Cardioplegia

1. Cardioplegia session
-Dr Raja Lahiri

2. Topics
 Alternative arresting agents &
additives
 Crystalloid vs Blood cardioplegia
 Potential newer technology

5. Adenosine receptors
 Four types of adenosine receptors: A1, A2a, A2b, A3
 Activation of adenosine A 1 receptors leads to:
◦ inhibition of cyclic AMP production
◦ inhibition of the slow calcium channel
◦ opening of an adenosine-activated ATPsensitive potassium (K
ATP ) channel
 This leads to hyperpolarization, which delays conduction
through the AV node and slows the ventricular response to
atrial tachycardia.
 It also causes endothelial-dependent relaxation of smooth
muscle as is found inside the artery walls.
 Activation of A2A receptors produces a constellation of
responses that in general can be classified as anti-
inflammatory
 Pretreatment with adenosine confers a cardioprotective effect
during ischemia and can inhibit the inflammatory responses
initiated by ischemia and reperfusion

7. Minute work & Oxygen demand
 Minute work = Heart rate x Stroke volume x Pressure
 However, minute work is not the direct determinant of oxygen
consumption
 The primary determinant of oxygen demand is the wall
tension or stress developed in each cardiac cycle.
 The energetic cost of ejecting blood from the ventricular
chamber is approximately 20 to 30% of that required for
isovolumic contraction.
 An increase in afterload requires greater energy than an
increase in volume ejected.
 Oxygen consumption is also increased as the heart dilates
and begins ejection from a greater diastolic volume.
 Cardiac efficiency = Work/MVO2

8. Alternative arresting agents &
Additives
 Beta Blockers:
◦ As the ascending aorta is clamped, the non-
exocytotic release of norepinephrine from the
cardiac sympathetic nerves acts on β-adrenergic
receptors on the outer surface of the sarcolemma,
causing an increase in cAMPdependent protein
kinase activity, phosphorylation of the calcium
release channels, and increased Ca2+ influx,
resulting in increased Ca2+-dependent
contractility and rapid depletion of glycogen
stores.
◦ Early studies suggested that long-acting beta
blockers improved myocardialprotection during
ischemia but unfortunately have a prolonged
negative inotropic effect, which limits their clinical
use.

9.  Beta blockers such as propranolol have been used as
an adjunct to anesthesia to block β-adrenergic–
stimulating episodes associated with coronary
ischemia during the course of the operative procedure.
 Ultra-short-acting cardioselective beta blockers such
as landiolol and esmolol provide polarized cardiac
arrest by maintaining the membrane potential at or
near the resting membrane potential
 Esmolol has been used to enhance myocardial
protection during intermittent arrest and has been
shown to provide myocardial preservation equivalent
to or better than cold crystalloid or blood cardioplegia.
 With esmolol cardioplegia, there is a slow undulating
ventricular contraction that may decrease myocardial
edema but does not provide a quiescent operating
field

10. Adenocaine
 Adenosine-lidocaine (adenocaine)
cardioplegia provides an exciting
alternative to depolarizing cardioplegia.
 Adenosine-lidocaine cardioplegia has
been shown to provide a shorter time to
electromechanical arrest, greater
postischemic recoveries of aortic flow, a
lower coronary vascular resistance
during infusion, and greater MVO2 as
compared to St. Thomas’ Hospital
solution, while maintaining the
myocardial cell membrane potential at its
resting state

11. Agents Affecting Calcium
Transport The infusion of calcium-free cardioplegic solutions induces rapid
diastolic cardiac arrest by inhibiting excitation-coupling and
increases permeability of the sarcolemma.
 When a calcium-containing perfusate is then reinfused, during
reperfusion, there is a rapid influx of calcium into the cell, resulting
in myocardial contracture and extensive ultrastructural damage, the
“calcium paradox.”
 Calcium antagonist agents administered before ischemia have been
proposed as a possible mechanism to reduce ischemic cellular
injury.
 Calcium channel blocking agents, including verapamil, diltiazem,
and nifedipine, prevent calcium-induced calcium release in
myocardial cells and, as an adjunct to normothermic cardioplegia,
have been shown to improve postischemic systolic function.
 Calcium blockers have no effect if they are administered before
reperfusion, are temperature dependent, and have limited effect
during hypothermia.
 Because high concentrations are required for cardioprotection, their
prolonged membrane binding prevents rapid recovery, thus limiting
their clinical usefulness.

