium potential (K+ equilibrium potential (nicorandilnicorandil, ,

pinacidilpinacidil, , diazoxidediazoxide) )

Polarized cardiac arrest

Even if adverse side effects Even if adverse side effects can be anticipated, can be anticipated, K+ CPL is K+ CPL is

today the only reliable tool today the only reliable tool we have to arrest the heartwe have to arrest the heart. .

Different agents can be used Different agents can be used as additive, but we are far as additive, but we are far from clinical utilization of from clinical utilization of

polarizing or hyperpolarizing polarizing or hyperpolarizing solutions.solutions.

There are two types of There are two types of crystalloid crystalloid cardioplegic solutionscardioplegic solutions: the : the intracellularintracellular (absent or low concentration of Na+ and (absent or low concentration of Na+ and

Ca++) and the Ca++) and the extracellularextracellular (high (high concentration of Na+, Ca++ and Mg++) concentration of Na+, Ca++ and Mg++) one. [K+] is between 10 and 40 mEq/L, one. [K+] is between 10 and 40 mEq/L,

and both contains bicarbonate for and both contains bicarbonate for buffering. buffering. HypothermiaHypothermia is a fundamental is a fundamental component of the cardioplegic strategy.component of the cardioplegic strategy.

Cardioplegic solutions

Blood cardioplegiaBlood cardioplegia can be used with a can be used with a variety of different dilutions, variety of different dilutions,

temperature, components and temperature, components and delivered, as the crystalloid one, with delivered, as the crystalloid one, with

different routes.different routes.In the last decade, with the introduction In the last decade, with the introduction

of of warm blood cardioplegiawarm blood cardioplegia, many , many publications suggested the following publications suggested the following

trends. trends.


The assumption that The assumption that continuous continuous oxygenated perfusion of the oxygenated perfusion of the

normothermically arrested heartnormothermically arrested heart enables the perfect matching of energy enables the perfect matching of energy demand and supply so that ischemia is demand and supply so that ischemia is

eliminated is probably an eliminated is probably an oversemplification. Some metabolic oversemplification. Some metabolic

damage can occur, probably due to loss damage can occur, probably due to loss of contraction and consequent of contraction and consequent

interruption of lymphatic flow and interruption of lymphatic flow and edema.edema.


The assumption that The assumption that hyopothermia hyopothermia gives superior protectiongives superior protection is is discussed. Randomized trial discussed. Randomized trial

showed lower showed lower TnI releaseTnI release (lower (lower myocardial damage) myocardial damage) in intermittent in intermittent

lukewarm or warm blood lukewarm or warm blood cardioplegia (CPL) if compared with cardioplegia (CPL) if compared with

cold blood CPL. cold blood CPL.


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The initially attractive concept of The initially attractive concept of aerobic arrest inherent in aerobic arrest inherent in continuous oxygenated continuous oxygenated

perfusion has been somewhat perfusion has been somewhat diverted in an diverted in an intermittent pattern intermittent pattern

of CPL delivery. of CPL delivery.


A A 3131P-nuclear magnetic resonance study of intermittent warm blood P-nuclear magnetic resonance study of intermittent warm blood

Cardioplegia.Cardioplegia. Tian e coll.Tian e coll. J Thorac Cardiovasc Surg 1995;109:1155-63. J Thorac Cardiovasc Surg 1995;109:1155-63.

This is not an homogeneous entity, This is not an homogeneous entity, as as ischemic ischemic intervalintervalss are still not are still not clearly stated. It is very likely that clearly stated. It is very likely that

13-15 min of ischemia in such 13-15 min of ischemia in such conditions are well tolerated, but conditions are well tolerated, but

temperature of the perfusate, temperature of the perfusate, duration of the reperfusion phases duration of the reperfusion phases

are part of the equation.are part of the equation.


Retrograde CPL administrationRetrograde CPL administration is very is very popular among the cardiac surgeons. popular among the cardiac surgeons.

However, there are evidences that However, there are evidences that retroperfusion of the heart is less retroperfusion of the heart is less effective than the antegradeeffective than the antegrade. The . The

particular anatomy of the coronary particular anatomy of the coronary veins is the main reason, as its veins is the main reason, as its

ununpredictibility avoids an uniform CPL predictibility avoids an uniform CPL distribution. This was demonstrated in distribution. This was demonstrated in

the animals and in the humans.the animals and in the humans.

