antonio maria calafiore choices and possibilities to optimise myocardial protection during ischemic...
TRANSCRIPT
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.
Ischemia/reperfusion injury
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.
Ischemia/reperfusion 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.
Ischemia/reperfusion injury
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..
Ischemia/reperfusion injury
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.
Ischemia/reperfusion injury
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.
Ischemia/reperfusion injury
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.
Depolarized cardiac arrest
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. .
Depolarized cardiac arrest
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.
Depolarized cardiac arrest
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..
Depolarized cardiac arrest
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.
Cardioplegic solutions
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.
Cardioplegic solutions
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.
Cardioplegic solutions
0
2
4
6
8
10
12
37 °C 32 °C 10 °C
BeatingworkingArrest
Myo
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ial
oxy
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up
take
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0 m
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Myo
card
ial
oxy
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up
take
mL
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0 m
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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.
Cardioplegic solutions
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.
Cardioplegic solutions
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
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.
Route of administration
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.
Cardioplegic strategy
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. .
Cardioplegic strategy
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
Intermittent Antegrade Intermittent Antegrade Warm Blood CardioplegiaWarm Blood Cardioplegia
Doses following the first one are administered after each anastomoses during coronary surgery and after
15 minutes during non coronary surgery.
Intermittent Antegrade Intermittent Antegrade Warm Blood CardioplegiaWarm Blood Cardioplegia
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).
Intermittent Antegrade Intermittent Antegrade Warm Blood CardioplegiaWarm Blood Cardioplegia
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.
Intermittent Antegrade Intermittent Antegrade Warm Blood CardioplegiaWarm Blood Cardioplegia
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.
Intermittent Antegrade Intermittent Antegrade Warm Blood CardioplegiaWarm Blood Cardioplegia
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.
Cardioplegic strategy
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.
Cardioplegic strategy
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..
Cardioplegic strategy
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..
Cardioplegic strategy
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.
Cardioplegic strategy
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
Cu
m S
urv
iva
l
1,00
,95
,90
,85
,80
,75
,70
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
96847260483624120
Cu
m S
urv
iva
l1,00
,95
,90
,85
,80
,75
,70
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