12.  Magnesium:
◦ Magnesium inhibits calcium entry into the cell by
displacing calcium from its binding sites in the
sarcolemmal membrane.
◦ It has limited use as an arresting agent because high
concentrations are required, cardiac arrest is delayed,
and postischemic functional recovery is decreased in
comparison to potassium cardioplegia.
◦ The advantages of magnesium have been shown to
be optimal when it is included with high-potassium
cardioplegia, in which it has been demonstrated to
ameliorate cytosolic, nuclear, and mitochondrial
calcium accumulation; preserve high-energy
phosphate moieties; and enhance postischemic
functional recovery.

13. Avoidance of Substrate
Depletion
 Metabolic substrates have been added
to cardioplegic solutions to enhance
anaerobic metabolism during ischemia or
to provide citric acid cycle intermediaries
to facilitate homeostasis during
reperfusion.
 Agents used include glucose and insulin;
nucleosides, such as adenosine,
aspartate, and glutamate; and L-arginine
to stimulate nitric oxide production.
 Although metabolic substrate
enhancement has been used in various
clinical situations, none has achieved
universal adoption.

14. Blood v/s Crystalloid cardioplegia
 Crystalloid cardioplegia:
◦ these solutions contain minimal amounts (0.6
mL/100 mL at a PO2 of 100 mm Hg at a
temperature of 10° C) of dissolved oxygen,
whereas the myocardium consumes 0.33 mL of
oxygen per 100 g at 15° C.
◦ Because even a short period of ischemia results
in the gradual accumulation of oxygen debt,
moderate to severe myocardial hypothermia is
necessary to prevent the rapid degradation of
energy stores
◦ To overcome the oxygen deficit issue,
oxygenation of crystalloid cardioplegia has been
clinically used and has demonstrated a decrease
in creatine kinase MB levels

15. Clinical steps for myocardial protection with
use of
crystalloid cardioplegia
1. Before the onset of surgery, the operating room temperature
is cooled to 17° C to 19° C to avoid warming of the anterior
surface of the heart by convection and radiation from
highintensity lighting.
2. Cardiopulmonary bypass is initiated at a temperature of 28°
C.
3. A myocardial electrocardiographic lead and temperature
probe are placed on the anterior wall of the right ventricle
because it constitutes two thirds of the anterior surface of
the heart, and its rewarming during surgically induced
ischemia may partially explain the occasional observation of
selective right ventricular failure after the termination of
bypass
4. an insulation pad is placed in the posterior pericardial sac
and along the left ventricular lateral wall to protect the left
phrenic nerve from thermal injury associated with regional

16. 5. The systemic perfusate temperature is temporarily decreased to
10° C to 15° C to “precool” the heart (infusion hypothermia), and
iced saline slush is placed into the pericardial sac to achieve rapid
myocardial cooling
6. When a myocardial temperature of 28° C is reached, the
ascending aorta is cross-clamped and cold crystalloid cardioplegia
solution at a temperature of 5° C is infused into the aortic root at a
pressure not exceeding 90 mm Hg @10ml/kg
7. At the termination of the initial cardioplegic infusion, the systemic
temperature is elevated to 20° C, and the systemic perfusion flow
rate is decreased from 2.2 to 1.5 liter/min/m2 .Increase in
myocardial temperature above 20° C or if there is any
electrocardiographic activity or observed ventricular motion, the
solution is reinfused at a volume of 5 mL/kg.
8. Five minutes before removal of the aortic clamp, the systemic
perfusate temperature is raised to 30° C, and flow is increased to
2.2 liter/min/m2.
9. After the aortic cross-clamp is removed, the perfusate temperature
is raised to 38° C and the room temperature is raised to 25° C to
30° C.
10. Cardiopulmonary bypass is continued until the esophageal
temperature is 37° C and the rectal temperature is in the range of
35° C to 37° C.

