FLUID RESUSCITATION IN SEPSIS :

UPDATE
Dr. SATRIAWAN ABADI, Sp.PD-KIC
 CASE
• Laki laki 60 tahun, masuk ke IGD RS dengan
keluhan demam 1 minggu disertai luka pada
kaki kiri. Riwayat DM (+) 4 tahun
• PF : TD : 120/80, N : 114, P : 20 , S : 38,9
• Status lokalis kaki : Wagner derajat III
• Leukosit ; 18.000
• Hb: 10,6
• Trombosit : 156.000
• Dx kerja :
• Sepsis
• Bukan Sepsis
• 2 hari perawatan, kesadaran pasien menjadi
somnolen, GCS E2M4V2
• PF : TD ; 90/60, N : 120x, P : 24 x, S: 39,3
• Leukosit 22.000
• Hb : 10,1
• Trombosit : 132.000
• Dx : Sepsis /Bukan
• Pemeriksaan tambahan : PCT / Kultur /
Lainnya
• Kapan diberikan cairan : klo tekanan darah
sistole turun dari 80 / lainnya
• Jenis cairan : Kristaloid / Koloid / Campuran
• Berapa banyak : 30 ml /kg BB atau lainnya
Epidemiology
Number of cases 
with age
Mortality  with age
 What is sepsis?

• Infection
• Triggering an host response
• Leads to organ dysfunction &
death
10
 ACCP/SCCM Consensus Conference
1991 (Sepsis-1)
Sepsis =
Infection +
two or more
SIRS criteria

Severe Sepsis
= Sepsis +
Organ
dysfunction
or hypo-
perfusion

Septic Shock =
Severe sepsis
with
persistent
hypotension
despite
adequate
fluids
 SEVERE
SEPSIS SEPSIS Severe Sepsis
+
Sepsis
(Any 2) + Persistent ** :
2 SIRS Organ Damage
HR > 90 (1 of the following):  SBP <90 mmHg OR
+  MAP < 65 OR
Temp  SBP < 90 mmHg  SBP decrease of
> 38.3 C / 101 F  MAP < 65 > 40 mmHg
OR Confirmed  SBP decrease of
< 36.0 C / 96.8 F ** In hour after
OR > 40 mmHg
30mL/kg fluid bolus
RR > 20 Suspected  Bili > 2
 Creat >2
WBC Infection  PLT < 100
OR
> 12,000 OR  INR > 1.5  Lactate > 4
< 4,000 OR  PTT > 60
> 10% bands  Lactate > 2
12
In 2001, more
detailed
categories added
to help clinicians
recognize sepsis

(Sepsis-2)
Levy MM, Fink MP, Marshall JC,
et al.
2001CCM/ESICM/ACCP/ATS/SIS
InternationalSepsis Definitions
Conference.Crit Care Med
2003;31:1250-6.
JAMA. 2016;315(8):762-774. doi:10.1001/jama.2016.0288

Suggested Clinical Criteria for Sepsis

(if in ICU?)

Infection + 2 or more SOFA points

(above baseline)

Consider Sepsis outside ICU if

Infection + 2 or more qSOFA points

 2016
Sepsis-3
qSOFA (quick SOFA)

Respiration rate ≥ 22/min

Altered Mentation Clinical Tool

Systolic Blood Pressure ≤

100 mmHg
RECOMMENDATIONS

Other Initial
Supportive Resuscitation
Therapy of and Infection
Severe Issues
Sepsis

Hemodynamic
Support and
Adjunctive Therapy
 Early insertion of
Rivers Protocol ScvO2 catheter

Therapy
titrated to CVP,
MAP and
ScvO2

Potential for RBC

and Inotropes
3 Recent Large Randomized Control Trials:
Although advanced severe sepsis therapies (such as central line
placement, SVO2 goals, etc) did not show improved outcomes, all
were randomized after early recognition and standard therapies
including antibiotics and fluid resuscitation which are the goals of
UNC Code Sepsis
 Sepsis Resuscitation Bundle (2017)

• Hour One Bundle : initial resuscitation in sepsis and septic

shock ( start immidiately)
1. Measure lactate level*
2. Obtain blood cultures prior to administration of antibiotics
3. Administer broad spectrum antibiotics
4. Administer 30ml/kg crystalloid for hypotension or lactate
≥4mmol/L
5. Apply vasopressors during or after initial fluid resuscitation
to maintain a mean arterial pressure (MAP) ≥65mmHg

* Re-measure lactate if initial lactate elevated (> 2mmol/L)

