Organ Dysfunction in Sepsis

(ALI,AKI, Septic Heart)

Dr. Jevelin Sinuraya SpAn KIC

INTRODUCTION
• new definition of sepsis captures this concept, centering the clinical
essence of sepsis on the development of a ‘life-threatening organ
dysfunction caused by a dysregulated host response to infection,’
• Three of these disruptive ideas are of particular relevance here. The
first is that organs can develop dysfunction during sepsis in the
absence of decreased oxygen delivery.
• The second is the absence of significant cell death
• The third concept is the recognition that the action of the immune
system against invading pathogens (also known as resistance
capacity) is only part of the body’s defense mechanisms against
infection.
MICROVASCULAR DYSFUNCTION
Consequences of Altered Microvascular Flow
Metabolic Reprogramming as a Cell Survival
Strategy
Mechanisms of sepsis - induced
organ injury and organ failure
 1971 Swan Ganz
Hemodynamic parameter
SVR ↓ : → Hypotension

1990-2000
Endothelial dysfunction and coagulation disorder

2000→
videomicroscopy
Microcirculation disorder

Mitochondria dysfunction
 Infection

Vasodilation Inflammatory
SVR↓ Mediators

Hypotension

Era of pressure
Monitoring: MAP, CO, SVR
Target therapy: ↑ MAP, ↑ CO, ↑ SVR

Organ Dysfunction
 Infection

Vasodilation Inflammatory
SVR↓ Mediators
Oxygen Delivery (DO2)= Cardiac Output x (Hb x SaO2)
Hypoxemia, Anemia, low
Hypotension
cardiac ouput

Era of Perfusion/Goal-directed therapy:

A new concept
Monitoring: of
SvO2shock;
Shock
Target is not
therapy: hypotension,
Normal DO2 based on SvO2

shock is hypoperfusion (↓DO2)

Hypoperfusion/DO
2 drop

Mitochondria
dysfunction

Organ Dysfunction
So, low DO2 is a causal of organ
dysfunction in sepsis

How to monitor the effectiveness of

DO2?

SvO2
 Why is SvO2 important?
Hypoxemia Acute ↓ DO2
Hypoperfusion Anemia CO↓

Cellular Hypoxia /
PtissueO2 ↓

OO  == 25%
VO2 
2ER
2ER 50%

SvO2 ↓ 50%
 Supplemental oxygen+
Early Goal-Directed Therapy
and IPPV E. Rivers et al. N Eng J Med. Nov 2001. 1368

CVP + Art line

< 8mmHg Crystaloid

8 –12 mmHg CVP Colloid

< 65mmHg
>65 - < 90 mmHg MAP > 90mmHg
Vasoactive Agents

< 70% Blood until > 70%

> 70%
ScvO2 Hct > 30%
< 70%
Inotropes
Goals achieved
Hospital admission
 Infection

Inflammatory Endothelial
Vasodilation
Mediators Dysfunction

Hypoxemia, Anemia, low Vasoconstriction

Edema
Hypotension Microvascular Plugging
cardiac output

Hypoperfusion/DO
2 drop

Era of endothelial and microcirculation

Mitochondria
dysfunction SvO2, Tissue PO2
Monitoring: Microcirculation,
Target therapy: Improving microcirculation

Organ Dysfunction
 Endothelial dysfunction
is sepsis
COAGULATION
Endothelium CASCADE

Tissue Factor
Factor VIIIa
PAI-1
IL-6
IL-1
TNF-
Bacteria Factor Va
Monocyte

Suppressed
fibrinolysis
THROMBIN
ENDOTOXIN TAFI

Neutrophil Fibrin Microvascular

trombosis
Tissue Factor
IL-6 Fibrin clot

Inflammatory Response Thrombotic Response Fibrinolytic Response

to Infection to Infection to Infection
 Representative examples of the sublingual microvasculature in a
healthy volunteer (A) and in a patient with septic shock (B). Note
the rich density in large and small vessels in the volunteer and the
decrease in the density of small vessels in sepsis.
Target therapy

Activated Protein C
Bernard GR et al.
N Engl J Med
2001;344:670.
 Infection

Vasodilation Inflammatory Endothelial

SVR↓ Mediators Dysfunction

Impaired Mitochondria
Cardiac dysfunction, hypoxemia Vasoconstriction
Hypotension anemia, preload drop Microvascular Plugging
Edema

respiration
Era of Oxidative Stress and mitochondrial respiration
Monitoring: mitochondria function, SvO2, Tissue PO2
Target therapy: Improving mitochondria function (antioxidant), inhibitor
NOS, PARP, etc)

Hypoperfusion/DO
2 drop

Mitochondria
dysfunction
Impaired of mitochondrial respiration as a cause of organ
dysfunction
Organ Dysfunction
EVIDENCE FOR IMPAIRED
MITOCHONDRIAL RESPIRATION IN
SEPSIS..1
• Improving systemic DO2 early improve outcome
for patients with septic shock (Rivers 2001)
• Improving systemic DO2 later in the course of
sepsis are ineffective and at worst deleterious
(Gattinoni 1995, Hayes 1994)
 improving perfusion and O2 delivery
in patients with established sepsis
fails to improve survival or prevent
organ system dysfunction
Optimisation of Patients in ICU
Hayes, Timmins et al. N Eng J Med. 1994: 330; 1717.

