2/24/12
Outline
Crystalloids and Colloids
– does it really make a
difference?
n 
n 
Andrew Shaw MB FRCA FCCM
Associate Professor of Anesthesiology
Duke University Medical Center/
DurhamVAMC
n 
n 
Colloids vs. crystalloids.
It is a long debate…….
n 
n 
n 
n 
n 
n 
Properties of resuscitation fluids
Abnormal saline 58 Da
Volume expansion lasts 30-60 min
Hillman K. Colloid versus crystalloids in shock. Indian J Crit Care Med
2004;8:14-21
Choi PT-L, Yip G, Quinonez LG, Cook DJ. Crystalloids vs colloids in
fluid resuscitation: A systematic review. Crit Care Med
1999;27:200-10.
Astiz ME, Rackow EC. Crystalloid-colloid controversy revisited. Crit
Care Med 1999;27:34-5.
Velanovich V. Crystalloid versus colloid fluid resuscitation: A metaanalysis of mortality. Surgery 1989;105:65-71
Shoemaker WC, Schluchter M, Hopkins JA, et al. Comparison of the
relative effectiveness of colloids and crystalloids in emergency
resuscitation. Am J Surg 1981;9:367-68.
Allardyce DB. Parenteral fluid therapy in septic shock: An evaluation
of crystalloid and colloid. American Surgeon 1974;40:542-7
Saline cannot be excreted easily → Interstitial oedema
Very large volumes required
Massive load of Na, Cl, water
They are different products!
Properties of resuscitation fluids
HES 130 kDa
Volume expansion lasts 6-18 h
Anti-inflammatory, less capillary leak
Less Na, Cl and water
Assign the crystalloid / colloid debate to
history and outline a physiologic approach
Describe properties of colloid solutions, and
the different products available
Review current controversies in HES use –
focusing on renal and coagulation effects.
Discuss the potential advantages of the
newer third generation tetrastarches
n 
“…the primary indication of crystalloids is
replacement of fluid losses via 1) insensible
perspiration and 2) urinary output.”
n 
“Colloids, by contrast, are indicated to replace
plasma deficits due to 1) acute blood loss or
2) protein-rich fluid shifts toward the interstitial
space (pathologic type 2 shift).”
Chappell D Anesthesiology. 2008; 109:723-40.
1
2/24/12
Does a balanced fluid algorithm
reduce complications?
A rationale approach to fluid therapy
Crystalloids
Amount
Preoperative deficits
The deficit after usual fasting is low
n 
Insensible perspiration
The basal fluid loss via insensible perspiration is
approximately 1ml/kg/h during major abdominal
surgery
n 
Third space
A primarily fluid-consuming third space does not
exist
n 
Urine Output
Should be replaced
n 
n 
n 
Colloids
Amount
Plasma losses from the circulation
due to fluid shifting of acute
bleeding
Timely replacement with an iso-oncotic
colloid via a goal-directed approach
Chappell D Anesthesiology. 2008; 109:723-40.
7|
RCT, 90 patients
Major surgery with expected
blood loss > 500 ml
Standardized anesthetic
LR 7ml/Kg bolus
then 5ml/Kg/hour
Randomized to boluses of
hetastarch or LR
Postoperative morbidity
survey
Moretti, et al. Anesth Analg 2003; 96: 611-7
Reduction in complications
Less PONV with a balanced fluid
algorithm
Variable
Relative Risk
P value
Nausea
0.26 (0.10 – 0.69)
0.007
Emesis
0.3 (0.12 – 0.75)
0.01
Rescue antiemetics
0.26 (0.10 - 0.66)
0.005
Dependent edema
0.51 (0.20 – 1.30)
0.16
Orbital edema and
double vision
0.34 (0.13 – 0.9)
0.03
Pain severity
0.1 (0.02 – 0.5)
0.005
Nausea severity
0.28 (0.12 – 0.65)
0.003
*
80
70
*
60
*
* P <0.05
50
% of
patients 40
Hetastarch/LR
LR
30
20
10
0
Nausea
Vomiting
Antiemetic
Moretti, et al. Anesth Analg 2003; 96: 611-7
Moretti, et al. Anesth Analg 2003; 96: 611-7
Goal Directed Fluid Therapy
reduces length of stay
Colloids
n 
Background crystalloid infusions
with targeted colloid boluses
n 
n 
Contain water and electrolytes
BUT have the added component of a colloidal
substance that does not freely diffuse across a
semi-permeable membrane.
