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Intraoperative Fluid Management and Choice of Fluids

Tong J. Gan, M.D. Durham, North Carolina

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Review the physiology of fluid compartment, intraoperative fluid requirement and electrolyte composition of colloids and
crystalloids. Discuss the choice of fluids and present data on the impact of using different fluids on patient outcome. Review the
literature on the evidence of goal-directed intraoperative fluid management strategy. Discuss the optimal use of colloids and
crystalloids for fluid management.

Fluid management is an essential part of patient care in the perioperative period. Adequate plasma volume is essential in
maintaining cardiac output and hence tissue perfusion. Inadequate tissue perfusion is associated with poor outcome following
Fluid management strategies have undergone several shifts over the past fifty years. Prior to the sixties, fluid restriction
during the intraoperative period was widely practiced. In the early 1960s, it was demonstrated that major surgery and trauma
were associated with fluid requirements that significantly exceeded the usual rate of fluid maintenance.
As a result, fluid
administration became less restrictive. A decade later, the choice of fluid became the subject of intense debate, and continued till
today. In the late eighties and early nineties, the concept of achieving a “supranormal” oxygen delivery attracted much interest.
More recently, goal directed fluid management appear to show benefits in surgical settings. The last few years saw the
development of new colloid solution, with its physical characteristics and its “balanced electrolyte” carrier.

Accurate replacement of fluid deficits requires an understanding of the distribution volume of body fluids. About 60% of a
human’s body weight is made up of water. For a person weighing 70 kg, total body water (TBW) is about 42 L. The total body
water exists within discreet but dynamic fluid compartments. Two thirds of the TBW (28 liters) is intracellular water. The
remaining third (14 liters) in the extracellular compartment is divided into the intravascular (5L) and extravascular (9L)
compartments. Blood is composed of around 60% plasma (extracellular compartment) and 40% red and white blood cells and
platelets (intracellular compartment).
Plasma consists of inorganic ions (predominantly sodium chloride), simple molecules such
as urea and larger organic molecules (predominantly albumin and the globulins) dissolved in water. Interstitial fluid bathes the
cells and allows metabolic substrates and wastes to be diffused between the capillaries and cells in the tissue. Excess free
interstitial fluid enters the lymphatic channels and is ultimately returned to the plasma. The majority of the interstitial water is not
free, but exists within a proteoglycan matrix in a gel form. This arrangement allows for easy diffusion of solutes through the
interstitium, but significantly retards bulk water flow. The “transcellular fluids” are extracellular and extravascular and include
the cerebrospinal fluid, aqueous humor, pleural, pericardial, peritoneal and synovial fluids.

Colloid Oncotic Pressure and Fluid Flux
Colloid Oncotic Pressure (COP) is the osmotic pressure exerted by the macromolecules (the colloid molecules). This can be
measured using a membrane transducer system in which the membrane is freely permeable to small ions and water but largely
impermeable to the colloid molecules. The membrane pore size and the molecular size distribution of the colloid being studied
will dictate the measured value. The molecular size distribution of a colloid in solution is commonly described as a ratio of the
measured COPs across two membranes with different pore sizes - e.g. the pressure across a membrane with a nominal 50
Kilodalton pore size compared with the pressure across a membrane with a nominal pore size of 10 Kilodalton: the
COP50/COP10 ratio.
Solutes that can pass freely across a semi-permeable membrane do not generate any oncotic pressure - they
are effectively a component of the solvent with respect to that membrane. Where membranes are selectively permeable to solutes
the water content of the fluid compartments is dictated by solute distribution as water moves down any osmotic pressure gradient
to produce isotonicity.

