Assessment of Cell Injury

Tissue Hypoxia

How to detect, how to correct,

how to prevent?

Sun Sunatrio
Department of Anesthesiology , Faculty of Medicine,
University of Indonesia, Jakarta
 Tissue Hypoxia (TH)

decrease in O2 utilisation associated with

anerobic metabolism
decreased O2 transport and low flow often
precedes the onset of anerobic metabolism and
early detection of this physiological abnormality
could possibly prevent TH
How to detect TH by clinical
and biochemical methods in the
critically ill?
Clinical Assessment

this should be the first approach taken to

assess the critically ill pts
signs of TH are somewhat
insensitive and non specific
 Clinical Assessment

several signs (abnormal skin perfusion, urine

output , BP etc) often indicate organs
dysfunction caused by TH should prompt a
search for reversible causes of TH
The physiological and biochemical tests for
TH should be used to complement clinical
assessment
Transcutaneus O2 Pressure

Some limitation
Not yet widely utilized
 PH and Lactate
a common abnormality in pts with TH is a
metabolic acidosis often due to lactic acidosis
the major reasons to measure arterial lactate
are to assess TH and to investigate metabolic
acidosis
Plasma arterial lactate is a goal prognostic
indicator and can be followed sequentially to
assess the pts response to th/ designed to
reverse TH
 Glucose Metabolism
Glucose
CYTOPLASM
Glucose
Cori MITOCHONDRIA
Cycle
Pyruvate Pyruvate Krebs
Cycle ATP
AcetylCoA

Lactate
Lactate

Lieberman MA, Vester JW. Carbohydrates. In: Nutrition and Metabolism in the Surgical Patient.
Boston, MA: Little, Brown and Company;1996:203-236.
 Inflammatory Response

Glucose CYTOPLASM

Glucose
Cori MITOCHONDRIA
Cycle Pyruvate
Pyruvate TNF
Krebs
IL1X Cycle ATP
IL6
Acetyl CoA

Lactate
Lactate
BLOCKAGE
 DO2 VO2 Relationship

has been suggested as a sensitive method of

determining whether TH exists
there are a number of methodological
problems
this approach is not particularly useful in the
care of the critically ill pt
 Mixed Venous O2 Sat & Mixed Venous
Arterial CO2 Gradient

decreased mixed venous O2 sat and pressure can

be caused by decreased DO2 and/or increased O2
demand
a normal or increased value does not rule out
significant TH, especially in sepsis
decreases in mixed venous O2 sat and pressure
are more likely in cardiogenic & hypovolemic
shock than septic shock
 Gastric Intramucosal pH

it appears to be a good prognostic indicator of

pt outcome in the ICU in
a selected series of pts
it is not certain that it is much better than other
predictors in unselected pts
relatively expansive, difficult to use, operator-
dependent, and time consuming to measure
 Gastric Intramucosal pH

the gastric mucosal-arterial CO2 difference is

more specific than gastric intramucosal pH
further studies are required before we can
recommend this potentially promising
technique for routine clinical use
How to Correct TH
Optimization of DO2
* early fluid resuscitation
* blood transfusion
* vasoactive drugs (dopa, dobu, NA)
Reduction in O2 demand
* sedation
* abolition of pain, stress & anxiety
* increased sympathetic activity
* muscle relaxant
* mechanical ventilation
A major goal of managing
critically ill patients is to ensure
adequate tissue oxygenation.
 O2 O2
160 torr 104 torr

100 torr
Hb

Cytosol +
H H+ H
+

c Hb 50 torr
III IV
I Q bc1 aa3
DH II Fo
TMPD
NADH FADH ADP ATP
+
Substrates Succinate H H
+ 1-10 torr
Matrix

Mitochondrial Respiratory Chain

A major goal of managing critically ill
patients is to ensure adequate tissue
oxygenation.

Hemodynamic monitoring assists the

clinician in meeting that goal.
Fundamentals of
Oxygen Delivery
Components of Oxygen Delivery

DO2 = CO x CaO2

DO2 = CO x (HbO2 + Diss. O2)

DO2 = CO x Hb x SaO2 x 1.34

= 5000 x 15/100 x 100/100 x 1,34 = 1000 ml/men.

= 5000 x 20/100
BW 70 kg Hb 15 g %
Normal basal O2 demand = 280 mL

Oxygen transport = CO x (Sa O2 x Hb x 1,34 +

pO2 x 0,003)
= 5 L/min x 20 mL O2/100mL
= 1 L O2/min
Hb 10 g% = 5 L/min x 14 mL O2/100mL
= 700 ml O2/min
Hb 5 g% = 15 L/min x 6,6 mL O2/100mL
= 1 L O2/min
 Oxygen Transport
CaO2 = 17-20 vol%
Pulmonary SaO2 = 95-100%
Artery DO2 = 1000 ml/min

Aorta
CvO2 = 12-15 vol %
SvO2 = 60-80%
DO2 = 750 ml/min

ScvO2
= 60-80%

VO2 = CO x Hb x (SaO2 SvO2) x 1.34 = 250 ml/min.

