Pathophysiology of Critically

Ill
ADE WINATA
PERSAGI
MEDAN
2019
Statement
• Critical illness is any disease state
• medical or surgical, that requires treatment in the intensive care unit
(ICU).
• Although critical illness is frequently associated with infection or
sepsis, other conditions such as severe trauma, the postsurgical state,
pancreatitis, burn injury, hemorrhage, and ischemia can produce the
same clinical findings as microbial invasion, even in the absence of an
infectious organism
Critically illness
• A Disease or state in which Death is possible or imminent. • Organ
dysfunction or failure
• Vital Sign plus physiological parametere
• Oxygen Delivery – Oxygen Consumption
• Scoring System and Excalating policy by trigger system.
 Why Focus on Sepsis?
• Sepsis is the leading cause of death in non-coronary care intensive
care units, with a mortality rate between 30% and 50%
• From 2007 to 2009, over 2,047,038 patients were admitted with a
sepsis-related illness
• 52.4% are diagnosed in the ED

• 34.8% on the hospital wards

• 12.8% in the ICU

 Severe Sepsis:
Comparison With Other Major Diseases

Incidence of Severe Sepsis Mortality of Severe Sepsis

300 250.000

250 200.000
Cases/100,000

Deaths/Year
200
150.000
150
100.000
100

50 50.000

0 0
AIDS* Colon Breast CHF† Severe AIDS* Breast AMI† Severe
Cancer§ Sepsis‡ Cancer§ Sepsis‡

†National
Center for Health Statistics, 2001. *American Heart Association. 2000.
§American Cancer Society, 2001. ‡Angus DC et al. Crit Care Med. 2001 (In Press).
Mortality Increases in Septic Shock
Patients
Incidence Mortality

Sepsis
400,000 7-17%

Severe Sepsis 20-53%

300,000

Septic
53-63%
Shock

Balk, R.A. Crit Care Clin 2000;337:52

SEPSIS 3
• Sepsis is A life-threatening organ dysfunction caused by a dysregulated
host response to infection.
SEPSIS SHOCK
Define as subset of sepsis, clinically identified by a vasopressor
requirement to maintain a MAP of 65 mmHg or greater and serum lactate
> 2 mmol/L in the absence of hypovolemia (Sepsis-3)
Characterized by a combination of hypovolemia, peripheral dysfunction
(arteri-venodilation) that resulting in hypotension and abnormality of
loco-regional distribution of blood flow, cardiac failure and cell
dysfunction
In clinical finding, predominant can be differ; hypovolemia or vasoplegia
or cardiac depression
Patofisiologi sepsis
PATHOPHYSIOLOGY OF SEPSIS
No positive blood cultures
despite sepsis - Why?

Bacterial components (endotoxines)

trigger the sepsis
DEATH OF GRAM-NEGATIVE BACTERIUM AND
RELEASE OF ENDOTOXIN

Antibiotic
 The Host Response in Severe Sepsis

Angus DC, van der Poll T. N Engl J Med 2013;369:840-851.

From Localized Insult to
“Cytokine Storm”
Systemic Activation of
Inflammation in Sepsis

14

IL-6 (U/mL)
Endotoxin (ng/L)
12

10
8

6
4

TNF (ng/L)
2

0
0 60 120 180 240 300 360
Minutes After LPS Infusion

Chart adapted from: van Deventer SJ et al. Blood. 1990;76:2520-6.

 SIRS;
Fever
TNF- Tachycardia
Hypertension
IL-1ß
Leucocytosis/CRP
IL-6
IL-8
PAF
iNOS
COX2

IL-1 ra
IL-10
sTNFr-1/11
TGF-
IL-4

endotoxin
 SIRS;
Fever
Tachycardia
Hypertension
Leucocytosis/CRP

D-Dimer ++
 SIRS;
Fever
Tachycardia
Hypertension
Leucocytosis/CRP

Microemboli →
Hypoperfusion organ →
lactate 
 Imbalance between Pro-Inflamatory and
Anti-inflamatory response

Clinical presentation TNF- Biologic sequelae

IL-1ß IL-1 ra
IL-6 SIRS = IL-10
IL-8 SYSTEMIC INFLAMATORY sTNFr-1/11
PAF RESPONSE SYNDROME TGF-
iNOS IL-4
COX2
Sepsis / Monocyte
SIRS PROINFLAMMATORY ANTI-INFLAMMATORY activation