Examples
n 
n 
n 
n 
WMD -2.94 days (-4.22, -.1.66)
p < 0.00001
Hydroxyethyl starch (HES)
Gelatin
Albumin
Dextran solutions
European Society of Intensive
Care Medicine 2006
With permission – Dr M Mythen
2
2/24/12
HES molecular structure
Hydroxyethyl starches
n 
n 
n 
•  Classified by:
–  Molecular weight
–  Substitution ratio
–  C2:C6 ratio
Most are modified corn
starches
Used clinically since
1970s
Diverse pharmacology
poorly understood by
many
Concentration of solution
C2:6 ratio
High = 9:1
Low = 3:1
Average molecular
weight (kDa)
High = 450-670
Medium = 130-260
Low = 40-70
Adverse Effects
6% - Iso-oncotic
10% - Hyper-oncotic
6% HES (200/0.5/9)
Degree of molar
(hydroxyethyl)
substitution (MS)
High = 450-670
Medium = 130-260
High
= 0.6-0.7
Low
= 40-70
Medium = 0.45-0.6
High =Low
9:1
= 0.4
Low = 3:1
Renal injury
}
Hypocoagulability
Retention
RES uptake
More
450/0.7
(1st Gen. HES)
200/0.5
(2nd Gen. HES)
130/0.4
(3rd Gen. HES)
Less
High = 0.6-0.7
Medium = 0.45-0.6
Low = 0.4
Renal risk of HES
Renal Issues
n 
n 
n 
n 
RCT
69 brain dead
kidney donors
HES vs. gelatin
6% Elohes
(200/0.62) used 33 ml/Kg
p = 0.009
Cittanova et al. Lancet 1996;348:1620-1622
3
2/24/12
RRT in Transplant Patients
10
9
8
7
6
5
4
3
2
1
0
p = 0.029
Dialysis
HES
White arrow = Normal proximal tubule
Black arrow = Osmotic-nephrosis-like lesions in
most tubules in patients in HES group
Reversible swelling of tubular cells
GEL
Cittanova et al. Lancet 1996;348:1620-1622
Cittanova et al. Lancet 1996;348:1620-1622
HES vs Gelatin - Renal Failure
n 
n 
n 
HES vs Gelatin - Renal Failure
n 
129 patients with
severe sepsis or
septic shock
RCT
6% HES 200/0.6
or gelatin.
n 
p = 0.018
Schortgen et al. Lancet 2001; 357: 911-6
Higher median creatinine
in the HES group
n  Significant on days 6
and 7
Limitations
n  Mean creatinine at
baseline was outside
the normal range in
the HES group
Schortgen et al. Lancet 2001; 357: 911-6
VISEP study
n 
n 
n 
n 
RCT, 537 patients
Severe sepsis or septic shock
2 x 2 factorial design
Either gelatin or 10% pentastarch (200/0.5)
almost exclusively
n 
n 
hyperchloremic, hyperoncotic
median cumulative HES dose 70 ml/Kg
Brunkhorst et al. NEJM 2008; 358: 125-39
Brunkhorst et al. NEJM 2008; 358: 125-39
4
2/24/12
HES and bleeding
...and coagulation???
HES introduced in 1960
By 1968 concerns about bleeding
Since then increased risk of bleeding
complications well established
HES macromolecules interact with platelets and
coagulation cascade
n 
n 
n 
n 
n 
n 
Causes decrease in FVIII and vWF levels
Exact mechanisms unknown
Cope JT et al. Ann Thor Surg 1997; 63: 78-82
de Jonge E et al, Intensive Care Medicine. 2001; 27(11):1825-9.
HES and bleeding
vWF levels
n 
n 
n 
Healthy volunteer
study
Received either:
n  1 liter HES 200/0.5
(HAES-steril 6%)
n  4% albumin
(control)
n 
n 
n 
Meta-analysis –
16 trials, 653
patients
Cardiac surgery
Albumin vs HES
Mediastinal blood
loss in first 24 hours
after CPB
SMD 0.24 ml/Kg (0.08 – 0.4)
de Jonge E et al, Intensive Care Medicine.
2001; 27(11):1825-9.
