Inotropes

Jonathan Trinh
Kenneth Palmer
Abstract
Inotropes increase the force of contraction of cardiac muscle and thereby
increase cardiac output. In general, they are used to prevent anaerobic
metabolism by improving oxygen delivery to the tissues. Inotropic agents
have varying pharmacological proles; drug selection according to the
clinical circumstance enables benets to be maximized while minimizing
side effects. Most inotropes act to increase intracellular calcium levels.
Adrenoceptor agonists (e.g. epinephrine) achieve this by activating
adenylate cyclase and increasing cyclic adenosine monophosphate
(cAMP) levels and protein kinase activity, which potentiates the opening
of voltage-gated calcium channels and increases the amount of calcium
released from the sarcoplasmic reticulum. Phosphodiesterase inhibitors
(e.g. milrinone) block the degradation of cAMP, thereby increasing protein
kinase activity and calcium levels. Raised intracellular calcium is,
however, associated with arrhythmias and cell death, leading to the
development of newer agents that act by different mechanisms. Levosi-
mendan improves the sensitivity of the contractile apparatus to calcium,
thereby increasing inotropy. Epinephrine remains the drug of choice in
emergencies (cardiac arrest, anaphylaxis). Inotropes are commonly
administered by controlled infusion in the critical care environment, to
allow close monitoring and careful titration. The combined use of several
inotropes in lower doses may confer a benet over single agents used at
high doses.
Keywords Cardiac output; dobutamine; dopamine; dopexamine; enox-
imone; epinephrine; inotropy; isoprenaline; levosimendan; lusiotropy;
milrinone; norepinephrine
Royal College of Anaesthetists CPD Matrix: 1A02 2C03
Introduction
Inotropic agents are drugs that affect the force of contraction of
myocardial muscles and their effects can either be positive or
negative. In clinical practice, however, inotropes are synony-
mous with positive inotropes. They are the mainstay in the
treatment of important cardiovascular syndromes which severely
compromise cardiac output and thus oxygen delivery, and are
routinely used in anaesthesia, intensive care and coronary care.
However as recent evidence shows, their use can have
unintended consequences leading to toxicity and harm. They can
precipitate malignant arrhythmias, damage to arterial walls
leading to focal myocardial contraction band necrosis and
directly stimulate myocyte apoptosis. As such it is important to
have a clear understanding of their pharmacology to allow for the
precise selection of the appropriate agent for the clinical situation
at hand in order to achieve a targeted clinical outcome. We will
rst review the physiology of cardiac output and myocyte
contractility prior to an in-depth review of the pharmacology of
the different inotropic agents. Finally, we will review what is on
the horizon in the development of novel inotropic agents.
Cardiac output
The heart acts as the pump which delivers oxygen to all cells in the
body to fuel aerobic metabolism. Cardiac output along with the
oxygen content of arterial blood (both bound to haemoglobin and
dissolved) the essential components of oxygen delivery as shown
by the oxygen delivery equation (Do
2
COCao
2
). Cardiac output
is the product of heart rate and ventricular stroke volume (COHR
SV). It can be manipulated through changes in preload (Franke
Starling mechanism), contractility and afterload. The cellular
mechanism by which cardiac myocytes shorten and produce the
force needed to propel blood from the ventricle, is discussed in
Anaesthesia & Intensive Care Medicine 2012; 13(8): 388e390.
Inotropic agents act to increase contractility, thereby
increasing cardiac output and oxygen delivery to tissues. The
healthy heart has considerable reserve and cardiac output can
increase by sevenfold to match oxygen delivery requirements
during intense exercise. This is achieved through increases in
preload (via increasing venous return), heart rate (chrono-
tropicity, via sympathetic system activation) and contractility
(inotropy, via sympathetic system activation).
The diastolic function of the heart is also crucial to its func-
tion, with diastolic dysfunction recognized as an independent
cause of heart failure. Optimal ventricular lling is dependent on
efcient myocardial relaxation (lusiotropy) and ventricular
chamber compliance. Lusiotropy is an active process requiring
energy and can be upregulated by b-adrenergic stimulation.
Clinical use of inotrope
Inotropes are used to restore cardiac output and thereby tissue
perfusion and oxygenation when haemodynamic insufciency
limits oxygen supply to tissues (Figure 1). As with any inter-
vention it should never be commenced blindly and a careful
assessment of the underlying pathology leading to shock should
be undertaken. This will allow for the selection of the most
appropriate inotrope for the clinical circumstance in order to
maximize the benet and minimize harmful side effects.
Learning objectives
After reading this article, you should be able to:
C
explain the term lusiotropy
C
describe the haemodynamic effects of epinephrine
C
have a brief understanding of the future of inotropes
Jonathan Trinh FANZCA is an Anaesthetic Fellow at the Liverpool Heart
and Chest Hospital, Liverpool, UK. Conicts of interest: none declared.
Kenneth Palmer FRCA FFICM is a Consultant in Anaesthesia & Intensive
Care at the Liverpool Heart and Chest Hospital, Liverpool, UK. Conicts
of interest: none declared.
CARDIAC ANAESTHESIA
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Inotropes should be administered and titrated in a critical care
environment with cardiovascular and haemodynamic monitoring
given the potency and potential side effects. This should include
continuous electrocardiogram (ECG) and invasive blood pressure
monitoring as well as oxygen saturation, urine output and
regular neurological assessments. Regular metabolic assessments
of perfusions via arterial blood gas sampling can aid inotrope
selection and titration. Filling status is important and can be
estimated by central venous pressure from a central venous
catheter, which also allows for administration of inotropic
agents. More advanced monitoring of haemodynamics may be
employed in patients who are unstable and on multiple inotropic
agents. This may include monitoring of cardiac output, systemic
and pulmonary vascular resistances and mixed venous oxygen-
ation via the pulmonary artery otation catheter or pulse contour
analysis techniques such as the PiCCO.
1
Finally echocardiog-
raphy can be employed to diagnose the cause of shock and to
assess the effectiveness of inotropic therapy.
2
Classication of inotrope
When examining the cellular mechanism of force production by
the cardiac myocytes it is clear that inotropy is dependent on
three factors: (1) the concentration of intracellular calcium, (2)
the sensitivity of the contractile proteins to the intracellular
calcium present and (3) the duration of actinemyosin cross-
bridge binding. Hence, the classication of inotropes can be
based on these dependent variables (Table 1):
increase in concentration of intracellular calcium:
calcium salts
increase in cyclic adenosine monophosphate (cAMP)
concentrations:
e b
1
agonists
e phosphodiesterase inhibitors
e glucagon
Na

