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[e-drug] Rational and economic use of Plasma Expanders? (2)

E-DRUG: Rational and economic use of Plasma Expanders? (2)

Dear E-druggers

Mariam has raised an issue that has defeated many selection processes -
there seems to be no end to the crystalloid vs. colloid debate. There as
many adherents to one side as to the other, and equal numbers of critics
of each option. There are perhaps as many final answers as there are
"types" of clinical cases - be those elective surgery (and types of
surgery), trauma, adult, paediatric, renally-compromised or otherwise
altered function .... the list is endless.

As a result, systematic reviews have been of limited use. Below are the
abstracts and plain language summaries for a selection of Cochrane
Reviews to address the comparison or one or other of the options,
followed by an accessible summary of the issue from Intensive Care Unit:
Emergency Diagnosis and Treatment. Not that colloids also differ
markedly from one another, giving rise to yet another set of debates.

There are some head-to-head comparisons under way (e.g.
ClinicalTrials.gov Identifier:  NCT00517127), but even these may not
resolve the entire question.


Colloids versus crystalloids for fluid resuscitation in critically ill

Pablo Perel1, Ian Roberts1, Mia Pearson2

1Cochrane Injuries Group, London School of Hygiene & Tropical Medicine,
London, UK. 2c/o Cochrane Injuries Group, London, UK

Contact address: Pablo Perel, Cochrane Injuries Group, London School of
Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, UK.

Editorial group: Cochrane Injuries Group.
Publication status and date: New search for studies and content updated
(no change to conclusions), published in Issue 3, 2009.
Review content assessed as up-to-date: 29 September 2008.

Citation: Perel P, Roberts I, Pearson M. Colloids versus crystalloids
for fluid resuscitation in critically ill patients. Cochrane Database of
Systematic Reviews 2007, Issue 4. Art. No.: CD000567. DOI:

Copyright © 2009 The Cochrane Collaboration. Published by John Wiley &
Sons, Ltd.


Colloid solutions are widely used in fluid resuscitation of critically
ill patients. There are several choices of colloid and there is ongoing
debate about the relative effectiveness of colloids compared to
crystalloid fluids.

To assess the effects of colloids compared to crystalloids for fluid
resuscitation in critically ill patients.

Search strategy
We searched the Cochrane Injuries Group Specialised Register, CENTRAL
(The Cochrane Library 2008, Issue 3), MEDLINE, EMBASE, ISI Web of
Science: Science Citation Index Expanded (SCI-EXPANDED), ISI Web of
Science: Conference Proceedings Citation Index-Science (CPCI-S), and The
Controlled Trials metaRegister (www.controlled-trials.com). Reference
lists of relevant studies and review articles were searched for further
trials. The searches were last updated in September 2008.

Selection criteria
Randomised controlled trials (RCTs) of colloids compared to
crystalloids, in patients requiring volume replacement. We excluded
cross-over trials and trials in pregnant women and neonates.

Data collection and analysis
Two authors independently extracted data and rated quality of
allocation concealment. We analysed trials with a 'double-intervention',
such as those comparing colloid in hypertonic crystalloid to isotonic
crystalloid, separately. We stratified the analysis according to colloid
type and quality of allocation concealment.

Main results
We identified 65 eligible trials; 56 of these presented mortality

Colloids compared to crystalloids

Albumin or plasma protein fraction - 23 trials reported data on
mortality, including a total of 7754 patients. The pooled relative risk
(RR) from these trials was 1.01 (95% confidence interval (95% CI) 0.92
to 1.10). When we excluded the trial with poor quality allocation
ealment, pooled RR was 1.00 (95% CI 0.91 to 1.09). 
Hydroxyethyl starch - 17 trials compared hydroxyethyl starch with
crystalloids, n = 1172 patients. The pooled RR was 1.18 (95% CI 0.96 to
Modified gelatin - 11 trials compared modified gelatin with
crystalloid, n = 506 patients. The pooled RR was 0.91 (95% CI 0.49 to
Dextran - nine trials compared dextran with a crystalloid, n = 834
patients. The pooled RR was 1.24 (95% CI 0.94 to 1.65).

Colloids in hypertonic crystalloid compared to isotonic crystalloid

Eight trials compared dextran in hypertonic crystalloid with isotonic
crystalloid, including 1283 randomised participants. Pooled RR was 0.88
(95% CI 0.74 to 1.05).

Authors' conclusions
There is no evidence from RCTs that resuscitation with colloids reduces
the risk of death, compared to resuscitation with crystalloids, in
patients with trauma, burns or following surgery. As colloids are not
associated with an improvement in survival, and as they are more
expensive than crystalloids, it is hard to see how their continued use
in these patients can be justified outside the context of RCTs.

