This document discusses the effects of different fluid resuscitation solutions on microcirculatory oxygen transport and renal function. It summarizes research showing that balanced solutions like Ringer's lactate performed better than unbalanced solutions like saline in restoring microcirculatory blood flow, oxygen levels, and limiting renal injury after hemorrhagic shock. Unbalanced solutions were found to cause acidosis, decrease strong ion difference, and impair oxygen transport compared to balanced solutions. The document advocates for using balanced salt solutions and colloids like hydroxyethyl starch over saline for fluid resuscitation based on their superior microcirculatory and renal effects.

1. Pushing the bounderies:
What’s beyond the final frontier?
Can Ince PhD
Dept. of Intensive Care Dept. of Translational Physiology
Erasmus Medical Center Academic Medical Center
Erasmus University Rotterdam University of Amsterdam
Declared interests:

3. Boyd JH et al (2011) Crit Care Med 39:259 –265

4. a multicenter observational cohort study to which 198
ICUs from 24 European countries contributed
resulting in inclusion of 3,147 patients

5. Boldt J, Ince C (2010) Intensive Care Med 36(8):1299-308.
Balancing fluids; a tricky affair

6. Fluids are drugs.
• blood flow (distribution)
• pO2
• Hb
• Acid-base/SID
• osmotic balance
• volume
• blood sheer stress
• (auto) regulation
• Ht
• Viscosity
• metabolic
• inflammation

7. D x A ( cappO2 - mitpO2)
VO2 =
__________________
L
VO2 volume of transported
O2 transported by
diffusion
D diffusion constant
A systemic capillary surface area
cappO2 capillary pO2
Convection (flow) and Diffusion (functional capillary density rate limite
oxygen transport to the tissues.
heart failure normal diffusion low convection

9. Microcirculatory changes in one and the same sub-lingual location
before and after switch to CPB for cardiac surgery show diffusion limitation

10. Blood Transfusions Recruit the Microcirculation during Cardiac Surgery
Yuruk K, Almac E, Bezemer R, Goedhart P, de Mol B, Ince C
Transfusion (2010)51(5):961-7 ,
Results show that blood transfusion s improve oxygen tranport by reducing
diffusion distances and not by augmenting convection.

11. Higher hemoglobin concentrations (p < 0.001) and blood transfusions
(p = 0.031) were independently associated with a lower risk of in-hospital
death, especially in patients aged from 66 to 80 years, in patients admitted
to the ICU after non-cardiovascular surgery, in patients with higher
severity scores, and in patients with severe sepsis.
Main Finding

13. Hydroxyethyl starch 130/0.4 is superior to Saline solution
For resuscitation of the microcirculation
A Dubin A, Pozo MO, Casabella CA, Murias G, Pálizas F,
Moseinco m, Pálizas F, Kanoore Edul VS, Ince C

15. Changes in blood flow and vessel density in the sublingual
microcirculation on ascent to high altitude
Daniel Martin D, Goedhart P, Vercueil A, Ince C, Levett D, Grocott M

16. Fluids are drugs.
• blood flow (distribution)
• pO2
• Hb
• Acid-base/SID
• osmotic balance
• volume
• blood sheer stress
• (auto) regulation
• Ht
• Viscosity
• metabolic
• inflammation

17. Critical Care (2006) 10:R88:1-13

18. Fluids are drugs.
• blood flow (distribution)
• pO2
• Hb
• Acid-base/SID
• osmotic balance
• volume
• blood sheer stress
• (auto) regulation
• Ht
• Viscosity
• metabolic
• inflammation

19. no
resus
Renal arterial flow Cortex Micro Cortex Micro Speckle perfusion
perfusion distribution oxygen distribution imaging of cortex
MAP
Plasma inflammatory markers Creatinine clearance
HES130/0.4/NaCl

20. The main function of red blood cells is to
transport oxygen to the tissue cells.
Don’t forget oxygenation.
of all oxygen in
blood~97% is

21. †
-15 0 15 30 45 60 75 90 105 120 135 150 165 180
0
20
40
60
80
#
# #
† † †
##
##
####
†
† † † † †
†
‡ ‡ ‡ ‡
‡ ‡ ‡ ‡ ‡
‡
#
*
†
min
mmHg
**
*
# #
-15 0 15 30 45 60 75 90 105 120 135 150 165 180
0
20
40
60
80
NS40
NS80
HS40
HS80
CONTROL
‡ ‡‡ ‡ ‡ ‡ ‡ ‡
† †
† † † † † † † †
## #
# # # # # #
* ***
#
*
** **
***
min
mmHg
0.9%NaCl Blood
p<0.001
0
5
10
15
NS 40
NS 80
HS 40
HS 80
control
t120 t180
p<0.05
p<0.05
lactatemmol/l
0.9%NaCl Blood
Legrand M, Mik EG, Ballestra G, Pirracchio R, Payen D, Ince C (2010)
Anesthesiology. 112(1):119-27.
Volume targeting a MAP of 40 or 80 mmHg
Normal Saline (NS) or Hyper Saline (HS)

