Fluid Therapy in Critical Care:

Type of Fluid
Assoc. Prof . Ranistha Ratanarat, MD
Siriraj Hospital, Mahidol University,
Bangkok, Thailand
Myburgh.NEJM 2013;369:1243-51
 OUTLINE

• Type of fluid: Colloid vs Crystalloid
• Volume of resuscitation (belief vs Fact)
• Effect to clinical outcomes
• Mortality
• Kidney function
• New trend of fluid use in critically ill patients
• Balanced solution vs NSS: Siriraj Study
Different tendencies of colloid and crystalloid fluids to flow out of the vascular space and into the
interstitial space. The large spheres in the colloid fluid represent large molecules that do not pass
readily through the semi-permeable barrier that separates the vascular and interstitial spaces.
Note that the colloid fluid has a smaller stream flowing out of the vascular space
The effects of selected colloid and crystalloid fluids
on the plasma volume and interstitial fluid volume

275 ml

825 ml

Imm A, Carlson RW, Fluid resuscitation in circulatory shock. Crit Care Clin 1993;9:313
 All resuscitation fluids can contribute to the
formation of interstitial edema
and volume efficacy (colloid:crystalloid ratio)
Is approximately 1:1.2 - 1:1.5
Crystalloids and Colloids
 IV crystalloid versus colloid

Arguments in favor of crystalloid

• Adverse effects of colloid
• Extravascular penetration: renal toxicity
• Coagulation abnormalities : starch
preparations
• Anaphylaxis risk
 OUTLINE

• Type of fluid: Colloid vs Crystalloid
• Volume of resuscitation (belief vs Fact)
• Effect to clinical outcomes
• Mortality
• Kidney function
• New trend of fluid use in critically ill patients
• Balanced solution vs NSS: Siriraj Study
Fluid resuscitation: Type of fluid
Albumin vs. Crystalloid
Fluid resuscitation: SAFE study

• Critically ill patients
• 4%Albumin
• Safe
• No more effective than NSS
• Pts in the albumin arm
• Received 27% less  fluid 
compared to the saline arm 
(2247 vs.3096 ml)
• Were 1 liter less positive in  
overall fluid balance

SAFE Study Investigators. New Engl J Med 2004;350:2247-56.

Saline or Albumin for Fluid Resuscitation in Patients with 
Traumatic Brain Injury
The SAFE Study Investigators

28 days 24 months

SAFE Study Investigators. New Engl J Med 2007;357:874-84.

 Sepsis/Septic shock 
:Fluid therapy

• Crystalloid is the fluid of choice for initial 
resuscitation
( Strong recommendation , moderate quality)
• Using albumin in addition to crystalloids for 
initial resuscitation when patients required 
substantial amount of crystalloids 
( Weak recommendation, low quality)
Crit Care Med 2017; 45:486–552
Albumin Replacement in Patients with Severe Sepsis or Septic Shock
The ALBIOS Study Investigators

ALBIOS Study Investigators. New Engl J Med 2014; 370:1412-21

Albumin replacement: ALBIOS study

• Severe sepsis/ septic 
shock patients
• 20 %Albumin + crystalloid
• Pts in the albumin arm
• Target serum [albumin] 
was 30 g per liter or more 
until discharge from the 
ICU or 28 days after 
randomization

ALBIOS Study Investigators. New Engl J Med 2014; 370:1412-21

Albumin Replacement in Patients with Severe Sepsis or Septic Shock
The ALBIOS Study Investigators

ALBIOS Study Investigators. New Engl J Med 2014; 370:1412-21

 The Cochrane Library 2013, Issue 2
Albumin or plasma protein fraction: Death

Favourcolloid Favour Crystalloid

 Fluid resuscitation: Type of fluid
Hydroxyethylstarch (HES) vs. Crystalloid
 VISEP CRYSTMAS 6S CHEST CRISTAL

Number 537 196 804 7,000 2857

Population Severe sepsis Severe sepsis Severe sepsis ICU (S 29%) ICU (S 54%)