Plain language summary

No evidence that colloids are more effective than crystalloids in
reducing mortality in people who are critically ill or injured
Trauma, burns or surgery can cause people to lose large amounts of
blood. Fluid replacement, giving fluids intravenously (into a vein) to
replace lost blood, is used to try to maintain blood pressure and reduce
the risk of dying. Blood products, non-blood products or combinations
are used, including colloid or crystalloid solutions. Colloids are
increasingly used but they are more expensive than crystalloids. The
review of trials found no evidence that colloids reduce the risk of
dying compared with crystalloids.

Colloid solutions for fluid resuscitation

Frances Bunn1, Daksha Trivedi1, Syed Ashraf2

1Centre for Research in Primary and Community Care, University of
Hertfordshire, Hatfield, UK. 2Psychiatry, Bedfordshire and Luton Mental
Health Social Care Partnership NHS Trust, Bedford, UK

Contact address: Frances Bunn, Centre for Research in Primary and
Community Care, University of Hertfordshire, College Lane, Hatfield,
Hertfordshire, AL10 9PN, UK. f.bunn@herts.ac.uk. 

Editorial group: Cochrane Injuries Group.
Publication status and date: Edited (no change to conclusions),
published in Issue 4, 2008.
Review content assessed as up-to-date: 1 October 2007.

Citation: Bunn F, Trivedi D, Ashraf S. Colloid solutions for fluid
resuscitation. Cochrane Database of Systematic Reviews 2008, Issue 1.
Art. No.: CD001319. DOI: 10.1002/14651858.CD001319.pub2.

Copyright © 2008 The Cochrane Collaboration. Published by John Wiley &
Sons, Ltd.

Colloids are widely used in the replacement of fluid volume. However
doubts remain as to which colloid is best. Different colloids vary in
their molecular weight and therefore in the length of time they remain
in the circulatory system. Because of this and their other
characteristics, they may differ in their safety and efficacy.

To compare the effects of different colloid solutions in patients
thought to need volume replacement.

Search strategy
We searched the Cochrane Injuries Group specialised register, CENTRAL
(2007, Issue 1), MEDLINE (1994 to March 2007), EMBASE (1974 to March
2007), and the National Research Register (2007, issue 1).
Bibliographies of trials retrieved were searched, and drug companies
manufacturing colloids were contacted for information. The search was
last updated in March 2007.

Selection criteria
Randomised and quasi-randomised trials comparing colloid solutions in
critically ill and surgical patients thought to need volume replacement.
The outcomes mea
sured were death, amount of whole blood transfused, and
incidence of adverse reactions.

Data collection and analysis
Two authors independently extracted the data and assessed the quality
of the trials.

Main results
Seventy trials, with a total of 4375 participants, met the inclusion
criteria. Quality of allocation concealment was judged to be adequate in
24 trials and poor or uncertain in the rest.

Deaths were obtained in 46 trials. For albumin or PPF versus
hydroxyethyl starch (HES) 25 trials (n = 1234) reported mortality. The
pooled relative risk (RR) was 1.14 (95% CI 0.91 to 1.43). For albumin or
PPF versus gelatin, seven trials (n = 636) reported mortality. The RR
was 0.97 (95% CI 0.68 to 1.39). For albumin or PPF versus Dextran four
trials (n = 360) reported mortality. The RR was 3.75 (95% CI 0.42 to
33.09). For gelatin versus HES 18 trials (n = 1337) reported mortality
and RR was 1.00 (95% CI 0.80 to 1.25). RR was not estimable in the
gelatin versus dextran and HES versus dextran groups.

Thirty-seven trials recorded the amount of blood transfused, however
quantitative analysis was not possible due to skewness and variable
reporting. Nineteen trials recorded adverse reactions, but none

Authors' conclusions
>From this review, there is no evidence that one colloid solution is
more effective or safe than any other, although the confidence intervals
are wide and do not exclude clinically significant differences between
colloids. Larger trials of fluid therapy are needed if clinically
significant differences in mortality are to be detected or excluded.


Plain language summary

There is no strong evidence to be certain of the safety of any
particular type of colloid solution for replacing blood fluids
When a person is bleeding heavily, the loss of fluid volume in their
veins can lead to shock, so they need fluid resuscitation. Colloids and
crystalloids are two types of solutions used to replace lost blood fluid
(plasma). They include blood and synthetic products. Both colloids and
crystalloids appear to be similarly effective at resuscitation. There
are different types of colloids and these may have different effects.
However, the review of trials found there is not enough evidence to be
sure that any particular colloid is safer than any other.

Intravenous fluids for abdominal aortic surgery

Patiparn Toomtong1, Sirilak Suksompong1

1Department of Anesthesiology, Faculty of Medicine, Siriraj Hospital,
Mahidol University, Bangkok, Thailand

Contact address: Patiparn Toomtong, Department of Anesthesiology,
Faculty of Medicine, Siriraj Hospital, Mahidol University, 2 Prannok
Road, Siriraj, Bangkok-noi, Bangkok, 10700, Thailand.

Editorial group: Cochrane Peripheral Vascular Diseases Group.
Publication status and date: New search for studies and content updated
(no change to conclusions), published in Issue 1, 2010.
Review content assessed as up-to-date: 9 September 2009.