22. Fluids are drugs.
• blood flow (distribution)
• pO2
• Hb
• Acid-base/SID
• osmotic balance
• volume
• blood sheer stress
• (auto) regulation
• Ht
• Viscosity (hypotension)
• metabolic
• inflammation

23. Solutions for Volume Replacement
Synthetic Colloids
Hydroxyethyl Starch Solutions (HES)
Gelatins
Dextrans
Human Colloids
Albumin
Colloids
Crystalloids The Four Fluids of Life

24. Haemodilution and strong ion
difference (SID)
• Blood contains strong ions that completely dissociate, such as
Na+
, K+
, Ca++
, Mg++
and Cl-
• Blood also contains substances that almost completely
dissociate, such as sulphate, acetate, lactate and β-
hydroxybutyrate
• SID = [strong cations] minus [strong anions]
For normal plasma, SID is about 42 mEq/L (molar equivalent )
• NaCl is completely dissociated, giving a SID of zero: massive
infusion of pure NaCl will reduce the plasma SID, so the SID
will shift in the direction of zero, causing a metabolic acidosis
Morgan. Crit Care 2005;9:204–11

25. History of volume replacement
"I dissolved from two to three drachms of muriate of soda and two
scruples of the subcarbonate of soda in six pints of water, and
injected it at temperature 112°; Fah". (This is approximately 90
mmol/l sodium; 78 mmol/l chloride; 10 mmol/l Bicarbonate)Na/Cl
proportion 1.15 (Plasma 1.36)Latta T. No.3. Letter from Dr Latta, of Leith, detailing

26. Sydney Ringer’s solution
• Clinician and Pharmacologist
• The effect of Electrolytes on
cardiac and involuntary muscle =
Organ bath with tap water
• Ringer S. Concerning the influence exerted by each of
the constituents of the blood on the contraction of the
ventricle Journal of Physiology 1882;3:380-393
• “The salts of sodium, potassium, calcium and chloride
in definite concentrations and in precise proportions are
necessary for protoplasmatic activity”

27. Hartmann’s solution.
Alexis Frank Hartmann (1898 – 1964)
Clinical Paediatrician and Biochemist
1932 added Sodium lactate to Ringer’s
solution
“Normal” Saline rehydration of children with diabetic ketoacidosis increased
acidosis and worsened the prognosis
“Need proportionally more sodium than chloride in parenteral solutions to avoid

28. Baseline (BL)
Hemorrhagic
Shock (HS)
15 min
in resuscitation
(R15)
60 min
in resuscitation
(R60)
MAP (mmHg)
HES-NaCl 102 ± 2,71*** 30,47 ± 0,78 67,16 ± 6,19*** 57,98 ± 4,81***
HES-RA 100,6 ± 3,18*** 32,4 ± 1,49 61,66 ± 3,22*** 52,13 ± 3,01***
AoBF (ml.min-1
)
HES-NaCl 34,28 ± 2,46*** 10,52 ± 0,88 27,73 ± 2,34*** 31,54 ± 1,70***
HES-RA 36,7 ± 2,81*** 12,08 ± 0,97 31,03 ± 2,42*** 35,13 ± 2,55***
RBF (ml.min-1
)
HES-NaCl 5,54 ± 0,26*** 1,72 ± 0,29 3,09 ± 0,31* 3,44 ± 0,47**
HES-RA 5,93 ± 0,27*** 1,85 ± 0,07 4,9 ± 0,49*** 5,12 ± 0,21***
RVR (dyn.s.sec-5
)
HES-NaCl 18,62 ± 1,34 19,93 ± 2,99 21,36 ± 3,54 18,71 ± 2,78
HES-RA 17,14 ± 0,96 17,55 ± 0,9 13,1 ± 1,06 10,2 ± 0,50*
Hemodynamic parameters at 4 time points: BL, HS, R60, T60 (
*
p<0.05,
**
p<0.01 and
***
p<0.001,
versus Hemorrhagic Shock (HS);
†
p<0.05 and
†††
p<0.001, versus 15
th
min in same group of
Resuscitation (R15)).