/K

ATPase inhibitors: digoxin

new approaches to rebalance intracellular calcium
concentration:
e SERCA activation
e Ryoanodine receptor stabilization
increase in afnity of troponin C for Ca
2
: levosimendin
increase in response of myobrillar proteins to a given
concentration of Ca
2
: omecamtiv mecarbil.
The benecial effects of the most widely used inotropic agents in
critical care are derived from their ability to increase intracellular
calcium which coincidentally is also directly responsible for the
adverse effects including ischaemia, arrhythmia, ventricular
ectopy, band necrosis and myocyte apoptosis. As a result, recent
inotropic drug development have been aimed at increasing
contractile protein function without the need to increase
Summary of myocyte physiology and sites of
inotrope action
ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate;
G, G protein; PDE, phosphodiesterase; PK, protein kinase; SERCA, sarco/endoplasmic
reticulum Ca
2+
ATPase; SR, sarcoplasmic reticulum.
-receptor
-receptor
Adenylate cyclase
Receptor
L-type Ca
2+
channel
Ca
2+
2+
Ca
2+
Ca
2+
5-AMP
PDE
PK cAMP ATP
PDE
Relaxation Contraction
Actin
Myosin
5-AMP

2
-agonists
PDE inhibitors
Levosimendan
Glucagon Digoxin
G
SECRA
SR
Na
+
/K
+
pump
Na
+
/K
+
pump
Figure 1
Classication of inotropic agents
Mechanism of action Cellular mechanism Example
[ [Ca
2
]
intracellular
Calcium salts Calcium chloride
[ [cAMP]
intracellular
b
1
Agonist
(epinephrine,
dobutamine,
dopamine)
Phosphodiesterase
inhibitor (milrinone,
enoximone)
Glucagon
Na