Citation: Toomtong P, Suksompong S. Intravenous fluids for abdominal
aortic surgery. Cochrane Database of Systematic Reviews 2010, Issue 1.
Art. No.: CD000991. DOI: 10.1002/14651858.CD000991.pub2.

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley &
Sons, Ltd.

Surgery on the abdominal aorta to treat aneurysms or occlusive disease
is a major undertaking which requires intensive physiological support
and fluid management. Blood products are often used but the main fluid
replacement is with crystalloids or colloids. For years there has been
controversy over which fluid is optimal and a number of studies have
examined the subject. This is an update of a Cochrane review first
published in 2000 and previously updated in 2002.

To determine the effect
iveness of different non-blood replacement
fluids used in abdominal aorta procedures with a view to identifying the
optimal fluid for use.

Search strategy
The Cochrane Peripheral Vascular Diseases Group searched their
Specialised Register (August 2009) and the Cochrane Central Register of
Controlled Trials (CENTRAL) (The Cochrane Library 2009, Issue 3) for
publications describing randomised controlled trials of non-blood
replacement fluids in abdominal aortic surgery. In addition, the
reference lists from retrieved trials were screened for further
information about trials.

Selection criteria
Randomised controlled trials assessing the effects of at least one
specific non-blood fluid used for replacement therapy in operations on,
and confined to, the abdominal aorta.

Data collection and analysis
Data were extracted and then entered into the Review Manager software
where statistical analyses were performed.

Main results
Thirty-eight trials involving 1589 patients were included. Patients
undergoing aortic surgery had various physiological parameters measured
before and after their operation (these were cardiac, respiratory,
haematological, and biochemical). Patients were randomised to a fluid
type. This review demonstrated that no single fluid affects any outcome
measure significantly more than another fluid across a range of
outcomes. The death rate in these studies was 2.45% (39 patients).

Authors' conclusions
Despite the confirmed beneficial effects of colloids in this review,
further studies are still required. There are no studies examining the
effects of combination fluid therapy. The primary research outcome was
death, for which results were limited; therefore, future studies should
pay more attention to short-term outcomes such as minimising the need
for allogenic blood transfusion, complications (organ failure), and
length of stay in both the intensive care unit and hospital.
Plain language summary

Intravenous fluids for body fluid management during abdominal aortic
There is not enough evidence to show the best fluid replacement to use
during and following surgery on the abdominal aorta. Surgery on the
abdominal aorta is a major surgical procedure with a mortality of 1.5%
in elective patients and up to 5% in emergency surgery. Fluid
replacement is needed to replace tissue fluids lost during surgery.
Blood products, non-blood products, or combinations including
crystalloid solutions and colloids are used. Combination therapy is most
common. The review of trials found that although 38 randomised trials
involving 1589 patients were identified, there was not enough evidence
on the benefits of any particular individual or combination fluid
therapy. No single fluid affected any outcome measure significantly more
than another fluid across a range of outcomes. The trials used many
different fluid replacement comparisons so that few results could be
pooled. Important outcomes are the need for allogenic blood transfusion,
complications of organ failure, and length of stay in both the intensive
care unit and hospital.

Hydroxyethyl starch (HES) versus other fluid therapies: effects on
kidney function

Allison B Dart1, Thomas C Mutter2, Chelsea A Ruth1, Shayne P Taback1

1Department of Pediatrics and Child Health, University of Manitoba,
Winnipeg, Canada. 2Department of Anesthesia, University of Manitoba,
Winnipeg, Canada

Contact address: Allison B Dart, Department of Pediatrics and Child
Health, University of Manitoba, FE-009 840 Sherbrook St, Winnipeg,
Manitoba, R3A 1S1, Canada. adart@hsc.mb.ca. 

Editorial group: Cochrane Renal Group.
Publication status and date: New, published in Issue 1, 2010.
Review content assessed as up-to-date: 7 May 2009.

Citation: Dart AB, Mutter TC, Ruth CA, Taback SP. Hydroxyethyl starch
(HES) versus other fluid therapies: effects on kidney 
function. Cochrane
Database of Systematic Reviews 2010, Issue 1. Art. No.: CD007594. DOI:

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley &
Sons, Ltd.

Hydroxyethyl starches (HES) are synthetic colloids commonly used for
fluid resuscitation, yet controversy exists about their impact on kidney

To examine the effects of HES on kidney function compared to other
fluid resuscitation therapies in different patient populations.

Search strategy
We searched the Cochrane Renal Group's specialised register, the
Cochrane Central Register of Controlled Trials (CENTRAL, in The Cochrane
Library), MEDLINE, EMBASE, MetaRegister and reference lists of

Selection criteria
Randomised controlled trials (RCTs) and quasi-RCTs in which HES was
compared to an alternate fluid therapy for the prevention or treatment
of effective intravascular volume depletion. Primary outcomes were renal
replacement therapy (RRT), author-defined kidney failure and acute
kidney injury (AKI) as defined by the RIFLE criteria. Secondary outcomes
included serum creatinine and creatinine clearance.  

