Septic Cardiomyopathy is a distinct entity

1. Sepsis Induced Cardiomyopathy
Dr Palepu B Gopal
MD,FRCA,CCST,FCCM,FICCM
Consultant & HOD
Critical Care Medicine
Continental Hospitals
Hyderabad

2. Cardiovascular Changes in Sepsis

3. Prespsis Normal
Early phase of sepsis
Normal EF but SV is low
Insufficient cardiac preload
High vascular permeability and vasodilation
Compensatory but insufficient Tachycaridia
Resolution Phase
Preload optimization and good adaptation
SV recovers, especially in survivors
LVEF is temporarily decreased
Later Phase
Non-survivors have lower LVEDV than survivors
Persistent vascular hyperpermeability & preload
deficiency
Retained LVEF but low LVEDV
Harmful adrenergic over-stimulation
Septic Shock & Sec. Myocardial
Dysfunction
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4. Incidence Variable - reports : 20-65% in first few days
Barraud D et al. Crit Care Med 2007 Confirmed presence of severe
depressed intrinsic LV contractility using LV pressure/volume loops in
LPS treated rabbit
Vieillard-Baron A et al. Ann Intensive Care 2001 Defined as a global
(systolic and diastolic) but reversible dysfunction of both the left and right
sides of the heart
Tend to be either hypokinetic or normokinetic but not hyperkinetic
Sepsis-induced Cardiomyopathy
Parker MM et al. Ann Intern Med. 1984;100(4)

5. Normal Mouse Cardiomyocytes
18% to 20% shortening on contraction
Exposure to Heat-killed
Staph. aureus and E. coli
Rapidly produce ICAM-1
Disruption of cellular cytoskeleton
Reduce calcium flux
Extreme reduction in cardiac contractility
Reduction in Mouse Cardiomyosite Contractility
on Exposure to Bacterial Toxins
Boyd JH et al. Cardiovasc Res 2006;72(3):384–93

6. 3 Cardinal Features of Sepsis Induced Cardiomyopa
First LV dilatation with normal or low filling pressure
An increase in the LV compliance
Consequent abnormal increase in LVEDV to volume loading
Second Depressed EF by ventricular dilatation and not by
decreased SV Increased or Normal LVEDV & SV in survivors
Depressed LV systolic function is associated with normal or low LV
filling pressure, unlike the “classic” pattern of cardiogenic shock
where LV filling pressures are elevated
Vincent JL et al. Acta Anaesthesiol Scand. 1989;33
Third Sepsis-induced cardiomyopathy should normalize within 7–10 days
Bouhemad B et al.Crit Care Med 2009, 37: 441-447.
Sato and Nasu Journal of Intensive Care 2015 3:48

7. Two possible causative mechanisms
Ischemic
Myocardial ischemia from inadequate coronary blood flow (animal studies)
Myocardial depression was observed in 4 of 7 patients who had coronary
flow similar to or higher than that of controls
Human have ruled out coronary hypoperfusion requiring coronary
intervention as a cause of LV systolic dysfunction
Cunnion RE et al. Circulation. 1986;73(4)
Chemical
Mediators, such as endotoxins,
cytokines & nitric oxide as agents
Complex interaction between
alterations of genetic, molecular
metabolic, structural,autonomic
and hemodynamic variables
Pathogenesis of Septic Cardiomyopath

8. TLR 3 & 4
Molecular Factors in Septic Myocardial
Depression
Secondary reduction
of contractility &
shortened repolarization time.
Glutathione depletion
↑oxidative stress
Apoptosis or necrosis

9. Normal LV Filling Pressures in SCM
Pulmonary Capillary Wedge Pressure Measurement
Parker MM et al Ann Intern Med. 1984;100(4):483–90
PCWP of 14 mmHg on average in patients with LVEF <45%
Suffredini A et al N Engl J Med 1989, 321: 280-287
Injection of endotoxin In 12 normal healthy volunteers induced
depression of LV systolic function associated with significant
decrease in the ratio of PCWP to LVEDVI
Jardin F et al Crit Care Med 1990, 18: 1055-1060
Average PCWP of 11 mmHg in patients with decreased LV EF, which is
not significantly different from pts with a preserved EF
Reason1 RV Dysfunction and Pulm. Hypertension(ARDS)
Reason 2 A true but slight increase in LV compliance with
decreased LV EF