Circulation in Septic Shock

Dellinger RP. Crit Care Med 2003;31:946-955

Circulation in Septic Shock

Septic shock, pre-fluid resuscitation

Vasodilatation
Increased PVR
Decreased contractility
Capillary leak

Low Cardiac Output

Dellinger RP. Crit Care Med 2003;31:946-955

Circulation in Septic Shock

Septic shock, pre-fluid resuscitation

Vasodilatation
Increased PVR
Decreased contractility
Capillary leak

The net result after fluid resuscitation:

Low CO Optimal CO
Low SVR
Better prognosis

Dellinger RP. Crit Care Med 2003;31:946-955

 Oxygen Delivery & Mortality in Septic
Shock
100

80
% Mortality

60

40

20

0
0 - 8.5 9.0 - 12.9 3.0 - 16.9 17.0 - 20.9 21.0 - 24.9 25 +
Oxygen Delivery (ml/kg/min)

Tuchsmidt J, Fried J, Astiz M, Rackow E. Chest 1992; 102: 216-220

Most investigators currently agree that
increased DO2 is associated with better
survival.

Does increasing DO2 in the critically ill

patient improve survival or is it a marker
for the healthier patient who is more
likely to survive ?
Why Measure SvO2
Typically a decrease in SvO2 is one
of the earliest indicators of the
threat to tissue oxygenation.
What is the Normal Value of SvO2?

The normal value of SvO2 is 68% to 77%

Values less than 50% are worrisome

Values less than 30% suggest anaerobic metabolism

It is more useful to follow trends (in response to

treatment changes) than to just look at the number
at a given point in time
 SvO2 < 60%
DO2 = CO x Hb x SaO2 x 1.34
Decrease in oxygen delivery (DO2)
Decrease in hemoglobin (Hb)

Anemia, hemorrhage

Decrease in arterial oxygen saturation (SaO2)

Hypoxemia, lung disease

Decrease in cardiac output (CO)

LV dysfunction, shock, hypovolemia

Increase in oxygen consumption (VO2)

Fever, seizures, shivering, work of breathing
 Initial Resuscitation
Resuscitation should begin as soon as severe sepsis Grade B
or sepsis induced tissue hypoperfusion is recognized
Elevated Serum lactate identifies tissue
hypoperfusion in patients at risk who are not
hypotensive
Goals of therapy within first 6 hours are
Central Venous Pressure 8-12 mm Hg (12-15 in ventilator
pts) -
Mean arterial pressure > 65 mm Hg
Urine output > 0.5 mL/kg/hr
ScvO2 or SvO2 70%;
if not achieved with fluid resuscitation during first 6 hours:
- Transfuse PRBC to hematocrit > 30% and/or
- Administer dobutamine (max 20 mcg/kg/min) to goal
Rivers E, et al. N Engl J Med 2001; 345:1368-1377
Fluid Therapy: Choice of Fluid
Grade C
Fluid resuscitation may consist of natural or
artificial colloids or crystalloids
No evidenced-based support for one type of fluid
over another
Crystalloids have a much larger volume of
distribution compared to colloids
Crystalloid resuscitation requires more
fluid to achieve the same endpoints as
colloid
Crystalloids result in more edema

Choi PTL. Crit care Med 1999;27:200-210

Cook D. Ann Intern Med 2001;135:205-208
Scierhout G. BMJ 1998;316:961-964
Fluid Therapy: Fluid Challenge
Grade E
Fluid challenge in patients with suspected hypovolemia
may be given
500 - 1000 mL of crystalloids over 30 mins
300 - 500 mL of colloids over 30 mins
Repeat based on:
Response (increase in blood pressure and urine
output) and
Tolerance (evidence of intravascular volume
overload)
Input is typically greater than output due to
venodilation and capillary leak
Most patients require continuing aggressive fluid
resuscitation during the first 24 hours of management
 Vasopressors
Initiate vasopressor therapy if appropriate fluid challenge fails
to restore adequate blood pressure and organ perfusion Grade E
Vasopressor therapy should also be used transiently in
the face of life-threatening hypotension, even when fluid
challenge is in progress

Either norepinephrine or dopamine are first line agents to

correct hypotension in septic shock Grade D
Norepinephrine is more potent than dopamine and may
be more effective at reversing hypotension in septic
shock patients
Dopamine may be particularly useful in patients with
compromised systolic function but causes more
tachycardia and may be more arrhythmogenic