HES (circles)
Albumin (triangles)
Wilkes et al. Ann Thor Surg 2001;72:727-533
HES and bleeding
n 
Mean blood loss:
n 
n 
n 
Albumin group – 693ml
HES group – 789 ml
Proportion of patients with blood loss > 1 liter.
n 
n 
Albumin group - 19%
HES group - 33%
Third generation starches
n 
n 
n 
n 
n 
n 
Wilkes et al. Ann Thor Surg 2001;72:727-533
Molecularly engineered to be
different
Lower molecular weight
No significant plasma
accumulation
Greater number of osmotically
active particles
#1 iso-oncotic Plasma Volume
Expander (PVE) in Europe
Over 30 million patients treated
in 10 years
5
2/24/12
Molecular weight distribution curve
TATM 2000; 2: 13-21
Plasma volume changes with HES
James M. Anesthesia 2004: 59; 738-742
In-vivo degradation
n 
n 
SOAP study
HES molecules are
steadily reduced over
time as a result of
enzymatic cleavage with
amylase
At any one point in time,
there is a range of
molecules of different
sizes
n 
n 
n 
n 
n 
n 
Westphal. Anesthesiology 2009; 111: 187-202
Retrospective study
3147 critically ill patients
1075 patients received HES
Neither the use of HES per se or the dose
administered was associated with an increased risk
of renal replacement therapy, even in the subgroup
with severe sepsis or septic shock (n = 822).
High incidence of CVS dysfunction and preexisting
renal impairment
Type of HES not specified but mainly third generation
Sakr Y. BJA; 2007: 216-24
Third generation starch in sepsis
n 
n 
n 
Observational study
No group differences
in survival or renal
outcomes
Volume expansion
with HES 130/0.4 was
not associated with
AKI
James et al.
Table 3 Characteristics of patients analysed in the study. Data are presented as mean (SD), except for age [mean (range)], and the ISS and NISS
which are given as median (range). MVA, motor vehicle accident. There were no significant differences apart from ISS and NISS where the B-HES
group was significantly different from B-SAL (*P,0.01, Mann – Whitney U-test). ISS P-HES vs P-SAL, P¼0.52; NISS P-HES vs P-SAL, P¼0.41
P-HES
P-SAL
B-HES
B-SAL
n
36
31
20
Age (yr)
27.6 (18 – 49)
32.6 (21 –56)
33.0 (18 –50)
35.7 (20 – 58)
Height (cm)
170.1 (6.1)
172.5 (8.0)
171.6 (6.6)
172.1 (6.6)
22
Weight (kg)
72.2 (7.6)
M/F
77.4 (13.7)
76.8 (14.4)
78.8 (13.6)
33/3
27/4
15/5
15/7
Gunshot (n)
23
22
Stabbing (n)
13
9
18
19
2
3
ISS
18 (9 –45)
16 (8– 34)
29.5 (9–57)*
18 (9– 66)
NISS
34 (10 – 57)
27 (10 –66)
36 (22 – 66)*
27 (13 –66)
Injury mechanism
MVA (n)
Train collision (n)
Table 4 Volumes of FIRST fluid, PRBCs, FFP, and Plt administered in the first 24 h (in ml) according to the group. Data presented as mean (SD),
together with urine output after the first 24 and for the first 3 days. *P¼0.0002 for the difference between P-HES and P-SAL. †P¼0.005 for the
difference between B-HES and B-SAL
James
BJA 2011
Fluid type
B-HES
B-SAL
FIRST
5093 (2733)*
7473 (4321)
6113 (1919)
6295 (2197)
PRBC
P-HES
1553 (1562)
P-SAL
1796 (1361)
2943 (1628)†
1473 (1071)
FFP
503 (773)
640 (788)
1045 (894)†
Plt
80 (168)
85 (142)
225 (291)†
45 (125)
Urine 24
2891 (1264)
2581 (1349)
2520 (1048)
2005 (816)
Urine day 1
1556 (1080)
1273 (912)
1917 (1076)
1568 (769)
Urine day 2
2441 (1159)
2282 (1193)
1561 (900)
2045 (1043)
Urine day 3
2231 (868)
2298 (1301)
1593 (1044)
2430 (1186)
Ninety patients were available for follow-up at 30 days. In
those patients receiving HES, the average total dose was 12
litres over the 30 days of the study. Skin itching was reported
by seven patients in total, five in the saline group, and two in
the HES group.
