Septic shock is a major cause of mortality in children. Myocardial dysfunction in severe sepsis and septic shock is well recognized but its pathogenesis could be multifactorial. As a result of complex interplay of various factors, hemodynamic changes observed in pediatric age group may be different from those observed in adult. Sepsis induced myocardial dysfunction (SIMD) is a known consequence of severe sepsis and septic shock. Although there is no universally accepted defi nition of this entity, it can be best defi ned as reversible intrinsic myocardial systolic and diastolic dysfunction of both the left and right sides of the heart induced by sepsis. In this review we discuss the pathogenesis, pathophysiology of clinical manifestations, diagnosis and management of SIMD in children. Key words: Sepsis induced myocardial dysfunction (SIMD), Severe Sepsis, Septic Shock

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Myocardial Dysfunction in Sepsis
Lokesh Tiwari*, Jyoti Chaturvedi**, Chhitiz Anand***
*Associate Pofessor and Head,***Sr. Resident, Department of Pediatrics, All India Institute of Medical Sciences Patna,
**Consultant Anaesthesiologist, Mahavir Cancer Hospital and Research Institute Patna,Bihar, India.
Received: 01-Aug-18/Accepted: 09-Aug-18/Published online: 30-Aug-18
Correspondence:
Dr.Lokesh Tiwari,Department of Pediatrics, All India Institute
of Medical Sciences Patna,Bihar,India.
Phone:+919631638095, E-mail : lokeshdoc@yahoo.com
Background
Severe sepsis and septic shock are major cause
of death (40-70% mortality rate) in children.1
Approximately 50% of patients with sepsis exhibit
signs of myocardial dysfunction. Alterations in
preload, afterload and myocardial contractility due
to dysregulated response to infection lead to failure
of cardiovascular system in sepsis and septic shock.
In adults, it is hyperdynamic warm shock due
to vasomotor paralysis leading to low systemic
vascular resistance (SVR) where cardiac output (CO)
is maintained or increased by reflex tachycardia
and ventricular dilation.2
However, progression to
decreased ejection fraction (EF) in these patients
indicates development of sepsis related myocardial
dysfunction. Contrary to the adults, predominant
manifestationofpediatricsepticshockishypodynamic
cold shock with low CO and reflexively increased
SVR.3,4
This indicates myocardial dysfunction as
primary mechanism of cardiovascular failure in sepsis
in children.
Cardiovascular dysfunction in sepsis or sepsis
induced myocardial dysfunction (SIMD) is associated
with a significantly increased mortality rate of
70–90 % as compared to 20 % among patients with
sepsis which is not accompanied by cardiovascular
impairment.5
Better understanding of the pathogenesis
of SIMD to timely decide the specific intervention
will improve the outcomes in children with severe
sepsis and septic shock. The aim of this review is to
discuss the pathogenesis, pathophysiology of clinical
manifestations, diagnosis and management of SIMD
in children.
Definition
SIMD has conventionally been defined in numerous
clinical investigations as a reversible decrease in EF
of both ventricles, with ventricular dilation and less
response to fluid resuscitation and catecholamines.6,7
However, this definition is too simplistic as left
ventricular EF does not reflect intrinsic myocardial
contractile function. Rather it is a load-dependent
indexthatreflectsthecouplingbetweenleftventricular
afterload and contractility.
There is a global impairment in cardiac function in
sepsis and septic shock. It is important to understand
that LVEF depends on pressor gradient between
left ventricle (contractility) and arteriolar system
(arterial compliance or afterload). With seriously
impaired left ventricularintrinsic contractility, left
ventricularejection fraction (LVEF) may still be
normal due to severely reduced afterload. Thus,
LVEF does not truly indicate intrinsic myocardial
dysfunction. Based on above observation, recently
suggested definition of SIMD is reversible intrinsic
myocardial systolic and diastolic dysfunction of
both the left and right sides of the heart induced by
sepsis.8,9,10
To truly diagnose SIMD, intrinsic
myocardial activity should preferably be
determined by using the load-independent parameters
ofsystolic and diastolic function.