17. Disadvantage of crystalloid
cardioplegia
 Extensive rewarming period, which
may exceed 30 to 45 minutes.
 Slow recovery of myocardial
metabolism
 Poor response to postoperative
hemodynamic stress
 Gradual accumulation of oxygen debt
and myocardial damage if adequate
hypothermia not maintained

18. Blood Cardioplegia
 Advantages:
◦ Optimum oxygenation (superior to
oxygenated crystalloids)
◦ Better removal of carbon-dioxide
◦ Buffering action and reducing agent
◦ Presence of colloid avoids adverse
oncotic pressure gradients
◦ presence of oxygen free radical
scavengers
◦ Preserves microvascular responses
compared with crystalloid cardioplegia

19. Blood Cardioplegia
 Concerns:
◦ the hypothermic shift to the left of the
oxyhemoglobin dissociation curve,
thereby reducing the release of oxygen at
the tissue level
◦ the experimental evidence that blood
cardioplegia may not protect the
myocardium at low temperatures
◦ the potential of hypothermia induced
sludging and red cell rouleau formation.

20. Warm blood cardioplegia
 In 1982 Rosenkranz and colleagues reported that
warm induction with normothermic blood
cardioplegia, with multidose cold blood
cardioplegia maintenance of arrest, resulted in
better recovery of function in canines than a
similar protocol using cold blood induction
 In 1986, Teoh and colleagues provided
experimental evidence that a terminal infusion of
warm blood cardioplegia before removing the
cross-clamp (a “hot shot”) accelerated myocardial
metabolic recovery
 This was followed by a report in 1991 by
Lichtenstein and colleagues that normothermic
blood cardioplegia in humans is an effective
cardio-protective approach.

21.  Despite these encouraging reports, there are
concerns that for any given patient, it is difficult to
determine how long a warm heart can tolerate an
ischemic insult if the infusion is interrupted or flow
rates are reduced owing to an obscured surgical
field or a maldistribution of the cardioplegic
solution.
 Another concern is the report by Martin and
colleagues that warm cardioplegia is associated
with a threefold increased incidence of neurologic
deficits.
 Subsequent studies have indicated however that
appropriately designed protocols using intermittent
antegrade warm blood cardioplegia provide
clinically acceptable myocardial protection

22. Tepid blood cardioplegia
 Both cold blood (4 to 10°C) and warm blood
cardioplegic solutions (37°C) have temperature-
related advantages and disadvantages.
 Hayashida and colleagues were one of the first groups
to study specifically the efficacy of tepid blood (29°C)
cardioplegia. Their study showed that tepid antegrade
cardioplegia was the most effective in reducing
anaerobic lactate acid release during the arrest period.
 Mallidi et al showed that warm or tepid blood
cardioplegia may be associated with better early and
late event-free survivals after CABG
 Although tepid blood cardioplegia may be safe and
effective, the majority of studies have been single-
center studies conducted in relatively small cohorts of
patients. Whether tepid cardioplegia confers superior
protection over other current methodologies remains
to be determined.

23. Miniplegia
 The use of undiluted blood cardioplegia, or
“miniplegia” (using a minimum amount of
crystalloid additives), also has been reported to
be effective.
 Petrucci et al. studied the use of all blood
miniplegia in a clinically relevant swine
preparation and compared miniplegia with
crystalloid cardioplegia.
 They concluded that the use of all blood
miniplegia was effective or superior in the acutely
ischemic heart.
 Rousou and colleagues showed that it is the level
of hypothermia that is important in blood
cardioplegia, not necessarily the hematocrit.