Data collection and analysis
Screening, selection, data extraction and quality assessments for each
retrieved article were carried out by two authors using standardised
forms. Authors were contacted when published data were incomplete.
Preplanned sensitivity and subgroup analyses were performed after data
were analysed with a random effects model.

Main results
The review included 34 studies (2607 patients). Overall, the RR of
author-defined kidney failure was 1.50 (95% CI 1.20 to 1.87; n = 1199)
and 1.38 for requiring RRT (95% CI 0.89 to 2.16; n = 1236) in HES
treated individuals compared with other fluid therapies. Subgroup
analyses suggested increased risk in septic patients compared to
non-septic (surgical/trauma) patients. Non-septic patient studies were
smaller and had lower event rates, so subgroup differences may have been
due to lack of statistical power in these studies. Only limited data was
obtained for analysis of kidney outcomes by the RIFLE criteria. Overall,
methodological quality of studies was good but subjective outcomes were
potentially biased because most studies were unblinded.

Authors' conclusions
Potential for increased risk of AKI should be considered when weighing
the risks and benefits of HES for volume resuscitation, particularly in
septic patients. Large studies with adequate follow-up are required to
evaluate the renal safety of HES products in non-septic patient
populations. RIFLE criteria should be applied to evaluate kidney
function in future studies of HES and, where data is available, to
re-analyse those studies already published. There is inadequate clinical
data to address the claim that safety differences exist between
different HES products.  
Plain language summary

Hydroxyethyl starch (HES) versus other fluid therapies: effects on
kidney function
Hydroxyethyl starches (HES) are synthetic fluid products that are
commonly used in clinical practice, however controversy exists about
their effect on kidney function. This review examined the effects of HES
on kidney function compared to other fluid therapies in critically ill
patients. Thirty-four randomised clinical trials comparing HES to
another fluid therapy qualified for the review. In surgical and trauma
patients there was no difference with respect to risk of kidney failure
or need for dialysis between treatment groups, possibly due to the low
number of outcomes in these studies. In contrast, studies including
sepsis patients revealed that HES treated individuals had a 55%
increased risk of developing kidney failure and a 59% increased risk of
requiring dialysis. Serum creatinine and creatinine clearance were
evaluated as outcomes, however results were too different between
patients and studies to be evaluated. Small studies of surgical patients
comparing different HES products did not reveal significant differences,
however there were too few patients to properly evaluate this outcome.
Products with lower molecular weight and degree of substitution are
reported to have better safety profiles, however insufficient evidence
exists in the literature to support this.

Hypertonic versus near isotonic crystalloid for fluid resuscitation in
critically ill patients

Frances Bunn1, Ian G Roberts2, Robert Tasker3, Daksha Trivedi1

1Centre for Research in Primary and Community Care, University of
Hertfordshire, Hatfield, UK. 2Cochrane Injuries Group, London School of
Hygiene & Tropical Medicine, London, UK. 3University of Cambridge School
of Clinical Medicine, Department of Paediatrics, Cambridge, UK

Contact address: Frances Bunn, Centre for Research in Primary and
Community Care, University of Hertfordshire, College Lane, Hatfield,
Hertfordshire, AL10 9PN, UK. f.bunn@herts.ac.uk. 

Editorial group: Cochrane Injuries Group.
Publication status and date: Edited (no change to conclusions),
published in Issue 4, 2008.
Review content assessed as up-to-date: 14 October 2007.

Citation: Bunn F, Roberts IG, Tasker R, Trivedi D. Hypertonic versus
near isotonic crystalloid for fluid resuscitation in critically ill
patients. Cochrane Database of Systematic Reviews 2004, Issue 3. Art.
No.: CD002045. DOI: 10.1002/14651858.CD002045.pub2.

Copyright © 2008 The Cochrane Collaboration. Published by John Wiley &
Sons, Ltd.

Hypertonic solutions are considered to have a greater ability to expand
blood volume and thus elevate blood pressure and can be administered as
a small volume infusion over a short time period. On the other hand, the
use of hypertonic solutions for volume replacement may also have
important disadvantages.

To determine whether hypertonic crystalloid decreases mortality in
patients with hypovolaemia.

Search strategy
We searched the Cochrane Injuries Group's specialised register,
MEDLINE, EMBASE, The Cochrane Library, issue 3, 2007, The National
Research Register issue 3, 2007 and the British Library's Electronic
Table of Contents ZETOC. We also checked reference lists of all articles
identified. The searches were last updated in October 2007

Selection criteria
Randomised trials comparing hypertonic to isotonic and near isotonic
crystalloid in patients with trauma or burns or who were undergoing

Data collection and analysis
Two authors independently extracted the data and assessed the quality
of the trials.