ABSTRACT
Septic shock is a major cause of mortality in children. Myocardial dysfunction in severe sepsis and septic shock
is well recognized but its pathogenesis could be multifactorial. As a result of complex interplay of various factors,
hemodynamic changes observed in pediatric age group may be different from those observed in adult. Sepsis induced
myocardial dysfunction (SIMD) is a known consequence of severe sepsis and septic shock. Although there is no
universally accepted definition of this entity, it can be best defined as reversible intrinsic myocardial systolic and
diastolic dysfunction of both the left and right sides of the heart induced by sepsis. In this review we discuss the
pathogenesis, pathophysiology of clinical manifestations, diagnosis and management of SIMD in children.
Key words: Sepsis induced myocardial dysfunction (SIMD), Severe Sepsis, Septic Shock
DOI-10.21304/2018.0504.00409

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Pathogenesis
Global myocardial ischemia
In shock there is oxygen supply-demand imbalance
in various organs and it was suggested that
globalmyocardial ischemia might be responsible
for myocardialdysfunction in sepsis. However,
studies have shown that macro-circulatory coronary
blood flow is increased in patients with established
septicshock but cardiac microcirculation undergoes
major changes during sepsis with endothelial
disruption and blood flow maldistribution.11, 12
Fewmagneticresonancestudieshaveidentifiednormal
levels of high-energy phosphate in the myocardium
of animal models of sepsis.13
The adequate ATP in
myocardial tissue suggests adequate O2 supply in
sepsis and refutes the theory of myocardial tissue
hypoperfusion. It may be related to circulating
depressant factors or other mechanisms including
endothelial damage and induction of the coagulatory
system.
Direct myocardial depression
A major mechanism of direct cardiac depression
insepsis is catecholamine “desensitization” atthe
cardiomyocyte level due to down-regulation of
β-adrenergic receptors and depression of intracellular
post-receptorsignaling pathways. These changes are
mediatedby various cytokines and nitricoxide. Toxins,
complements, damage associated molecular patterns
(DAMPs) and many unidentified depressants lead to
mitochondrial dysfunction and direct cardiomyocyte
injury or death.8
Several myocardial depressant factor (MDFs) have
been identified.14
Among all, the combination of
TNF-α and IL-1β is extremely cardio depressive.15
These cytokines play key roles in the early decrease in
myocardial contractility. TNF-α and IL-1β induce the
release of additional factors such as nitric oxide (NO)
and oxygen-free radicals which are responsible for
prolongedmyocardialdysfunction.16
Aconstellationof
factors influences the onset of septic cardiomyopathy
through the release, activation, orinhibition of other
cellular mediators.
Complex interplay of various isoforms of nitric
oxide synthase (NOS) regulates balance among
NO, superoxide, and peroxy nitrite affecting
cardiomyocyte homeostasis and function. Sepsis
induced expression of inducible NO synthase (iNOS)
in the myocardium leads to high levels of sarcoplasmic
reticulum Ca2+ and myofilament sensitivity to Ca2+
contributing tomyocardial dysfunction.17
On the other
hand, endothelial NOS (eNOS) in the sarcolemmal
membrane produces NO that modifies L-calcium
channels to inhibit calciumentry and induces myofibril
relaxation, which mightplay an important protective
role against sepsis-induced myocardial dysfunction.
Neuronal NOS (nNOS) can regulate the β-adrenergic
receptor pathway. Recently identified red blood
cells NOS (rbcNOS) regulatesthe deformability of
erythrocyte membranes and inhibitsplatelet activation
in sepsis.8,18
Understanding of the complex NO
biology and its derived reactive nitrogen species
promises new, more specific, and effective therapeutic
strategies in sepsis related myocardial dysfunction.