• APACHE II 20 - - 17 -
• SAPS II - 50 50 - 49

Shock na na 84% (septic) na 100%

Phase of Flu Rx Resuscitation Optimization Optimization Resuscitation

10% HES 6% HES 6% HES
Intervention 6% HES 130/0.4 Any colloid
200/0.5 130/0.4 130/0.4

Control RLS NSS Ringer’s Acetate NSS Any crystalloid

28-d mortality
24.1 vs 26.7% 25.3 vs 31% 36 vs 39% 13.1 vs 13.8% 27 vs 25.4%
(control vs Rx)
90-d mortality 43 vs 51%* 34.2 vs 30.7%*
33.9 vs 41% 34 vs 40% 17 vs 18%
(control vs Rx) RR 1.17 RR 0.92

AKI (%) 23 vs 35%# 20 vs 24.5% na na na

16 vs 22%* 5.8 vs 7.0%*

RRT (%) 18.8 vs 31%@ na 12.5 vs 11.0%
RR 1.35 RR 1.21

*p < 0.05, # p < 0.01, @ p = 0.001

• Meta‐analysis of HES  versus crystalloid or albumin
• 6S trial group
• 9 studies: 4/9 studies low risk of bias
RRT
 The Cochrane Library 2013, Issue 7

HES versus others: Effect on kidney functio

OUTCOME No of studies No of pts RR (95% CI)

RRT 19 9857 1.32 (1.17,1.50)

Kidney failure  15 1361 1.59 (1.26, 2.00)

(author defined)
RIFLE‐R 20 8769 0.95 (0.91, 0.99)

RIFLE‐I 18 8583 1.1 (0.88, 1.17)

RIFLE‐F 15 8402 1.14 (1.01, 1.30)

The Cochrane Library 2013, Issue 7

Hydroxyethyl starch: Death The Cochrane Library 2013, Issue 2

Favourcolloid Favour Crystalloid

 Sepsis/Septic shock 
:Fluid therapy

• Crystalloid is the fluid of choice for initial 
resuscitation
( Strong recommendation , moderate quality)
• Using albumin in addition to crystalloids for 
initial resuscitation when patients required 
substantial amount of crystalloids 
( Weak recommendation, low quality)
Crit Care Med 2017; 45:486–552
Conceptual model illustrating relationship between time,
volume of fluid, and potential complications

colloid

crystalloid
 COLLOID

Mn COP PV T1/2 Duration of vol

Dose Limit
effect(100%)
(ml/kg/d)

5%albumin 69  20      0.7‐1.3     16h 4 h none

25% albumin 69 70      4.0‐5.0     16h 4‐6h none
10%dextran40  26 40      1.0‐1.5      6h  3‐4h 20
6%dextran70  41 40        0.8        12h 4‐6h 20

6%Hetastarch 69 30      1.0‐1.3     17d             4h                          33
10%Pentastarch      120        40 1.5 10h             4h 20
Modified Gelatin 35 40      0.8‐1.0     3‐4h           1‐2h none
 Type of fluid: Practical Points for Clinical
Use
• Hydroyethyl starches
• Probably dangerous in the ICU: Sepsis, patients at risk of AKI
• 35‐40 times more expensive than RLS and NSS
• Albumin
• Safe but expensive
• Not good for compromised blood brain barrier
• ???? Modified gelatin
 OUTLINE

• Type of fluid: Colloid vs Crystalloid
• Volume of resuscitation (belief vs Fact)
• Effect to clinical outcomes
• Mortality
• Kidney function
• New trend of fluid use in critically ill patients
• Balanced solution vs NSS: Siriraj Study
 Type of fluid: New trends
• Crystalloid
• 0.9% saline may be bad: AKI
• Balanced solution (LRS, Acetar, plasmolyte, sterofundin) may 
be better
 How normal is (ab)normal Saline?

