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C a rdi a c Fu n c t i o n an d

Dysfunction in Sepsis
Kimberly E. Fenton, MD, FAAP*, Margaret M. Parker, MD, MCCM

KEYWORDS
 Cardiac dysfunction  Sepsis  Ventricular function  Hemodynamics  Echocardiography
 Troponin

KEY POINTS
 Cardiac function and dysfunction are important in the clinical outcomes of sepsis and septic shock.
 Cardiac dysfunction results from a variety of pathophysiologic, metabolic microvascular, functional,
and anatomic derangements.
 Intrinsic cardiac function is greatly affected by extrinsic factors such as preload, afterload, and
neurohumoral responses to sepsis.

INTRODUCTION component of the cardiovascular system, it is


also affected by perturbations of the peripheral
Cardiac dysfunction plays a pivotal role in the clin- vascular system during sepsis. These changes in
ical outcomes of severe sepsis and septic shock. the peripheral vascular system have direct and
Myocardial depression was first described in indirect effects on the loading conditions of the
1984, and since then numerous studies have myocardium. The cardiac response to alterations
focused on further elucidating the mechanisms in preload, afterload, and the neurohumoral
causing myocardial depression.1,2 Although response during sepsis may be clinically indistin-
much remains unknown, cardiac dysfunction is guishable from direct septic cardiotoxicity, which
not a single clinical entity but is a broad spectrum makes accurate diagnosis and treatment of
of syndromes with a multitude of pathophysiologic, cardiovascular failure during sepsis a highly com-
metabolic, microvascular, functional, and ana- plex task.
tomic derangements. The term septic cardiomy-
opathy has evolved to describe many of these
PATHOPHYSIOLOGY
conditions.3,4 Further elucidation of the underlying
Functional Abnormalities
pathophysiology has focused primarily on func-
tional disturbances of the myocardium rather The underlying pathophysiology of cardiac
than anatomic abnormalities. However, recent ev- dysfunction in sepsis is caused by a myriad of
idence from both human studies and experimental genetic, molecular, metabolic, and structural
models of sepsis shows that structural changes mechanisms that are highly complex and may
occur as well.57 In addition, cardiac dysfunction have both stand-alone unique contributions as
in sepsis is a principal cause of morbidity and well as highly complex intricate influences on
mortality in severe sepsis and septic shock; each other. Although much is known, many of
many therapies have focused on treating func- the pathophysiologic mechanisms are proposed
tional abnormalities, with only limited success. and the full influence of each is yet to be
Furthermore, although the heart is the central elucidated.
chestmed.theclinics.com

Disclosures: The authors have nothing to disclose.


Department of Pediatrics, Stony Brook University School of Medicine, Stony Brook, NY 11794-8111, USA
* Corresponding author. Health Sciences Center, T11 Room 040, Stony Brook, NY 11790-8111.
E-mail address: kimberly.fenton@stonybrookmedicine.edu

Clin Chest Med 37 (2016) 289298


http://dx.doi.org/10.1016/j.ccm.2016.01.014
0272-5231/16/$ see front matter 2016 Elsevier Inc. All rights reserved.
290 Fenton & Parker