Mitochondrial dysfunction
Sepsis mediators such as TNF-α, IL-1β, NO and
others lead to diminished activities of complexes I
and II of the mitochondrial respiratory chain. Altered
mitochondrial permeability transition pores might also
lead to internal edema within mitochondria causing
mitochondrial dysfunction. Recent studieshave
found that damaged and fragmented mitochondria
generate a significant amount of damage associated
molecular patterns (DAMPs), including mtROS,
mtDNA fragments, ATP, and cytochrome C initiating
inflammatory responses through multifactorial
pathways.19-21
Calcium channel dysfunction
Experimental studies have also suggested the role
of calcium channel alterations in the pathogenesis
of myocardial depression insepsis. Studies
have highlighted a down regulation of cardiac
dihydropyridine receptors (i.e. L-type calcium
channels) during induced endotoxemia; however,
the exact role of calcium channels in human septic
myocardial depression is yet to be elucidated fully.22,23
Other mediators like endothelin 1 (ET-1) and Toll-like
receptors (TLRs) are also suggested in some studies
to play important rolesin inflammation and immune
response related cardiac dysfunction in sepsis.22
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Pathophysiology
Interplay of ventriculo-arterial system
LVEF reflects the coupling between LV afterload
and LVcontractility. LVEF depends on interaction
between the left ventricle and the arterial system and
can be estimated by VA coupling that is defined as the
ratio of the arterial elastance (Ea) to the ventricular
elastance (Ees). Arterial elastance is a measure of the
net arterial load against which left ventricle has to
work, whereas ventricular elastance (Ees) indicates
how much the LV end-systolic volume will increase
in response to an increase in end-systolic pressures.
Ea and Ees can be estimated with invasive devices
like intraventricular catheters. Cardiovascular system
works most efficiently (best possible stroke work)
when they are optimally coupledi. e. V-A coupling
(Ea/Ees)is < 1 or approximately 1.24
In most patients with septic shock, ventriculoarterial
system is uncoupled (Ea/Ees>1) and cardiovascular
efficiency isimpaired leading to poor tissue perfusion.
In these cases, there is decrease in Ees (intrinsic
myocardial contractility) and arterial elastance may
be low or high (disease related or induced by therapy).
An optimal Ea/Ees coupling may be obtained by
balancing volume, inotropic, and vasoconstrictor
therapies.25
Assessment of LVEF being simple
bedside tool, has become most widely used surrogate
index of LV contractility. However, LVEF is “load-
dependent” parameter and represents the interaction
between the left ventricle and the arterial system (VA
coupling). As explained, load-dependant indices like
LVEF, cardiac index (CI) and stroke volume index
may be observed as normal in septic patients even
when intrinsic myocardial contractility is poor in
presenceofseverelyreducedarterialtone.Considering
that myocardial depression is constant in patients with
sepsis and septic shock, LV systolic function should
be considered more as a reflection of the vascular
tone status than of intrinsic LV contractility.22
Use
of pulmonary artery catheter and echo doppler
techniques like tissue doppler imaging have greater
diagnostic accuracy for myocardial depression.
Recent echocardiographic studies have also suggested
that diastolic dysfunction is common in patients with
severe sepsis and septic shock however, its impact in
prognosis and management is still unclear and more
studies are needed.26
Vincent et al found significantly lower right
ventricular ejection fraction in patients with septic
shock using thermodilution technique in a series of
127 consecutive critically ill patients. RVEF can be
reduced due to peripheral vasodilation and preload
reduction in early phase of septic shock. However,
both myocardial depression and pulmonary artery
hypertension may also be responsible for RV
dysfunction.27
Hemodynamic changes
Reduced preload
Sepsis induced hemodynamic alterations are due
to intravascular volume depletion, loss of vascular
tone, inhomogeneous distribution of blood flow
between organs, microcirculatory imbalance, VO2
/
DO2
dependency, and high lactate levels. The
decreased intravascular volume is due toabsolute or
relative hypovolemia leading to reduced preload.
Microvascular barrier dysfunction and increased
capillary permeability due to sepsis related cytokines
and other inflammatory mediators leads to absolute
volume loss whereas endotoxemia related venous
pooling, especially in the splanchnic compartment,
leads to reduction in the effective compliance of the
total vascular bed and relative hypovolemia.28
Decreased vascular tone (reduced afterload)
As explained above, decreased vascular tone may
temporarily mask myocardial depression, allowing
maintained LVsystolic function despite myocardial
depression in early phase of septic shock. Normal
LVEF may be observed, despite seriously impaired
intrinsic LV contractility if arterial tone is severely
depressed.