10. LV global hypokinesia without a major dilatation
Doppler profile - highly suggestive of Normal LV Filling Pressure
Filling Pressures in Cardiogenic & Septic Shock
with TEE
Cardiogeni
c
Shock
Septic
Shock
LV global hypokinesia of with major dilatation and Restrictive filling
pattern
Dopple Profile- high E wave velocity & very low A wave velocity
highly suggestive of a high LV Filling Pressure

11.  LVEF Vs CI in 183 patients with septic shock with ECHO
 Depressed LV intrinsic contractility is constant
 Four parts according to SVR, Volume status & RV function
Relationship Between LVEF & Cardiac Index In Sepsis
Patients
LVEF %
CI(L/min/m2

12. LV Function in Septic Shock-Time Course
Increased LV EF to 60% after 2 and 3 days
i) Due restoration of a normal LV afterload by norepinephrine
ii) By natural evolution of the infectious process
Vieillard-Baron A et al. Crit Care Med 2008, 36: 1701-
Short-axis View of LV by a Transgastric Approach In Patient with Septic Shock

13. Incidence of LV Systolic Dysfunction in Septic
Shock
According to Time of Evaluation
Study Mode of
Measurement
Time of
study
LV systolic
dysfunct
ion
% of cases
Parker et al PAC +
Radionuclide
Cineangio
Day 1 65%
Jardin et al TEE
0-6 hours 29%
Vieillard-Baron et
al
TEE
0-6 hours 18%
Vieillard-Baron et
al
TEE
Day 1, 2, 3 60%
Etchecopar et al TEE
12 hours 46%

14. Is Septic Cardiomyopathy
Protective ?
Parker MM et al.
Ann Int Med
100:483-490, 1984

15. Prognosis of Sepsis Induced Cardiomyopathy
Myocardial State Mortality
Hypokinetic 43%
Normokinetic 24%
Hyperkinetic 100%
Vieillard Baron A et al.
Early preload adaptation
In septic shock?
A TEE study.
Anesthesiology 2001
Huang et al.
Is early ventricular dysfunction
or dilatation associated with lower
mortality rate in adult severe
sepsis
and septic shock? A meta-
analysis
Critical Care, 2013Pooled results do not suggest survivors
from severe sepsis or septic shock had
lower ejection fractions

16. Standardized mean difference
(SMD) for LV function in survivor
and
non-survivors of Septic
Cardiomyopathy
Left Ventricular Characters as Prognosticator in SC
Huang et al. Critical Care 2013, 17:R96
Standardized mean difference
(SMD)
for LV Dimention in survivor and
non-survivors of Septic
Cardiomyopathy

17. LV EF & CI in Survivors & Non-survivors of
Septic Shock
Survivors
(n = 99)
Non-survivors
(n = 101)
Parker et al.
20 patients
LVEF 32 ± 4%
CI 4.1 ± 0.4 L/min/m2
55 ± 3
5.4 ± 0.7 L/min/m2
Jardin et al.
90 patients
LVEF 44 ± 16%
CI 3.6 ± 0.3 L/min/m2
52 ± 14%
3.7 ± 0.4 L/min/m2
Vieillard-Baron et al.
67 patients
LVEF 49 ± 18%
CI 3.1 ± 0.9 L/min/m2
55 ± 15%
3.8 ± 1.3 L/min/m2
Kumar et al.
23 patients
LVEF 50 ± 5%
CI 2.78 ± 0.3 L/min/m2
57 ± 4%
3.01 ± 0.3 L/min/m2