Fluid therapy
• Fluid resuscitation may consist of natural or
artificial colloids or crystalloids. There is no
evidence-based support for one type of fluid
over another.
• Grade C
• Fluid challenge in patients with suspected
hypovolemia (suspected inadequate arterial
circulation) may be given at a rate of 500–
1000 mL of crystalloids or 300–500 mL of
colloids over 30 mins and repeated based on
response (increase in blood pressure and
urine output) and tolerance (evidence of
intravascular volume overload).
• Grade E
 Fluid therapy
• Fluid-resuscitate using crystalloids or colloids (1B)
• Target a CVP of 8 mm Hg (12 mm Hg if mechanically
ventilated) (1C)
• Use a fluid challenge technique while associated with a
hemodynamic improvement (1D)
• Give fluid challenges of 1000 mL of crystalloids or 300–
500 mL of colloids over 30 mins. More rapid and larger
volumes may be required in sepsis-induced tissue
hypoperfusion (1D)
• Rate of fluid administration should be reduced if
cardiac filling pressures increase without concurrent
hemodynamic improvement (1D)
 7. FLUID THERAPY IN SEVERE SEPSIS

Crystalloids as the initial fluid of choice in the resuscitation of

severe sepsis and septic shock (1B)

Against the use of hydroxyethyl starches for fluid resuscitation

of severe sepsis and septic shock (1B)

Albumin in the fluid resuscitation of severe sepsis and septic

shock when patients require substantial amounts of crystalloids
(2C)
 7. FLUID
FLUID THERAPY
THERAPY ININSEVERE
SEVERESEPSIS
SEPSIS

Initial fluid challenge in patients with sepsis-induced

tissue hypoperfusion with suspicion of hypovolemia to
achieve a minimum of 30 mL/kg of crystalloids (a
portion of this may be albumin equivalent) (1C)

More rapid administration and greater amounts of fluid

may be needed in some patients (1C)

Fluid challenge technique be applied wherein fluid

administration is continued as long as there is
hemodynamic improvement either based on dynamic
(eg, change in pulse pressure, stroke volume variation)
or static (eg, arterial pressure, heart rate) variables (UG)
 Initial Resuscitation
• We recommend that in the resuscitation from
sepsis-induced hypoperfusion, at least 30ml/kg
of intravenous crystalloid fluid be given within
the first 3 hours.
(Strong recommendation; low quality of evidence)

• We recommend that following initial fluid

resuscitation, additional fluids be guided by
frequent reassessment of hemodynamic status.
(Best Practice Statement)
 Fluid Therapy
• We recommend crystalloids as the fluid of
choice for initial resuscitation and subsequent
intravascular volume replacement in patients
with sepsis and septic shock
(Strong recommendation, moderate quality of
evidence).

• We suggest using albumin in addition to

crystalloids when patients require substantial
amounts of crystalloids
(weak recommendation, low quality of evidence).
 Hypovolemia
• Hypovolemia → sepsis → worse outcome.
• The management → low quality of the
evidence
• Type :
– absolute (blood volume lost)
– relative (blood volume redistributed)
 Hypovolemia
insufficient to maintain
• vascular wall tension
• mean systemic filling pressure
• venous return
• cardiac filling and cardiac output
• arterial blood pressure.
Why should we give fluids in sepsis?

Vasoplegia
Capillary leak

SEPTIC SHOCK
Vasodilatory shock
Distributive shock

No volume loss !!!

 Fluid resuscitation and
Mortality

Figure 3. Mean hospital mortality among patients with decreased lactate within 8 hours of index test, stratified by total fluid received in increments of
7.5 ml/kg based on medication administration record.

Annals ATS, 2013

http://www.atsjournals.org/doi/abs/10.1513/AnnalsATS.201304-099OC
“RUN THE
FLUIDS
WIDE
OPEN!!”
• the degree of hypovolemia → difficult to
assess → clinical markers ?
• SSC → blood volume → first-line intervention
→ At any rate
• fluid expansion → higher mean systemic filling
pressure even in vasodilatory shock
Doing it right guideline → big difference for the patient,
• balance between under-resuscitation and over-
resuscitation
• the benefit vs. harm of intravenous (IV) fluids.

The risk
• toxicity of synthetic colloid solutions
• potential renal impairment with isotonic saline
• increasing evidence of multiple organ impairment of
fluid overload in patients with sepsis
 Controversies
• complexity of the settings, pathophysiology
• need for multiple interventions among
patients with sepsis
• limited evidence base for the majority of
recommendations → The 2016-iteration of
the Surviving Sepsis Campaign (SSC) guideline
→ low or very low quality of evidence [3].
 Triggers and targets
fluid therapy → resuscitation of sepsis-induced hypoperfusion,
• acute organ dysfunction
• low blood pressure
• elevated plasma lactate
• fluid therapy → guided by repeated assessment → non-invasive
and invasive parameters

The theoretical base

• sepsis induced organ
• caused by hypoperfusion
• low cardiac output and/or low blood pressure
• fluids may improve cardiac output, blood pressure, and organ
dysfunction
• Early Goal- Directed Therapy (EGDT) trial →
R/ sepsis → with guided fluid therapy
• PROCESS, ARISE, and PROMISE → no
improvements .
 Triggers
• lack good data → triggers to initiate fluid
resuscitation

