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HEART DYSFUNCTION IN SEPSIS

Dr Ricardo Poveda-Jaramillo

PII: S1053-0770(20)30656-X
DOI: https://doi.org/10.1053/j.jvca.2020.07.026
Reference: YJCAN 6065

To appear in: Journal of Cardiothoracic and Vascular Anesthesia

Please cite this article as: Dr Ricardo Poveda-Jaramillo , HEART DYSFUNCTION IN SEPSIS, Journal
of Cardiothoracic and Vascular Anesthesia (2020), doi: https://doi.org/10.1053/j.jvca.2020.07.026

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 HEART DYSFUNCTION IN SEPSIS

Full names of authors in preferred order: Dr RICARDO POVEDA-JARAMILLO

Separate list of authors by name, title, and institution: Dr RICARDO POVEDA-

JARAMILLO, Cardiovascular & Thoracic Anesthesiologist, ANESTESIAR

Notice of Corresponding Author with full contact information including e-mail address: Dr
RICARDO POVEDA-JARAMILLO, Carrera 27AA #37B Sur-60, Loma de Las Brujas,
Edificio Entrepinos, Torre 1, Apt 1402, Código Postal 055420, Envigado, Antioquia,
Colombia. Telephone: (57) 3102989437, (57) 4- 5399448. e-mail address:
ricardopovedamd@yahoo.com

Statements of funding: This manuscript has not had financial support from any person or
entity.

Declarations of interest: none.

Acknowledgements: To my wife for her patience while I prepared this manuscript.

Abstract

Cardiac involvement during sepsis occurs frequently. A series of molecules induces a set of

changes at the cellular level that result in the malfunction of the myocardium. The

understanding of these molecular alterations has simultaneously promoted the

implementation of diagnostic strategies that are much more precise and allowed us to

advance the therapeutics.

1
Introduction

The heart is a vital organ for survival. Its well-being ensures the adequate supply of

essential elements for organs and tissues.

Sepsis is a major health problem that affects millions of individuals worldwide each year,
(1-3)
killing 1 in 4 individuals with this infection . Sepsis-induced myocardial dysfunction

(SIMD) is a common complication in patients with sepsis. Many studies have shown that

myocardial dysfunction is a usual finding in sepsis; approximately 50% of patients with

sepsis exhibit signs of myocardial dysfunction. Heart involvement is critical in sepsis

because it marks the therapeutic path to follow and defines the prognosis of these patients
(4-6)
.

Definitions

Sepsis is a life-threatening organic dysfunction caused by a dysregulated host response to

infection. In sepsis, the body's response to infection is responsible for damage to the tissues

and organs. The organic dysfunction can be represented by an acute increase in the total

SOFA (Sequential Organ Failure Assessment) score of 2 points or more consequent to the

infection (7).

Septic shock is a subtype of sepsis in which the underlying circulatory, cellular and

metabolic abnormalities are sufficiently deep to substantially increase mortality. Patients

with septic shock can be identified as those with a vasopressor requirement to maintain

mean arterial pressure (MAP) of ≥65 mmHg, and with a serum lactate level of >2 mmol/L

(18 mg/dL) despite adequate resuscitation with liquids (7).

2
According to our review of the literature, there is no universally accepted definition of

SIMD. SIMD was defined as a reversible decrease in ejection fraction (EF) of both

ventricles, with ventricular dilation and poor response to resuscitation with fluids and
(8)
catecholamines . However, it has since been demonstrated that left ventricular EF is a

measurement that reflects the coupling between the left ventricular afterload and

contractility, rather than the intrinsic contractile function of the myocardium. Therefore, the

literature has recently been suggested that SIMD should be defined as intrinsic myocardial

systolic and diastolic dysfunction of the left and right sides of the heart induced by sepsis (9,
10)
.

Molecular mechanisms

The most recent extensive research on cardiomyopathy in sepsis has identified several

complex underlying molecular mechanisms, and metabolic and structural changes.

- Coronary flow and adrenergic response

Global hypoperfusion and hypoxia do not seem to have a crucial role in septic

cardiomyopathy, according to studies of positron emission tomography and 18F-

(11, 12)
fluorodeoxyglucose studies . The molecular mechanisms responsible for cardiac

dysfunction in sepsis are more complex than the simple absence of coronary irrigation.

Septic shock is a hyperdynamic process characterized by an increase in cardiac output and

low systemic vascular resistance. Prolonged peripheral vasodilation and increased cardiac

index in sepsis can lead to high-output heart failure, or they can mask underlying
(13)
myocardial depression . Myocardial dysfunction is common in sepsis and is believed to

3
be explained by a phenomenon of non-ischemic myocardial depression, and possibly even a
(14)
self-protective "hibernation" of the myocardium . Although coronary blood flow has

been shown to increase in sepsis, the difference in oxygen tension between the coronary
(15)
arteries and the coronary sinus is less than expected . This finding suggests that a

combination of altered cell metabolism and autoregulatory changes in the microvasculature

of the heart underlie altered cardiac contractility in sepsis (16).