Altered systemic resistance is related to autonomic
dysregulation and an imbalance between
vasoconstrictor and vasodilator factors. Various
vasodilating factors released during sepsis are NO,
TNF-α, histamine, kinins, and prostaglandins.
Vascular hyporesponsiveness in the form of
lower vasoconstrictor response to angiotensin II,
catecholamines, serotonin, and potassium chloride
is reported in experimental models of sepsis related
conditions.22, 29
State of catecholamine “desensitization” could be
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Myocardial Dysfunction in Sepsis
a result of either down-regulation of α1-adrenergic
receptor or uncoupling between receptors and
their intracellular messengers. Decreased plasma
vasopressin levels and down-regulated V1 receptor
expression has also been reported in sepsis. Other
reported factors causing vasoplegia in sepsis
are increased production of superoxide anion,
peroxynitrite, and prostacyclin; decreased steroid
sensitivity; corticosteroid insufficiency and activation
of ATP-sensitive (KATP) potassium channels.22, 30,31
Microcirculatory alterations
Microcirculatory changes in the form of reduction
in functional capillary density and altered perfusion
(intermittent, reduced, or stopped blood flow)
have been reported to appear much before the
macrocirculatory changes (clinical signs of altered
hemodynamics) in severe sepsis and septic shock.
Persisting changes are related to poor survival
outcome.32
Microcirculatory alterations leading to
impaired oxygen extraction explain the dissociation
between myocardial depression and elevated mixed
venous oxygen saturation(ScvO2
) values observed in
septic patients.
VO2/DO2 dependency
Poorperfusioninsepsisfrequentlyleadstodependence
of tissue oxygen uptake (VO2 ) on tissue oxygen
delivery (DO2); so-called VO2/DO2 dependency.
Lactate
Serum lactate values greater than 2 mEq/L reflect
the presence of circulatory failure. Increased lactate
levels may also be due to seizures, hyperventilation
or altered metabolism (liver failure, mitochondrial
inhibition). High lactate is related to poor survival
outcome however “lactate clearance” (rate necessary
to metabolize lactate ina certain time) has been
reported to have better predictive value for organ
failureand mortality.33
Investigations
Use of the pulmonary artery catheter (PAC) and echo-
Doppler techniques are promising in the diagnostic
approach to sepsis related myocardial depression.
Although the benefits of PAC use on patient outcome
have never been convincingly demonstrated,
continuous monitoring of central venous pressure,
right-sided intracardiac pressure, pulmonary artery
pressure, pulmonary artery occlusion pressure and
mixed SvO2
helps bedside clinician for assessing the
RV function and response to therapy. PAC can be used
to measure CO using thermodilution techniques.34, 35
Tissue Doppler imaging
Echocardiography is the most commonly used bedside
tool to assess myocardial function in sepsis and septic
shock. Global systolic function can be assessed by
quantitative metrics such as fractional shortening (FS)
and ejection fraction (EF). Various load dependant
echocardiographic parameters toassess LV function
such as ejection fraction, cardiac index (CI), and
stroke volume index may be inaccurate because they
are influencedby changes in heart rate, preload, and
afterload as discussed earlier. Tissue Doppler Imaging
(TDI) and two-dimensional strain echocardiography
(SE) is a contemporary angle-independent method for
evaluating cardiac function by tracking cardiac tissue
deformation. TDI provides quantitative information
about myocardial motion with high temporal and
spatial resolution. It is less load dependent and has
greater diagnostic and prognostic use compared with
conventional echocardiography.36,37
Myocardial performance index (MPI) also known as
Tei index represents global myocardial performance
and provides an evaluation of both systolic and
diastolic function. Peak systolic velocity measured
at the mitral annulus reflects the systolic motion of
the ventricle long axis, whereas the early diastolic
velocity of the mitralannulus reflects the rate of
myocardial relaxation.38
These values have been demonstrated to be useful in
diagnosis and prognosis of different cardiovascular
diseases, however careful interpretation is needed
in relation to preload variations, common in patients
with sepsis and septic shock undergoing resuscitation
and optimization of hemodynamic status.