/K

ATPase
inhibition
Digoxin
Na

/K

ATPase
inhibition
with SERCA activation
Istaroxime
Calcium
sensitization
[ Troponin C afnity
for Ca
2
Levosimendan
Cardiac myosin
activators
Accelerate rate of
actin-dependent
phosphate release
of the actinemyosin
cross-bridge
Omecamtiv
mercarbil
SERCA activation Reduce sarcoplasmic
reticulum re-uptake
of calcium and abnormal
leak of calcium into the
SR
Nitroxyl
Ryanodine
receptor
stabilization
Reduce abnormal
calcium leak from
the SR
S44121
ATPase, adenosine triphosphatase; cAMP, cyclic adenosine monophosphate;
SERCA, sarco/endoplasmic reticulum Ca
2
ATPase; SR, sarcoplasmic retic-
ulum.
Table 1
CARDIAC ANAESTHESIA
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intracellular calcium and to restore to the diseased heart
a normal balance of intracellular, sarcoplasmic reticulum and
extracellular calcium concentration.
Generally, inotropic agents will activate receptors beyond just
those on the cardiac myocytes. This will lead to other effects such
as lusiotropy, chronotropy, vasoconstriction and or vasodilata-
tion. The major effects of the commonly used inotropes are
summarized in Table 2.
b-receptor inotropes
Physiological increases in cardiac output (e.g. during exercise) are
mediated by the adrenal hormones epinephrine and norepinephrine
via the sympathetic nervous system. In 1948 Ahlquist postulated the
existence of the receptor subtypes aandb. Further subdivisionbased
on receptor location and clinical effect has identied two a-receptor
subtypes (a
1
anda
2
) andthreeb-receptor subtypes (b
1
, b
2
andb
3
). All
adrenoceptors are G-proteincoupled; however, only a
1
-receptors are
coupled to phospholipase C. The other adrenoceptors act via ade-
nylate cyclase to adjust intracellular cAMP levels. Whereas a
2
-
receptors inhibit adenylate cyclase, all b-receptor subtypes stimulate
it, increasing cAMP and therefore protein kinase A activity. Phos-
phorylation of ion channels and receptors leads to an increase in the
concentration of Ca
2
in the cytosol: L-type Ca
2
channel leading to
an inux of Ca
2
from the extracellular space and ryanodine recep-
tors leading to an inux of Ca
2
from the sarcoplasmic reticulum.
This leads to an increase in the myocardial contractility (positive
inotropy). Furthermore, byphosphorylationof other proteins thereis
an enhancement of the withdrawal of calcium from the cytosol
duringdiastole leadingtopositive lusitropy. The major effects caused
by activation of each receptor subtype are summarized in Table 3.
Epinephrine (adrenaline) is an endogenous catecholamine which
has potent agonist activity at the a
1,
b
1
and b
2
receptors. It is
produced in the adrenal medulla from the amino acid phenylala-
nine via the same biochemical pathway that also produces dopa-
mine and noradrenaline (Figure 2). There are two pathways for
metabolism: oxidation by monoamine oxidase or conjugation by
catechol-O-methyl transferase. At low doses the b-adrenergic
effects are more pronounced with this balance shifting to the a-
adrenergic effects at higher doses. Owing to the widespread pres-
ence of adrenergic receptors, epinephrine has wide ranging effects
on many body systems. Its cardiovascular effects are arguably its
most important: positive inotropy by increasing contractility (b
1
),
positive chronotropy (b
2
), vasoconstriction and venoconstriction
(a
1
). Coronary blood ow is increased through a relative increase
in the duration of diastole and through myocyte release of local
vasodilators which together counterbalance the direct a
1
vaso-
constriction effects. At high doses myocardial ischaemia and
dysrhythmias can occur and intense vasoconstriction can lead to
intestinal, renal and peripheral ischaemia. Metabolically,
epinephrine can lead to hyperglycaemia from increased hepatic