29. Baseline Resuscitation
AG
Control 20.8 + 0.5 22.3 + 3.2††
HS 18.6 + 2.5 30.2 + 1.6†††
HS + Lyte 22.6 + 3.3 29.8 + 6.2††
HS + NaCl 16.3 + 1.2 0.6 + 4.0
negative SID
Control 39.7 + 1.8 34.3 + 6.0
HS 37.1 + 2.6 26.2 + 3.1
HS + Lyte 39.2 + 2.6 47.6 + 5.3++†††
HS + NaCl 36.0 + 0.8 12.6 + 5.1*
pH
Control 7.38 + 0.01 7.38 + 0.01+
HS 7.37 + 0.01 7.18 + 0.04*
HS + Lyte 7.38 + 0.03 7.36 + 0.04+
HS + NaCl 7.39 + 0.03 7.18 + 0.05*/
Strong ion differences (SID), anion gap values and some plasma ions of groups
at baseline and the end of resuscitation time point.
Biochemical parameters at baseline (t0) and resuscitation (t150) time points. (
*
p < 0.05,
**
p < 0.01,
* **
p < 0.001 vs. control group,
+
p < 0.05,
++
p < 0.01 and
+++
p < 0.001vs.HS group,
†
p < 0.05,
††
p < 0.01,
†††
p < 0.001 vs. HS + % 0.9 NaCl group
/
p <

30. LPS T30min
T60 min
T90 min
T120 min
Aksu U, Bezemer R, Demirci C, Ince C (2011) Shock (in press)
Acute effects of balanced vs unbalanced colloid
resuscitation on renal macro- and microcirculatory
perfusion during endotoxemic shock.

31. LPS
LPS + NaCl
CONTROL

32. LPS + Colloid
LPS T90min
LPS T60min
Control

33. Acidemia and Chloride can do many things
It can cause vasoconstriction and influence responsiveness [1,2]
It increases endogenous catecholamine release, which induces the release of both pro-
and anti-inflammatory cytokines [3] and nitric oxide (NO) [4].
Acidemia can cause macrophages increase their tumor necrosis factor secretion [5]References
1. Quilley CP et al (1993) Br J Pharmacol 108:106-110
2. Wilcox CS (1983) J Clin Invest 71:726-735

34. Fluids are drugs.
• blood flow (distribution)
• pO2
• Hb
• Acid-base/SID
• osmotic balance
• volume
• blood sheer stress
• (auto) regulation
• Ht
• Viscosity
• metabolic
• inflammation

35. 0 30 60 90 120 150
0
20
40
60
80
Time (min)
Shock ResuscitationBaseline
CortexµpO2(mmHg)
0 30 60 90 120 150
0
20
40
60
80
Time (min)
HS
HS + NaCl
HS + Lyte
Control
Shock ResuscitationBaseline
MedullaµpO2(mmHg)
Renal cortex and medulla microcirculatory pO2
following balanced and unbalanced crystalloid resuscitation
after hemorrhagic shock.
Bolus Infusion
(ml)
Continuous Infusion
(ml)
Total
(ml)
Saline 12.6±0.9 12.2±2.5 24.8
Ringers Acetate 11.8±1.2 9.9±1.5 21.7
Starch in Saline 2.4±0.4 3.5±0.6 5.9
Plasma Volume 2.5±0.3 3.5±0.5 6
Colloids: You need less!

36. Balancing fluids, a tricky affair
TIM
E
CO
N
TR
O
L
H
S
H
S-LYTE
HS-R
A
H
S-N
aC
l
0.0
0.2
0.4
0.6
0.8
***
+++
**
+++
+
***
MPOstainingleukocytes
distributioninGlomerulus
TIM
E
C
O
N
TR
O
L
H
S
H
S-LYTE
H
S-R
A
H
S-N
aC
l
0
50
100
150
200
250
***
***
**
***
+++
+++
HSCORE(L-FABP)
Control HS NaCl Lyte
0
1
2
3
4
5
* * *
*
TissueMDA/proteincontent
(umol/g)
Control HS NaCl Lyte
0
50
100
150
200
250
*
*
*
Plasmahyaluronan
(ng/ml)
malondialdehyde (MDA)

37. ROS scavenging using vitamin C and TEMPOL
to reduce I/R injury

38. How to rescue the failing kidney: a hypothesis
Must integratively improve microcirculatory function by
promoting perfusion and reduction of shunting
oxygenation
inhibiting iNOS
reducing oxidative stress
Kidney a la Szechuan
Le Dorze M, Legrand M, Payen D, Ince C (2009)

39. What is the future?
Are there alternatives for
homologous blood transfusion
and are they affective in transporting oxygen
to the microcirculation and tissue cells?