• Studied 109 critically ill patients in ICU.

• Treatment goals using dobutamine were:
• Oxygen delivery > 600 ml/min/m2.
• Oxygen consumption > 170 ml/min/m2.
• In those particular case, 17 pts received > 50
μg/kg/min of dobutamine and 68% of the total
group received NE
Optimisation of Patients in ICU
Hayes, Timmins et al. N Eng J Med. 1994: 330; 1717.

Treatment group
Treatment group

Control group
Control group
 Result

Treatment group

Control group
EVIDENCE FOR IMPAIRED
MITOCHONDRIAL RESPIRATION IN
SEPSIS..1
• Conclusion:
• If improving perfusion and O2 delivery in patients
with established sepsis fails to improve survival or
prevent organ system dysfunction, one might
wonder whether alterations in energy
metabolism are important at all in the
pathogenesis of the syndrome
Organ failure and
Septic Shock

O2 is available but
cells are unable to extract Cellular/Mitochondrial
Dysoxia
oxygen dysfunction

O2ER = 10%

PO2 tissue ↑

SvO2 90%
POTENTIAL MECHANISMS OF
CYTOPATHIC HYPOXIA IN SEPSIS
• Inhibition of Pyruvate dehydrogenase
• Nitric oxide-mediated inhibition of cytochrome
oxidase
• Peroxynitrite-mediated inhibition of mitochondrial
enzymes
• The PARP hypothesis
 Production of ROS in endothelium and neutrophils
Rolling Adhesion Transmigration
Selectins
Integrins
Microorganism
VESSEL
ENDOTHEL L-Arg + iNOS Hypoxanthine + XO → Xanthine

TISSUE
O2- O2
DNA Strand Breaks= NO O2- O2
Cell Death, apoptosis
NADP+

NADPH
OONO-
PEROXYNITRITE
NADPH
oxidase
ORGAN CROSSTALK
• Dysfunctional organs may impact other remote organs through
complex, and incompletely understood, biological communication
processes known as organ crosstalk.
• Kidney-brain crosstalk was observed in animal models of AKI in which
local renal inflammation secondary to TNFa administration was
associated with a disrupted more permeable blood-brain barrier and
activation of brain astrocytes.
• In other animal models, AKI has been associated with alterations in
cerebral neurotransmitter concentrations and depletion of brain
catecholamine concentrations.
• Lung-brain crosstalk occurs in patients following lung injury with
subsequent development of brain damage despite otherwise normal
prior neurologic function
• LPS-challenged rats subjected to moderate positive end expiratory
pressure (7 cm H O) and low tidal volume ventilation showed
2

decreased lung injury and systemic inflammation compared with rats

ventilated with high tidal volumes
• Inflammatory crosstalk via systemic cytokines between the kidney
and lungs has been observed in preclinical and clinical studies with
ventilator-induced lung injury (VILI) associated with high tidal volume
mechanical ventilation contributing to the development of AKI.
Pathogenic mechanisms of sepsis-related acute kidney injury
Systemic inflamation
Ischemic Insultlipopolysaccharide/endotoxinSepsis
direct-indirect
(cytokine)
hypoxia
Hemodynamic changes oxidatie stress Toxins
hypoperfusion exogenous
toxicity
global and/or regional heme proteins
endothelial
ishemia-reperfusion antibiotics, contras media
dysfunction
microtrombus vasopressor
nitric oxide
Renal cell injury

Sublethal injury Apoptosis and necrosis

Renal cell repair and regeneration Cell loss

Ronco, Clin J Am Soc Nephrol. 2008
Glomerular Structure:

Efferent
Afferent
Glomerulus in Sepsis
Vasodilatation Greater efferent vasodilatation
 Constriction of Efferent Arteriole
ConstrictionNor-epinephrine effect
of Efferent Arteriole Nor-epinephrine effect
• ARDS and acute kidney injury are frequent complications in critically
ill patients with MODS. Pannu and Mehta proposed a number of
mechanisms to explain the effects of positive pressure ventilation on
renal function, including a reduction in cardiac output, redistribution
of intrarenal blood flow, stimulation of sympathetic and hormonal
pathways, and release of systemic inflammatory mediators as a
consequence of VILI.
Karakterisasi fungsi jantung pada syok septik
• Studi, Parrillo :
• 1. penurunan fraksi ejeksi biventrikular
• 2. peningkatan volume akhir diastolik ventrikel
kiri dan kanan
• 3. peningkatan denyut jantung dan cardiac
output
• 4. penurunan resistensi vaskuler sistemik
 Uncopling protein

Permeability trasision pore

 darah
paru

ginjal
jantung
Disfungsi diastolik

Disfungsi sistolik