glycogenolysis, increased lipolysis and decreased release of and
sensitivity to insulin. Epinephrine can be administered via intra-
muscular, intradermal, intraosseous and transtracheal routes,
however most commonly it is administered intravascularly by
either bolus administration (i.e. during cardiac arrest) or by
controlled infusion. Tachyphylaxis though uncommon can occur
especially in chronic heart failure.
Norepinephrine (noradrenaline) as seen in Figure 2 is the
precursor to epinephrine. It is a neurotransmitter centrally and
Summary of commonly used inotropes
Inotrope Main site of action Suggested dose Major effects
Epinephrine b
2
b
1
a
1
Cardiac arrest 1 mg IV [ INO, HR, CO, SVR, BP
Anaphylaxis 0.5 mg IM [ Glucose
Infusion 0.01e0.1 mg/kg/min
Norepinephrine a
1
Infusion 0.01e0.1 mg/kg/min [ SVR, BP
Dopamine DA
1
Infusion 1e5 mg/kg/min Reno-splanchnic dilatation
b
1
5e10 mg/kg/min [ INO, CO
a
1
>10 mg/kg/min [ SVR, BP
Isoprenaline b
1
b
2
Infusion 0.01e0.03 mg/kg/min [ HR, CO
Y SVR
Dobutamine b
2
b
1
Infusion 2.5e25 mg/kg/min [ INO, HR, CO
Y SVR
Dopexamine DA
1
b
2
Infusion 0.5e6.0 mg/kg/min Reno-splanchnic dilatation
[ HR
Enoximone PDE inhibitor Loading 0.5 mg/kg [ INO, CO
Infusion 1e5 mg/kg/min Y SVR, PVR
Levosimendan Ca
2
sensitizer Loading 6e12 mg/kg [ INO, CO
Infusion 0.05e0.4 mg/kg/min Y SVR
Vasopressin V
1
Cardiac arrest 40 IU [ SVR
Infusion 0.01e0.1 units/min
BP, blood pressure; CO, cardiac output; HR, heart rate; INO, inotropy; IM, intramuscularly; IV, intravenously; min, minute; PDE, phosphodiesterase; PVR, pulmonary
vascular resistance; SVR, systemic vascular resistance.
Table 2
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at postganglionic sympathetic neurones. It is a potent a-adren-
ergic agonist with minimal b activity which renders it a powerful
vasoconstrictor with modest direct inotropic action. The
increase in systolic, diastolic, pulmonary arterial and central
venous pressures leads to a reex bradycardia mediated by the
baroreceptor reex. Any direct inotropic activity is offset by an
increase in afterload such that cardiac output changes very little.
Despite an increase in myocardial oxygen consumption driven
by an increase in afterload, coronary blood ow and therefore
oxygen delivery is increased by an elevation in diastolic pressure
and the release of local vasodilators through indirect stimulation
of myocytes. Prolonged and high-dose infusions can lead to
direct toxic effects inducing apoptosis, ventricular dysrhythmias
and mesenteric, renal and peripheral tissue ischaemia secondary
to intense vasoconstriction. Norepinephrine is best suited to
shock secondary to a failure in afterload such as in sepsis or
systemic inammatory response syndrome. Intravascular infu-
sions must be administered centrally as extravasation of
peripherally administered norepinephrine can lead to local
tissue necrosis.
Dopamine is an endogenous central neurotransmitter crucial to
the control of movement. When administered therapeutically it
has a multitude of dose-dependent cardiovascular clinical effects
via its agonist stimulation of the dopaminergic (DA
1
and DA
2
)
and adrenergic (a and b) receptors. At low doses (1e5 mg/kg/
min) dopaminergic effects predominate via post-synaptic DA
1
-
receptors activation of coronary, cerebral, renal and mesenteric
vascular bed, and pre-synaptic DA
2
-receptor activation in the
vasculature and renal tissue which all culminate in vasodilation
and increased blood ow to these tissues. Furthermore, dopa-
mine has a direct natriuretic effect through action on the renal
tubules. Clinically, the renal protective effects of low-dose
dopamine have not been demonstrated and it is no longer used
in this setting in intensive care. At intermediate doses (5e10 mg/