There is growing evidence that the adrenergic response of cardiomyocyte filaments is

(17, 18)
attenuated in sepsis . β1 adrenergic receptors and stimulant G proteins decrease, and

β3 receptors and inhibitory G proteins increase (19, 20). These changes translate into reduced

activity of adenylate cyclase and reduced levels of cyclic adenosine monophosphate

(cAMP). Thus, it seems, in this manner, that impaired myocardial responsiveness to

catecholamines in sepsis can be attributed to the downregulation of adrenergic receptors

and/or post-receptor signaling (21, 22).

The membrane potential is disrupted by the inhibition of the Na+/K+-ATPase pump, which

interferes with the repolarization of the depolarized myocyte (23). Experimental models have

observed an extension of the duration of the action potential and alteration of the resting

membrane potential (23).

- Circulating factors

The systemic inflammatory reaction in sepsis is induced and sustained by endogenous

"danger molecules" called damage-associated molecular patterns (DAMPs); they circulate

in the blood and trigger systemic inflammation. An example of these molecules is heparan

4
sulfate (HS), which is separated from the cell surface by the enzyme heparanase. Under the
(24-26)
influence of proinflammatory cytokines, heparanase becomes functionally prolific by
(27, 28)
releasing proinflammatory HS into the circulation and increasing microvascular

permeability (29). Circulating HS in the blood triggers cardiomyocyte inflammation because

the stimulation of cardiomyocytes by HS through a Toll-like receptors (TLRs), leads to an

increase in the nuclear transcription of proinflammatory cytokines (30).

Histones are another type of DAMP: They act through TLR2 and TLR4 leading to a
(31)
reduction in mitochondrial membrane potential and cellular ATP levels . High levels of

plasma histones are significantly associated with the occurrence of left ventricular
(32)
dysfunction and arrhythmias . Additionally, the high mobility group protein B1

(HMGB1) is a DAMP released from lipopolysaccharides of the cardiomyocyte cell wall

and exerts its deleterious effect by increasing the calcium output from the sarcoplasmic
(33)
reticulum (SR) . An increased plasma HMGB1 level has produced a negative inotropic

effect in isolated rat hearts (34, 35).

Circulating myocardium-depressing factors increased the expression of intercellular

adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM1) in

coronary endothelial cells and cardiomyocytes. A blockade of VCAM-1 and ICAM-1 has

reduced LPS-induced cardiac dysfunction (36-38).

- Inside the cell

(39)
In the heart, many infiltrating immune cells and the cardiomyocytes express TLR .

Transduction of signals dependent on these TLRs results in increased expression of several

5
proinflammatory cytokines. Lipopolysaccharide (LPS) and DAMPs interact with TLRs in

immune cells and other cells. All TLRs, except TLR3, signal through the myeloid

differentiation factor 88 (MyD88)-dependent pathway and activate c-Jun N terminal kinase

(JNK), extracellular signal-regulated kinases 1/2 (ERK1/2), p38 mitogen-activated protein

kinase (MAPK), and the transcription factor nuclear factor (NF)-kB signaling pathways,

which induces the production of multiple cytokines, including interleukin (IL)-1, IL-6, and
(40, 41)
TNF-α . These cytokines together with complementary anaphylatoxin (C5a) and LPS

have been considered myocardial depressive factors (9, 10).

- Contractile mechanism

The pathophysiological mechanisms described can only contribute to cardiomyocyte

contraction disorder by influencing the intracellular calcium content or myofilamentary

(42)
integrity . In addition to the decrease in calcium sensitivity of cardiac myofilaments
(43)
because of increased phosphorylation of inhibitory troponin I , dysfunction of
(42)
intracellular calcium transporters plays a decisive role . Cardiomyocytes, isolated from

patients with sepsis, show in vitro a decrease in the amplitude of contraction, which is

because of the decrease in the amplitude of intracellular calcium currents and the decrease

in sarcoplasmic calcium levels (44).

Under physiological conditions, calcium entrance to cardiomyocytes occurs during

electromechanical coupling through type L calcium channels, resulting in the release of

calcium from the sarcoplasmic reticulum. When calcium binds to troponin C, it causes

conformational changes that lead to the dislocation of troponin I and eventually,

tropomyosin leaves the site of myosin binding in actin, which leads to muscle contraction

6
(45)
. In the end, active reuptake of intracellular calcium in the sarcoplasmic reticulum occurs

through sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), and calcium is pumped out

of the cell through the Na+-Ca2+ exchanger (NCX). During septic cardiomyopathy, the

function of SERCA and NCX is inhibited (39-53).