Unit Plasma NaCl 0.9%

Sodium mmol/l 142 154 • Adding NaCl to plasma 

Potassium mmol/l 4.5 0 increases the Cl 
Calcium mmol/l 2.5 0 concentration more than 
Magnesium mmol/l 1.25 0 that of Na
Chloride mmol/l 103 154

Bicarbonate mmol/l 25 0

Lactate mmol/l 0 • 0.9% saline reduces 

Acetate/Malate mmol/l 0 0
plasma SID and leads to 
Theoretical osmolarity mmol/l 291 308
hypochloremic metabolic 
Colloid Albumin
acidosis
‐

31
Effects of Hyperchloremia
on Kidney

DN Lobo. Chloride-rich crystalloids: con. Kidney International 2014; 86: 1096-1105

 What’s Balanced ?

• Lower chloride content 
• Buffered salt solution

Thomas Langer et al, Intravenous balanced solutions. Anesthesiology Intensive Therapy 2015; 47: S78-s88.
DN Lobo. Chloride-rich crystalloids: con. Kidney International 2014; 86: 1096-1105.
 Disturbances of the acid-base balance from

The problem: Acidosis
The solution: Metabolizable anions
Malate
• Metabolizable anions Lactate Acetate
• Lactate
• Acetate
• Malate
• They are metabolized in 
the body and form 
bicarbonate.
Bicarbonate
 The Evidences

• Chloride‐Liberal vs Chloride‐Restrictive Trial (Yuno’s)

• SPLIT Trial

• SALT Trial

• Siriraj study
 Yunos, et al SPLIT SALT Siriraj study
JAMA 2012 JAMA 2015 AJRCCM 2017
Number 1,533 2,278 974 247
RCT, cluster, RCT, cluster, RCT,
Study type Before and after
double-blind open-label open-label
Population Critically ill Critically ill Critically ill
6‐mo duration of Rx due to  Shock patients
• APACHE II
15.9
changing ICU fluid policy
14.1 na 23.6
• Creatinine at
0.97, 1.02 1.18, 1.15 - 1.5, 1.4
enrollment, mg/dl
Shock na na na 100%
• Septic shock na na na 78%
• Sepsis/septic shock 8% 4% 27% -
Phase of Fluid Rx Optimization Optimization Optimization Resuscitation
Intervention Chloride-restrictive Plasmalyte® Balanced(most LRS) Sterofundin®

Control Chloride-liberal 0.9% Saline 0.9% Saline 0.9% Saline

ICU mortality, %
7.6 vs 8.6 6.6 vs 7.2 8.7 vs 9.7 13.9 vs 22.1
(Rx vs control)
Hospital mortality, %
13.2 vs 14.7 7.6 vs 8.6 16.7 vs 18.3 21.6 vs 26.6
(Rx vs control)
incidence of AKI, %
• RIFLE 15.8 vs 23.1 21.1 vs 19.6 na 77.5 vs 81.7
• KDIGO na 28.0 vs 29.1 na 76.6 vs 80.7
Incidence of AKI, %
• RIFLE ≥ injury 8.4 vs 14.0* (P<.001) 9.6 vs 9.2 na 54.9 vs 55.9
• KDIGO ≥ stage 2 na 9.8 vs 10.1 26.0 vs 28.4 48.6 vs 51.3
RRT, % 6.3 vs 10*(P=.005) 3.3 vs 3.4 4.6 vs 3.1 6.3 vs 14.7*(P=0.04)
(Rx vs control) RR RR RR RR
0.9% Saline versus Sterofundin® in 
shock patient
Single center, RCT (Siriraj Hospital)
N = 220
Primary Outcome: AKI per KDIGO 
criteria in 7 days 
Secondary Outcome: Need for RRT, 
28‐day mortality, LOS, Number of 
organ support, Metabolic 
derangements

Best abstract award session, ESICM 2017
 Balanced Crystalloids

Electrolytes   Human Plasma Sterofundin®ISO NaCl  Ringer’s  Ringer’s 

(mmol/ l) 0.9% Lactate Acetate

Na+ 142 145 154 130 130

K+ 4.5 4 ‐ 4 4
Ca 2+ 2.5 2.5 ‐ 1.5 1.4
Mg 2+ 1.25 1.0 ‐ ‐ ‐
Cl‐ 103 127 154 109 108.7
HCO3‐ 24 ‐ ‐ ‐ ‐
Lactate‐ 1.5 ‐ ‐ 28 ‐
Acetate‐ ‐ 24 ‐ ‐ 28
Malete2‐ ‐ 5 ‐ ‐ ‐
Real Osmolality 287 287 286 256 256
(mOsmol/ kg H2O)
 Baseline characteristics (n =
220)
Baseline Characteristic Balanced Crystalloid Saline  P Value
(n = 111) (n = 109)