24. Advantages of Blood
cardioplegia
(1) provides an oxygenated environment and a
method for intermittent reoxygenation of the
heart during arrest
(2) limits hemodilution when large volumes of
cardioplegic solution are used
(3) affords an excellent buffering capacity and
osmotic properties
(4) allows for electrolyte composition and pH
that are physiologic
(5) offers a number of endogenous antioxidants
and free-radical scavengers
(6) is less complex than other solutions to
prepare.

27. Novel strategies for
cardioprotection
 Physiologic:
◦ Ischaemic preconditioning
◦ Post conditioning
◦ Remote ischaemic preconditioning
◦ Autophagy
 Pharmacologic:
◦ Adenosine
◦ Acadesine
◦ Sodium-Hydrogen exchanger inhibitors
◦ Glucose-Insulin-Potassium (GIK)

28. Ischaemic preconditioning
 “Precondition with ischemia” is an endogenous
adaptive phenomenon whereby the heart becomes
more tolerant to a period of prolonged ischemia if first
exposed to brief episodes of coronary artery
occlusion.
 IPC has been demonstrated to persist as long as 1 to
2 hours after the ischemic preconditioning stimulus &
becomes ineffective when the sustained ischemic
insult exceeds 3 hours
 A second phase of protection appears 24 hours later
and is sustained for up to 72 hours. This has been
referred to as the second window of protection, late-
phase preconditioning, or delayed preconditioning.
 Unlike classic IPC, which protects only against
infarction, the late phase protects against both
infarction and myocardial stunning.

29. 1

30. Clinical relevance of IPC
 Patients experiencing angina before an MI have
a better in-hospital prognosis and a reduced
incidence of cardiogenic shock, fewer and less
severe episodes of congestive heart failure, and
smaller infarcts as assessed by cardiac enzyme
release and better long term survival rates
 Patients who undergo percutaneous coronary
interventions (PCI) have an enhanced tolerance
to ischemia after the first balloon inflation,
provided that the first balloon inflation exceeds
60 to 90 seconds
 Intermittent cross-clamping with the heart paced
at 90 beats per minute to induce ischemia,
followed by 2 minutes of reperfusion before a 10-
minute period of global ischemia and ventricular
fibrillation has shown attenuation of troponin
release

31. Post conditioning
 First reported by Zhao et al in canine model
 Rapid intermittent interruptions of blood flow in the early
phase of reperfusion, i.e., relief of ischemia in a stuttered or
staccato manner.
 The reduction in infarct size appears to be comparable with
that observed with IPC.
 Patients receiving brief balloon inflations/deflations in the
initial minutes of reperfusion during PCI exhibited smaller ST-
segment changes and lower levels of total creatine kinase
release compared with patients that were not subjected to
stuttering reperfusion
 Luo et al in their study on post-op patients after total
correction of TOF showed that aortic reclamping for 30
seconds and declamping for 30 seconds, repeated twice,
reduced perioperative troponin T and CK-MB release and
decreased the need for inotropic support after surgery

32. Remote Ischaemic
Preconditioning
 Remote ischemic preconditioning is a
phenomenon whereby brief ischemia of one organ
or tissue confers protection on a distant naive
organ or tissue against a sustained ischemia-
reperfusion injury
 Brief intermittent lower limb ischemia was
associated with attenuated troponin release and a
reduction in the need for postoperative inotropic
support in children undergoing congenital heart
surgery
 Similar findings were demonstrated in adult
patients undergoing CABG where RIPC was
induced by three 5-minute cycles of right forearm
ischemia by inflating a blood pressure cuff on the
upper arm to 200 mm Hg with an intervening 5-

33. Autophagy
 Autophagy is the process whereby a
doublemembrane structure called the
autophagosome sequesters cytoplasmic
components such as ubiquitinated protein
aggregates or organelles including
mitochondria, peroxisomes, and endoplasmic
reticulum.
 It is involved in degradation of long-lived
proteins and the removal of excess or
damaged organelles
 The outer autophagosomal membrane fuses
with a lysosomal membrane to deliver its
contents into an autophagolysosome where
the cargo is degraded by lysosomal
hydrolases and the resulting macromolecules
recycled