Alterations in the Ca2+ balance in cardiomyocytes during sepsis seem to be the product of

specific molecular factors such as tumor necrosis factor alpha (TNFα), interleukin 1 beta
(54-60)
(IL-1β), interleukin 6 (IL-6), and complement component 5a (C5a) . These cytokines

apparently mediate their deleterious cardiomyocyte effect through the induction of the
(61, 62)
release of reactive oxygen species (ROS) . ROS influence contractile function by

modifying the proteins involved in the excitation-contraction process, increasing the

probability of the Ca2+/ryanodine receptor/channel (RyR) being open, annulling the L type

calcium channel, and inhibiting the reuptake of calcium in the sarcoplasmic reticulum

through SERCA (63, 64). The RyR transports Ca2+ into the cytosol by recognizing Ca2+ on its

cytosolic side, establishing a positive feedback mechanism; a small amount of Ca2+ in the

cytosol near the receptor causes it to release even more Ca2+. However, as the concentration

of intracellular Ca2+ increases, this can trigger the closing of the RyR, preventing the total

depletion of sarcoplasmic reticulum; this organelle regulates the level of intracellular Ca2+,
(65)
but when this capacity is altered, it is responsible for the generation of arrhythmias . The

degree of cardiac dysfunction correlates directly with the serum C5a levels found in septic

humans (66).

- Cardiomyocyte metabolism

7
Sepsis produces a reprogramming of cardiomyocyte metabolism, through reduced

expression of fatty acid binding protein, acyl-CoA synthetase, and transcription factors

associated with fatty acid oxidation, including peroxisome proliferator-activated receptors

(PPARs) and PPARγ-coactivator-1 (67, 68). Cardiomyocyte Krüppel-like factor 5 upregulated

(67, 68)
PPARγ expression through direct promoter binding, which is blocked in sepsis .

Depletion of the Krüppel-like factor 5 of cardiomyocytes reduces myocardial expression of

PPARγ, fatty acid oxidation, and ATP levels. Drosatos et al. showed that rosiglitazone

increased PPARγ expression, increased the oxidation of fatty acids in cardiomyocytes, and

prevented cardiac dysfunction induced by LPS (69).

Mitochondria are also damaged during septic cardiomyopathy. The microstructural

breakdown of mitochondria leads to an increase in its permeability (70) and the release of its
(71)
DNA . Perhaps this mitochondrial fragmentation makes this cellular organelle an

eloquent source of DAMPs (ROS, mitochondrial DNA, ATP, and cytochrome C) to not

only favor the systemic inflammatory response, but also undermine the enzymatic activities

of the respiratory chain and lower the bioavailability of ATP (72).

Monitoring

Invasive arterial and venous blood pressures are important methods for the diagnosis and

monitoring of therapy in patients who are in critical condition. The pulmonary artery

catheter (PAC), compared with the central venous catheter, allows a much more

differentiated measurement of hemodynamic conditions (cardiac output [CO], pulmonary

artery vascular resistance, and systemic vascular resistance). In addition, the mixed venous

8
saturation measured by PAC in the pulmonary vessels is an indirect measurement of the
(73)
oxygen supply or its consumption . However, PAC did not alter the mortality, length of

stay in intensive care unit and hospital or cost for adult patients in intensive care (74).

PiCCO System (Pulse-Induced Contour Cardiac Output) is an invasive hemodynamic

monitoring system capable of measuring CO by transpulmonary thermodilution and

estimating preload by means of intrathoracic blood volume; its use has reduced the duration
(75)
of mechanical ventilation . In a prospective multicenter study, Uchino et al observed

that when the choice of the type of monitoring is left to the caregiver's discretion, it varies

according to the patient's condition: the use of the PAC catheter increases in patients with

cardiogenic shock and the PiCCO system in septic patients. Once the confounding variables

were adjusted, the choice of one technique or another did not imply differences at the

prognostic level (76).

Less invasive pulse contour analysis techniques (FloTrac/Vigileo) show a strong

dependence on systemic vascular resistance; because this can vary widely in sepsis, this
(77)
method is of limited use for the diagnosis of septic cardiomyopathy . Monnet et al.

compared cardiac output measured by the PiCCO and Vigileo systems in 80 patients in a

state of septic shock and observed that the PiCCO system showed greater accuracy in

detecting changes in cardiac output with volume expansion and with norepinephrine’s use
(78)
.