Age, yr, mean ± SD  67 ± 16 67 ± 14 0.76

Male,  n (%) 60 (54%) 63 (58%) 0.58
APACHE II, mean ± SD  23.5 ± 5.3 23.6 ± 6.7 0.86
Baseline vital  signs, mean ± SD 
‐Temperature, °C 37.8 ± 1.2 37.6 ± 1.1 0.22
‐HR, beat per min 102 ± 25 103 ± 25 0.90
‐SBP, mmHg 77.3 ± 9.1 77.5 ± 9.9 0.90
‐DBP, mmHg 46.0 ± 7.0 47.3 ± 6.9 0.15
‐MAP, mmHg 56.3 ± 6.3 57.0 ± 7.0 0.39
‐RR, per min  26.4 ± 6.8 26.4 ± 7.5 0.98
Shock type at enrollment, n (%) 0.17
‐ Septic shock 82 (73.9%) 89 (81.7%)
‐ Sepsis induced hypotension  29 (26.1%) 20 (18.3%)
/Hypovolemic shock

ICU admission, n (%) 72 (64.9%) 77 (74.6%) 0.2

Best abstract award session, ESICM 2017
 Results: Volume of fluid
Fluid Balanced  Saline  P Value
mean ± SD; median (IQR) Crystalloid (n = 109) Mann 
(n = 111) whiney
Other fluids  during 72 hr, ml
- FFP, blood component 0 (0‐429) 160 (0‐848) 0.008

- Albumin 0 (0‐0) 0 (0‐0) 0.78

Study fluids  during 72 hr, ml
- NSS 800 (600‐1,000) 4,770 (3,730‐6,100) < 0.001

- Sterofundin® 4,500 (3,400‐5,995) 0 < 0.001

- Total study fluid 5,330 (4,200‐6,475) 4,770 (3,730‐6,100) 0.05

Total fluid intake 72hr.(ml) 10,485  10,429 0.72

(8,386‐12,910) (8,681‐12,826)

Best abstract award session, ESICM 2017
 Fluid Balanced Crystalloid Saline  P Value
Median (IQR) (n = 111) (n = 109) Mann whiney

Study fluids during first 6 hr, ml
‐ 0.9% Saline 800 (600‐1,000) 2,250 (1,700‐2,800) < 0.001

‐ Sterofundin® 1,500 (1,050‐2,200) 0 < 0.001

Study fluids during 6 ‐24 hr, ml
‐ NSS 0 900 (600‐ 1,450) < 0.001

‐ Sterofundin® 1,200 (750‐2,075) 0 < 0.001

Total study fluids during first 24 hr,  3,710 (2,890‐4,550) 3,350 (2,500‐3,990) .007

ml
Total fluid intake during first 24 hr, 4,700 (3,680‐5,807) 4,432 (3,570‐5,808) 0.39
ml
Best abstract award session, ESICM 2017
 Results: Acute kidney
injury
Outcomes Balanced Crystalloid Saline RR P
(n = 111) (n = 109) (95%CI) Value
Primary outcome
Cumulative incidence of  AKI 
during 7 day (by KDIGO), n (%) 85 (76.6%) 88 (80.7%) 0.95 (0.83‐1.09) 0.45

Stage,  n (%) 0.34

‐ KDIGO1 31 (27.9%) 32 (29.4%) 0.95 (0.63‐1.44) 0.82
‐ KDIGO2 24 (21.6%) 18 (16.5%) 1.31 (0.75‐2.27) 0.34
‐ KDIGO3 30 (27.0%) 38 (34.9%) 0.78 (0.52‐1.16) 0.21
Secondary outcome
AKI incident at day 7th 24 (21.6%) 32 (29.4%) 0.74 (0.47‐1.16) 0.19
(by KDIGO), n (%)