LeDoux D. Crit Care Med 2000;28:2729-2732 Regnier B. Intensive Care Med 1977;3:47-53
Martin C. Chest 1993;103:1826-1831 Martin C. Crit care Med 2000;28:2758-2765
DeBacker D. Crit Care Med 2003;31:1659-1667 Hollenberg SM. Crit Care Med 1999;27:639-660
 Vasopressors (cont)
Low dose dopamine should not be used for renal protection

in severe sepsis
Grade B

An arterial catheter should be placed as soon as practical in

all patients requiring vasopressors Grade E
Arterial catheters provide more accurate and
reproducible measurement of arterial pressure in shock
states when compared to using a cuff
Vasopressin may be considered in refractory shock patients
that are refractory to fluid resuscitation and high dose Grade E
vasopressors
Infusion rate of 0.01-0.04 units/min in adults
May decrease stroke volume
Hollenberg SM. Crit Care Med 1999;27:639-660
Bellomo R. Lancet 356:2139-2143
Kellum J. Crit Care Med 2001;29:1526-1531
 Inotropic Therapy
In patients with low cardiac output despite adequate fluid Grade E
resuscitation, dobutamine may be used to increase cardiac
output
Should be combined with vasopressor therapy in the
presence of hypotension

It is not recommended to increase cardiac index to target

Grade A
an arbitrarily predefined elevated level
Patients with severe sepsis failed to benefit from
increasing oxygen delivery to supranormal levels by
use of dobutamine

Yu, et al. CCM 1993; 21:830-838

Hayes, et al. NEJM 1994; 330-1717-1722
Gattinoni, et al. NEJM 1995; 333:1025-1032
Early Goal-Directed Therapy (EGDT)

Rivers E, et al. NEJM

2001;345:1368-1377
Early Goal-Directed Therapy Trial Protocol
Airway Breathing - Circulation
Supplemental oxygen +/-
Endotracheal intubation and
Mechanical ventilation EGDT in the treatment
of severe sepsis and
Central venous and
Arterial catheterization
septic shock

Sedation,paralysis
(if intubated) Minimize VO2
Or both
crystalloid
Volume load
CVP
8-12 mmHg
colloid
MAP
<65mmHg
Vasoactive agents Vasoactive drugs
>90mmHg
>65 and<90mmHg
<70% Transfusion of red cells >70% O2 carrying
ScvO2
Until hematocrit>30% capacity
<70%
>70%
No Inotropic agents Inotrope
Goals
achieved
Yes
ICU admission Rivers E, et al. NEJM 2001;345:1368-1377
BPs often Yet, the patients
normal are sick
Pathophysiology Septic Shock

1. Hypoxia
2. Hypovolemia
3. afterload
4. Possible anemia
5. contractility

Dellinger RP. Crit Care Med 2003;31:946-955

 Optimizing Oxygen Delivery in Shock
4 transfusion

DO2= CO x Hb x SaO2 x 1.36

1
Oxygenation/ mech.
ventilation vent.
HR x SV
2 3
fluid Preload Afterload vasoactive

Contractility inotrope 5
 Early Goal-Directed Therapy (EGDT)
yields significant reductions in sepsis
related mortality
Standard Therapy (n=133) Early Goal-Directed Therapy (n=130)

60 56.9

49.2
50 46.5
44.3

40
33.3
30.5
30

20

10

0
In-hospital Mortality 28-day Mortality 60-day Mortality
P Value 0.009 0.01 0.03

Kaplan-Meier estimates of mortality and causes of in-hospital deaths

Rivers E, et al. NEJM 2001;345:1368-1377
 EGDT Benefits

$ 12,000 Reduction in total hospital charges

34 % Reduction in sepsis-related mortality

3,8 Reduction in hospital days

 Therapeutic interventions:
Standard Therapy versus EGDT
7-72 0-72
Intervention 0-6 hours
hours hours
Fluid therapy (liters) -2.94a +1.98b +0.085

Receiving vasopressors (%) +2.9 +13.8d +14.5c

Receiving inotropes (%) -12.9a -6.1 -6.2

Receiving red blood cell transfusion (%) -45.6a -21.7a -23.9a

Mechanical ventilation instituted (%) +0.8 +14.6a +15.0c

Pulmonary artery catheter use (%) +3.4 +10.6e +13.9b

A negative or positive value indicates how the control group therapy compares with the treatment group.
a P<0.001 , b P=0.01, c P= 0.02, d P =0.03, e P=0.04.