Serious adverse events
Apart from the deaths, 17 other patients suffered serious
adverse events, including prolonged intensive care unit
stay, sepsis, and multiple organ failure. There were four
patients who experienced adverse events in the B-SAL
group, three in the B-HES group, eight in the P-SAL group,
and two in the P-HES group. Only the three secondary
abdominal compartment syndromes were considered to be
349 (732)
resolution of increased plasma lactate concentrations in penetrating trauma up to the first post-resuscitation day, despite
similar haemodynamic measurements between the groups.
In penetrating trauma, a colloid to crystalloid ratio of 1:1.5
was found. However, the better lactate clearance in the
P-HES group indicated superior tissue resuscitation with the
colloid. The lower maximum SOFA scores and the absence of
renal injury seen in the P-HES group further support the argument that this group showed better early resuscitation. These
results are supported by a recent observational study, in which
mortality was significantly lower when HES was included in the
early resuscitation strategy, particularly in penetrating
trauma.9 In blunt trauma, it is much more difficult to draw conclusions, given the large difference in injury severity. While it
Downloaded from bja.oxfordjournals.org at Medical Center Library, Duke University on September 8, 2011
Boussekey et al., Critical Care, 2010
What about trauma??
BJA
6
BJA
Resuscitation with HES improves renal function and lactate clearance
A
2/24/12
Plasma lactate: blunt trauma
10.0
9.0
Lactate (mmol litre–1)
8.0
7.0
6.0
5.0
B-HES
4.0
B-SAL
3.0
2.0
1.0
Lower lactates in starch group
No difference in blood loss
0.0
Pre
H1
H2
H3
H4
Time (h)
7000
1800
1600
8.0
Lactate (mmol litre–1)
mL
8000
1400
6000
1200
5000
4000
3000
P-HES
1000
P-HES
P-SAL
800
P-SAL
600
2000
400
1000
6.0
5.0
P-HES
4.0
P-SAL
3.0
1.0
0
FIRST
7.0
2.0
200
0
Plasma lactate: penetrating trauma
10.0
9.0
Downloaded from bja.oxfordjournals.org at Medical Center Library, Duke University on September 8, 2011
B
0.0
BLOOD
FFP
Pre
H1
H2
H3
H4
Time (h)
C BJA 2011
James
5.0
Lactate least square mean (mmol/L)
James BJA 2011
Less renal injury with HES
Plasma lactate changes: penetrating trauma
4.5
4.0
P-HES
P-SAL
3.5
3.0
2.5
2.0
Pre
H1
H2
Time (h)
H3
H4
Factor VIII and vWF activity
Fig 3 (A, B and C) Mean plasma lactate concentrations (SD) in the two categories of trauma patients. together with a linear, mixed effect,
regression model of change in lactate over time (SEM) with baseline adjustment to 5 mmol litre-1. B-SAL, blunt trauma allocated to the
saline group; B-HES, blunt trauma, HES group; P-SAL, penetrating trauma, saline group; P-HES, penetrating trauma, HES group. P-HES demonstrated a small but statistically significantly greater lactate clearance than P-SAL (P¼0.029).
F VIII
20
vWF
15
Page 7 of 10
Risk
% 10
%
Injury
Dialysis
5
0
P-HES
P-SAL
James BJA 2011
Less effect of platelet function
Gandhi et al. Anesthesiology 2007; 106: 1120-7
Less bleeding during major surgery
N = 449 in 7 studies
Franz. Anesth Analg. 2001; 92:1402-7
Kozek-Langenecker SA. Anesth Analg 2008; 107 : 382-90
7
Age (mo)
Sex (M/F)
Weight (kg)
Body surface area (m2)
American Society of Anesthesiology class (II/III/IV)
SpO2 (%)
Surgical procedures
Atrial septal defect, ventricular septal defect,
atrioventricular septal defect
Tetralogy of Fallot, double outlet right ventricle
Mitral surgery
Senning procedure
Rastelli procedure
Cavopulmonary derivation
Switch procedure
Aortic coarctation
Miscellaneous
Cardiopulmonary bypass time (min)
Aortic cross-clamping time (min)
Circulatory arrest (min)
PRISM score
Ventilation time (hr)
Intensive care unit stay (days)
Hospital stay (days)
Postoperative weight (kg)b
11.0 (5–42)
38/21
6.9 (5.1–13.2)
0.38 (0.30–0.60)
9/48/2
98 (80–99)
20 (8–46)
32/28
8.3 (5.7–13.5)
0.43 (0.33–0.62)
8/48/4
95 (80–98)
21
23
10
6
7
4
3
1
3
4
105 " 40
51 " 26
4 (2–24)
6 (4–7)
19 (9–37)
4 (2–6)
12 (10–17)
7.0 (5.4–12.7)
8
2
3
5
4
3
2
10
112 " 35
59 " 34
6 (2–20)
6 (2–8)
30 (14–65)a
5 (3–8)
14 (11–19)
8.4 (5.9–14.1)
2/24/12
Alb group, 4% albumin group; HES group, 6% hydroxyethyl starch 130/0.4 group; PRISM, scores
of the Pediatric Risk of Mortality measured on postoperative day 1; assessment range from 0 –76, with
higher scores indicating a greater risk of death; SpO2, peripheral oxygen saturation measured at room air.