Genetics catecholamine resistance.13,14 Autonomic


The Human Genome Project and many others dysfunction is further exacerbated by glial
have sought to elucidate the genetic expression and neuronal apoptosis in cardiovascular
of specific diseases and syndromes. However, autonomic centers.15
these important links exist only in animal models  Mitochondrial dysfunction9: adequate ATP
of sepsis in which there is a suggestion that induc- and oxygen delivery is essential for cardiac
ible nitric oxide synthase (iNOS) deficiency may be function. Several mitochondrial disturbances
cardioprotective.8 Further research must be done are proposed to play a significant role in car-
to identify the linkage between genomics and diac dysfunction during sepsis:
sepsis-induced cardiac dysfunction.  Edema of the mitochondrial matrix, which
may lead to functional impairment of car-
Molecular diac myocytes.
 Oxidative stress: increased superoxide
 Cytokines: activation of the immune system
(O2 ) and NO production can cause direct
plays a key role in the pathogenesis of sepsis.
oxidative damage or inhibition of oxidative
The innate immune system essentially goes
phosphorylation, decreased mitochondrial
into overdrive with a production of proinflam-
membrane potential, and ultimately
matory mediators. Tumor necrosis factor
decreased oxygen consumption.
alpha, interleukin (IL)-1beta, and IL-6 are
 Altered membrane permeability: affecting
considered to be the main mediators that cause
the electron transport chain and impaired
cardiac dysfunction in sepsis and are consid-
mitochondrial calcium handling, which
ered to be direct myocardial depressants.2
may lead to mitochondrial calcium overload
 Nitric oxide (NO) is a widely recognized
and impaired membrane permeability,
contributor in sepsis and causes the following:
which in turn, may contribute to cardiac
 Vasodilation, which in turn causes reduced
mitochondrial contractile dysfunction.16
preload, afterload, and cardiac perfusion.
 Mitochondrial uncoupling: ATP synthesis
It may also serve as a myocardial
may be physiologically uncoupled from
depressant.8,9
oxygen consumption whereby ATP is not
 Glutathione depletion, which leads to
synthesized in response to cardiac oxygen
oxidative stress and mitochondrial
consumption.
dysfunction.10
 Mitochondrial biogenesis: the process of
 Calcium: intracellular calcium is a potent ino-
mitochondrial growth and division may be
trope. Experimental models suggest calcium
impaired by a variety of mechanisms (eg,
channel alterations, which reduce intracellular
NO, oxidative stress) that occur during
calcium and ultimately cause myocardial
sepsis. Mitochondrial biogenesis is thought
depression11 (Fig. 1).
to be responsible for the reversal of organ
 Toll-like receptors (TLRs): critical to the
damage in sepsis. However, it is possible
initiation of the innate inflammatory response.
that mitochondrial biogenesis may not be
TLRs recognize specific pathogen-associated
sufficient or that, alternatively, the newly
patterns of bacterial and viral structures and
produced mitochondria are dysfunctional.
nucleic acid composition.
 Mitophagy: the removal of dysfunctional
 Endothelin-1 (ET-1) is known to play a role in
mitochondria via autophagy is important
myocardial contractility. In sepsis, ET-1 levels
for organ recovery. Ideally, mitophagy and
are increased in both the blood and myocar-
mitochondrial biogenesis should be
dium. There is a suggestion that increased
balanced; however, mitophagy has been
levels are associated with myocardial
shown to be increased in various organs
dysfunction.12
in sepsis (which is proposed to occur in
Metabolic the heart as well). However, decreased
mitochondrial mass may occur if mitophagy
 Neurohumoral: early sepsis causes a cate- exceeds mitochondrial biogenesis.
cholamine surge from the autonomic nervous
system, gut, white blood cells, and macro-
Structural Abnormalities
phages, resulting in massive sympathetic
response and stimulation of alpha-adrenergic In addition to functional derangements, recent ev-
and beta-adrenergic receptors. This adren- idence suggests that structural abnormalities may
ergic stimulation leads to a downregulation play a role in the pathophysiology of cardiac
of catecholamine receptors, and ultimately dysfunction of sepsis. Increased serum levels of
Cardiac Function and Dysfunction in Sepsis
Fig. 1. Molecular factors involved in myocardial depression. ET, endothelin-1; NOS, nitric oxide synthase; ROS, reactive oxygen species; TNF-a, tumor necrosis factor alpha. (From
Antonucci E, Fiaccador E, Donadella K, et al. Myocardial depression in sepsis: from pathogenesis to clinical manifestations and treatment. J Crit Care 2014;29:502; with permission.)