In many studies, blood troponin concentration
is reported to correlate well with poor cardiac
functionand response to therapy in children with
septic shock.39
Laboratory markers of cardiac function
and oxygen delivery: utilization balance include
troponin and lactate. Lactate is recommended as
an important laboratory testfor both diagnosis and
subsequent monitoring of patient with septic shock.
However, it primarily reflects balance of oxygen

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delivery and utilization in body rather than cardiac
dysfunction.
Treatment
As myocardial dysfunction is part of a systemic
dysregulated response to infection, causal line of
therapy remains sepsis control using prompt and
adequate antibiotic therapy along with measures to
control source of infection including surgical removal
of infectious focus.
Myocardial dysfunction being reversible process in
most of the cases, organ support remains lifesaving
strategy. Optimum fluid therapy, vasopressors and
inotropic agents along with good supportive care
is crucial to improve outcomes. Surviving sepsis
guidelines may be taken as good starting point in
treatment of septic shock and sepsis associated
myocardial dysfunction.40
Adults are more likely
to have vasomotor dysfunction in sepsis where
vasopressor therapy shows good response. However,
mechanism of sepsis related cardiac dysfunction
is not well elucidated in children and management
of septic shock in children is based on predominant
pathophysiological status (warm shock or cold shock).
Children respond well to inotropic and at times
to vasodilating agents suggesting that myocardial
dysfunction is a major player in children as compared
to vasomotor dysfunction in adults.
With evolving evidence and better understanding
of pathophysiological changes, management of
septic shock is going through a paradigm shift
from protocolized guidelines-based approach like
surviving sepsis bundle or early goal-directed therapy
to an individualized physiology-based management
strategy. It is important to acheive therapeutic targets
with background understanding of cardiovascular
interaction in sepsis and septic shock.
Septic shock treatment should target restoration of
normal mental status, threshold HRs, peripheral
perfusion (capillary refill < 3 s), palpable distal pulses,
and blood pressure for age.41
Further evaluation and
treatment should also be guided by hemodynamic
variables including perfusion pressure (MAP –
CVP) and CO to maintain effective blood flow in
individual organs. Measurement of cardiac outputand
accurate blood pressure needs invasive catheter
placement though it may not be feasible in most of the
settings.35
Non-invasive methods to monitor cardiac
output also need expertise. Measuring Scvo2 may act
as surrogate marker to estimate CO as discussed later.
Cardiac index (CI) is a haemodynamic parameter that
relates the cardiac output (CO) from left ventricle
in one minute to body surface area (BSA). It can be
derived as CI = CO/BSA = (HR X SV)/ BSA (L/min/
m2
). A CI between 3.3 and 6.0 L/min/m2 is reported
to have best outcomes in patients with septic shock
compared to patients without septic shock for whom
a CI above 2.0 L/min/m2 is sufficient.35
Because CO = HR × SV, targeted CO is often
dependent on attaining threshold HRs. Myocardial
perfusion through coronary arteries occurs during
diastolic phase. If there is significant tachycardia,
there is not enough time to fill the coronary
arteries during diastole, causing further myocardial
depression, poor contractility and low CO. Coronary
perfusion is further compromised if diastolic blood
pressure (DBP) is low and/or end diastolic ventricular
pressure is high.
Fluid bolus may restore end-diastolic volume and
improve coronary perfusion pressure. Addition of
inotrope will improve myocardial contractility (SV)
and CO and will reflexively reduce HR. This will
be evident in improvement of the shock index (HR/
systolic blood pressure) as well as CO Reported
normal cut off values of Pediatric Adjusted shock
index (SIPA) are 1.2 for 4-6 years; 1 for 6-12 years;
and 0.9 for > 12 years. For normal healthy adults it is
0.5 to 0.7.42
Increased systemic vascular resistance (SVR) is
clinically identified by cool extremities, prolonged
capillary refill, absent or weak distal pulses and
narrow pulse pressure with relatively increased DBP.
Vasodilator therapy is useful in this scenario as it
reduces after load and increases vascular capacitance
for which additional fluid volume should be given.