Data are presented as median (interquartile range), mean " standard deviation according to the
result of the Kolmogorov-Smirnov distribution test. For American Society of Anesthesiology class
score and surgical procedures, number of patients are presented.
a
p ! 0.022 vs. Alb. group Mann-Whitney U test.
b
measured on postoperative day 2.
No difference in blood loss in
pediatric cardiac surgery
Table 3. Fluids and blood product use in the operating room and initial 24 hrs in intensive care unit
Alb Group (N ! 59)
HES Group (N ! 60)
217 (152–382)
50 (45–50)
58 (39–89)
22 (10–33)
19 (14–26)
16 (11–24)
8 (4–18)
52 (44–63)
48 (35–64)
35 (18–53)
53 (36–74)
25 (13–32)
78 (46/59)
29 (6–42)
1.7 (1/59)
1.7 (1/59)
242 (170–414)
50 (37–50)
48 (35–70)
22 (13–37)
20 (16–26)
15 (11–23)
12 (5–25)
54 (38–64)
47 (38–58)
37 (22–54)
53 (34–73)
19 (9–31)
57 (34/60)a
18 (0–40)
8.3 (5/60)
1.6 (1/60)
Preop RBC mass (mL)
Intraop colloids (mL/kg)
Intraop crystalloids (mL/kg)
Intraop urine output (mL/kg)
Hemofiltration (mL/kg)
Intraop measured blood loss (mL/kg)
Postop colloids (mL/kg)
Postop crystalloids (mL/kg)
Postop urine output (mL/kg)
Postop measured blood loss (mL/kg)
24 hrs measured blood loss (mL/kg)
24 hrs calculated blood loss (mL/kg)
Allogeneic RBC exposure (%)
Allogeneic RBC (mL/kg)
Fresh-frozen plasma exposure (%)
Platelet concentrates exposure (%)
Alb group, 4% albumin group; HES group, 6% hydroxyethyl starch 130/0.4 group; Preop, preoperative; intraop, intraoperative; postop, postoperative; RBC, red blood cell.
Data are presented as median (interquartile range) or mean " standard deviation according to the
Hanart result
Crit
Care
Med. 2009 37: 696-701.
of the Kolmogorov-Smirnov distribution test.
a
p ! 0.0188 Fisher’s exact test.
dren necessitated allogeneic blood transfusion in the Alb group (78% vs. 57%;
difference between proportions: 0.21;
95% confidence interval 0.05– 0.38; p !
0.0188). One patient in the Alb group and
five patients in the HES group required
fresh-frozen plasma infusion (difference
not statistically significant). One patient
HES and coagulation
Well established effects in older
generation starches
n  Newer HES products have greatly
reduced effect on the coagulation
process, even in high dose
n  Probably no longer a clinically relevant
problem
n 
Figure 1. Intraoperative fluid intake (intraoperative fluid in: includes intraoperative colloids and
crystalloids, and the volume of blood collected in
the cardiopulmonary bypass already retransfused
to the patient); intraoperative fluid loss (intraoperative fluid out: includes intraoperative urine
output, hemofiltration fluid, blood lost through intraoperative blood samples, blood lost in the oxygenator, blood lost in the sponges and the surgical
aspiration, and blood collected in the cardiopulmonary bypass not yet retransfused to the patient) and
fluid balance (intraoperative fluid balance) expressed in milliliter per kilogram in the two groups.