Rivers E, et al. NEJM 2001;345:1368-1377

EGDT vs Standard therapy
EGDT, during the first 6 hours: No difference in:
More fluid Vasopressor
Mechanical ventilation
More transfusion

More inotrope (dobutamin)

ScvO2 detect profound global myocardial dysfunction

corrected CVP more fluid loading (almost 3.5 liters
more fluids in the first 6 hours than the control patients)
EGDT, 7 72 hours:
More fluid loading (first 6 hrs) less mechanical

ventilation!
Less fluid : more aggressive (0-6 hrs) less

complications!
 Why was cardiovascular collapse a
significant cause of death in the control
group?

Concealed shock (shock with normal vital signs):

frequent in early severe sepsis and septic shock.
Standard therapy normal MAP, CVP, urine output,
but decreased ScvO2 and increased lactate levels
global tissue hypoxia (almost 40% of control patients
)

2-fold increase in hemodynamic deterioration

More mechanical ventilation
More swan-ganz catheterization
How do severe sepsis and septic shock differ
hemodynamically in the early stages compared with that
classically described in the ICU?

Patients presenting with early sepsis and septic shock

are characterized by
Hypovolemia (low CVP)

Blood pressures: N/

cardiac output ( ScvO2 and CI)

This is in contrast to ICU patients who are:

Euvolemic

ScvO2

cardiac indices

Rivers E, et al. NEJM 2001;345:1368-1377

What are the most important ways in
which EGDT can improve outcomes?

The key factors are early detection of high risk

patients in concealed shock resulting:
Early reversal of hemodynamic changes and global

tissue hypoxia
Prevention of acute cardiovascular collapse

And the possibility of preventing the inflammatory

aspects of global tissue hypoxia that accompany

the inflammation or infection

Rivers E, et al. NEJM 2001;345:1368-1377

I dont have continuous ScvO2
monitoring
Use serial BGA obtained from CVC

I dont have CVP monitoring

Well, you are in trouble
Send the patient to the referral hospital
But try to resuscitate first
 Fluid Resuscitation

Aggressive fluid resuscitation with boluses of 20

ml/kg over 5-10 min
Blood pressure by itself is not a reliable endpoint for
resuscitation
Initial resuscitation usually requires 40-60 ml/kg, but
more may be required
Therapeutic Endpoints
Capillary refill < 2 sec
Warm extremities
Urine output > 1 ml/kg/hr
Normal mental status
Decreased lactate
Central venous O2 saturation > 70%
The goal is achieved, but lactate
Microcirculation mitochondrial distress syndrome
(MMDS)
Resuscitation of the microcirculation
 Initial Hit

Comorbidity Time
Genetics Therapy

Circulatory shock + Inflammation Time

Resuscitation based on correction
of systemic hemodynamics and oxygen-derived variables Therapy

Microcirculatory dysfunction

Endothelium RBC Leukocytes SMCs Coagulation

Signal transduction Deformability Adhesion Adrenergic Microvascular
Coagulation Aggregation Cytokines signaling Thrombosis
regulation O2 transport ROS NO

Microcirculatory Cellular distress

Shunting Mitochondria Organ
O2 supply demand mismatch Hybernation failure
Hypoxia Apoptosis
 OPS Imaging
1. Normal: RR 120/80; SO2 98%;
MFI small = 3, medium = 3, large
= 3.
2. Septic Shock: HR 82/min; RR
90/35; SO2 98%; CVP 25; Tcentral
35.6; Tperipheral 29.4; MFI: small
= 0.8, medium = 0.3, large = 0.3.
3. Resuscitation with
nitroglycerin: HR 76/min; RR
75/30; SO2 97%; CVP 27; Tcentral
36.8; Tperipheral 32.6; MFI: small
= 2.7, medium = 2, large = 2.3.

MFI = microcirculatory flow index = a semi-quantitative scoring (0=no flow;

1=sludging; 2=moderate flow; 3=normal flow) of flow-patterns in small (10 - 25
m), medium (25 - 50 m), and large-sized (50 - 100 m) microvessels
OPS ImagingOrthogonal Polarization Spectroscopy)
Conclusions
Relying on BP to decide sick or not sick is not very
sensitive
Early treatment for sepsis/septic shock leads to
better outcomes, or better yet, early critical care in
the ED leads to better outcome (sort of intuitive)
Multiple infectious sources need to be considered e.g.
intraabdominal causes
Current approach to sepsis (esp. in Indonesia) is not
adequate and downright bad
Setiati T. (unpublished data)
HAES Steril 6% vs RL for volume replacement
in children with DSS (Pediatric pts)

Haes-steril gr : CVP 15 - 18 cmH2O

RL gr : CVP < 12 cmH2O
Mortality in RL group (n=30, mean age 6.6
yrs): 26.67%
Mortality in HAES Steril group (n=30, mean
age 6.9 yrs): 6.67%
 Acute Phase (AP)
local responses: vasodilatation, platelet aggregation,
neutrophil chemotaxis and release of lysosomal
enzymes
systemic responses: fever, leucocytosis and change in
the hepatic synthesis of AP prot
stimuli to the AP: many different forms of tissue injury,
eg: infection, immuno/alergic reaction, thermal injury,
hypoxia injury, trauma, surgery and malignancy
C-Reactive Prot (CRP) & Erytrocyte
Sedimentation Rate (ESR)