kg/minute) dopamine weakly binds to b
1
-receptors leading to
positive inotropy and chronotropy and a mild increase in
systemic vascular resistance. At higher infusion rates (>10 mg/
kg/min) a
1
-mediated vasoconstriction dominates increasing
venous return and blood pressure at the expense of reduced renal
and splanchnic blood ow and tachyarrhythmias.
Isoprenaline is a potent non-selective synthetic b
1
and b
2
agonist
with a very low afnity for a-adrenergic receptors. It is
Characteristics of adrenoceptors
Adrenoceptor Agonist Major clinical effects
a
1
Norepinephrine Vasoconstriction
Epinephrine Relaxation GI smooth muscle
Phenylephrine Hepatic glycogenolysis
a
2
Clonidine Inhibition of norepinephrine
release
Dexmetomidine Platelet aggregation
Inhibition of insulin release
b
1
Isoprenaline Increased inotropy
Epinephrine Increased chronotropy
Norepinephrine Increased lusiotropy
Dobutamine
b
2
Epinephrine Bronchodilation
Salbutamol Vasodilation
Hepatic glycogenolysis
b
3
Isoprenaline Lipolysis
Norepinephrine
GI, gastrointestinal.
Table 3
Phenylalanine
Phenylalanine hydroxylase
Tyrosine
Tyrosine hydroxylase
Dihydroxyphenylalanin
(DOPA)
DOPA decarboxylase
Dopamine
Dopamine -hydroxylase
Noradrenaline
Phenylethanolamine-N-
methyltransferase
Adrenaline
O
OH
NH
2
O
OH
HO
NH
2
O
OH
HO
HO
NH
2
HO
HO NH
2
OH
OH
(R)
HO
HO NH
2
OH
OH
(R)
HO
H
N
Synthesis pathway of epinephrine, norepinephrine
and dopamine
Figure 2
CARDIAC ANAESTHESIA
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a powerful inotrope and chronotrope with potent systemic and
pulmonary vasodilatory effects. Myocardial oxygen consumption
is increased and arrhythmias are common. b
2
-agonism leads to
vascular and respiratory effects: decrease in systemic and
pulmonary vascular resistance and bronchodilation, increasing
anatomical dead space and ventilationeperfusion mismatching,
which may lead to hypoxia. Although formerly used for acute
severe asthma, isoprenaline is currently indicated in the treat-
ment of bradyarrhythmias and in certain atrioventricular heart
blocks as a temporary measure until a transvenous pacing
system is inserted.
Dobutamine is a synthetic derivative of isoprenaline with
a strong afnity for both b
1
- and b
2
-receptors binding at a 3:1
ratio. It is therefore a potent inotrope with mild chrontropic
activity. As a result of the b
2
activity on vascular smooth muscle
dobutamine often produce mild vasodilatation, particularly at
low doses (<5 mg/kg/minute). At higher doses (up to 15 mg/kg/
minute) there is an increase in contractility with minimal
changes in peripheral vascular resistance as there is increasing a
1
activity. Vasoconstriction dominates at higher infusion rates.
Dobutamine signicantly increase myocardial oxygen consump-
tion, which is the basis on which it is used in pharmacological
stress testing for diagnostic perfusion imaging. Conversely, this
also limits its use in clinical conditions where induction of
cardiac ischaemia is dangerous. As with other b-agonists
ventricular arrhythmias can be observed at any doses.
Dopexamine is a synthetic dopamine analogue that acts on
dopaminergic and b
2
-receptors to cause smooth muscle relaxa-
tion in the renal and mesenteric arterial beds. Although it has no
direct b
1
- or a-adrenoceptor activity, dopexamine does inhibit the
neuronal re-uptake of norepinephrine by uptake.
1
Cardiac output
is improved because heart rate and inotropy are increased,
whereas afterload is reduced by b
2
-peripheral vasodilation. It is
generally thought that the effect of dopexamine on the vascular
supply to the kidneys and gut may reduce the ischaemia found in
sepsis and heart failure; however, supportive data are lacking.
Clinical use is often limited by dysrhythmias.
Phenylephrine is a potent synthetic directly acting a-agonist