Starling in 1896 first described the forces affecting the flux of fluid across the capillary membrane.
These forces can be
expressed in the following equation:

) - !

in which Q
= total flow of fluid across the capillary membrane; K = fluid filtration coefficient; P
= capillary hydrostatic
pressure; P
= interstitial hydrostatic pressure; !
= reflection coefficient; "
= capillary COP (plasma); "
= interstitial COP.
The filtration coefficient is a function of the permeability and surface area of the capillary bed in question. The numeric value
represents the net volume of fluid crossing the capillary membrane under a specific set of conditions. The reflection coefficient is
a mathematical expression (from 0 to 1) of the capillary membrane’s permeability to a particular substance. Thus the reflection
coefficient will vary with both the tissue bed and substance in question. If a substance is completely permeable to the capillary
membrane, the reflection coefficient will be 0; if it is totally impermeable, the coefficient will be 1. For protein, the approximate

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reflection coefficients for liver, lung, and brain are 0.1, 0.7, and 0.99, respectively.
When a pulmonary insult creates a leaky
capillary state, the protein-lung reflection coefficient may decrease to approximately 0.4.
The reflection coefficient for albumin,
the source of 60% of the normal oncotic pressure in the pulmonary circulation, is approximately 0.7.

The composition of administered fluids will therefore dictate their distribution. Pure water expands all body fluid compartments
and therefore provides minimal expansion of the intravascular volume. Intravenous infusion of an isotonic solution of sodium
chloride expands only the extracellular compartment and will increase intravascular volume by about one fifth of the volume
infused. Colloidal solutions containing large molecules are maintained within the circulation, at least initially, and so provide
greater intravascular volume expansion per unit volume infused. Lamke and Liljedahl
demonstrated that 90 minutes following
infusion of 1000 mL of 6% hetastarch, albumin or saline in postoperative surgical patients, 75%, 50% and <20% of the
hetastarch, albumin and saline respectively, remain in the intravascular space.

The choice of intravenous fluids may broadly be categorized as colloids and crystalloids. Crystalloids are effective and
appropriate for the initial management of extracellular compartment losses associated with hemorrhagic shock, major surgery or
trauma. After this acute resuscitation phase, there usually is a significant degree of hemodilution and a diminished plasma COP.
This reduction in plasma COP has been associated with the development of edema and transudates. It is therefore appropriate that
continued fluid resuscitation should include colloid solutions in an attempt to minimize interstitial edema within vital organs e.g.
heart, lung and brain. Colloid-containing resuscitation protocols have been demonstrated to be able to maintain or increase the
plasma COP.

The choice of colloid may be an important factor in patients with established sepsis, as capillary permeability increases, and
moderate size colloid may have shorter intravascular half-life. Using a radioisotope dilution technique, Ernst and colleagues

found that albumin increased not only the intravascular volume but also the interstitial volume, and by an amount that was
approximately equivalent to the increase in plasma volume. The authors concluded that the infusion of albumin produced a
translocation of fluid from the intracellular to the interstitial compartment in septic patients. This was due to the increase in
vascular permeability with leakage of albumin into the interstitium, and the resulting increase in colloid oncotic pressure of
interstitial fluid, therefore a shift of fluid from the intracellular to the interstitial fluid compartment. Colloids available in the US
include synthetic starches, albumin and dextran. The physical characteristics of the various colloids are presented in Table 1.

Table 1. Physical Properties of Colloids



(mm Hg)
5% albumin 69 69 19 None
20% albumin 69 69 78 None
Dextran 70 70 41 40 None
Pentastarch 280 120 40 0.5
Pentafraction 350 110 40 0.5
6% hetastarch 450 69 30 0.7
wMW=weight-average molecular weight; nMW=number-average molecular weight; COP=colloid oncotic pressure

