The Physiology of Cardioplegia
To rapidly arrest the myocardium in diastole and maintain it in a
depolarised state, it is necessary to understand the underlying
electrophysiology behind hyperkalaemia, which is a fundamental
constituent of most cardioplegic solutions. Hyperkalaemia induces
diastolic arrest by establishing a new resting membrane potential (RMP)
that is more depolarised (i.e. more positive) than
normal(11). It is worth noting that the RMP is
maintained by the ATP-driven
Na+/K+ pump, which creates an
electrochemical gradient across the sarcolemmal membrane
(Fig.2 ).
In physiological states, AP generation occurs due to activation of
voltage-gated channels which allow influx of cations. Following
sinoatrial node stimulation, voltage-gated
Na+ channels (VGNCs) open, provided the -65mV
threshold is reached which enables a rapid influx of
Na+ ions, depolarising cardiomyocytes to +20mV
(Fig.2 ). This potentiates the opening of L-type
Ca2+ channels (LTCCs) leading to a further influx of
cations whilst the VGNCs become inactivated. Calcium-induced calcium
release from the sarcoplasmic reticulum via ryanodine receptors allows
electromechanical coupling, forming the characteristic prolonged plateau
of AP in cardiomyocytes (Fig.2 ). As the membrane
potential reaches more negative values, LTCCs close and delayed K
channels return the RMP back to -85mV.
In the hyperkalemic states of cardioplegia, the constant influx of
K+ increase the RMP to -55mV which is beyond the VGNCs
threshold thus they remain inactivated. Consequently, both adequate
repolarisation and conduction of another AP are prevented – rapid
cardiac arrest is induced. Additionally, the myocardial oxygen
consumption and significant cellular ATP depletion, both of which are
characteristic of I-R injury, are reduced as per Hearse’s principles of
cardioplegia(12).
Mitochondrial ATP-sensitive K+ channels allow coupling
of membrane potential to the cellular metabolism and therefore play a
significant role in myocardial protection(13). This is
established by reducing post-ischaemic infarct size and apoptosis,
possibly via altering mitochondrial Ca2+ and
modulating reactive oxygen species formation(14).
Solutions for Myocardial Protection
Cardioplegic solutions can either be intracellular or
extracellular(15). Extracellular solutions contain
high concentrations of potassium, magnesium and sodium ions and work by
preventing repolarisation of myocytes(15).
Intracellular solutions contain low electrolyte concentrations and work
by decreasing the sodium-potassium concentration gradients and stopping
potassium efflux, thus preventing action potential
generation(15). There are several types of these
solutions used in clinical practice, some of which are listed below.
Histidine-tryptophan-ketoglutarate
(HTK)/Custodiol/Bretschneider’s
The main advantage of HTK is the buffering capacity of histidine which
enhances the efficiency of anaerobic glycolysis, providing better
myocardial preservation(15,16). The ketoglutarate
component is an intermediary in the Krebs cycle and acts as a high
energy ATP provider during reperfusion(15,16). The
tryptophan component stabilises cell membranes(15).
Mannitol, an osmotic diuretic is also added(15). It
decreases cellular oedema and has free radical scavenging properties,
thus reducing ischaemic injury(15).
HTK induces cardiac arrest by lowering the sodium and calcium
concentrations and preventing action potential
depolarisation(15). This means that longer time is
required to initiate cardiac arrest, which causes greater ischaemic and
reperfusion damage(16). However, only a single dose
is required which simplifies the procedure(16).
St Thomas’s solution (STH)
STH is an extracellular cardioplegic solution(15). The
original St Thomas’s solution (STH1) was formed by Hearse and colleagues
in the early 1970s(17). This STH1 solution was then
refined to form Plegisol or St Thomas’s Hospital solution No. 2 (STH2)
which is now the most widely used crystalloid cardioplegic solution in
the world(17). Many studies show STH2 to have better
myocardial protective and antiarrhythmic effects than STH1.
Due to the high potassium and magnesium concentration in STH, it induces
rapid cardiac arrest(15). It is effective in providing
myocardial protection in patients undergoing procedures like coronary
artery bypass graft (CABG)(16). However, it is less
protective in patients requiring longer cross-clamp times. STH also
increases cellular oedema and damages endothelial function. It thus
needs repeated perfusion during ischaemia and must be administered every
20-40 minutes(16).
Del Nido solution
In the early 1990s, Pedro del Nido and colleagues developed a
cardioplegic solution that satisfied the requirements of the paediatric
heart during surgery(18). It has mainly been used in
paediatrics and not very commonly for adults. Due to this there is
scarce data available to support the safety and efficacy of its use in
adult heart surgery(18).
Del Nido solution is very dilute and consists of lidocaine and
magnesium and has lower concentrations of calcium(18).
It induces cardiac arrest during surgery and decreases intracellular
calcium, slows down rate of energy consumption and scavenges free
radicals(18). It also reduces myocardial oedema,
preserves high-energy phosphates and also promotes anaerobic
glycolysis(18).
It allows uninterrupted surgery due to single cardioplegia dosing, thus
reduced overall surgical times(18). However, concerns
regarding its use in adults exist due to lack of prospective randomised
trials and evidence for safe use(18). The properties
of the different cardioplegic solutions are summarised in Table 1.