Main results
Fourteen trials with a total of 956 participants are included in the
meta-analysis. The pooled relative risk (RR) for death in trauma
patients was 0.84 (95% confidence interval [CI] 0.69 to1.04); in
patients with burns 1.49 (95% CI 0.56 to 3.95); and in patients
undergoing surgery 0.51 (95% CI 0.09 to 2.73). In the one trial that
gave data on disability using the Glasgow outcome scale, the relative
risk for a poor outcome was 1.00 (95% CI 0.82 to 1.22).

Authors' conclusions
This review does not give us enough data to be able to say whether
hypertonic crystalloid is better than isotonic and near isotonic
crystalloid for the resuscitation of patients with trauma or burns, or
those undergoing surgery. However, the confidence intervals are wide and
do not exclude clinically significant differences. Further trials which
clearly state the type and amount of fluid used and that are large
enough to detect a clinically important difference are needed.
Plain language summary

More evidence needed as to the best concentration of crystalloid to use
in resuscitation fluids
Fluid resusci
tation is usually given when a patient has lost a lot of
blood, but there is continuing uncertainty as to the best sort of fluid
to use. Some of the fluids used contain substances classified as
"crystalloids", but should the concentration of crystalloids in the
fluid be about the same as their concentration in human blood
("isotonic") or higher ("hypertonic")? It is commonly believed that
hypertonic crystalloid is the more effective at increasing blood volume
but that there could be some disadvantages to using it. This review has
assessed the evidence from studies that compared the use of the two
types of fluid with patients who had been injured or burned, or were
having surgery. Not enough evidence is available, however, to decide
which crystalloid concentration is best. More research is needed.

Posted on January 23, 2009 


In 1861, Thomas Graham’s investigations on diffusion led him to
classify substances as crystalloids or colloids based on their ability
to diffuse through a parchment membrane. Crystalloids passed readily
through the membrane, whereas colloids (from the Greek word for glue)
did not. Intravenous fluids are similarly classified based on their
ability to pass through barriers separating body fluid compartments,
particularly the one between intravascular and extravascular
(interstitial) fluid compartments. This chapter describes the salient
features of crystalloid and colloid fluids, both individually and as a
group. This is a must-know topic in the care of hospitalized patients,
and several reviews are included at the end of the chapter to supplement
the text. 


The principal component of crystalloid fluids is the inorganic salt
sodium chloride (NaCl). Sodium is the most abundant solute in the
extracellular fluids, and it is distributed uniformly throughout the
extracellular space. Because 75 to 80% of the extracellular fluids are
located in the extravascular (interstitial) space, a similar proportion
of the total body sodium is in the interstitial fluids. Exogenously
administered sodium follows the same distribution, so 75 to 80% of the
volume of sodium-based intravenous fluids are distributed in the
interstitial space. This means that the predominant effect of volume
resuscitation with crystalloid fluids is to expand the interstitial
volume rather than the plasma volume. 


As indicated by the horizontal bar that is second from the top,
infusion of 1 L of 0.9% sodium chloride (isotonic saline) adds 275 mL to
the plasma volume and 825 mL to the interstitial volume. Note that the
total volume expansion (1100 mL) is slightly greater than the infused
volume. This is the result of a fluid shift from the intracellular to
extracellular space, which occurs because isotonic saline is actually
hypertonic to the extracellular fluids. 


The prototype crystalloid fluid is 0.9% sodium chloride (NaCl), also
called isotonic saline or normal saline. The latter term is
inappropriate because a one normal (1 N) NaCl solution contains 58 g
NaCl per liter (the combined molecular weights of sodium and chloride),
whereas isotonic (0.9%) NaCl contains only 9 g NaCl per liter. 


The pH of isotonic saline is also considerably lower than the plasma
pH. These differences are rarely of any clinical significance. 


The chloride content of isotonic saline is particularly high relative
to plasma (154 mEq/L versus 103 mEq/L, respectively), so hyperchloremic
metabolic acidosis is a potential risk with large-volume isotonic saline
resuscitation. Hyperchloremia has been reported, but acidosis is rare. 


Ringer’s solution was introduced in 1880 by Sydney Ringer, a British
physician and research investigator who studied mechanisms of cardiac
contraction. The solution was designed to promote the contraction of

isolated frog hearts, and contained calcium and potassium in a sodium
chloride diluent. In the 1930s, an American pediatrician named Alexis
Hartmann proposed the addition of sodium lactate buffer to Ringer’s
solution for the treatment of metabolic acidoses. The lactated
Ringer’s solution, also known as Hartmann’s solution, gradually
gained in popularity and eventually replaced the standard Ringer’s
solution for routine intravenous therapy. 


Lactated Ringer’s solution contains potassium and calcium in
concentrations that approximate the free (ionic) concentrations in
plasma. The addition of these cations requires a reduction in sodium
concentration for electrical neutrality, so lactated Ringer’s solution
has less sodium than isotonic saline. The addition of lactate (28 mEq/L)
similarly requires a reduction in chloride concentration, and the
chloride in lactated Ringer’s more closely approximates plasma
chloride levels than does isotonic saline. 