Additional fluid volume to restore filling pressure
results in a net increase in end-diastolic volume (i.e.,
preload) and improved CO.
If the HR is below the threshold minimum HR,
then CO will also be too low (CO = HR × SV).
Use of inotrope with chronotropic property such as
epinephrine will be helpful in such cases. If diastolic
blood pressure or DBP – CVP is too low, an inotrope/
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vasopressor agent such as norepinephrine will be
required to improve diastolic coronary blood flow.
In significant myocardial depression or in fluid
overload, a diuretic may be required to improve stroke
volume (SV) by moving leftward on the overfilled
Starling function curve. One of the targets of initial
resuscitation in EGDT protocol was achievement of
Scvo2
> 70%. Scvo2 < 70% indicates poor CO. In
contrast, supra-normal Scvo2 (> 80–85%) that reflects
narrowed arteriovenous difference in oxygen content
is indicator of either mitochondrial dysfunction (poor
oxygen extract), a high CO state, or overly aggressive
resuscitation (35, 43). Serial monitoring of multiple
variables (multimodal monitoring) such as HR/SBP
shock index, CO, and SVR along with clinical signs
such as distal pulses, skin temperature, capillary refill,
serum lactate level and urine output is important to
determine the underlying hemodynamic status and
response to therapy. 44
Hemodynamic stabilization
In adults, sepsis and septic shock is often characterized
by a hyperdynamic circulation having higher cardiac
output in response to systemic vasodilatation and
relative and/or absolute hypovolemia. However,
hypodynamic pattern is also quite common, more so
in children usually due to myocardial dysfunction
related to sepsis. Rapid and effective fluid therapy
to restore adequate volemia is most important. Early
goal directed therapy protocol has been standard of
care for management of septic shock in emergency
for more than a decade, however recently conducted
large multicentre randomized controlled trials failed
toreplicate the mortality benefit of EGDT.45-47
The
above trials challenged the necessity of targeting each
of the components of the 6-hour resuscitation bundle
of EGDT. Similar outcomes with usual standard
care in these studies, indicate towards importance of
individualized clinical judgement and care based on
physiologic status of the patient and setting in which
patient is being treated.
As we target cerebral perfusion pressor in
management of raised intracranial pressure,
importance of targeting organ perfusion pressor is
equally valid for other organs during management
of septic shock.48
The primary therapeutic target
is to restore tissue perfusion by ensuring targeted
perfusion pressure.In children perfusion pressure of
MAP – CVP is calculated using formula 55 + age x
1.5. Here CVP is considered 0 but in setting of higher
CVP or intra abdominal pressure (IAP), appropriate
correction of targeted perfusion pressure should be
done by adding actual value of CVP or IAP to this
formula. Other targets are Scvo2 greater than 70%
and/or CI 3.3–6.0L/min/m2. 35
In view of marked individual variability, patients
should undergo frequent clinical evaluation of shock
parameters to adjust targets for clinical variables of
shock management.