AP prot which reflect a measure of the AP

response
the clinical use of AP prot is an aid to
diagnosis
relatively nonspecific the value of
measuring AP prot is to assess the extent of
inflammation reflecting momentary disease
activity
C-Reactive Prot (CRP) & Erytrocyte
Sedimentation Rate (ESR)

may monitor the course of disease in

response to therapeutic intervention
unlike other AP prots, CRP and ESR increase
in concentration relatively high compared to
basal concentration, have a relatively short
lag time from the moment of stimulus and
are cost-effective
 CRP

CRP > ESR (ESR is affected by a multitude of

factors)
plasma level of CRP in healthy subject: 1mg/L
(N: <10mg/L)
4-6 hr after initial tissue injury: CRP and
continue to increase several hundred fold within
24-48 hr
 CRP

remains elevated during the AP response and

reduces to normal with restoration of tissue
structure and function
the use in CRP is exponential, doubling every
8-9 hr
half life < 24 hr
 CRP

is a direct and quantitative measure of the AP

reaction
serial measurements can be used as a
diagnostic tool for infection, monitoring effect
of treatment, or early detection of relaps
ESR
Normal: male <50 yr: 15 mm/hr
female <50 yr: 20 mm/hr
Indirect measure of the AP reaction
Simple and inexpensive laboratory test for
assessing inflammation
has even been used for the prognosis of non-
inflammatory conditions (CAD, prostate Ca,
stroke)
 Comparison of ESR & CRP

ESR CRP

Results affected by Gender Y N

Age Y N
Pregnancy Y N
Temperature Y N
Drugs (eg, steroids, salicylates) Y N
Smoking Y N
Level of plasma prot Y N
RBC factors Hematocrit Y N
Morphology Y N
Aggregability Y N
 Comparison of ESR & CRP

ESR CRP

Response to disease process intermediate early

Clinical assessment Normal range of results wide narrow

Specificity moderate high
Sensitivity moderate high
Reproducibility low/moderate high
Check for technical errors may be difficult readily

Availability > 60 min <20 min

Relative cost x1 x 2-3

Kebocoran kapiler, edema & gagal organ:
Peran HES (100.000-300.000)
The reflection coefficient. The capillary wall is represented
with punched holes through which molecules may pass.

Medium molecular size Large molecules

Leaky capillary Normal capillary
Little impedance No passage
near 0 =1

Small molecules Medium molecular size

Normal capillary Normal capillary
No impedance Some steric impedance
=0 near 1
INFLAMASI & GAGAL ORGAN
Respons inflamatori lokal respons seluruh tubuh umum
mengancam nyawa (kerusakan inflamatori organ yg
jauh dari lokasi primer cedera).
Walau survive dari bedah yg kompleks tetap ada risiko
mati akibat MOF ssd bbrp hari, pekan bahkan bulan di
ICU.
Kombinasi INFLAMASI sering

KEBOCORAN KAPILER bertanggung

CAIRAN IV jawab
 Th/ agresif : MATI
Ps: trauma darah
infeksi cairan
cedera op obat vasoaktif
ventilator SURVIVE
dsb

hari

pekan
MATI MOF
 CEDERA
INFLAMASI

PERUBAHAN PERMEABILITAS KAPILER

PATOGENESIS MOF
 INFLAMASI & GAGAL ORGAN
Serum C reactive protein mg/L

Days post injury

Konsentrasi protein C-reaktif serial pada dua pasien trauma. Grafik bawah mewakili pasien
laki-laki 24 tahun,yang menderita fraktur femur dan iga, dan grafik atas mewakili wanita
60 tahun dengan fraktur beberapa iga yang kemudian menderita ARDS.
SINDROMA KEBOCORAN KAPILER KLINIS

Stimulasi inflamatori >>> OF

Imbang cairan positif MOF
Cedera tdk pernah BB
BB selalu iatrogenik.
Sindroma kebocoran kapiler klinis
Resusitasi cairan dan penambahan BB : esensial utk Th/ syok.
Fase pasca syok : kebalikannya.