TNF-
IL-1 ra
IL-1ß CARS =
IL-10
IL-6
COMPENSATED sTNFr-1/11
IL-8
ANTI-INFLAMATORY TGF-
SEPTIC SHOCK/ PAF
RESPONSE SYNDROME IL-4 Monocyte
iNOS deactivation
MOF
COX2

PROINFLAMMATORY ANTI-INFLAMMATORY → CELL HYPORESPONSIVENESS /

IMMUNOPARALYSIS
 HOST FACTOR IN SEPTIC SHOCK: DEPENDS ON THE BODY’S FIRST RESPONSE TO
INFECTION, SIRS OR CARS? GENETIC POLYMORPHISME

Clinical presentation TNF- Biologic sequelae

IL-1ß IL-1 ra
IL-6 IL-10
IL-8 sTNFr-1/11
PAF
iNOS
SIRS TGF-
IL-4
COX2

Sepsis / SIRS Monocyte

PROINFLAMMATORY ANTI-INFLAMMATORY
activation

TNF- IL-1 ra
IL-1ß IL-10
IL-6 sTNFr-1/11
IL-8 TGF-
SEPTIC SHOCK/ PAF CARS IL-4 Monocyte
MOF iNOS deactivation
COX2

PROINFLAMMATORY ANTI-INFLAMMATORY → CELL HYPORESPONSIVENESS /

IMMUNOPARALYSIS
How to identify systemic sepsis-induced immunoparalysis
Guillaume Monneret, Advances in Sepsis 2005;4(2)42-9.
The Pathophysiology
and Treatment of
Sepsis, Hotchkiss,
NEJM, 2003
Sir William Osler - 1904
The Evolution of Modern Medicine

Sir William Osler - 1904

The Evolution of Modern
Medicine

“Except on few occations, the

patient appears to die from
the body´s response to
infection rather than from it.”
The earliest te better
 6 Key steps in oxygen cascade
O2
Uptake in the Lung Oxygenation PaO2
CaO2
Carrying capacity Haemoglobin SaO2 DO2

Delivery Cardiac Output Flow rate - ø

Organ distribution Autoregulation

VO2
Diffusion Distance
O2ER
Cellular use Mitochondria

ATP = energy
 •Hypoxemia Acute ↓ DO2
In Shock or
Catabolic State •Anemia •CO↓

O2ER 

Cellular Hypoxia

OO  == 25%
2ER
2ER 50% VO2 

SvO2
DO2  50%

SvO2 ↓ 50% O2 return

↓ 500
• If SvO2 decreases, it means that DO2 is not high enough to meet tissue
needs VO2
1.This might be due to inadequate DO2 (poor saturation, anemia, low
cardiac output)
2.Or, it might be due to increased tissue extraction VO2 (fever, shivering,
thyrotoxicosis, agitation, exercise, etc.)
 Organ failure and
Septic Shock

O2 is available but
cells are unable to extract oxygen

Dysoxia

Cellular/Mitochondrial
O2ER = 10%
dysfunction

SvO2
DO2 n/ 90%

SvO2 90% O2 return

900

• Increases in SvO2 combined with rising lactate levels indicate tissues are
unable to extract oxygen
• This can be seen in such things as septic shock, cyanide toxicity,
carbon monoxide, methemoglobin. Might also indicate hypothermia,
shunt, inotrope excess, etc.
I mean it

How much fluid

you give?
ROOT CAUSE ANALYSIS
THE PROBLEM
WHAT IS THE CAUSE OF HYPOTENSION
IN SEPSIS?
THE PATHOPHYSIOLOGY OF SEPSIS

LOSS AUTOREGULATION
NEED NOR-EPINEPHRINE
NOT FLUID George 2018
MIS-INTERPRETATION…??
HYPOVOLEMIA ?

DYSFUNGSI MULTIORGAN
George 2018
 Summary
First Hit Second Hit
IL-1,TNF-a,IL-6
Early MODS
Reperfusion
injury SIRS 1-2 weeks
Survivor
Major Surgery
24-48 hrs CARS Infection

IL-4,IL-10,TGF-, Sepsis
IL-1ra

Late MODS
55