Hydroxyethyl Starch
The hydroxyethyl starch (HES) compounds are a group of polydisperse synthetic colloids that resembles glycogen structurally.
Hetastarch is a high molecular weight HES, with an average molecular weight of 450,000 d with 80% of the polymers falling in
the range of 30,000 d to 2,500.000 d. However, for polydisperse colloids, the number-average molecular weight (nMW) provides
a better representation of the number of particles of a given size as opposed to the weight-average molecular weight.
Hydroxyethyl starches are synthesized from amylopectin, a waxy starch derived from maize or sorghum. Amylopectin is a D-
glucose polymer with a branching structure. The majority of these substitutions occur at carbon 2 in the glucose ring with the rest
occurring at carbon’s 3 and 6. Increased C2/C6 substitution ratio results in slower enzymatic degradation.
The unsubstituted
starch is rapidly hydrolyzed by non-specific #-amylases in the plasma and substitution with hydroxyethyl groups substantially
slows this process. The degree of substitution indicates the proportion of glucose moieties that have been substituted and can be
expressed as a number from 0-1. Starches with a degree of substitution close to 1 have a greater resistant to hydrolysis than those
with a lower degree of substitution.

Hetastarch is primarily excreted via the kidneys. Particles weighing less than 50,000 d are rapidly filtered through the kidneys
with 40% -50% of the administered dose eliminated within 48 hours.
Pentastarch is a smaller molecular weight molecule with
an average molecular weight of about 200,000. It has a shorter half-life of a few days, and does not seem to affect the reticulo-

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endothelial system. Pentastarch 10% has a good initial volume-expanding capacity of 1.5 times the infused volume. About 90%
is eliminated within 24 hours and most is undetectable after 96 hours. In critically ill patients, pentastarch has been found to be
equivalent to albumin for fluid resuscitation.

Albumin is a naturally occurring plasma protein composed of 584 amino acid residues. The molecular weight of albumin ranges
from 66,000 to 69,000 depending on the technique of measurement.
The molecule is highly soluble and carries a strong
negative charge at physiological pH. Consequently, albumin migrates in the electrical fields. Depending on the salt and buffer
concentration of the plasma, albumin is isoelectric in the pH range of 4.4 and 5.4. In serum, albumin is in part bound to either
cations or anions. This property accounts for its role as a carrier protein for the transport and activation of drugs, hormones,
enzymes, fatty acids, amino acids, bilirubin and other metabolites. The half-life of circulating albumin is approximately 18 to 20

Albumin provides approximately 70% of the plasma colloid oncotic pressure in normal human subjects. Human albumin is
available for infusions as either 5% or 25% solution. The 5% solution contains 50 g albumin/L physiological salt solution and has
a COP of about 20 mmHg. The 25% solution contains 12.5 g albumin in 50 mL buffered diluent containing 130-160 mmol/L of
sodium. The 5% solution is approximately iso-oncotic, whereas the 25% solution is markedly hyperoncotic.

Plasma protein fraction (PPF) is a 5% solution of selected proteins prepared from pooled human blood, serum, or plasma. It
undergoes the same pasteurization process used for albumin and is a mixture of proteins consisting mostly of albumin in an
amount equal to or greater than 83% of the total protein composition. The two solutions are similar in costs, and hence are used

Dextrans are high molecular weight D-glucose polymers linked by alpha1,6 bonds into predominantly linear macromolecules.
They are biosynthesized commercially from sucrose by the B512 strain of leuconostoc mesenteroides using the enzyme dextran
This produces a high molecular weight dextran that is then cleaved by acid hydrolysis and separated by repeated
ethanol fractionation to produce a final product with a relatively narrow molecular weight range. The products in current clinical
use are described by their MWn: Dextran 40 and Dextran 70 having MWns of 40000 and 70000 dalton respectively.

Dextrans, like all the other semisynthetic colloids, are polydisperse with 90% of the molecules of Dextran 40 having molecular
weights between 10000 and 80000 dalton. The renal threshold for Dextrans is between 50000 and 55000 dalton. Molecules with
a MW less than this threshold are freely filtered at the glomerulus and molecules with a MW less than 15000 have a clearance
similar to creatinine. Approximately 70% of an administered dose of Dextran 40 will be excreted into the urine within 24 hours.
Larger molecules are excreted through the gut or phagocytozed by cells of the reticuloendothelial system where they are either
metabolized by endogenous dextranases or recirculated into the systemic circulation.