Representasi imbang cairan pada dua pasien sesudah bedah

mayor
untuk aneurisma aorta yang pecah.
INSULT:
~ HIPOKSIA
~ CEDERA JAR
SIRS
~ SEPSIS

KAPILER BOCOR :
PLASMA PROT
EDEMA ELEKTROLIT
AIR
Sindroma kebocoran kapiler klinis
INJURY MULTIPLE
ORGAN FAILURE
Histamine INJURY TO:
[V] Polymorphs/Cytokines LUNGS
KIDNEY
LIVER
LEAK BOWEL

ALBUMIN
CAPILLARY INTERSTI. CELL
SPACE

WATER

OEDEMA

Slowing of oxygen diffusion

Daur umpan balik yang berakibat gagal organ multipel. Injury mewakili
serangan inflamatori berat. (Gosling P)
Sindroma kebocoran kapiler klinis
Hipoalbuminemia akibat bocor ke dlm
ruang interstisial.
Mikroalbuminuria (refleksi permeab
vaskular sistemik ).
Imbang cairan +++
Edema menyeluruh.
DO2
VO2
Mungkin pireksia.
 Mediator yg meningkatkan permeab vaskular &
mrpkan komponen respons inflamatori terintegrasi
thd cedera / iskemia.

Histamin.
Bradikinin. TNF.
Platelet activiting Activated
factor. complement.
Proteasis (lepas dr Leukotrien B4.
PMN). Tromboksan.
Radikal bebas O2.
IMBANG CAIRAN YG MELEWATI
ENDOTELIUM KAPILER

Jantung, paru & ginjal sangat sensitif thd

edema permeab.
Pd paru, edema interstisial dpt melebihi efek
surfaktan & tek. dinding alveolar.
Pd ginjal, edema interstisial meningkatkan tek.
intrakapsular shg memperlambat filtrasi.
MONITORING PERMEAB KAPILER PD
SAKIT KRITIS

Perubahan-perubahan permeab kapiler tercermin pd

ginjal (yg menerima 25% CO).
Perubahan kecil pd permeab glomerular perubahan
besar pd kandungan mikroalbumin urin.
Stimulus inflamatori akut (op & iskemia) ekskresi
mikroalbumin dlm bbrp mnt & dpt meramalkan
komplikasi paru dlm 4 jam pasca-op aorta & bbrp jam
pasca trauma.
Ssd cedera: ekskresi mikroalbumin berbanding terbalik
dg rasio pO2 / FiO2.
 Ekskresi albumin kumulatif > 4 hari
berkorelasi positif dg imbang cairan
8 to 24 hours 8 to 72 hours
1000 1000

900 900
800 800

700 700

Cum ulative ACR

Cum ulative ACR

600 600

500 500

400 400

300 300

200 200

100 100

0 0
0 500 1000 1500 2000 2500 3000 3500 4000 4500 0 500 1000 1500 2000 2500 3000 3500 4000 4500

Fluid Balance m L Fluid Balance m L

8 to 96 hours
1000
900
800
700
Cum ulative ACR

600
500

400
300
200
100
0
0 500 1000 1500 2000 2500 3000 3500 4000 4500
Fluid Balance m L

Kebocoran albumin kumulatif dinyatakan sebagai rasio albumin kreatinin (ACR) dibandingkan
dengan imbang cairan untuk 4 pasien trauma. Pasien di ujung paling kanan mati akibat MOF
Penyesuaian macam cairan iv thd
permeab kapiler.

Tujuan utama th/ cairan iv adalah untuk

mempertahankan oksigenasi jar dengan mengisi
kompartemen vaskular.
Bila permeab vask me (sakit kritis) shg edema
interstisial mengganggu DO2 jar maka lar iv yg
paling efektif adalah yang menetap lama dlm
ruang vask & memblok kebocoran prot plasma
& air ke dlm ruang interstisial.
SEALING EFFECT

HES 200/0.5 lebih baik daripada

ALBUMIN 5%
RINGER LAKTAT
HES dg BM < 50.000
HES dg BM > 300.000
Zikria BA et al. A biophysical approach to capillary
permeability. Surgery 1989; 105;625.
Penyesuaian macam cairan iv thd
permeab kapiler.
1. Pd saat kebocoran kapiler maks:
Koloid BM besar, rentang sempit > efektif.
Koloid BM sedang, rentang sempit > bagus krn
menyumpal kebocoran & sekaligus mengekspansi vol
vask.
Bbrp koloid dpt mekan adesi leukosit & mekan
kaskade mediator.
Perlu sedikit kristaloid utk mempertahankan laju
aliran urin.
2. Bila sdh tdk bocor lagi dpt diberikan lebih banyak
kristaloid k.p
 PREVENSI & TERAPI
Sindroma kebocoran kapiler klinis

ANTIOKSIDAN
INHIBITOR ENZIM

ZAT-ZAT FARMAKOLOGIS
masih dlm tahap
ANTIBODI eksperimental
Sindroma kebocoran kapiler klinis
Sealling effect of HES 200/0.5

Zikria (1990) : sumbatan koroner &

iskemia tungkai.
Webb (1989) : peritonitis. animal
Schell (1992) : iskemia serebral.
Tanaka (1993) : cedera paru akut.
Traber (1992) : sepsis.
Yeh (1992) : penelitian CP bypass pd
neonatal.
~ kebocoran plasma
~ edema
~ kebutuhan lar koloid
Sindroma kebocoran kapiler klinis

KOMBUSTIO: 24 JAM PASCA INJURI

HES vs ALBUMIN 4,5%.