Box plots show median, interquartile range, and
outliers (*). §p ! 0.005 vs. 4% albumin, MannWhitney U test. HES, hydroxyethyl starch.
in each group required platelet concentrates. Exposure to any blood product was
significantly higher in the Alb group than
in the HES group (78% vs. 58%; difference between proportions: 0.20; 95%
confidence interval 0.03– 0.36; p !
0.022).
Intraoperative colloid and crystalloid
administration was not different between
groups (Table 3). However, intraoperative
fluid balance was lower in the HES group
than in the Alb group (Fig. 1). Postoper-
698
Crit Care Med 2009 Vol. 37, No. 2
Albumin
Ongoing Trials
n 
CHEST trial – Crystalloid vs. HydroxyEthyl
Starch
n 
Scandinavian 6S sepsis trial - 800 patients
Cardiac surgery – 500 patients
n 
n 
n 
7000 patients ICU patients
n 
n 
Serum albumin
replaced plasma
during Korean War
Used as a
resuscitation fluid for
over 50 years
But, Roberts et al,
BMJ 1998 – slated it!
Response of the medical profession
SAFE Trial
§  6997 ICU patients
§  Randomized
§  0.9% NaCl, or
§  4% Albumin
§  28 day all-cause mortality
§  No difference in overall outcome, but
Reduction in albumin sales by 49% necessitates attempts
to resuscitate the ailing $1.5 billion (U.S.) global albumin
market
Roberts et al BMJ 1999;318:1214-1215.
§  Albumin worse outcome in TBI
§  ? Benefit in sepsis
Finfer et al, NEJM 2004
Myburgh et al, NEJM 2007
8
2/24/12
SAFE Trial
Albumin is expensive
§  6997 ICU patients
§  Randomized
n  500ml
§  0.9% NaCl, or
§  4% Albumin
fluid costs
n  LR
$1
$27
$35
$84
n  Hextend
§  28 day all-cause
mortality
§  No difference in
overall outcome, but
n  Voluven
n  Albumin
§  Albumin worse
outcome in TBI
§  ? Benefit in sepsis
Finfer et al, NEJM 2004; 350: 22
Duke OR pharmacy – personal communication
Colloid summary
Albumin – The Bottom Line!
n 
Hydroxyethyl starches
n 
No benefit over other colloids
More expensive
n 
n 
Prion transmission???
Albumin
n 
Minor to no adverse coagulation effects
n 
n 
n 
n 
n 
68 yo lady
Liver resection and hepaticojejunostomy for
biliary stricture status post cholecystectomy (bile
duct injury) and recurrent bilomas
Admitted as an emergency 1 week preop.
n 
n 
n 
IVF, analgesia
Plan – GA, lines, stepdown/ICU postop
Uneventful induction
Safe but expensive
Recommended for hypoalbuminemia in sepsis
Use crystalloids and colloids together
n 
Case Report
Diverse group of compounds
Newer products have a significantly improved safety
profile
Background crystalloid infusions with colloid boluses
First blood gas
BLOOD GASES, ARTERIAL
VALUE
REFERENCE
PATIENT TEMPERATURE, ARTERIAL
PH, BLOOD ARTERIAL
PCO2, ARTERIAL
PO2, ARTERIAL
[75-100]
BASE EXCESS,ARTERIAL
BICARBONATE, ARTERIAL
CO2 TOTAL, ARTERIAL
HEMOGLOBIN, ARTERIAL
[12.0-15.5]
%O2 HEMOGLOBIN, ARTERIAL
[94.0-99.0]
%CO HEMOGLOBIN, ARTERIAL
[0.0-2.0]
LACTATE
37.0
7.26
[7.35-7.45]
29 mmHg
[35-45]
307 mmHg
-13 mmol/L
[-3-3]
13 mmol/L
[20-28]
14 mmol/L
[21-30]
8.0 g/dL
97.3 %
0.9 %
0.6
[0.6-1.8]
9
2/24/12
Chloride since admission
Labs
SODIUM
POTASSIUM
CHLORIDE
CARBON DIOXIDE
UREA NITROGEN
CREATININE
CALCIUM
GLUCOSE
BILIRUBIN, CONJUGATED