• low blood pressure , elevated lactate , oliguria

→ main trigger for fluid ?
• mottling, low skin temperature, prolonged
capillary refill time, and altered consciousness
?
 WHAT IS FLUID CHALLENGE
Fluid challenges require the definition of four
components:
• The type of fluid to be administered (e.g. natural or
artificial colloids, crystalloids).
• The rate of fluid infusion (e.g., 500-1000ml over
30mins).
• The end points (e.g., mean arterial pressure of >
70mm Hg, heart rate of < 110 beats/min).
• The safety limits (e.g. development of pulmonary
oedema).
 Fluid Challenge
Step 1: Give volume
(e.g. 250 – 500 ml bolus)
Step 2: Observe change in SV
(e.g. after 20 minutes)
Stroke Volume

No change in stroke volume

 Further volume will likely not
improve output

Change in stroke volume

 Further volume may improve
Preload / Volume output
 Passive Leg Raising (PLR)

i-
Passive
er’s
45 ° Leg Raising

• Equivalent to 150 – 300 ml volume

• Effects < 30 sec.. Not more than 4 minutes
• Self-volume challenge
• Reversible
• Clinical studies show that if a patient is responsive to PLR
(change in SV), they will be responsive to fluid
fluid responsiveness →
• proof-of-concept,
• outcomes with sepsis ?

• advanced hemodynamic monitoring ?

• critical care ultrasonography / echocardiography

→ has not been tested.
• TARTARE- 2S trial → the effects of
microcirculatory vs. macrocirculatory targets
● IVC collapsible index = (IVCd exp – IVCd insp)/ IVCd exp
● 0% is overloaded, 100% is volume depleted
● 2.04 - 1.51/2.04 = 25%. (Volume overloaded)

mfda
 Volume
The SSC guideline → fixed volume of 30 mL/ kg
of IV crystalloid → ????
• low quality of the supporting
• complex circulatory failure in sepsis
• fluid loss and hypovolemia may not be
prominent in all patients .
• insufficient in patients with heart failure,
hypothermia, or a lactate above 4.0 mmol/L .
Results of these trials →
• heterogeneity ( setting, timing, and fluid
dosing strategy)
• no or limited better outcomes with lower
fluid volumes
 Mana
yang harus
dipilih

Kristaloid

Dextrose

Koloid
 VOLUME KINETICS FOR INFUSION FLUIDS

capillary cell
membrane membrane

Mineral, protein,
ECW ICW gycogen, fat
20% 40% 40%

Plasma Interstitial
o CRYSTALLOID LEAVES THE PLASMA SPACE,
Volume 4.3% fluid 15.7%
EQUILIBRATES WITH INTERSTITIAL SPACE AFTER 20-
30 MIN
colloids
crystalloid:
75-80% leaves vasculature after 20 minutes

5% dextrose
Hahn GR, Anesthesiology 2010
 Type of fluid
• In general → more crystalloid solutions (buffered solutions)
• crystalloids → first-line fluid in sepsis
• saline or buffered solutions ?? → the SSC guideline makes
no recommendation
SMART (n = 15,802) and SPLIT (n = 2278)
• SMART indicated worse renal outcomes with saline vs.
buffered solutions
• SPLIT indicated no differences in rates of AKI saline vs. an
acetate/gluconate-buffered solution

On going → PLUS trial (n = 8800) and the BASICS trial (n =

11,000)
• Traditionally, colloid solutions → higher
potency for plasma expansion → largely
unexplained heterogeneity across studies .
• less colloid solutions → synthetic colloid
solutions → hydroxyethyl starch, gelatine, and
dextran.
• the use of albumin is increasing
• RCTs → harm of hydroxyethyl starch
SSC guideline →
• albumin in patients requiring substantial
amounts of crystalloids
• use crystalloids rather than gelatine
• gelatine vs. albumin or crystalloid → increased
use of renal replacement therapy with
gelatine
Factors affecting tissue
penetration of antimicrobials
 Concentration of antimicrobial in blood
 Molecular size of antimicrobial
 Protein binding of antimicrobial
 Lipid solubility of antimicrobial
 Ionic charge of antimicrobial
 Antimicrobial binding to exudate or tissue
 Presence of inflammation
 Active transport mechanism
 Pathway of excretion of antimicrobial

(Marie et al, 2000)

61
The number of lives saved among the 11 137 patients was 513. The average life expectancy of
the 5156 patients who left the hospital alive was estimated to be 9.78 years. The costs per life
saved and per year life saved were €6037 and €617, respectively. Sensitivity analyses
confirmed the robustness of the results

62 62
Japannese attack at Pearl Harbour 1941

Resuscitation with natural colloids

(Albumin 5%)

63
 Vasopressor and vasodilators
When to start ??
• Early start may increase blood pressure, venous
return, and cardiac output even in patients with
hypovolemia .
• Guyton → reduced venous return and cardiac
output by vasoplegia [62].

• Corticosteroids → reduction in the degree of

vasoplegia → increase blood pressure in patients
with septic shock → less inclined to given fluid to
patients receiving steroids.
TAKE HOME MESSAGE
THANK YOU