with no b-adrenoceptor activity. It causes intense vasoconstric-
tion, raising systolic and diastolic blood pressures, leading to
a reex bradycardia. By virtue of the increase in diastolic blood
pressure, coronary artery blood ow is increased.
Ephedrine is a synthetic sympathomimetic agent commonly
used to treat hypotension associated with general and neuroaxial
anaesthesia. It acts directly by stimulating a- and b-receptors,
and indirectly by releasing norepinephrine from nerve endings
and inhibiting its breakdown by monoamine oxidase. Heart rate,
inotropy and blood pressure are increased, and widespread
vasoconstriction occurs except in uterine and placental vessels,
making it popular in obstetric regional anaesthesia. Tachyphy-
laxis occurs with repeat dosing as a result of depletion of
endogenous norepinephrine stores and ongoing receptor occu-
pation by previously administered doses of ephedrine secondary
to longer half-life. Similarly, metaraminol acts by both direct and
indirect mechanisms. It is taken up into synaptic nerve terminals,
acting as a false neurotransmitter for norepinephrine and causing
predominantly a effects and an associated reex bradycardia.
Phosphodiesterase inhibitors
Phosphodiesterase (PDE) is the enzyme responsible for the
degradation of cAMP and cGMP. Five subtypes have been iden-
tied with PDE type III being found to be concentrated in the
myocardium and vascular smooth muscles. In the myocardium
phosphodiesterase inhibitors (PDIs) inhibit cAMP breakdown,
allowing it to continue to activate protein kinase A and thereby
keeping intracellular Ca
2
concentrations elevated leading to
positive inotropic and lusitropic effects. In vascular smooth
muscles, the increase in cAMP levels lead to a decrease in
intracellular concentration of Ca
2
, causing marked vasodilation
of peripheral and pulmonary vessels. For this reason, PDE
inhibitors are often referred to as inodilators. Heart rate is
affected minimally and myocardial oxygen demand remains
largely unaltered. PDE inhibitors are frequently used in combi-
nation with other inotropes with benecial synergism.
Enoximone is an imidazole derivative with selective PDE III
inhibition. It is useful for the short-term support of cardiac output
in patients with chronic heart failure, in whom elevated cate-
cholamine levels lead to the downregulation of b-receptors.
Similarly, it can be used in patients after cardiopulmonary bypass
and in those with refractory cardiogenic shock from other causes.
Available only as an intravenous therapy, enoximone requires
a loading dose followed by a continuous infusion, and takes up to
30 minutes to act. The half-life of 4e6 hours can be greatly
extended in hepatorenal failure because it is metabolized by the
liver and excreted in the urine. Oral preparations undergo
extensive rst-pass metabolism, rendering them useless.
Milrinone is the PDI most commonly used for cardiovascular
indications. It is a bipyridine derivative and selective PDE III
inhibitor with similar effects to enoximone. Although oral prep-
arations are available, their long-term use has been shown to
increase mortality in patients with congestive heart failure
(PROMISE trial). Compared with other PDE III inhibitors, results
from studies have indicated more prominent effects on contrac-
tility and relaxation at clinically relevant concentrations, and
a shorter duration of action (half-life 2.5 hours). Amrinone is
also a bipyridine derivative PDE III inhibitor, however, its use is
limited by dose-related thrombocytopenia. It is not available in
the UK.
Cardiac glycosides
Digoxin is a cardiac glycoside extracted from the leaves of the
foxglove. More commonly used to treat supraventricular
arrhythmias, it has inotropic properties secondary to its inhibi-
tion of the Na