- Cardiac output related to afterload

9
In shock states, in addition to there being absolute and relative hypovolemia because of

decreased intravascular content and redistribution of blood flow (which determines the

decrease in preload), there is a reduction in vascular tone (reduced afterload). Namely, the

reduction in vascular tone may temporarily mask cardiac dysfunction because the left

ventricular ejection fraction (LVEF) in the context of shock reflects the state of systemic
(79)
vascular resistance (SVR) instead of myocardial contractility . With the decrease in

SVR, CO increases to the maximum physiological limit. An increase in SVR for vasoactive

substances leads to a decrease in CO and the unmasking of any myocardial dysfunction (80).

Patients with low LVEF have low survival, but patients with normal LVEF and low left

ventricular afterload have increased mortality (79).

A suggested method to improve the prognosis is to complement echocardiography by

quantifying myocardial performance through advanced hemodynamic monitoring.

Afterload-related cardiac output (ACO) is less than 60% in 63% of patients who die, and

75% of survivors have an ACO greater than 60% (80).

( )

Where:

ACO is cardiac output related to afterload, CO is cardiac output, MAP is mean arterial pressure,

and CVP is central venous pressure.

10
Please check Table 1 for the degrees of severity of cardiac dysfunction according to the

ACO.

- Electrocardiogram

A 12-lead ECG is easy to perform and should therefore be a natural diagnostic basis at the

bedside if cardiac dysfunction is presumed. Sepsis associated ECG findings reported in the

literature in patients with or without ischemic heart disease include prolongation of the PR
(81) (82, 83) (84, 85)
interval , loss of QRS amplitude , increases in QT interval , development of

narrowed or wide QRS intervals, deformed bundle branch blocks, and positively deflected
(75)
J waves (commonly known as Osborn waves) and are also common findings in sepsis
(86)
. Sepsis is an independent risk factor for prolongation of the QTc interval, which is

associated with a longer duration of hospital stay and greater probability of hospital

mortality, because prolongation of the QT interval on the electrocardiogram is associated

with Torsades de Pointes (84). Septic cardiomyopathy can simulate acute coronary syndrome

with ST segment elevation and elevated biomarkers; however, if the inexperienced clinician

falls into the trap and attempts to stage this patient, coronary angiography without lesions is

the result (75). ECG changes usually return to normal after recovery from sepsis (83).

- Echocardiography

The evaluation of cardiac function using conventional echocardiographic parameters, such

as LVEF, is strongly influenced by changes in pre- and afterload. Other echocardiographic

methods for the quantification of ventricular contractility such as tissue Doppler are limited

by their angular dependence.

11
Speckle tracking echocardiography is a method of quantifying cardiac function introduced

in 2004. The method is based on a semiautomatic algorithm that tracks the change in

acoustic "motes" in the myocardium. Compared with LVEF, this "mottled" change is

significantly less affected by preload and afterload because it directly quantifies segmental

myocardial deformation (87).

The maximum global left ventricular longitudinal systolic tension that is measured with

speckle tracking at the time of admission of patients with sepsis correlates well with their

mortality rate (6). Up to 50% of patients with sepsis with preserved LVEF have a depressed
(88)
global left ventricular longitudinal function (detectable through speckle tracking) . The

research has indicated that left ventricular and right ventricular systolic dysfunction in

patients with early septic shock and preserved LVEF can be discovered by speckle tracking
(86)
echocardiography . The clinical features of segmental ventricular dysfunction during

SIMD are sometimes consistent with Takotsubo cardiomyopathy, in which the contractile

function of the middle-to-apical segments of the left ventricle is depressed and there is

hyperkinesis of the basal walls, inducing the balloon-like appearance of the distal ventricle
(89)
.

Speckle tracking has a substantial advantage over tissue Doppler echocardiography that can
(45)
be performed independent of the angle . Tissue Doppler echocardiography measures the

velocity of the myocardium through 1 or more heartbeats by the reflected ultrasound. The

technique is the same as for flow Doppler echocardiography, which measures flow

velocities. However, tissue signals have a higher amplitude and lower velocities. Tissue

Doppler echocardiography depends on the angle between the reflected ultrasound from the

12
myocardium and the transducer because the tissue velocity is multiplied by the cosine of
(90)
that angle _the cosine of 0º is 1 and the cosine of 90º is 0 _ thus, the smaller the angle

between the sound beam emitted by the ultrasound probe and the myocardium, the more

accurate the measurement of tissue velocity.

Diastolic dysfunction, compared with cardiac biomarkers, is a better independent predictor

of mortality (87-89). E/e’ correlates with the end-diastole pressure of the left ventricle: a high
(91, 92)
E/e’ ratio represents low compliance or, what is the same, diastolic dysfunction. E is

the wave of early mitral input velocity obtained with pulsed wave Doppler. The e’ wave is

the mitral annular early diastolic peak velocity obtained by tissue Doppler and is one of the

most load-independent measures of diastolic dysfunction. A reduced e’ wave and an

increased E/e’ ratio are common findings in patients with sepsis (86).