291
292 Fenton & Parker

cardiac troponins T and I in sepsis suggest that associated with mortality.19,20 Diastolic dysfunc-
there has been myocardial injury but do not define tion is reported in nearly half of patients with sepsis
whether there is necrosis versus a troponin and is strongly associated with mortality.21,22 Left
leakage caused by reversible cell membrane ventricular systolic dysfunction has been the
disruption. Necrosis and apoptosis cause cell most studied and well characterized in the litera-
death, which implies an irreversible process in ture and is highly dependent on left ventricular
the septic heart; however, myocardial dysfunction afterload (discussed later).1,23 When afterload is
is well known clinically to be a reversible process.1 reduced, cardiac function may seem normal or
Necrosis has been identified in autopsies from increased despite reduced intrinsic cardiac
septic human hearts, whereas apoptosis has contractility. Aside from imaging techniques, this
only been identified in experimental models of may not be clinically apparent until impaired after-
sepsis.6 Autopsies from human hearts show load is corrected, and it can be challenging to clin-
myocardial infiltration by white blood cells and ically separate reduced afterload from impaired
macrophages, disruption of the contractile appa- cardiac performance.20
ratus, increased collagen, and damaged
mitochrondria.7,17  Left ventricular diastolic dysfunction: tachy-
cardia and left ventricular dilatation resulting
Necrosis and apoptosis in an increased left ventricular end-diastolic
Myocardial cell apoptosis has not been found in volume may contribute to impaired ventricular
human autopsy specimens but is described exper- relaxation during diastole. Diastolic dysfunc-
imentally in models of sepsis.6 Focal myocardial tion has been shown to occur independently
necrosis and subendocardial necrosis have been of systolic dysfunction24,25 and is primarily
identified in experimental models of sepsis, and diagnosed by echocardiography. Clinically,
myocardial contraction band necrosis was identi- diastolic dysfunction may affect fluid manage-
fied by Schmittinger and colleagues7 in a prospec- ment, requiring a more conservative approach.
tive histologic autopsy study in 20 human hearts. In addition, diastolic dysfunction is an inde-
Contraction band necrosis was found in 95% of pendent risk factor for mortality even when
the autopsy specimens and was generalized and APACHE-II (Acute Physiology and Chronic
distributed homogeneously in all heart cross sec- Health Evaluation) score is adjusted.25
tions. Contraction band necrosis has been experi-  Right ventricular function may be caused by a
mentally induced by infusion of catecholamines reduced preload causing decreased right ven-
and is observed in diseases associated with adren- tricular ejection fraction but is primarily charac-
ergic overstimulation (eg, pheochromocytoma).7 terized by increased right atrial pressure and
decreased systemic venous return. It may
Myocardial infiltration occur alone or in association with left ventricu-
Inflammatory cardiomyopathy is a hallmark histo- lar systolic dysfunction.20 Similarly to the left
logic finding in the septic human heart character- ventricle, right ventricular systolic function is
ized by interstitial infiltration by neutrophils and affected by afterload; however, right ventricular
monocytes/macrophages.5,7 The inflammation is afterload is usually increased /because of
also concomitantly associated with interstitial acute respiratory distress syndrome.3,26,27 Un-
myocardial edema, fibrosis, and thrombi in the like the left ventricle, the right ventricle is unable
vasculature. to anatomically and physiologically adapt to
rapid increases in afterload, therefore the right
Hemodynamic Abnormalities ventricle is more prone to early dysfunction.
Contractile dysfunction Recent data suggest increased mortality with
Impaired cardiac contractility is the hallmark of se- early right ventricular dysfunction.3,28,29
vere sepsis and involves biventricular dysfunction Although biventricular cardiac dysfunction may
characterized by cardiac dilatation and decreased occur independently, cardiac function overall is
stroke volume.1 Because patients with septic extremely dependent on loading conditions (ie,
shock typically present with a hyperdynamic he- preload and afterload); alterations of either or
modynamic state, myocardial depression may both produce direct cardiac and hemodynamic
not be readily apparent.18 Both radionuclide imag- consequences26,30 and the clinical management
ing and, more recently, increasingly sophisticated of sepsis must take these loading conditions into
echocardiographic techniques have shown that account.
either systolic or diastolic dysfunction, or both, is
commonly present.1,1922 Systolic dysfunction oc-  Impaired preload: absolute or relative hypovo-
curs in 30% to 60% of patients, and is not clearly lemia is frequently observed in sepsis. In
Cardiac Function and Dysfunction in Sepsis 293

addition, maldistribution of blood flow (ie, MECHANISMS OF CARDIAC DYSFUNCTION


venous pooling and capillary leak) occurs
and further exacerbates a reduction in intra- Experimental models of sepsis suggest that
vascular volume.26 These findings are impaired loading conditions of the heart caused
observed clinically in humans and in experi- by altered vascular tone, and microcirculatory
mental models of sepsis. dysfunction frequently lead to a reduced oxygen
 Impaired afterload: decreased afterload is extraction even in the presence of normal oxygen
frequently observed in adults with septic delivery. Clinically this may translate to an
shock.18,23 Children frequently have increased central venous oxygen saturation in
increased afterload in sepsis.30 Alterations in the presence of severe cardiac dysfunction26,33
afterload are caused by reduced vascular (Fig. 2).
tone (ie, systemic vascular resistance), which
Impact of Chronic Heart Disease on Acute
may in turn help preserve systolic cardiac
Hemodynamics
function in early shock, allowing a hyperdy-
namic state. However, as contractility In a recent study by Ouellette and Shah,34 patients
worsens and afterload decreases, cardiac with preexisting left ventricular dysfunction were
function may seem grossly normal, but be not shown to have different clinical outcomes
severely impaired.26 Furthermore, impaired compared with patients with no underlying cardiac
contractility and afterload-related cardiac disease. Although, in the first 24 hours, patients
performance correlate with a worse prog- with underlying cardiac dysfunction received
nosis.4,26 The cause of afterload abnormalities similar amounts of fluid resuscitation as the control
is multifactorial but includes a vasodilatory group, there was no difference in respiratory mea-
response to cytokines, autonomic dysregula- sures at 24 hours or other clinical outcomes, sug-
tion, and NO abnormalities.26,27 Wilhelm and gesting that volume resuscitation in early sepsis is
colleagues31 used afterload-related cardiac appropriate for those patients with underlying car-
performance (ACP) to determine whether the diac dysfunction. For patients with preexisting left
cardiac output in patients with sepsis was ventricular dysfunction, low central venous oxygen
appropriate for the patients systemic saturation was an independent risk factor for mor-
vascular resistance. ACP is calculated as tality, which it was not in the control patients.
follows: In summary, the hemodynamic responses of pa-
tients with sepsis may be heterogeneous and are
ACP (%) 5 100  CO/[560.68  ((MAP likely influenced by the patients underlying cardio-
CVP)  80/CO) 0.645] vascular status and by acute changes in preload
and afterload that accompany sepsis.