/K

ATPase pump on the myocyte. The accu-

mulation of intracellular Na

alters the driving forces on the

Na

/Ca
2
exchanger, leading to an accumulation of intracellular
Ca
2
and thereby causing positive inotropy. Antiarrhythmic
properties are secondary to direct prolongation of the refractory
period and the indirect release of acetylcholine at cardiac
muscarinic receptors, which further slows conduction. The
therapeutic window of digoxin is narrow, with toxicity causing
dysrhythmias and metabolic disturbances.
CARDIAC ANAESTHESIA
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Calcium salts
Calcium salts can increase inotropy after cardiopulmonary
bypass, and when hypocalcaemia has been caused by the
use of calcium-free uids or citrated blood products after
haemorrhage. Increased extracellular calcium will increase
intracellular concentrations, producing inotropy. High con-
centrations are, however, associated with vasoconstriction and
arrhythmias.
Hormones
Glucagon is a hormone secreted by the a cells of the pancreatic
islets. It acts on adenylate cyclase to increase intracellular cAMP
levels, causing glycogenolysis and an increase in glucose. In
myocardial cells, cAMP levels are also increased, thus improving
contractility. Because the adrenoceptor is bypassed, glucagon is
used in the emergency treatment of poisoning by b-blockers.
Calcium sensitizers
Levosimendan is a calcium sensitizer. Its binding to troponin C
is Ca
2
dependent. When bound, levosimendan produces
a conformational change of troponin C leading to a prolonging of
the systolic interaction between actin and myosin. Improved
inotropicity results without increasing myocardial oxygen
demand or intracellular Ca
2
. Furthermore, its Ca
2
sensitizing
effects only occurs during systole as it detaches from troponin C
at reduced Ca
2
concentrations. Indeed it has been shown that
levosimendan has a positive lusitropic effect. An additional effect
of levosimendan is the opening of the ATP-dependent K

chan-
nels on the specic sites in the cardiovascular system. By
opening the mitochondrial ATP-dependent K

channels on the
cardiac myocytes it confers protection of the mitochondria during
ischaemia and reperfusion. Through opening of ATP-dependent
K