35.  Autophagy has been reported to be upregulated in isolated
cells subjected to simulated ischemia and reperfusion and
rodent models of ex vivo and in vivo ischemia reperfusion
injury.
 Gurusamy et al. investigated the role of autophagy during
ischemia-reperfusion injury and reported that increased BAG-
1 expression in the heart correlated with the onset of
protection in an in vivo model of myocardial stunning.
 Studies suggest that upregulation of autophagy promotes
survival during stress such as ischemia-reperfusion
 There is also direct evidence that autophagy plays an
important role in mediating ischemic and pharmacologic
preconditioning.
 Autophagy may serve as an important mediator of protection
of the preconditioning agent CCPA. A more detailed
understanding of the role of autophagy in myocardial
protection may lead to a new therapeutic approach to the
management and treatment of ischemia-reperfusion injury.

36. Adenosine
 There is considerable experimental evidence that activation of
various adenosine receptor subtypes results in cardioprotection
similar to that induced by IPC.
 Preischemic administration of the nucleoside adenosine retards the
rate of ischemia-induced ATP depletion, prolongs the time to onset
of ischemic contracture, attenuates myocardial stunning, enhances
postischemic myocardial energetics, and reduces infarct size
 Recent preclinical reports suggest that an adenosine A 2b receptor
agonist confers cardioprotection when administered before the
onset of ischemia (preconditioning) and at reperfusion
(postconditioning)
 In clinical trials, low dose adenosine administration showed no
benefit on patient outcome
 However, trials involving administration of high doses of adenosine
in CABG patients showed reduction in postbypass inotropic drug
utilization, improved regional wall motion, and global function
measured by transthoracic echocardiography
 Its clinical use is limited because large doses are associated with
marked hypotension in patients not on cardiopulmonary bypass.

37. Acadesine
 This agent is a member of a class of drugs referred to as
adenosine regulating agents. It is a purine nucleoside analog
that raises adenosine tissue levels selectively during ischemic
conditions
 Early preclinical studies have indicated that acadesine
treatment:
◦ (1) improves left ventricular wall motion after intermittent
ischemia
◦ (2) attenuates frequency of ventricular arrhythmias
◦ (3) attenuates myocardial stunning and preserves
myocardial function after cardiac arrest and cold
cardioplegia.
 Mangano et al. examined the two-year all cause mortality
after perioperative MI in a follow-up of the Acadesine 1024
Trial. Although the primary outcome was negative, the
findings at two years among patients experiencing post

38. Sodium-Hydrogen Exchange
inhibitors
 The sodium-hydrogen exchangers (NHEs)
are a family of membrane proteins with nine
isoforms that are involved in the transport of
hydrogen ions in exchange for sodium ions.
 NHE-1 is the isoform that is expressed in the
heart and may play a minor role in the normal
excitation-contraction coupling process;
however, it has been implicated in the
etiology of arrhythmias, stunning, apoptosis,
necrosis associated with acute myocardial
ischemia-reperfusion injury, postinfarction
ventricular remodeling, and heart failure

39.  The driving forces for Na + /H + exchange are the
relative transmembrane N + and H + gradients.
 During ischemia, cytoplasmic pH falls as low as 6.6
because of increased production of H + from
anaerobic glycolysis, but upon reperfusion, NHE-1 is
activated to restore intracellular pH by exchange of
intracellular protons for extracellular sodium.
 The resulting accumulation of intracellular Na + is
further exacerbated by diminished activity of Na + /K +
ATPase as a result of ischemia and lowered ATP
availability.
 The increased intracellular Na + competes for sites on
the Na + /Ca ++ exchanger and can actually drive it to
run in reverse, resulting in cytosolic calcium overload.
 Calcium overload has numerous adverse
consequences including activation of calcium-
dependent proteases and phospholipases, gap
junction dysfunction, culminating in membrane rupture
and cell death