Despite the differences in composition, there is no evidence that
lactated Ringer’s provides any benefit over isotonic saline.
Furthermore, there is no evidence that the lactate in Ringer’s
solution provides any buffer effect. 


The calcium in lactated Ringer’s can bind to certain drugs and reduce
their bioavailability and efficacy. Of particular note is calcium
binding to the citrated anticoagulant in blood products. This can
inactivate the anticoagulant and promote the formation of clots in donor
blood. For this reason, lactated Ringer’s solution is contraindicated
as a diluent for blood transfusions. 



The major feature of these solutions is the added buffer capacity,
which gives them a pH that is equivalent to that of plasma. An
additional feature is the addition of magnesium, which may provide some
benefit in light of the high incidence of magnesium depletion in
hospitalized patients. 


Magnesium administration can promote hypermagnesemia in renal
insufficiency and can counteract compensatory vasoconstriction and
promote hypotension in low flow states. 


Dextrose is a common additive in intravenous solutions, for reasons
that are unclear. A 5% dextrose-in-water solution is not an effective
volume expander. The use of 5% dextrose solutions was originally
intended to supply nonprotein calories and thus provide a
protein-sparing effect. However, total enteral and parenteral nutrition
is now the standard of care for providing daily energy requirements, and
the use of 5% dextrose solutions to provide calories is obsolete. 


A 5% dextrose solution (50 g dextrose per liter) provides 170 kcal per
liter (3.4 kcal/g dextrose). 


The addition of dextrose to intravenous fluids increases osmolarity (50
g of dextrose adds 278 mosm to an intravenous fluid) and creates a
hypertonic infusion when 5% dextrose is added to lactated Ringer’s
solution (525 mOsm/L) or isotonic saline (560 mOsm/L). If glucose use is
impaired (as is common in critically ill patients), the infused glucose
accumulates and creates an undesirable osmotic force that can promote
cell dehydration. 

Other undesirable effects of glucose infusions in critically ill
patients include enhanced CO2 production (which can be a burden in
ventilator-dependent patients), enhanced lactate production, and
aggravation of ischemic brain injury. 

Lactate Production 

The proportion of a glucose load that contributes to lactate formation
can increase from 5% in healthy subjects to 85% in critically ill
patients. This can produce an increase in circulating lactate levels,
even when infusing 5% dextrose solutions. Patients undergoing abdominal
aortic aneurysm surgery were given either a Ringer’s solution or a 5%
dextrose solution intraoperatively to maintain normal cardiac filling
pressures. As shown, the 5% dextrose infusions were associated with a
125% increase in arterial lactate levels (from 1.85 
to 4.15 mmol/L).
Thus, in patients with circulatory compromise, abnormal glucose
metabolism can transform glucose from a source of useful energy to a
source of toxin production. 

The disadvantages noted above, when combined with a lack of documented
benefit, favor the recommendation that the routine use of 5% dextrose
infusions be abandoned in critically ill patients. 


As mentioned earlier, colloids are large molecules that do not pass
across diffusional barriers as readily as crystalloids. Colloid fluids
infused into the vascular space therefore have a greater tendency to
stay put and enhance the plasma volume than do crystalloid fluids. The
colloid fluid in this case is 5% albumin, and as demonstrated, the
plasma expansion with this colloid fluid is nearly twice that produced
by an equivalent volume of isotonic saline (500 mL versus 275 mL,
respectively). This is the principal benefit of colloid fluid
resuscitation: more effective resuscitation of plasma volume than that
produced by crystalloid fluids. Much of this potency is related to the
colloid osmotic pressure exerted by each fluid. 


Large solute molecules that do not move freely across barriers
separating fluid compartments create a force that draws water into the
large solute compartment. This force opposes the hydrostatic pressure
(which favors the movement of water out of a fluid compartment) and is
called the colloid osmotic pressure (COP) or oncotic pressure. As would
be expected, the ability of each fluid to expand the plasma volume is
directly related to the COP; that is, the higher the COP, the greater
the volume expansion. If the COP of a colloid fluid is greater than the
COP of plasma (i.e., greater than 25 mm Hg), the plasma volume expansion
exceeds the infused volume. The 25% albumin solution, which has a COP of
70 mm Hg and a plasma volume expansion that is 4 to 5 times the infused


Albumin is a transport protein that is responsible for 75% of the
oncotic pressure of plasma. Heat-treated preparations of human serum
albumin are commercially available in a 5% solution (50 g/L) and a 25%
solution (250 g/L) in an isotonic saline diluent. The 25% solution is
given in small volumes (50 to 100 mL) and because the accompanying
sodium load is small, 25% albumin is also called salt-poor albumin. 


A 5% albumin solution (50 g/L or 5 g/dL) has a COP of 20 mm Hg and thus
is similar in oncotic activity to plasma. Approximately half of the
infused volume of 5% albumin stays in the vascular space. The oncotic
effects of albumin last 12 to 18 hours. 