PROTEIN TOTAL
ALBUMIN
BILIRUBIN,TOTAL
ALKALINE PHOSPHATASE *
AST
ALT
134 mmol/L
4.7 mmol/L
* 117 mmol/L
15 mmol/L
15 mg/dL
* 1.4 mg/dL
9.1 mg/dL
95 mg/dL
0.2 mg/dL
7.6 g/dL
* 2.7 g/dL
0.5 mg/dL
217 U/L
20 U/L
34 U/L
Date / Time
Chloride
07/22/2011 23:35
117
07/22/2011 02:52
114
07/21/2011 06:33
112
07/20/2011 06:34
110
07/19/2011 13:00
108
07/19/2011 04:14
108
07/18/2011 03:00
108
07/17/2011 03:00
103
07/16/2011 10:45
101
Stewart’s Theory
• 
The only independent variables which vary pH
are
– 
SID
ATOT
– 
pCO2
– 
Strong ion difference
Total concentration of weak acid
Mainly albumin / (phosphate)
Respiratory
SID
n 
n 
n 
n 
n 
n 
n 
SID = [Na+] + [K+] + [Ca+] + [Mg+] - [Cl-] – [Lac-]
= 137 + 4.5 + 1.25 + 2.5 – 117 – 0.6
= 27.65
Expected BE – 12.35
Actual BE – 13
Iatrogenic hyperchloremic acidosis
BE +5 = SID 45
BE -5 = SID 35
NaCl excess
Our patient
n 
SID = [Na+] + [K+] + [Ca+] + [Mg+] - [Cl-] – [Lac-]
= 40mEq
It changes by about the same amount as
standard BE
n 
n 
n 
n 
n 
n 
n 
NaCl contains Na and Cl in equal amounts
Unlike plasma
Adding NaCl to plasma increases the Cl
concentration more than that of Na
SID = [Na+] + [K+] – [Cl-] = 40 mEq normally
Increase [Cl-] by 10, reduces SID by 10
Causes more H+ to dissociate from water to
defend electroneutrality
Increased [H+] means lower pH
10
2/24/12
Abnormal saline
n 
n 
n 
Is it physiological?
10 million L prescribed annually in UK
Origins of saline come from the 1832 cholera
epidemic in NE England
175 years of fallacy and misconceptions
Plasma
0.9% Saline
Na (mmol/L)
135–145
154
Cl (mmol/L)
95–105
154
K (mmol/L)
3.5–5.3
0
HCO3– (mmol/L)
24–32
0
Osmolality (mOsm/
kg)
275–295
308
pH
7.35–7.45
5.4
Awad et al. Clin Nutr 2008; 27: 473–8
Available crystalloids
Fluid
Na+
K+ Ca2+
Mg2+
Plasma
141
4.
5
2
Normal
saline
154
LR
130
4
Plasma-Lyte
140
5
Normosol
130
4
D 5W
5
Cl103
Buffers
Glucose
(g/L)
pH
Posm
(mOsm/L
Bic 26
Prot 16
0.7 – 1.1
7.4
290
6.0
308
6.5
274
7.4
294
7.4
290
4.5
252
154
3
109 Lac 28
3
Sidney Ringer - 1883
98
Acet 27
Gluc 23
98
Acet 27
n 
50
Ringer’s lactate = Hartmann’s solution
n 
n 
n 
n 
n 
n 
Alexis Frank Hartmann (1898–1964)
American clinical paediatrician and
biochemist at St Louis Children’s Hospital,
Missouri, USA
In 1930, he added sodium lactate to Ringer’s
solution
‘Need proportionally more sodium than
chloride in parenteral solutions to avoid the
development of an acidosis in children’
Hyperchloremic metabolic acidosis
Found that bathing the heart
muscle in saline solution
made with distilled water
made the ventricle grow
“weaker and weaker” leading
to cessation of contractility in
20 min.
“The salts of sodium,
potassium, calcium and
chloride in definite
concentrations and in precise
proportions are necessary for
protoplasmic activity”
The Abuse of Normal Salt Solution
George H. Evans, JAMA 1911
“One cannot fail to be impressed with the danger…
(of) the utter recklessness with which salt solution
is frequently prescribed, particularly in the
postoperative period…”
“…the disastrous role played by the salt solution is
often lost in light of the serious conditions that call
forth its use.”