Route of administration


Tian et al.Tian et al. Retrograde cardioplegia. Retrograde cardioplegia. J Thorac Cardiovasc Surg 2003;125:872-880J Thorac Cardiovasc Surg 2003;125:872-880

Nevertheless, clinical results are Nevertheless, clinical results are globally satisfying, but globally satisfying, but

retrograde CPL delivery has to be retrograde CPL delivery has to be used in conjunction with the used in conjunction with the antegrade route to obtain an antegrade route to obtain an effective cardioprotection.effective cardioprotection.


From what previously described, From what previously described, the best the best way to avoid ischemia/reperfusion way to avoid ischemia/reperfusion injury is to avoid ischemiainjury is to avoid ischemia. This is . This is

unrealistic, as: unrealistic, as: 1)1) it is not possible to it is not possible to reproduce the reproduce the

same conditions of working heartsame conditions of working heart while while operating on the heart, except in some operating on the heart, except in some

sporadic cases sporadic cases 2) a2) a compromise compromise is needed between the is needed between the

necessity of protecting the heart and necessity of protecting the heart and the quality of the surgical treatment.the quality of the surgical treatment.

Cardioplegic strategy

Since 1991 we heve been Since 1991 we heve been using a protocol for using a protocol for

intermittent antegrade warm intermittent antegrade warm blood cardioplegiablood cardioplegia in all the in all the

patients we are operated on. patients we are operated on.


The The cardioplegia temperaturecardioplegia temperature is the same is the same of the perfusateof the perfusate ( (isothermic isothermic

cardioplegiacardioplegia)). Today there is no . Today there is no conceptual evidence against the use of conceptual evidence against the use of a temperature between 32a temperature between 32°° and 37°C. and 37°C.

But, according to the surgeon’s But, according to the surgeon’s preference, preference, the perfusate temperature the perfusate temperature can be lowered as much as can be lowered as much as necessary, necessary,

as in case of DHCAas in case of DHCA. .


Blood is taken directly from the oxygenator and,

by means of a 1/4 inch tubing and a roller pump,

is injected into the aortic root

or coronary ostia.

The tubing is connected to a

syringe pump that delivers K+

(1 ml=2mEq). A bubble trap is

positioned before the aortic root.

Intermittent Antegrade Intermittent Antegrade Warm Blood CardioplegiaWarm Blood Cardioplegia

Flow rate

Dose Duration Roller pump Syringe pump [K+]

(min) (ml/min) (ml/h) (mEq/l)

1st 2 300 push 2 ml than 150 18-20

2nd 2 200 60 10

3th 2 200 60 10

4th 2 200 60 10

5th 2 200 40 6.7

6th 2 200 40 6.7

Infusion protocol


Doses following the first one are administered after each anastomoses during coronary surgery and after

15 minutes during non coronary surgery.


To prevent the opening of the Ca++ channels, we added to the previous

protocol the injection of 1 g of Mg++ sulphate

at the end of the 1st dose.If necessary, Mg++ sulphate can be further administered at lower dose

(200 mg).


In presence of In presence of waveform contractionwaveform contraction K+ K+ administration has not to be increased, administration has not to be increased, butbut reduced reduced, and Mg++ injected (Em is , and Mg++ injected (Em is higher than –40 mV with subsequent higher than –40 mV with subsequent opening of the slow Ca++-channels).opening of the slow Ca++-channels).

In presence of In presence of well organized well organized contractionscontractions a dose of CPL with higher a dose of CPL with higher

[K+] has to be repeated.[K+] has to be repeated.


This protocol is used everytime the This protocol is used everytime the ascending aorta is not openedascending aorta is not opened: :

coronary artery bypass grafting, mitral coronary artery bypass grafting, mitral valve surgery, surgery for LV scars, valve surgery, surgery for LV scars,

and so on. According to the surgeon’s and so on. According to the surgeon’s preference, ischemic interval can be preference, ischemic interval can be

shortened and/or reperfusion time can shortened and/or reperfusion time can be lengthened. be lengthened. This because of the This because of the flexibilityflexibility of the of the

technique. technique.