Laboratory

Type B natriuretic peptide (BNP) is a hormone synthesized in the myocardium. It is

produced in the form of a prohormone, and before secretion, it is divided into the inactive
(93)
NT-proBNP and the active BNP . Patients with sepsis have remarkably high plasma
(94, 95) (96, 97)
levels of BNP and NT-proBNP , which is an indicator of increased mortality .

However, many factors such as right ventricular overload, catecholamine therapy, and

increased cytokine production can contribute to the release of BNP during sepsis and

decrease its specificity. Post et al. analyzed the behavior of plasma BNP in a cohort of 93

patients with septic shock divided into 1 group with normal ventricular function (LVEF

>50%) on days 3 to 5 (n= 38) and 1 group with impaired left ventricular function (LVEF

<50%) (n= 55). On day 5, patients with impaired LVEF had an increased median plasma

13
BNP concentration (699 pg/nL vs 86 pg/nL [p < 0.0005]) and an EF of 38% versus 58% (<

0.0005) in patients without impaired LVEF. There was a close inverse relation between

increased plasma BNP concentrations and depressed LVEF (p < 0.05). In a comparison of

the 2 cohorts of patients who survived and those who did not survive the 30-day follow-up

period, the BNP concentration measured at day 5 was 119 pg/mL compared with 672

pg/mL (p < 0.016) (98).

Troponin levels cTnI and cTnT in plasma have also been identified as highly sensitive and
(8)
specific markers of SIMD in patients who are critically ill . Patients with sepsis with

elevated levels of troponins may have a risk of death 2–5 times higher, even in the absence
(99) (100)
of known cardiovascular disease . Mehta et al. , in a single-center prospective study

with 37 patients with severe sepsis, 16 (43%) had elevated cTnI and these were associated

with a higher need for inotropic or vasopressor support (p= 0.018), a higher APACHE II

score (p= 0.004), a higher incidence of segmentary abnormalities of wall motion on

(101)
echocardiography (p= 0.002), and lower LVEF (p= 0.04). John et al. conducted a

study using a subset of the PROWESS trial (n = 598) to analyze the prognostic value of

cTnI in patients with severe sepsis. The cTnI was elevated in 75% of the cases and the 28-

day mortality was higher when the cTnI was positive (32% vs 14% p = 0.0001).

Therapy for myocardial dysfunction in sepsis

The Surviving Sepsis Campaign recommends that resuscitation of sepsis-induced

hypoperfusion be performed with a bolus of at least 30 ml/kg of crystalloid fluids be given

(102)
within the first 3 hours . Afterwards, following initial fluid resuscitation, additional
(102)
fluids should be guided by frequent reassessment of hemodynamic status . They also

14
suggest using albumin in addition to crystalloids for initial resuscitation and subsequent

intravascular volume replacement in patients with sepsis and septic shock when patients

require substantial amounts of crystalloids (102).

Aggressive liquid administration cannot continue indefinitely. The persistence of a positive

(103-106)
fluid balance over time has been associated with increased mortality and even
(106)
constitutes a risk factor for new organ system dysfunction at hospital discharge . The

MAP target is 65 mmHg in patients with septic shock. This finding implies that if after the

start of fluid resuscitation the patient remains hypotensive, vasopressors should be started.

The time from the identification of septic shock to the start of vasopressors is an

independent predictor of mortality: Delayed start of vasopressor therapy increases mortality

rates. This consequence occurs even when vasopressors are started within the first 6 hours.

Mortality rates increase 5.3% for each 1 hour of delay in vasopressor onset (107).

To the best of our understanding, we designed flowchart 1 as an easy way to approach the

diagnostic and therapeutic process of patients with cardiac involvement from sepsis.

- Vasopressors

The most commonly used vasopressor and inotropic medications are synthetic

catecholamines that stimulate alpha, beta, and dopa receptors in the arteries, arterioles, and

veins. Typically, alpha effects predominate in vessels at standard doses. Stimulation of

alpha (α)-1 receptors in vascular smooth muscle cells leads to an increase in intracellular

calcium, and consequently, intense vasoconstriction and an increase in systemic blood

(106, 109)
pressure . The veins, by contrast, contract in response to the activation of alpha

15
 (110-112)
receptors and vasopressin receptors . Endogenous vasopressors increase venous

return to the heart through their ability to increase the pressure gradient between the veins

and the right atrium. And the heart is thus responsible for increasing the volume beating

because of the Frank-Starling mechanism (113, 114).