channels on the plasma membrane of the vascular smooth

muscles it causes arteriolar and venous dilatation particularly in
the coronary, cerebral, renal and splanchnic vascular bed. It
therefore reduces cardiac preload and afterload and offers
a further degree of protection in myocardial ischaemia by
improving myocardial O
2
supply. A recent meta-analysis of the
use of levosimendan in patients with acute severe heart failure
showed that its haemodynamic effects are more favourable
when compared with placebo or dobutamine and suggests that
its use is associated with reduced mortality when compared with
dobutamine.
Others
Vasopressin or antidiuretic hormone is released by the poste-
rior pituitary in response to increased plasma osmolarity,
hypotension, pain, nausea or hypoxia. It exerts its effects via
the vasopressin receptor. Stimulation of the V
2
-receptors on the
renal collecting ducts leads to the retention free water and
stimulation of the V
1
-receptors on peripheral arteriolar, capil-
lary and venules smooth muscle produce intense vasocon-
striction. The V
1
-receptor is linked to phosphodiesterase C,
thereby increasing intracellular Ca
2
in the vascular smooth
muscles. When compared with catecholamines, vasopressin
causes less direct coronary and cerebral vasoconstriction and
its pressor effects are not attenuated in hypoxic or acidotic
conditions. Aside from its direct vasoconstriction effect, it also
increase the sensitivity of the vasculature to catecholamines
thereby augmenting its pressor effects. In vasodilatory shock,
a low-dose infusion (0.01e0.04 units/minute) is recom-
mended. Higher infusion rates increase the incidence of
adverse effects (peripheral ischaemia, tissue necrosis and
arrhythmias) without improvement in haemodynamics
parameters. There is interest in the use of vasopressin during
cardiac arrest due to its retained action in acidotic and hypoxic
conditions and its prolonged half-life. However most recent
randomized controlled trials and meta-analysis failed to
demonstrate a difference in outcomes whether measured as
return of spontaneous circulation, survival to discharge or
neurologic outcomes. As such, vasopressin does not feature in
the 2010 Resuscitation Guidelines published by the Resuscita-
tion Council (UK).
Recent developments and future directions
With the exception of levosimendan, current inotropes all
produce their effects via an increase in the concentration of
intracellular calcium within the cardiac myocytes which also
directly leads to their adverse effects. Furthermore, advances in
research into the mechanisms of heart failure have revealed
that the excitationecontraction coupling within the diseased
cardiac myocytes are pathologically altered by a failure of
intracellular mechanisms which regulate the calcium balance in
the cytosol, sarcoplasmic and extracellular during the cardiac
cycle. Recent developments have been directed towards these
pathological changes in order to restore a normal calcium
balance without increasing to super-normal intracellular
calcium concentrations.
Istaroxime inhibits the Na

/K

ATPase to increase the intra-

cellular Ca
2
concentrations while at the same time stimulating
SERCA to restore normal Ca
2
re-uptake in diastole. It has been
shown in early animal and human trials to have positive
inotropic and lusitropic effects without an increase in myocardial
oxygen consumption or vasodilation.
Omecamtiv mecarbil belongs to a new class of inotropes whose
action is to promote actin-dependent phosphate release, the rate-
limiting step in the myocyte cross-bridge cycle, to initiate the
beginning of the power stroke by the myosin head. In early
human trials it has demonstrated an ability to increase systolic
ejection time, stroke volume, fractional shortening and ejection
fraction.
Nitroxyl (HNO) is related to nitric oxide and also functions as
a gaseous signalling molecule. In addition to actions similar to
nitro oxide (vasodilation) it has been found to be a positive
inotrope and lusitrope. While the mechanism by which it
produces positive inotropy and lusitropy is still to be fully
elucidated, it appears to function via modication of specic
cystine residues on phopholamban and or SERCA thereby
restoring a more normal calcium balance. It remains in the
experimental phase of development.
Ryanodine receptor stabilizers are a class of compounds that
restore normal function to the ryanodine receptor through which
calcium leaks abnormally from the sarcoplasmic reticulum in the
CARDIAC ANAESTHESIA
ANAESTHESIA AND INTENSIVE CARE MEDICINE 13:10 497 2012 Elsevier Ltd. All rights reserved.
pathological heart. The compound S44121 is currently being
studied in a phase 2 trial. A
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FURTHER READING
Hasenfuss G, Teerlink JR. Cardiac inotropes: current agents and future
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Holmes CL, Patel BM, Russell JA, Walley KR. Physiology of vaso-
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Housmans PR, Nuttall GA, eds. Advances in cardiovascular pharmacology.
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Overgaard CB, Dzavik V. Inotropes and vasopressors: review of physi-
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Rang HP, Dale MM, Ritter JM, eds. Pharmacology. 6th edn. Edinburgh:
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Toller WG, Stranz C. Levosimendan, a new inotropic and vasodilatory
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CARDIAC ANAESTHESIA
ANAESTHESIA AND INTENSIVE CARE MEDICINE 13:10 498 2012 Elsevier Ltd. All rights reserved.