HES ALBUMIN DLM HAL ME KAN:

CVP

TEK BAJI PARU

DO2

VO2
Waxman K et al. Hemodynamic and oxygen tranport effects
of pentastarch in burn resuscitation. Ann Surg 1989; 209:
341-5.
Managing the Inflammatory Response
to Critical Illness and Injury
Managing the Inflammatory Response to
Critical Illness and Injury

I. The inflammatory Response

II. Immune Stimulating Nutrients

a. Arginine
b. Glutamine

III. Inflammatory Modulating Nutrients

a. Eicospentaenoic acid (EPA)
b. Gamma-linolenic acid (GLA)
c. Antioxidants
 Nutrition in Critical Illness

Organisms seek homeostasis (balance) through

compensatory mechanisms.

Disease can be thought of as homeostasis failure.

 Examples of Inflammatory Response Mediators

Proinflammatory Anti-inflammatory
Mediators Mediators
Eicosanoids Eicosanoids
TBXA2 TBXA3
LTB2 LTB5
Prostaglandins Prostaglandins
PGE2 PGE1
PGE3
Cytokines Cytokines
IL-1 IL-1 Receptor Antagonist
IL-6 IL-4
IL-8 IL-10
Tumor Necrosis Factor (TNF) TNF Receptor
TBX = Thromboxane
LT = Leukotriene
PG = Prostaglandin
Bone RC: Ann Intern Med 1991;115:457-469 IL = Interleukin
 The Inflammatory Response

Pro-inflammatory Mediators

Normal Inflammatory Response

Homeostasis of pro- and anti-inflammatory mediators

Anti-inflammatory Mediators
Immune Suppression

Normal Inflammatory Response

Homeostasis of pro- and anti-inflammatory mediators

Anti-inflammatory
mediators predominate

Immune Suppression
(Risk for infection)
Conceptual Model of Normal
Immune Response
As the body fights off infection, the immune response increases.
However, in normal health, this response must decline in order for
healing & repair to take place.
Change in Immune Response

Fighting Healing

Time

Infection
 Balance of Infection and Inflammation

Galban C et al: Crit Care Med 2000;28:643-648

Beale RJ et al: Crit Care Med 1999;27:2799-2805
Heys SD et al: Ann Surg 1999;229:467-477
Suchner U et al: Proc Nutr Soc 2000;59:553-563
Uncontrolled Inflammation
(SIRS)
Uncontrolled Inflammation

Pro-inflammatory
mediators predominate

Normal Inflammatory Response

Homeostasis of pro- and anti-inflammatory mediators
 Immune Suppression
Anti- inflammatory Immune
Infection Risk
mediators predominate Suppression

Patients at risk
Trauma
Surgery
Wounds
More trauma patients develop infection than surgical
patients
Infection occurs in 34% of ICU patients

Applegren P et al: Acta Anaesthesiol Scand 2001;45:710-719

Angus DC et al: Crit Care Med 2001;29:1303-1310
Wallace WC et al: Am Surg 1999;65:987-990
Immune Stimulating Nutrients

Normal Inflammatory Response

Homeostasis of pro- and anti-inflammatory mediators

Immune enhancing nutrients:

Anti-inflammatory Arginine,
mediators predominate Glutamine,
Nucleotides
Elective surgery, Trauma, Wound healing
Immune Suppression
(Risk for infection)
 Immune Stimulating Nutrients
Arginine
Conditionally essential
A precursor of nitric oxide (a potent vasodilator)
Animal studies: supports thymic mass and T-
lymphocyte function, and wound healing
Animal studies: 2% of calories associated with
survival
6% of calories associated with mortality

Efron D, Barbul A: J Gastroenterol 2000;35:20-23

Kirk SJ, Barbul A: JPEN 1990;14:226S-229S
Albina JE: Pharmacological Nutrition Immune Nutrition., 1996 pp21-32
Saito H et al: Arch Surg 1987;122:784-789
Gonce SJ et al: JPEN 1990;14:237-244
 Immune Stimulating Nutrients

Glutamine
Conditionally essential
Fuels GI and immune cells
20-30g free glutamine/day
Inherent glutamine glutamate
free glutamine