18. Management of Sepsis and Septic Cardiomyopathy
Surviving Sepsis Guidelines 2016 – Early Goal Directed Therapy ?
1. Volume Expansion First to restore central blood volume in the case
of absolute or relative hypovolemia
2. Inotropic Drug Current guidance recommends dobutamine to
increase CI
Vincent JL et al.Crit Care Med.
1990;18(7)
Dobutamine - increases LV EF and cardiac index
For patients with persistent shock, lactic acidosis &
oliguria
Therapeutic or diagnostic - Dobutamine Stress Test
Patients with increased oxygen consumption (>15%) in
response to dobutamine infusion have a much

19. Dobutamine Challenge for SCM Outcomes- Heart Ra
 A prospective, non-randomised, non-blinded interventional study
 Graded dobutamine challenge (0, 5, 10, and 15 µg/kg/min) in adult patients
 PA cath within 48 hours of severe sepsis or septic shock
 8 survivors/15 non-survivors
 Radionuclide cineangiography to determine biventricular ejection fractions
Kumar A et al: Cardiovascular response to dobutamine stress predicts
outcome in severe sepsis and septic shock. Crit Care 2008, 12: R35

20. SVI Strongest predictor of outcome (p = 0.0003)
A cut-off value of 8.5 mL/m2 increase in SVI
correctly categorized outcome
Kumar A et al: Cardiovascular response to dobutamine stress predicts
outcome in severe sepsis and septic shock. Crit Care 2008, 12: R35
Dobutamine Challenge for SCM Outcomes- Heart Ra

21. Lower mean LVEF in survivors
did not reach statistical
significance
in comparison to the higher LV EF
in
non-survivors
Mean increase in LVEF was
Significantly Greater in survivors
than in non-survivors (p=
0.0160)
Kumar A et al: Cardiovascular response to dobutamine stress predicts
outcome in severe sepsis and septic shock. Crit Care 2008, 12: R35
Dobutamine Challenge for SCM Outcomes- Heart Ra

22. Baseline RVEDVI was similar in both
survivors and non-survivors
Mean increase in RVEDVI was
Significantly greater in survivors than
non-survivors (p = 0.0047)
Kumar A et al: Cardiovascular response to dobutamine stress predicts
outcome in severe sepsis and septic shock. Crit Care 2008, 12: R35
Dobutamine Challenge for SCM Outcomes- Heart Ra

23. Hayes MA et al NEJM 1994 Dobutamine deployed to boost the cardiac index did
not improve the outcome of critically ill patients
Gattinoni L etal NEJM 1995 Dobutamine and dopamine deployed to achieve
supranormal values for the CI failed to reduce morbidity or mortality among critically
ill patients
Lyte M et al. Lancet. 2003 Inotropes stimulate bacterial proliferation and biofilm
formation leading to development of intravascular catheter colonization and
CLABSI
Wilkman E et al. Acta Anaesthesiol Scand. 2013 Dobutamine was associated with
increased 90- day mortality from septic shock
Hernandez G et al. Intensive Care Med. 2013 Dobutamine did not improve sublingual
microcirculatory, metabolic, hepatosplanchnic, or peripheral perfusion
parameters in septic shock, increased sympathetic tone and created adverse
effects
Dobutamine for Septic Cardiomyopathy
Although dobutamine is recommended in current guidance,
recent trials have demonstrated that in patients with sepsis,
it does not improve the prognosis and may have adverse
effects

24. A positive inotropic drug
Increases systolic contractile myofilament sensitivity to Ca+
Diastolic relaxation remains largely unaffected
Does not cause arrhythmias or increase O2 consumption
Causes smooth muscle vasodilation (inodialator)
Levosimendan for Septic Cardiomyopathy
LV systolic elastance was restored during levosimendan infusion
Improved both systolic and diastolic cardiac functions in septic animals,
compared to milrinone and dobutamine which only improved systolic function
Barraud D et al. Crit Care Med 2007