Stage, n (%)
‐ KDIGO1 8 (7.2%) 8 (7.3%) 0.98 (0.38‐2.52) 0.97
‐ KDIGO2 7 (6.3%) 4 (3.7%) 1.72 (0.52‐5.7) 0.37
‐ KDIGO3 9 (8.1%) 20 (18.3%) 0.44 (0.21‐0.93) 0.03*

Best abstract award session, ESICM 2017
 Results: Renal Replacement
Therapy

Secondary outcomes Balanced  Saline RR P Value

Crystalloid (n = 109) (95%CI)
(n = 111)
RRT, n (%) 7 (6.3%) 16 (14.7%) 0.43  0.04
(0.18‐1.00)
Mortality, n (%)
‐ Death in ICU 10/72 (13.9%) 17/77 (22.1%) 0.63 0.28
(0.31‐1.28)
‐ Death at day 28 21 (18.9%) 25 (22.9%) 0.82 0.46
(0.49‐1.38)
‐ Death in hospital 24 (21.6%) 29 (26.6%) 0.81 0.39
(0.51‐1.30)

Best abstract award session, ESICM 2017
 SPLIT SALT
Use of 0.9% saline as a resuscitation fluid in Our
JAMA 2015 AJRCCM 2017 shock study

patients,
Population
as compared with a
RCT, cluster, double-blind
Critically ill
balanced crystalloid
RCT, cluster, open-label
Critically ill
was
RCT, open-label
Shock patients
significantly
• APACHE II increased 14.1
the number naof cases who23.6still
• Creatinine at enrollment,
mg/dl had AKI stage 1.18, 3 at 1.15
day 7, and need -
of renal1.5, 1.4
replacement
(most buffered therapy (RRT)
1,000-1,2000 ml
Fluid 24 h before enrollment,ml < 500 ml (mixed saline & < 1,000 ml (most
(median) buffered crystalloid) 0.9%saline)
crystalloid)
Study fluid, ml (median)
buffered vs saline group
1,250 vs 1410 na 3,710 vs 3,350
• Day 1
40 vs 95 na 1,000 vs 850
• Day 2
0 vs 0 na 200 vs 390
• Day 3
2,000 vs 2,000 1,617 vs 1,424 5,330 vs 4,770
• Total

Cumulative incidence of AKI, %

• RIFLE 21.1 vs 19.6 na 77.5 vs 81.7
• KDIGO 28.0 vs 29.1 na 76.6 vs 80.7

No. of AKI at D7, %

• RIFLE na na 23.0 vs 34.6
• KDIGO na na 21.6 vs 29.4
No. of severe AKI at D7, %
• RIFLE-F 8.1 vs 17.4*
• KDIGO stage 3 8.1 vs 18.3*
RRT, % 3.3 vs 3.4 4.6 vs 3.1 6.3 vs 14.7* (P=0.04)
(Rx vs control) RR 0.96 (0.62-1.50 RR: na RR 0.43 (0.18-1.00)
 Effect of chloride-rich solution to renal function:
“Dose-response relationship”

Severe AKI: KDIGO 3 and/or RRT MAKE30: major adverse kidney events within 30 d

“Dose–response relationship.” 
Higher %LR was associated with lower mortality and lower severe  Among patients exposed to larger volumes of crystalloid, the 
AKI. The association between higher %LR was more pronounced as the  incidence of MAKE30 was significantly higher in the saline group.
total volume of fluid increased.
Crit Care Med 2016; 44:2163–70 AJRCCM 2017;195:1362‐72                         
45
• Fluid therapy 4 phases: Resuscitation, Optimization, Stabilization, De‐escalation

• Fluid responsiveness test in Optimization phase

• Colloids maintain intravascular volume and limit interstitial edema but no 
evidence that colloids are superior to crystalloids.
‐ Resuscitation with albumin is safe

‐ HES increase risk of AKI and RRT

• Balanced salt solution may have more beneficial effects on kidney compared to 
isotonic saline,  especially when use in large volume