The denominator is based on the predicted normal Laboratory Studies


cardiac output (CO) calculated from the given sys-
temic vascular resistance SVR. A normal ACP is  Troponin: many studies have reported that an
greater than 80%.31 increased cardiac troponin level is common in
ACP was predictive of mortality at the time of patients with sepsis, in both adults and chil-
admission to the emergency department and a dren, and is associated with a worse prog-
decreased ACP indicated reduced cardiac func- nosis.3538 Landesberg and colleagues39
tion. These investigators further reported that performed advanced echocardiography as
ACP correlated significantly with troponin and well as troponin-T measurements in 106 pa-
with brain natriuretic peptide levels. Cardiac index tients with severe sepsis or septic shock.
was not associated with severity of sepsis, mortal- Left ventricular diastolic dysfunction and right
ity, or biomarker levels. ventricular end-systolic volume were associ-
ated with in-hospital mortality and troponin-T
 Microcirculatory dysfunction: perfusion ab- concentrations. Left ventricular systolic
normalities in the microcirculation occur dysfunction did not correlate with troponin-T
during sepsis whereby there is thrombin concentration. The cause of myocardial
deposition, increased inflammatory cell dysfunction in sepsis, and of troponin level in-
migration, and altered endothelial perme- creases, remains unclear. Troponin may be
ability leading to a decreased perfusion, released by damaged myocardial cells from
increased viscosity, and an impaired endothe- sepsis-induced myocardial injury, or possibly
lial response to vasoconstriction and by myocardial cells that are put under
vasodilation.26,27,32 increased demand in critically ill patients.
294 Fenton & Parker

Fig. 2. Main mechanisms of cardiac dysfunction, their consequences, and their incidences (in brackets) in severe
sepsis and septic shock. ALI, acute lung injury; ARDS, acute respiratory distress syndrome; LV, left ventricular; RV,
right ventricular. (From Vieillard-Baron A, Cecconi M. Understanding cardiac failure in sepsis. Intensive Care Med
2014;40:1561; with permission.)

Although the association of increased related Organ Failure Assessment) scores


troponin-T level and myocardial dysfunction were independently associated with BNP
is clearly present, it is unclear whether more levels, and BNP level on day 1 was an indepen-
aggressive treatment approaches would dent predictor of 28-day mortality. These inves-
improve mortality in these patients. tigators concluded that it is the severity of
 B-type natriuretic peptide (BNP): increased illness rather than cardiac dysfunction that ex-
BNP level has been described as a marker for plains the increase in BNP levels in patients
myocardial dysfunction, as well as a prognostic with severe sepsis or septic shock. Failure of
indicator, in patients with sepsis.40,41 Daily BNP the BNP level to decrease rapidly over the first
levels and echocardiographic and hemody- few days was associated with mortality. Trends
namic measurements were evaluated by Papa- in BNP levels may be helpful in assessing
nikolaou and colleagues42 in a prospective response to therapy and prognosis.
observational study of 42 patients with severe  Cytokines: in vitro studies have suggested
sepsis or septic shock. Patients with septic that inflammatory cytokines may cause
shock had markedly increased BNP levels, myocardial dysfunction in sepsis.2 Landes-
which correlated with right and left ventricular berg and colleagues43 measured inflamma-
ejection fraction on univariate analysis but tory cytokines, troponin-T, and BNP levels in
were not independently associated on multi- 105 patients with severe sepsis and septic
variate analysis. Severity of illness as defined shock. They evaluated myocardial function
by APACHE-II or maximum SOFA (Sepsis- by echocardiography, including tissue
Cardiac Function and Dysfunction in Sepsis 295