Fluid therapy
There is no myocardial protector fluid and SSC
guidelines recommend use of crystalloids as the initial
fluid of choice in the resuscitation of severe sepsis
and septic shock.40
In view of increasing concern
of hyperchloremia and acute kidney injury with
‘chloride liberal’ normal saline, balanced solutions
are being investigated as a better alternative, though,
normal saline remains the standard of care till we get
more evidence in this area.49, 50
Inotropes
Low-dose epinephrine (0.05–0.3μg/kg/min) is
suggested by many authors as first-line choice
for cold hypodynamic shock for its β2-adrenergic
effects in the peripheral vasculature with little
α-adrenergic effect at this dose.35,40
Dopamine
(5–9 μg/kg/min), being time tested in children is
still first line in otropic support in children at most
of the centres. Dobutamine may be used when
there is a low CO state with adequate or increased
SVR. Epinephrinestimulates gluconeogenesis and
glycogenolysis, and inhibitsthe action of insulin,
leading to increased blood glucose concentrations and
increasedplasma lactateconcentrations independent of
changes in organ perfusion. In an emergency, it may
be infusedthrough a peripheral IV route or through an
intraosseous needlewhile attaining central access.35, 51,
52, 53
Vasopressors
Norepinephrine is recommended as the first line agent
in adults with fluid-refractory shock. Use of low-dose
norepinephrine as a first-line agent for fluid-refractory
hypotensive hyperdynamic shock has also been
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suggested in children by many authors. Vasopressors
should be used in pediatric septic shock as per the
pathophysiological scenario discussed above (warm
shock or hyperdynamic septic shock with flash
capillary refill, warm extremities, low diastolic
pressure, and bounding pulses) however, excessive
vasoconstriction compromising microcirculatory
flow should be avoided. Dopamine > 15 μg/kg/min,
epinephrine > 0.3 μg/kg/min, or norepinephrine have
vasopressor effect and there is no sufficient evidence
to support one drug over another.35, 54, 55
Vasodilators
In children with fluid-refractory septic shock, who are
normotensive with a low CO and high SVR, initial
treatment consists of the use of an inotropic agent
such as epinephrine or dobutamine that tends to lower
SVR. A short-acting vasodilator such as sodium
nitroprusside or nitro glycerine may also be added
judiciously to recruit microcirculation.35,40
Type III
phosphodiesterase inhibitors (PDEIs) including
milrinone and inamrinone improve myocardial
contractility and reduce SVR (inodilator effect).
PDEIs have a synergistic effect with β-adrenergic
agonists and they maintain their action even when
the β-adrenergic receptors are down-regulated or
have reduced functional responsiveness (state of
catecholamine desensitization in sepsis). At times
these drugs may cause arrythmia and hypotension
and should be discontinued immediately due to longe
limination half-life. Hypotension can be potentially
overcome by promptly beginning vasopressor such
as norepinephrine.56,57
Enoximone is another type
III PDEI which is reported to have more β1 cAMP
hydrolysis inhibition than β2 cAMP hydrolysis
inhibition. Hence, it can be used to increase cardiac
performance with less risk of undesired hypotension.35
One of the pathogenic mechanisms of sepsis induced
cardiac dysfunctionis desensitization of Ca++
/ actin
/ tropomyosin complex binding as discussed above.
Levosimendan is a promising drug that increases Ca++
/ actin / tropomyosin complex binding sensitivity and
has some type III PDEI and adenosine triphosphate–
sensitive K+
channel activity.58
Vasopressin and
terlipressin have been shown to increase MAP, SVR,
and urine output in patients with vasodilatory septic
shock and hypo-responsiveness to catecholamines.35
Vasopressin’s action being independent of
catecholamine receptor stimulation, its efficacy is not
affected by α-adrenergic receptor down-regulation
oftenseeninsepticshock.Angiotensin,Phenylephrine,
Nitric oxide (NO) inhibitors and methylene blue are
considered investigational therapies in septic shock
refractory to norepinephrine.35
Conclusion
Sepsis is a major cause of mortality worldwide and
SIMD is a frequent consequence in severe sepsis and
septic shock. Alterations in preload, afterload and
myocardial contractility due to dysregulated response
to infection lead to failure of cardiovascular system in
sepsis and septic shock. The pathogenesis involves a
complex mix of systemic factors apart from genetic,
molecular, metabolic, autonomic and structural
alterations. In septic shock adults are more likely to
have vasomotor dysfunction where as children are
more likely to have myocardial dysfunction. SIMD
is reversible entity most of the time, if timely causal
treatment of sepsis (antibiotics and source control)
and organ support for failing cardiovascular system
can be provided. EGDT protocol advocates time
bound achievement of ‘goals’ in management of
septic shock however, findings of recent large trials
have challenged this approach and indicate towards
a paradigm shift from protocolized guidelines-based
approach to an individualized pathophysiology-based
management strategy.
Conflict of Interests:Nil
Source of Funding:Nil
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How to cite this article:
Tiwari L, Chaturvedi J, Anand C.Myocardial Dysfunction in Sepsis. J Pediatr Crit Care 2018;5(4):41-49.
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Tiwari L, Chaturvedi J, Anand C.Myocardial Dysfunction in Sepsis. J Pediatr Crit Care 2018;5(4):41-49.
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Myocardial Dysfunction in Sepsis