Infusions of hyperosmotic-hyperoncotic solutions such as hypertonic saline dextran have been shown to be very effective in
expanding plasma volume rapidly. The intravascular volume expansion efficiency, defined as milliliter plasma
expansion/milliliter fluid infused was 7 and 20 folds at 30 and 60 min after infusion, respectively when hypertonic saline dextran
was compared with LR.

Other Colloids
Gelatins are prepared by hydrolysis of bovine collagen. The commonly available preparations are succinylated gelatin
(Gelofusin) which is presented in isotonic saline and urea linked gelatin - polygeline (Haemaccel) which is presented in an
isotonic solution of sodium chloride with 5.1 mmol/L potassium and 6.25 mmol/L calcium.

Colloids and crystalloids may be divided into whether they are formulated in 0.9% sodium chloride or a variety of balanced
electrolyte solutions. Lactated Ringer’s and Normosol solutions consist of a number of electrolytes that are present in the plasma,
whereas 0.9% saline is made up of only sodium and chloride. A new hydroxyethyl starch, Hextend$ , is formulated in a
“balanced” electrolyte solution not dissimilar to those present in lactated Ringer’s solution. Recent studies have focused on the
differences between administering saline versus “balanced” electrolyte solutions to animals and humans. In a transplanted
greyhound kidney model, infusion of hypertonic sodium chloride containing fluid (saline or ammonium chloride solution)
resulted in progressive renal vasoconstriction and falls in the glomerular filtration rate and renal blood flow. This fall is
independent of the renal nerves, and is potentiated by prior salt depletion and correlated strongly with renal tubular chloride.

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Acid Base Balance and Renal Outcome
In a human volunteer crossed-over study, Williams and colleagues
found a significantly higher incidence of subjective mental
changes, abdominal discomfort, as well as a significant delay of time to first urination, in the group that received 50 mL/kg of
0.9% sodium chloride over 1 hr compared with the same volume of lactated Ringer’s solution. Sceingraber et al. demonstrated a
significant hyperchloremic acidosis at the end of surgery in patients undergoing major gynecological hysterectomies when 0.9%
sodium chloride was used as the intraoperative resuscitative fluid. The group that received lactated Ringer’s had a normal acid-
base balance. Interestingly, there was a trend towards greater estimated blood loss and lower urine output in the 0.9% sodium
chloride group. The perioperative use of balanced electrolyte solutions (Hartmann’s solution$ and Hextend$) was associated
with lower incidence of hyperchloremic metabolic acidosis and better gastrointestinal mucosal perfusion compared with sodium
chloride based solutions (0.9% saline and Hespan$). Other studies have demonstrated the predictability of acidosis following
rapid intraoperative administration of saline based fluid.

The type of fluid administered during the perioperative period could have a significant impact on several clinically relevant
outcomes following cardiac surgery. Serum creatinine levels were elevated by about 50% on postoperative day 2 in the groups
that received either 6% hetastarch in saline or albumin (saline based), but not Hextend$ or lactated Ringer’s groups. These
differences persisted up to postoperative day 7 and were mirrored by changes in lower creatinine clearance and urinary flow rate.
More patients in the Hespan$ group required postoperative hemodialysis.

Hemostatic Effects
The choices of fluid administered intraoperatively can result in differences in the coagulation effects. Hespan$ in larger volume
(>20 mL/kg) has been associated with reduced levels of the coagulations factors, e.g., fibrinogen, Factor VIII, and von
Willebrand’s factor and reduced platelet function, beyond the effect of hemodilution. Crystalloid administration, however, is
associated with a hypercoagulative state.