40.  The EXPEDITION trial was initiated to address the
safety and efficacy of NHE-1 inhibition by
cariporide in the prevention of death or MI in
patients undergoing CABG surgery.
 Although cariporide treatment was effective in
reducing the incidence of nonfatal MI, its efficacy
was associated with toxicity, and the overall
assessment of benefits and risks associated with
cariporide indicated that the imbalances in the
safety profile outweighed the reduction in the
observed MI rate
 The importance of the study, however, is that
myocardial necrosis after CABG is higher than
previously appreciated and it suggested NHE-1
inhibitors represent a new class of drugs that hold
promise for reduction of myocardial infarction
associated with ischemiareperfusion injury.

41. Glucose Insulin Potassium
 There are numerous studies that suggest glucose-
insulin-potassium (GIK) infusions are effective in
reducing perioperative MIs, postischemic myocardial
dysfunction, and atrial fibrillation in patients
undergoing heart surgery.
 The rationale for this form of treatment is based on the
concept that insulin stimulates potassium reuptake
through stimulation of the Na + ,K + - ATPase while it
stimulates glucose uptake for glycolytic energy
production.
 High glucose, insulin, and an increased glycolytic flux
also increase pyruvate generation and in turn preserve
the citric acid cycle.
 Additionally, glycolytic ATP protects membranes,
drives uptake of Ca 2+ by the sarcoplasmic reticulum,
and improves sodium homeostasis of ischemic

42.  Despite a strong rationale for its application in
surgery, the efficacy of GIK in heart surgery
remains controversial, due to mixed results with
the use of GIK to treat patients with acute
myocardial infarction
 Although a metaanalysis of randomized studies
using GIK suggests that it may improve
postoperative recovery of contractile function and
reduce atrial arrhythmias, the individual studies
have involved small numbers of patients and,
therefore, insufficiently powered to detect efficacy.
 Until a large randomized, multicenter clinical trial
has been performed, the use of GIK as a form of
myocardial protection will remain controversial.

43. Myocardial protection during
beating heart surgery
 The acceptance of OPCAB is due in part to the
development and refinement of a myriad of surgical
aids that allow for stabilization and local immobilization
of the heart during grafting.
 Ischemia during temporary occlusion of a coronary
artery during OPCAB may last from 6 to 25 minutes
based on the surgeon’s experience, quality and size of
the vessel, and adequacy of the exposure.
 Most patients with preexisting severe coronary heart
disease have experienced self-limiting episodes of
ischemia during daily life and may have imparted a
certain degree of tolerance to the surgically induced
ischemia.
 This tolerance has been documented using ECGs,
transesophageal echocardiography, and continuous
SVO2 monitoring

44.  In order to better understand the differences
between OPCAB and onpump surgery,
Chowdhury et al. investigated the release
pattern of various cardiac biomarkers in 50
patients undergoing cardioplegic and
noncardioplegic coronary artery bypass
surgery
 They observed a greater release of cardiac
troponin I, high-sensitivity C-reactive protein,
and heart-type fatty acid binding protein in
the cardioplegic group.
 They concluded that OPCAB surgery is
associated with less injury

45.  One approach to minimizing the risk of injury is to reduce
myocardial oxygen demand. Pharmacologic beta-blockade
is frequently instituted to reduce inotropy and achieve
negative chronotropy using ultra-short-acting beta blockers
such as esmolol and labetalol
 Another approach is to optimize the systemic mean blood
pressures while reducing afterload.
 Calcium channel blockers, such as diltiazem, have been
used to afford an effective reduction in blood pressure while
minimizing a depression in myocardial contractility that
may occur with beta blockers.
 Patients who become hypertensive during the operation may
benefit from intravenous nitrates, which allows for coronary
vasodilation and increased blood flow via collaterals.
 Gentle core cooling, by allowing the body temperature to
drift to 35–36°C and deepening the level of anesthesia are
concurrent measures that can also be employed.