The 25% albumin solution has a COP of 70 mm Hg and expands the plasma
volume by 4 to 5 times the volume infused. Thus, infusion of 100 mL of
25% albumin can increase the plasma volume 400 to 500 mL. This plasma
volume expansion occurs at the expense of the interstitial fluid volume,
so 25% albumin should not be used for volume resuscitation in
hypovolemia. It is intended for shifting fluid from the interstitial
space to the vascular space in hypoproteinemic conditions, although the
wisdom of this application is questionable. 


Because albumin preparations are heat-treated, there is no risk of
viral transmission (including human immunodeficiency virus). Allergic
reactions are rare, and although coagulopathies can occur, most are
dilutional and not accompanied by bleeding. 


Hetastarch is a synthetic colloid available as a 6% solution in
isotonic saline. It contains amylopectin molecules that vary in size
from a few hundred to over a million daltons. The average molecular
weight of the starch molecules is equivalent to that of albumin, and the
colloid effects are equivalent to those of 5% albumin. The main
advantage of hetastarch over albumin is its lower cost. 


Hetastarch is slightly more potent than 5% albumin as a colloid. It has
a higher COP than 5% albumin (30 versus 20 mm Hg, respectively) and
causes a greater plasma v
olume expansion (up to 30% greater than the
infused volume). It also has a long elimination half-life (17 days), but
this is misleading because the oncotic effects of hetastarch disappear
within 24 hours. 


Hetastarch molecules are constantly cleaved by amylase enzymes in the
bloodstream before their clearance by the kidneys. Serum amylase levels
are often elevated (2 to 3 times above normal levels) for the first few
days after hetastarch infusion, and return to normal at 5 to 7 days
after fluid therapy. This hyperamylasemia should not be mistaken for
early pancreatitis. Serum lipase levels remain normal, which is an
important distinguishing feature. 

Anaphylactic reactions to hetastarch are decidedly rare (incidence as
low as 0.0004%). Laboratory test coagulopathy (prolonged partial
thromboplastin time from an interaction with Factor VIII) can occur, but
is not accompanied by bleeding. Coagulopathy claims have dogged
hetastarch for years, without evidence of hetastarch-induced bleeding. 


Pentastarch is a low-molecular-weight-derivative of hetastarch that is
available as a 10% solution in isotonic saline. Although it is not
currently approved for clinical use in the United States, there is
considerable evidence indicating that pentastarch is an effective and
safe plasma volume expander. 


Pentastarch contains smaller but more numerous starch molecules than
hetastarch, and thus has a higher colloid osmotic pressure. It is more
effective as a volume expander than hetastarch, and can increase plasma
volume by 1.5 times the infusion volume. The oncotic effects dissipate
after 12 hours. Pentastarch shows less of a tendency to interact with
coagulation proteins than hetastarch, but the significance of this
tendency is unclear. 


The dextrans are glucose polymers produced by a bacterium (Leuconostoc)
incubated in a sucrose medium. First introduced in the 1940s, these
colloids are not popular (at least in the United States) because of the
perceived risk of adverse reactions. The two most common dextran
preparations are 10% dextran-40 and 6% dextran-70, both diluted in
isotonic saline. 


Both dextran preparations are hyperoncotic to plasma (COP = 40 mm Hg).
Dextran-40 causes a larger increase in plasma volume than dextran-70,
but the effects last only a few hours. Dextran-70 is the preferred
preparation because of its prolonged action. 


Dextrans produce a dose-related bleeding tendency by inhibiting
platelet aggregation, reducing activation of Factor VIII, and promoting
fibrinolysis. The hemostatic defects are minimized by limiting the daily
dextran dose to 20 mL/kg. 

Anaphylactic reactions were originally reported in as many as 5% of
patients receiving dextran infusions. However, this has improved
considerably in the last 20 years because of improvements in antigen
detection and desensitization and improvements in preparation purity.
The current incidence of anaphylaxis is 0.032%. 

Dextrans coat the surface of red blood cells and can interfere with the
ability to cross-match blood. Red cell preparations must be washed to
eliminate this problem. Dextrans also increase the erythrocyte
sedimentation rate as a result of their interactions with red blood

Finally, dextrans have been implicated as a cause of acute renal
failure. The proposed mechanism is a hyperoncotic state with reduced
filtration pressure. However, this mechanism is unproven, and renal
failure occurs only rarely in association with dextran infusions. 


There is considerable disagreement about the most appropriate fluid for
volume resuscitation in critically ill patients. The following is a
brief description of the issues involved in the colloid-crystalloid


Because crystalloid fluids fill primarily the interstitial space, these
fluids are not useful for filling the vascular space. The early
popularity of crystalloid fluid
 resuscitation in hypovolemia stems from
two observations made about 40 years ago. The first is the response to
mild hemorrhage, which involves a shift of fluid from the interstitial
space to the vascular space. The second observation stems from studies
in an animal model of hemorrhagic shock, where survival was much
improved if a crystalloid fluid was given along with reinfusion of the
shed blood volume. The combination of these two observations has been
interpreted as indicating that the major consequence of hemorrhage is an
interstitial fluid deficit, and that replacement of interstitial fluid
with crystalloid fluids is important for survival. 