11
2/24/12
Does Normal saline
cause any harm?
Healthy Volunteer
Studies
Saline vs Hartmann’s solution
0.9% saline:
adverse events
%
Reid et al, Clin Sci 2003
90
80
70
60
50
40
30
20
10
0
Normal saline
Lactated Ringer’s
CNS
changes
Abdominal
discomfort
Williams et al. Anesth Analg 1999
Ammonium chloride
poisoning:
–  Confusion
–  Headaches
–  Nausea and
vomiting
–  Abdominal pains
Chloride-Dependent Vasoconstriction
Animal
Studies
n 
Critical range of
vasoconstriction
(50-100%) lies in
the physiological
Cl- range of
80-110mmol/L
Hansen et al, Hypertension 1998
12
2/24/12
Changes in renal blood flow
20
*
Model of Hemorrhagic Shock
*p<0.05
*
n 
0
-10
*
-20
-30
*
% change
10
-40
-50
NaHCO3
Dextrose
NH4
Acetate
NaCl
Resuscitation of uncontrolled
haemorrhagic shock with NS requires
significantly greater volume and is
associated with hyperchloremic
acidosis, and dilutional coagulopathy as
compared with LR.
NH4Cl
Todd et al J Trauma 2007
Wilcox CS. J Clin Invest 1983
n 
Peak intraoperative potassium concentration
n 
Clinical studies
n 
n 
5.1 +/- 0.6 mEq/L in the NS group
5.1 +/- 1.1 mEq/L in the LR group.
Serum potassium concentration >6.0 mEq/L
n 
n 
5 of 26 (19%) patients in the NS group
no patients in the LR group (P 0.05)
n 
End of surgery pH
n 
Study terminated early for safety concerns
n 
7.28 vs 7.37 (p<0.0001)
O’Malley A&A 2005
Cumulative Na Balance (Days 0-4)
and Gastric Emptying Time (T50)
AAA Repair
2.9 (1.9, 4.0)
2.3 (1.6, 3.5)
Blood transfusion (ml)
780 (370, 1030)
560 (0, 1048)
FFP (ml)
552 (248, 600)
421 (229, 985)
Platelets (ml)
392 (265, 580)
223 (206, 240)
40.2 ± 60.4
3.8 ± 15.5
Blood loss, L
Volume of bicarbonate used (ml)
250
r=0.66
P=0.002
200
150
150
r=0.68
P=0.001
100
100
50
0
-400
0
400
800 1200 1600
Cumulative sodium balance:
days 0-4 (mmol)
Waters et al Anesth Analg 2005
Liquid phase gastric emptying time
T50 (min)
Ringer’s (n=33)
Solid phase gastric emptying time T50
(min)
200
0.9% Saline (n=33)
50
0
-400
0
400 800 1200 1600
Cumulative sodium balance:
days 0-4 (mmol)
Lobo et al, Lancet 2002
13
2/24/12
Dysnatremia in surgical patients
n 
55 (4%) of 1383 surgical patients (elective and
emergency) developed dysnatremia
n 
87% of hypernatremia cases were in ICU/HDU
n 
58% of hyponatremic patients and ALL hypernatremic
patients had a normal sodium level in the preceding 5
days
n 
Mortality rates
n 
2.3% for normonatremic patients
n 
12.7% for dysnatremic patients
Hospital patients with sodium > 149 mmol/L
401 Patients
ICU facilities
Herrod et al. World J Surg (2010)
* From University Hospital, Birmingham, UK
Major Complications, Mortality and Resource
Utilization after Open Abdominal Surgery:
0.9% saline compared to Plasma-Lyte
n 
n 
n 
Data from P. Gosling, with permission
Major complications
Retrospective cohort
study (Premier
database)
Major open abdominal
surgery
Patients who received
N-saline or Balanced
crystalloid alone on day
of surgery
Shaw A, Kellum J, Annals of surgery 2012; in press
Resource Utilization
Shaw A, Kellum J. Annals of surgery 2012; in press
When should we give abnormal saline?
n 
n 
n 
n 
Rarely
Head injury
With blood transfusion
It is carrier solution in some colloids
n 
n 
n 
Hespan, voluven, some albumin solutions
Renal failure patients
DKA
Shaw A, Kellum J. Annals of surgery 2012; in press
14