Norepinephrine is the vasopressor of choice in patients with sepsis who persist hypotensive
(115)
despite having received adequate volume replacement . It is a hydroxylated derivative

of dopamine and stimulates alpha and beta receptors, although its α-1 effects predominate

in therapeutic doses. Norepinephrine also provides moderate inotropic support through its

β-1 activity. The therapeutic dose is between 0.02–0.3 μg/kg/min. It is superior to

dopamine because it produces fewer arrhythmias (2.34 times more arrhythmias with

dopamine) (116) and improves survival (11% higher with norepinephrine) (117).

Epinephrine is a potent non-selective alpha and beta agonist recommended by the Surviving

Sepsis Campaign for hypotension associated with sepsis as a first-line medication or

associated with norepinephrine when the latter fails to maintain MAP ≥65 mmHg. The dose

is 0.01-0.20 μg/kg/min. Up to 0.1 μg/kg/min, beta effects predominate, and contractility

and heart rate increase powerfully (118); at higher doses, vasoconstrictor effects mediated by

α-1 receptors prevail. Caution should be exercised in epinephrine use because it inhibits

blood flow in the splanchnic area, causes more arrhythmias than norepinephrine, and

induces greater oxygen consumption of the myocardium. Compared with the combination

of norepinephrine and dobutamine, epinephrine lowers the pH and raises arterial lactate

significantly (119), although mortality at 30 and 90 days is not affected (120).

16
Activation of cardiomyocyte α1-adrenoceptor can suppress LPS-induced cardiomyocyte
(121)
TNF-α expression and improve cardiac dysfunction during endotoxemia . Additionally,

stimulation of cardiomyocyte β1-adrenoceptor promotes p38MAPK, JNK, and NF-kB

activation and subsequent TNF-α expression in LPS-treated cardiomyocytes (122).

Dopamine is no longer considered a first-line treatment for hypotension in sepsis or septic

(102, 123)
shock. In sepsis, it is only recommended for patients with bradycardia . As of 2013,

the American Heart Association does not recommend dopamine as a first-line vasoactive
(124)
medication in cardiogenic shock . Although not statistically significant, overall

mortality tends to be higher for patients receiving dopamine instead of norepinephrine in

the intensive care unit (50.2% vs 45.9%, p= 0.07) (125). It should also not be used for kidney

protection (102).

Vasopressin is an endogenous peptide hormone that causes vascular smooth muscle

(126)
contraction through the V1 receptors which are found throughout the circulation,
(127)
especially in the skin and splanchnic vessels . Under normal physiological conditions,

vasopressin is primarily responsible for free water homeostasis. In healthy subjects, at very

low doses, it can lead to pulmonary vasodilation by the release of endothelial nitric oxide
(128) (129)
, which may be useful in specific cases of acute right ventricular failure .

Vasopressin is an excellent therapeutic option in refractory septic shock but should not be

used as a primary vasopressor. The dose is 0.01–0.03 IU/min. The VASST study

(Vasopressin and Septic Shock Trial) showed that the use of low doses of vasopressin

decreases the requirements of norepinephrine and suggests lower mortality at 28 and 90

days (130).

17
Phenylephrine is a pure α1 agonist. Its use not recommended in sepsis because although it

effectively increases blood pressure, studies have shown that it is associated with decreased

ventricular performance and ventriculoarterial uncoupling (131, 132).

- Inotropes

The use of inotropes should be considered when there is evidence of myocardial

dysfunction, as suggested by low CO, increased filling pressures or continuous signs of

hypoperfusion despite restoration of intravascular volume, and normalization of MAP

through therapy with liquids and vasopressors (16, 115).

Dobutamine is the first option of the Surviving Sepsis Campaign for inotropic support in

patients with sepsis with evidence of impaired CO. Dobutamine is a dehydroxylated

derivative of isoproterenol, with predominantly β-1 agonism, and to a lesser extent, β-2
(133)
. Dobutamine is also a mild α-1 agonist at doses greater than 15 μg/kg/min, but SVR is

more likely to decrease at the usual dose from 5 to 15 μg/kg/min through its β-2 effect.

Positive effects of dobutamine on microcirculation and splanchnic perfusion at doses of 5

(134)
μg/kg/min have been demonstrated . Despite several clinical studies in which the

correction of cardiac and hemodynamic parameters is evident, patient survival is not

modified (115).