The interstitial fluid deficit is predominant only when blood loss is
mild (less than 15% of the blood volume), and in this situation, no
volume resuscitation is necessary (because the body is capable of fully
compensating for the loss of blood volume). When blood loss is more
severe, the priority is to keep the vascular space filled and thereby
support the cardiac output. Because colloid fluids are about three times
more potent than crystalloid fluids for increasing vascular volume and
supporting the cardiac output, colloid fluids are more effective than
crystalloid fluids for volume resuscitation in moderate to severe blood
loss. Crystalloid resuscitation can achieve the same endpoint as colloid
resuscitation, but larger volumes of crystalloid fluid (about three
times the volume of colloid fluids) must be used. This latter approach
is less efficient, yet it is the one favored by crystalloid users. 


Despite the superiority of colloid fluids for expanding plasma volume,
colloid fluid resuscitation does not confer a higher survival rate in
patients with hypovolemic shock. This lack of improved outcomes is a
major rallying point for crystalloid users, but it does not negate the
fact that colloid fluids are more effective for maintaining blood volume
in patients who are actively bleeding. 


The biggest disadvantage of colloid resuscitation is the higher cost of
colloid fluids. Using equivalent volumes of 250 mL for colloid fluids
and 1000 mL for crystalloid fluids, the cost of colloid resuscitation is
three times as high (if hetastarch is used) to six times as high (if
albumin is used) than volume resuscitation with isotonic saline. 


The risk of edema has been used to discredit each type of fluid.
Because crystalloid fluids distribute primarily in the interstitial
space, edema is an expected feature of crystalloid fluid resuscitation.
However, edema is also a risk with colloid fluid resuscitation. This is
particularly true with albumin-containing fluids; even though albumin is
the principal oncotic force in plasma, over half of the albumin in the
human body is in the interstitial fluid. Therefore, a large proportion
of infused albumin eventually finds its way into the interstitial fluid
and promotes edema. Furthermore, this egress of albumin from the
bloodstream is magnified when capillary permeability is disrupted, which
is a common occurrence in critically ill patients. Despite this risk,
troublesome edema (e.g., pulmonary edema) is not common with either type
of fluid resuscitation when capillary hydrostatic pressure is not


The following analogy helped me resolve the colloid-crystalloid
conundrum. Assume that the goal is to recreate the performance of
crystalloid and colloid fluids in expanding the plasma volume by filling
a bucket. Because the volume of crystalloid fluids neplasma volume (fill the 
bucket) is three times larger than the volume of
colloid fluid that fills the bucket, holes will need to be punched in
the bucket while it is filled with crystalloid fluids (to allow the
extra fluid to escape). Therefore, the question is this: If the goal is
to fill a bucket with fluid, do you want to punch holes in the bucket
(and make the bucket more difficult to fill)? Seen in this light, it is
more efficient to use
 colloid fluid resuscitation to expand the plasma


An interesting approach to volume resuscitation that has stalled in
recent years is the use of small-volume hypertonic saline solutions. A
7.5% sodium chloride solution is given either in a fixed volume of 250
mL or in a volume of 4 mL/kg. The volume increments in both fluid
compartments are similar to those produced by 1 L of 5% albumin. Thus,
hypertonic saline resuscitation can produce equivalent volume expansion
to colloid fluids, but at one-fourth the infused volume. Note that the
total volume expansion (1235 mL) produced by 7.5% saline is far greater
than the infused volume (250 mL). The additional volume comes from
intracellular fluid that moves out of cells and into the extracellular
space. This movement of intracellular fluid points to one of the feared
complications of hypertonic resuscitation: cell dehydration. 


Since the first report of its successful use in 1980, hypertonic saline
has been shown repeatedly (but not unanimously) to be safe and effective
in the early resuscitation of hypovolemia. However, there is little
evidence that hypertonic resuscitation is superior to standard volume
resuscitation. Hypertonic resuscitation seems best suited for
prehospital resuscitation in cases of trauma, but studies in trauma
resuscitation fail to document a clear benefit with this approach in
most patients. Select subgroups of patients (e.g., those with
penetrating truncal injuries who required surgery) may benefit from
hypertonic resuscitation, but these subgroups are small. Thus, after
over 15 years of evaluating this technique, hypertonic resuscitation has
few advocates.

Andy Gray MSc(Pharm) FPS
* Senior Lecturer
Dept of Therapeutics and Medicines Management
* Consultant Pharmacist
Centre for the AIDS Programme of Research 
in South Africa (CAPRISA)
Nelson R Mandela School of Medicine
University of KwaZulu-Natal
PBag 7 Congella 4013
South Africa
Tel: +27-31-2604334/4298 Fax: +27-31-2604338
email: graya1@ukzn.ac.za or andy@gray.za.net
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