25. Left ventricular (LV) pressure–volume loop tracings for one representative sham-treated
rabbit and several lipopolysaccharide (LPS)-treated rabbits before and after dobutamine,
milrinone, or levosimendan administration. Both systolic and diastolic functions are
impaired in an LPS-treated rabbit in comparison with a sham-treated control rabbit (top le
The decreased slope of the end-systolic elastance (Ees ) pressure–volume relationship
in the LPS-treated animal indicates loss of inotropy or systolic failure, whereas the upward
shift of the loop’s bottom and the increase in end-diastolic pressure–volume relationship (
reflects poor diastolic filling, features of diastolic failure. The three study drugs (other grap
restored systolic function, but only levosimendan partially restored LV diastolic compliance
as indicated by the downward shift of the loop bottom and the decrease in EDPVR
Barraud D, Faivre V, Damy T, Welschbillig S, Gayat E, Heymes C, Payen D,
Shah A, Mebazaa A: Levosimendan restores both systolic and diastolic
cardiac performance in lipopolysaccharide-treated rabbits: comparison
with dobutamine and milrinone. Crit Care Med 2007, 35: 1376-1382.

26. Levosimendan Reduces Mortality In Patients with
Severe Sepsis & Septic shock: A Meta-analysis of
RCTsZangrillo A, Putzu A et al. J Crit Care 2015
7 studies & total 246 patients
In patients with severe sepsis
and septic shock, levosimendan
is associated with a significant
reduction in mortality compared
with standard inotropic therapy

27. • Early norepinephrine adminstratiom aimed to achieve sufficient perfusion press
rapidly in severe hypotensive septic-shock is able to increase cardiac ou
• This seems to be related to increases in both cardiac preload and contractility
• This can be observed even with poor cardiac contractility, except when values
of MAP ≥75 mm Hg are achieved
Vasopressor
SVISVI
GEDVI GEDVI

28. Morelli A et al. JAMA. 2013;310(16)
Open-label, randomized phase 2 study, 154 patients
Univariate Survival Analysis
Cardiac Index
Stroke Volume Index

29. .
Vasopressin resulted in a 10%
reduction in heart rate during
first 24 hours, whereas
Esmolol resulted in 20% decrease.
When compared with Norepinephrine:
Levosimendan,Epinephrine and Dopamine
increased heart rate during first 24 hours
by 15%, with a trend toward higher mortality
Mortality Comparison Between Positive and
Negative Chronotropes - A Metanalysis
James A. Russell et al. Crit Care Clin 34 (2018) 43–61
Mortality Upon Exposure to
Positive Chronotropes
Mortality Upon Exposure to
Negative Chronotropes

30. Anti-TNF antibody Administration improved ventricular function
without changing the cardiac filling pressure Vincent JL et al. Chest.
1992
Methylene Blue Continuous infusion counteracted the myocardial
depression, maintained oxygen transport, and reduced the need for
concurrent adrenergic support Kirov MY et al. Crit Care Med. 2001
IABP Prolongs survival time and lowers vasopressor
requirements in canine model of severe septic shock with a low cardiac
index Solomon DB et al. Crit
Care Med. 2009
Polymyxin B-immobilized fiber column-direct hemoperfusion (PMX-
DHP) and IABP were used for the management of sepsis-induced
Novel & Extracorporeal Therapies

31.  Characterized by
Depressed ejection fraction
Left ventricular dilatation
Typically normalize within 7–10 days
 LV EF actually reflects the LV after load rather than the intrinsic contractility
 A hyperkinetic state is indicative of a profound and persistent vasoplegia
 A hyperkinetic state is associated with a high mortality rate.
 Routine use of dobutamine should no longer be recommended
 Early aggressive Noradrenalin may be useful
 Heart Rate Seems to hold the key
 Negative Chronotropic agents to be preferred over positive ones
 Esmolol may find a role in future
 Levosimendan may be of benefit
 Mechanical support with ECMO may be developed as a therapeutic option
SCM – What We Know & Want to Know