Unlike dobutamine, which exerts its main action through the stimulation of cardiac β-1

receptors, levosimendan has a cAMP-independent inotropic effect. The pharmacological

effects of levosimendan are exerted via three pathways: (1) increased sensitivity of troponin

18
C to calcium in myocardial cells, thereby inducing stabilization and prolongation of the

intracellular calcium binding to cardiac troponin C; (2) opening of adenosine triphosphate-

sensitive potassium channels (KATP channels) in the smooth muscle cells of the vasculature,

so inducing vasodilation; and (3) activation of KATP channels in cardiac mitochondria,

(135)
hereafter protecting cells against ischemia/reperfusion injury . In heart failure, the

alteration in the transport of calcium inside and outside the cell and inside and outside the

sarcoplasmic reticulum leads to an overload of cytoplasmic calcium, which is the origin of

many of the arrhythmias observed in patients with insufficient heart disease (136). Since it is
(137, 138)
a calcium sensitizer, not a calcium mobilizer , levosimendan does not increase
(139, 140)
myocardial oxygen consumption . In animal models of septic shock, levosimendan

has demonstrated an improvement in left ventricular contractility and global

hemodynamics, reduction of metabolic acidosis, and improvement of organic dysfunction

(141-144)
. In addition, in the advanced decompensated heart failure, levosimendan has

positive effects with respect to the reduction of proinflammatory cytokines, antioxidant

(145)
effects, and lower levels of BNP compared with dobutamine . Meta-analyses of

levosimendan data in various settings shown a trend towards a survival benefit that reached
(146-148)
statistical significance in some investigations . Levosimendan should be

administered intravenously at a rate of 0.05–0.1 μg/kg/min without a bolus load (to

minimize the risk of hypotension), continuously for 24 hours (149).

Milrinone is a non-adrenergic inodilator that exerts its effects through the inhibition of

phosphodiesterase 3 with a secondary increase in cyclic AMP (cAMP). Cyclic AMP is a

second critical messenger for heart cells by triggering the release of calcium from the

sarcoplasmic reticulum and increasing cytosolic calcium concentrations. On the periphery,

19
cAMP inhibits the myosin light chain kinase, which under normal conditions

phosphorylates the myosin light chain that is located in the myosin head. In smooth muscle,

the myosin light chain must be phosphorylated so that actin and myosin form bridges and

initiate contraction. In practice, vasodilation of the peripheral vasculature is observed, and

it has the same effect on pulmonary vascular resistance, which is why its use is indicated in

cases of cardiogenic shock due to right ventricular failure. This same peripheral vasodilator

effect explains why when milrinone is indicated by its inotropic properties it frequently

requires the concurrent use of a vasopressor. Because milrinone does not exert its effects

through the catecholaminergic pathway, its use is specifically recommended in patients

with chronic beta blockade, and in patients with long-standing heart failure who
(133)
demonstrate desensitization of adrenergic receptors . The dose is 0.25–0.75 μg/kg/min.

Dobutamine and milrinone have similar results of clinical efficacy and mortality in patients

with decompensated heart failure (150).

Regarding the intra-aortic balloon pump, the evidence is not unanimous. Thiele et al

showed that the intra-aortic balloon pump, in the context of cardiogenic shock, does not

lead to a reduction in mortality at 30 days (151). However, Chen et al collected data from 78

septic shock patients in late stage finding that mean arterial pressure, cardiac index, and

inotropic doses were significantly better in patients with the intra-aortic balloon pump;

likewise shock recovery time was significantly shorter and mortality within 28 days was

significantly lower (152).

Extracorporeal membrane oxygenation (ECMO) support can be prescribed when

(153-155)
cardiogenic shock not improved after antibiotic therapy and hemodynamic support .

20
This subset of patients who are unresponsive to standard resuscitation are often labeled as

having ‘refractory septic shock’ (156). Septicemia is not a contraindication to ECMO. In fact,

extracorporeal support is a rescue therapy for those patients with severe sepsis who would
(157)
otherwise die of inadequate cardiac output . In addition to improving myocardial

performance, ECMO improves global oxygen supply, reduces intrathoracic pressures

because ventilatory requirements are minimal, clears carbon dioxide, and optimizes acid-
(158)
base status . We could use a modification of the criteria of the European Society of

Pediatric and Neonatal Intensive Care to characterize the state of refractory shock: (1)

persistence of high lactate, (2) vaso-inotrope dependency (vaso-inotrope score _VIS_

>200), (3) myocardial dysfunction, defined as cardiac ultrasound findings with LVEF

<25%, a cardiac index <2.2 L/min/m2 (156) or ACO <60. The VIS is calculated as follows
(159)
:

VIS = (epinephrine + norepinephrine in mcg/kg/min) × 100 + (dobutamine + dopamine in

mcg/kg/min) + (vasopressin in Units/kg/min) × 10,000 + (milrinone in mcg/kg/min) × 10

Clinical and prognostic course

A patient with sepsis and a SOFA score ≥2 has a risk of death of approximately 10%. Even

those patients who have modest organic dysfunction may have a deeper deterioration,

stressing the gravity of this condition and the need for prompt, appropriate intervention, if

not already being instituted. Patients with septic shock may have a mortality greater than

40% (8), but in the case of a SIMD, the mortality rate may increase up to 70% (8)
. Notably,

in the study of sepsis and mortality by Blanco et al., the variables most strongly associated

with mortality in the intensive care unit were cardiovascular dysfunction on day 1 and the

21
variable ΔSOFA 3-1, defined as the difference in total SOFA scores on day 3 and day 1
(160)
.