In In particular conditionsparticular conditions, as when , as when the ascending aorta is opened, the ascending aorta is opened,

when there is a mild aortic when there is a mild aortic regurgitation or in selected regurgitation or in selected patients with low ejection patients with low ejection

fraction and/or dilated fraction and/or dilated cardiomyopathy, the cardiomyopathy, the retrograde retrograde

routeroute can be added. can be added.


Cardioplegia is always blood and K+, Cardioplegia is always blood and K+, supplemented, when necessary, with supplemented, when necessary, with

Mg++.Mg++.CPL is administered antegrade and CPL is administered antegrade and retrograderetrograde, antegrade (following the , antegrade (following the

usual protocol) at least every 30 usual protocol) at least every 30 minutes, retrograde as long as possibleminutes, retrograde as long as possible

at a fixed rate (at a fixed rate (150 ml/min150 ml/min)), in , in relationship with the surgical relationship with the surgical

necessities.necessities.


In the last part of the In the last part of the procedure, procedure, retrograde retrograde

administrationadministration can deliver can deliver only blood without K+ to only blood without K+ to facilitate intracellular K+ facilitate intracellular K+

washoutwashout and to re-establish and to re-establish energy storesenergy stores..


Purpose of any strategy Purpose of any strategy we use is to we use is to minimize minimize

TnI releaseTnI release, even if with , even if with long cross clamping long cross clamping

timestimes..


We must be aware that also We must be aware that also minor damagesminor damages to the heart to the heart

can produce, in the midterm, can produce, in the midterm, unsatisfying results, unsatisfying results,

compromising what was compromising what was done in the surgical theatre. done in the surgical theatre.


cold blood CPL 266 (9.2%)

IAWBC 2171 (74.8%)

cold cristalloid CPL 464 (16.0%)

January 1982 – December 2001CABG n = 2901

8y survival

months

96847260483624120

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,90

,85

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CKMB 19 UI/L

CKMB 20- 38 UI/L

CKMB 39- 57 UI/L

CKMB 58 UI/L

88.01.1

90.11.5

84.81.6

p 0.0012

91.41.3

8y event free survival

months

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CKMB 19 UI/L

CKMB 20- 38 UI/L

CKMB 39- 57 UI/L

CKMB 58 UI/L

85.91.1

86.41.6

79.61.9

p < 0.0001

88.71.5

0

10

20

30

40

50

60

cold cristalloid cold blood IAWBCMB 19 MB 20-38 MB 39-57 MB 58

%

@ @ simplesimple. If not always “the simpler . If not always “the simpler the better” is true, surely “the more the better” is true, surely “the more

complicated the better” is never complicated the better” is never true.true.

@ @ inexpensiveinexpensive. The circuit is . The circuit is represented by a ¼ inch tubing and represented by a ¼ inch tubing and

a connector with a conventional a connector with a conventional syringe pump. The additives are syringe pump. The additives are

only K+ and Mg++. only K+ and Mg++.

Advantages

@ @ flexibleflexible. This protocol can be . This protocol can be modified during surgery, as duration modified during surgery, as duration

of ischemic intervals and of of ischemic intervals and of reperfusion can be lengthened, and reperfusion can be lengthened, and

[K+] can be lowered.[K+] can be lowered.@ @ efficient. efficient. Clinical studies, from our Clinical studies, from our

group and from different teams, group and from different teams, have demonstrated that contractile have demonstrated that contractile function is preserved, especially in function is preserved, especially in

patients with low EF and in long patients with low EF and in long lasting procedures.lasting procedures.

Advantages

Mycardial protection is a Mycardial protection is a global stratgeyglobal stratgey that has the goal that has the goal to reduce the to reduce the

ischemia/perfusion injuryischemia/perfusion injury. This target . This target can be reached in different ways, but can be reached in different ways, but it it

is as important as the surgical is as important as the surgical procedure itselfprocedure itself. .

The choice of the proper strategy is today The choice of the proper strategy is today crucial, as the quality of the patients is crucial, as the quality of the patients is

rapidly worsening.rapidly worsening.

Conclusion

antonio maria calafiore choices and possibilities to optimise myocardial protection during ischemic...

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