40. Iterson van M, Sinaasappel M, Burhop K, Trouwborst A, Ince C (1998)
J Lab Clin Med 132(5):421-31
Low-volume resuscitation (5ml/kg) with a hemoglobin-based oxygen
carrier after hemorrhage (30ml/kg) improves gut microvascular
oxygenation in swine.

41. Synthesis technique of RBC-mimicking particles
Elastic modulus sRBCs measured using
atomic force microscopy
Biocompatible sRBCs Mouse RBCs
coating the sRBCs with
uncross-linked Hb
increased the
oxygen-binding
capacity to
comparable

42. Conclusions
NaCl and Cl containing colloid
solutions should be avoided
Balanced salt solutions are
better in this respect.
Of the starches, 130kD HES is best
for the microcirculation
Too much or too little fluids are bad.
Don’t forget tissue oxygenation.
Oxygen delivery and microcirculatory flow
are key targets for fluid therapy and can be clinically monitored.

43. Dept of Translational Physiology
Academic Medical Center
University of Amsterdam
Ugur Aksu
Bektas Atasever
Peter Goedhart
Tanja Johannes
Gianmarco Balestra
Matthieu Legrand
Can Ince
Bert Mik
Koray Yuruk
Martin Siegemund
Rick Bezemer
Christian Boerma

44. Dept of Intensive Care
Erasmus Medisch Centrum
Erasmus University Rotterdam
Denise Dos Miranda Reis
Ben van der Hoeven
Eva Klijn
Corstiaan den Uil
Lucia Jewbali
Diederik Gommers
Alex Lima
Tim Jansen
Jos LeNoble
Jasper van Bommel
Jan Bakker

45. November 3, 2008 Confidential Information of MicroVision Medical 45
Thank You
Dank je wel voor de uitnodiging, Manu

46. Fluids; Pharmacology, Physiology and Efficacy
Can Ince PhD
Dept. of Intensive Care Dept. of Translational Physiology
Erasmus Medical Center Academic Medical Center
Erasmus University Rotterdam University of Amsterdam
Declared interests:

47. Septic acute kidney injury accounts for close to 50% of all
cases of acute kidney injury in the intensive care unit and,
in its various forms, affects between 15% and 20% of
intensive care unit patients.
However, there is little we really know about its pathophysiology
Li Wan et al (2008)Crit Care Med 2008; 36:S198–S203

48. Heart microvascular PO2
0 10 20 30 40 50 60
0
25
50
75
Ht (%)
PO2(mmHg)
Kidney microvascular PO2
0 10 20 30 40 50 60
0
25
50
75
Ht (%)
PO2(mmHg)
Intestinal microvascular PO2
0 10 20 30 40 50 60
0
25
50
75
Ht (%)
PO2(mmHg)
A B
C
Figure 1.
Ht = 8.7 ± 3.5 % Ht = 38.5 ± 8.0 %
Ht = 17.5 ± 7.3 %
van Bommel J, Siegemund M,
Henny P, Ince C (2008)
Translational Research 151(2):110-7
Heart, kidney and intestine have a
different tolerance for severe anemia

49. Haemodilution and strong ion
difference (SID)
• Blood contains strong ions that completely dissociate, such as
Na+
, K+
, Ca++
, Mg++
and Cl-
• Blood also contains substances that almost completely
dissociate, such as sulphate, acetate, lactate and β-
hydroxybutyrate
• SID = [strong cations] minus [strong anions]
For normal plasma, SID is about 42 mEq/L (molar equivalent )
• NaCl is completely dissociated, giving a SID of zero: massive
infusion of pure NaCl will reduce the plasma SID, so the SID
will shift in the direction of zero, causing a metabolic acidosis
Morgan. Crit Care 2005;9:204–11

50. Septic acute kidney injury accounts for close to 50% of all
cases of acute kidney injury in the intensive care unit and,
in its various forms, affects between 15% and 20% of
intensive care unit patients.
However, there is little we really know about its pathophysiology
Li Wan et al (2008)Crit Care Med 2008; 36:S198–S203

51. Heart microvascular PO2
0 10 20 30 40 50 60
0
25
50
75
Ht (%)
PO2(mmHg)
Kidney microvascular PO2
0 10 20 30 40 50 60
0
25
50
75
Ht (%)
PO2(mmHg)
Intestinal microvascular PO2
0 10 20 30 40 50 60
0
25
50
75
Ht (%)
PO2(mmHg)
A B
C
Figure 1.
Ht = 8.7 ± 3.5 % Ht = 38.5 ± 8.0 %
Ht = 17.5 ± 7.3 %
van Bommel J, Siegemund M,
Henny P, Ince C (2008)
Translational Research 151(2):110-7
Mahmood BJ GELTatom
Geletin vs starch
Heart, kidney and intestine have a
different tolerance for severe anemia