With the implementation of the proposed treatment, up to 10%–-20% of patients are unable
(8)
to normalize the hemodynamics of patients with septic shock ; thus, further research is

necessary before a treatment is available that has a greater effect on morbidity and mortality

in patients with sepsis with cardiac dysfunction.

Future directions

Today’s therapy for myocardial dysfunction in sepsis remains mainly symptomatic (volume

substitution, inotropic/vasoactive agents). However, the causal principles are tested with a

nascent new therapeutic arsenal because of a greater understanding of pathophysiology.

As aforementioned, in early sepsis, the activation of the complement results in the

production of C5a, which acts directly on the C5aR1 and C5aR2 receptors. Therefore, at

least part of the problems of septic heart disease results from the interaction of C5a with its

receptors. A possible therapeutic target is the development of a molecule that prevents the

delivery of the message that occurs between one and the other. For this, a neutralizing

monoclonal antibody for C5a could represent an effective strategy for the treatment of

patients with sepsis (161).

In the same manner, treatment with a monoclonal antibody against TNF, considered a

myocardium-depressing factor, in patients within 24 hours of septic shock may improve

(21)
LVEF . Nonetheless, no correlations are observed between circulating cytokines and

22
systolic or diastolic myocardial dysfunction in severe sepsis or septic shock in the clinical

setting (162).

Beta-blocker therapy seems to go against the hemodynamic condition of the patient in

septic shock in whom tachycardia is the main mechanism to compensate for any decrease in

CO and does so because of the stimulation that catecholamines have in beta receptors. By

contrast, tachycardia of hypermetabolic states increases cardiac workload and cardiac

oxygen consumption, reduces diastolic relaxation time and coronary perfusion, lowers the

ischemic threshold, and impairs diastolic function. In patients with septic shock or sepsis,

excessive sympathetic activation can produce catecholamine-induced cardiomyocyte toxic

(23, 163, 164)
effects including inflammation, oxidative stress, and abnormal calcium handling .

It seems that tachycardia persists because of sympathetic overstimulation because of the

activation of peripheral afferent fibers by ischemia and irritation in bordering tissues (165).

Morelli showed that therapy with esmolol increases stroke volume, SVR, and left

ventricular stroke work indices and decreases mortality at 28 days in patients with septic

shock (49.4% vs 80.5%, P <.001) (166); notably, the arterial lactate concentration was lower

for the esmolol group. Therefore, control of the heart rate in septic cardiomyopathy may be

a potential therapeutic approach. Additionally, Wang found that low levels of endogenous

norepinephrine or β1 adrenoceptor block abolished cardiomyocyte apoptosis almost

(167)
completely in mice , and conversely, activation of the β1 adrenoceptor promotes
(122)
cardiomyocyte apoptosis induced by LPS . In patients with septic shock, the goal is to

achieve a targeted heart rate between 80/min and 94/min within the first 24 hours of

esmolol treatment. A meta-analysis showed that esmolol intervention can substantially

23
improve survival rate (RR = 1.71; 95% CI= 1.13 to 2.60; P= 0.01) and reduce TnI and CK-

MB levels (168).

Probably, in the next few years, more and better strategies will be introduced to diagnose

and treat patients with myocardial dysfunction in sepsis; for now, early diagnosis and

implementation of a timely targeted therapy help improve the prognosis for these patients.

Conflicts of Interest Statement

The author certify that he has NO affiliations with or involvement in any organization
or entity with any financial interest (such as honoraria; educational grants; participation
in speakers’ bureaus; membership, employment, consultancies, stock ownership, or
other equity interest; and expert testimony or patent-licensing arrangements), or non-
financial interest (such as personal or professional relationships, affiliations, knowledge
or beliefs) in the subject matter or materials discussed in this manuscript.

24
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 Tables
Table 1. Classification of cardiac output related to afterload (ACO)

Cardiac function ACO

Normal >80

Slightly restricted 60-80

Moderately restricted 40-60

Severely restricted <40

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52
Figure 1 explains the effect that sepsis has on the function of the cardiomyocyte. The

lightning bolt symbol indicate the place where the cellular process is hindered.

53