Lacey JM, Wilmore DW: Nutr Rev 1990;48:297-309

Souba WW: Annu Rev Nutr 1991;11:285-308
Jensen GL et al: Am J Clin Nutr 1996;64:615-621
 Immune Stimulating Nutrients
Nucleotides
Animal studies: adding nucleotides to a
protein-containing diet has no benefit

It is impossible to have a nucleotide-

deficient diet
Nucleotides are present in all protein
Nucleotides are salvaged by the body

Pizzini RP et al: Surg Infection Soc 1989:50

Adjei AA et al: JPEN 1993;17:148-152
Suchner U et al: Proc Nutr Soc 2000;59:553-563
 Immune Response in SIRS
(Systemic Inflammatory Response Syndrome)

In SIRS, the immune response is exaggerated, and remains

elevated, placing major organ tissue in all areas of the body
at risk.
Change in Immune

SIRS
Response

Fighting Healing

Infection
Time
Uncontrolled Inflammation
(SIRS)
Uncontrolled Inflammation

Risk for ALI,

Pro-inflammatory ARDS, MODS
mediators predominate
and Death

Normal Inflammatory Response

Homeostasis of pro- and anti-inflammatory mediators

SIRS occurs in:

33% of all hospitalized patients
> 50% of ICU patients
> 80% of surgical intensive care
Uncontrolled Inflammation

Inflammatory trigger- Sepsis, Infection (i.e. Pneumonia)

SIRS
Uncontrolled inflammatory response

Severe Shock Risk for

ALI/ARDS
MODS- (Lungs fail first)

Death

MODS Multi Organ Dysfunction Syndrome

Inflammation Modulating Nutrients
(SIRS)
Uncontrolled Inflammation
SIRS, ALI, Sepsis
Inflammation Modulating
Nutrients:
Pro-inflammatory EPA
mediators predominate GLA
Antioxidants

Normal Inflammatory Response

Homeostasis of pro- and anti-inflammatory mediators
 Dietary Modulation of Inflammation

Arachidonic Acid
Borage Oil
Fish Oil
GLA EPA
Cyclooxygenase
Lipoxygenase
DGLA
Replacing AA with
Replacing AA with
GLA results in X EPA results in

PGE1 and eicosanoids Decreased Eicosanoids

that are less proinflammatory that are less
inflammatory eicosanoids inflammatory
(LTB4, TXA2, PGE2) (TXA3, PGE3, LTB5)

E012373A 17
SIRS: Inflammation- Modulating Nutrients

Arachidonic Acid (AA)

(a proinflammatory fatty acid)
acted on by

Cyclooxygenase

Produces
Proinflammatory Eicosanoids
Antioxidants Interrupt the Cycle
 Nutritional Therapy for SIRS
Immunomodulation with n-3 fatty acids (EPA, fish oil) and n-6
fatty acids (GLA, borage oil)

Injury SIRS
Change in Immune

Immunomodulation
with EPA & GLA
Response

Fighting Healing

Infection
 EPA and GLA Do They Work?

Gadek JE et al: Crit Care Med 1999:1409-1420

 EPA and GLA Do They Work?

Gadek JE et al: Crit Care Med 1999;(27):1409-1420

Summary
(SIRS)
Uncontrolled Inflammation
SIRS, ALI, Sepsis

Pro-inflammatory Inflammation modulating nutrients

mediators predominate EPA, GLA, Antioxidants

Normal Inflammatory Response

Homeostasis of pro- and anti-inflammatory mediators

Anti-inflammatory Immune enhancing nutrients

mediators predominate Arginine, Glutamine, Nucleotides

Elective surgery, Trauma, Wound healing

Immune Suppression
(Risk for infection)
To Stimulate or Modulate?
Heyland meta-analysis and other recent publications (June
2002 ASPEN Journal) suggest Immune nutrition must take
clinical status of patient into consideration in determination
of special feeds

Arginine, when supplied as > or = 5% of total caloric intake,

is associated with increased complications and mortality
rates in subgroups of ICU patients D. Heyland et al, 2002

Systemic inflammation might be undesirably intensified by

immune-enhancing nutrients like arginine in critically ill
patients Suchner et al, 2002
 CRRT therapy overview
CRRT has become the dominant form of artificial
support for the treatment of Acute Renal Failure
(ARF) in the Intensive Care Units (ICU)
During CRRT the patients blood is circulated through an extracorporeal circuit
and
exchanges take place through the semi-permeable membrane of a hemofilter .
Several treatment alternatives are included within CRRT: hemofiltration,
hemodialysis,
and hemodiafiltration without or with blood pumps.

These therapies are selected according to the patients condition to accomplish the
following basic therapeutic goals:

eliminate fluid overload

remove waste products and inflammatory mediators
correct electrolyte abnormalities
restore the acid-base balance
give an adequate nutritionnal support
Terima Kasih