Doppler imaging. The cytokine levels pre- there is no specific treatment of the myocardial
dicted mortality, but did not correlate with depression that is commonly seen. Management
systolic or diastolic left ventricular dysfunc- is supportive, optimizing hemodynamic stability
tion. BNP and troponin-T levels did correlate by ensuring adequate ventricular filling, inotropic
with some measures of myocardial dysfunc- support with dobutamine, and vasopressor sup-
tion in this study. Measurement of cytokine port with norepinephrine, epinephrine, and/or
levels is not helpful in the evaluation or man- vasopressin.48
agement of myocardial dysfunction in patients
with septic shock.  Early goal-directed therapy: specific thera-
peutic goals based on central venous pres-
Imaging Studies sure and central venous oxygen saturation
were recommended by Rivers and col-
The initial studies reporting myocardial depression leagues49 in 2001 but were subject to much
in septic shock used radionuclide gated blood pool controversy. However, 3 recent multicenter,
scans to measure left and right ventricular ejection randomized trials of goal-directed therapy
fraction.1 Echocardiography is a useful and more compared with usual care failed to show an
easily available tool for evaluating myocardial func- improvement in outcomes with goal-directed
tion in critically ill patients with septic shock. therapy.5052
 Vasopressors: many studies have assessed
 Transthoracic echocardiography is a widely
vasopressor agents for their effectiveness in
available tool but the quality of images in crit-
septic shock. Dopamine was for many years
ically ill patients may be limited. In a retro-
considered the agent of choice, but recent
spective study in 76 patients with septic
studies have refuted that thought. DeBacker
shock who had a transthoracic echocardio-
and colleagues53 performed a meta-analysis
gram, Beraud and colleagues44 reported that
of dopamine versus norepinephrine for the
the left ventricular ejection fraction could be
treatment of septic shock, reviewing 5 obser-
calculated in 90% of patients and diastolic
vational and 6 randomized trials. They re-
function in 74%, showing that transthoracic
ported that dopamine administration was
echocardiography may be a useful tool to
associated with an increase in mortality and
evaluate cardiac function in patients with sep-
more arrhythmias than norepinephrine. Dopa-
tic shock. Significant valvular disease was the
mine is no longer recommended as a first-line
most frequent impediment to evaluation of
agent for patients with septic shock.54 Norepi-
diastolic dysfunction. This study confirmed
nephrine should be the first-choice vaso-
that myocardial dysfunction is common in pa-
pressor, with epinephrine or vasopressin as
tients with septic shock.
options if additional agents are needed.
 Speckle tracking echocardiography is a
Low-dose vasopressin as an adjunct to pa-
newer and more sensitive technique that
tients receiving norepinephrine is as effective
may identify systolic or diastolic dysfunc-
as norepinephrine alone but does not reduce
tion not appreciated with conventional
mortality compared with norepinephrine in
echocardiography.45,46 In septic patients
patients with septic shock receiving catechol-
with a normal left ventricular ejection frac-
amine vasopressors.55
tion, Dalla and colleagues46 identified left
 Dobutamine or milrinone may be considered
ventricular strain in 50%. Strain echocardi-
when there is evidence of cardiac dysfunction
ography may be useful for early detection
and/or hypoperfusion despite adequate intra-
of myocardial dysfunction in sepsis. In addi-
vascular volume resuscitation and adequate
tion, De Geer and colleagues47 showed that
mean arterial blood pressure.54 Dobutamine
global longitudinal peak strain remained
may be titrated up to 20 mg/kg/min or milrinone
reduced in patients with septic shock
may be added at 0.25 to 0.75 mg/kg/min. Do-
beyond 7 days, whereas the left ventricular
butamine use is cautioned in patients with
ejection fraction and BNP level improved
risks of tachyarrhythmias or absolute or rela-
over that time.
tive bradycardia and may lead to hypotension
given its vasodilatory affects. Milrinone in-
Management Goals and Treatment
creases inotropy but has little effect on the
Myocardial dysfunction can be readily identified in heart rate; however, given its long half-life, it
patients with severe sepsis and septic shock using may lead to a prolonged episode of vasodila-
echocardiography and measurement of the levels tory hypotension. Milrinone has been used pri-
of biomarkers troponin-T and BNP. However, marily in pediatric septic shock.54
296 Fenton & Parker

 b-Blocker therapy: the use of b-blocker ther- underlying abnormalities. Future research must
apy for heart rate control has recently been focus on targeted therapies designed to treat spe-
proposed for patients with septic shock. cific pathophysiologic abnormalities.
Although perhaps counterintuitive, there may
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