A recent study demonstrated a better thromboelastographic coagulation profile when larger volumes of Hextend$ (>20 mL/kg)
was used compared with equivalent volumes of 6% hetastarch in saline (Hespan$).
The use of Hespan$ was associated with a
hypocoagulable state with prolongation of both their r time and k time and a reduction in MA on thromboelastography. This
hypocoagulable state continued into the first 24 hours postoperatively with further increases in the r time and k time.
Ringer’s solution, however, was associated with a hypercoagulable state.
The TEG profiles with respect to Hextend$ showed
the least change at the end of surgery and 24 hours after surgery.
In another study when Hextend$ was compared with albumin,
there appeared to be no differences in the levels of Factor VIII, von Willebrands factors and platelets up to 24 hours following
major urological surgery.
Similar findings were demonstrated by Bennett-Gurrero et al.
in patients undergoing cardiac
surgery. Patients who received 6% hetastarch in saline required more units of red cells, fresh frozen plasma, and platelets
transfusion and more patients in this group returned to the operating room for surgical reexploration secondary to
hypocoagulopathy, when compared with similar groups receiving lactated Ringer’s, albumin or Hextend$.

Hypovolemia is common among patients scheduled for surgery. In addition to the inevitable losses in the perioperative period
due to surgical trauma, evaporation, and the use of dry anesthetic gases, the majority of patients are routinely required to starve
for a minimum of 6 hours preoperatively to reduce the risk of acid aspiration syndrome.
Hypovolemia during the perioperative
period is associated with a significant increase in postoperative morbidity and mortality, ranging from postoperative nausea and
to more serious complications such as organ dysfunction
, and prolongation of hospital stay.

Since the late 1950’s a succession of authors have described an association between perioperative cardiac output and survival
following major surgery: the survivors exhibiting higher values than the non-survivors.
. In 1988 Shoemaker was the first to
test this hypothesis in a randomized controlled clinical trial (RCT).
In a complex study he demonstrated that targeting specific
values for cardiac index, oxygen delivery and oxygen consumption, using fluids and inotropes to achieve these goals, resulted in
a reduction in mortality and morbidity.

Since then a number of single center randomized controlled trials have been conducted, the majority of which support this
original positive result. Five studies have used the same hemodynamic goals as the original study by Shoemaker. Two of these
were large (>100 patient) studies on high-risk general surgical and vascular patients and both demonstrated a statistically
significant reduction in mortality in the protocol groups.
Two were studies of major trauma surgery and were both conducted
by the same group.
The first smaller study showed a trend towards reduction in mortality in the protocol group and this was
confirmed by a statistically significant reduction in mortality in the protocol group in the second, larger trial. The fifth study in
this group was a small trial focusing on surgery for hepatobiliary carcinoma and demonstrated a reduction in liver failure and
hyperbilirubinemia although this was not their specified primary outcome variable.
An older study using a similar strategy, in
patients undergoing hip fracture surgery also demonstrated a significant mortality reduction.

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Somewhat different results have been obtained in a series of studies in which patients presenting for major vascular or aortic
surgery were studied.
. The goals for cardiac index and oxygen delivery used in these trials were significantly lower and the
overall mortality for each trial was also low. These studies did not demonstrate a significant reduction in mortality, or in some
cases complications, however in one study there were more deaths in the protocol than control groups.

Targeting mixed venous oxygen saturation (SvO2) as an indirect index of oxygen delivery has also been studied in two trials. The
first study in vascular patients failed to demonstrate a significant morbidity or mortality difference between control and protocol
More recently a large Scandinavian study of patients undergoing elective coronary revascularization
demonstrated a significant reduction in length of stay in those randomized to maintenance of SvO2 > 70% and lactate % 2
mmol·L-1 when compared with controls.

A number of published studies using intraoperative esophageal Doppler monitoring of cardiac output compared a stroke volume
optimization algorithm with standard fluid management. In the first study patients with normal left ventricular function
undergoing coronary artery revascularization had a statistically significant reduction in length of both ICU and overall hospital
stay in the protocol group.
The second study, of elderly patients having hip prosthesis surgery also demonstrated a reduction in
hospital length of stay in patients managed in the protocol group.
Neither of these studies were designed to demonstrate a
mortality difference. Gan and colleagues, in a recent study using a similar goal directed fluid administration algorithm also
demonstrated a reduction in hospital stay and earlier return to tolerating solid food in the protocol group.

The application of this management approach to patients with established critical illness have failed to show an outcome benefit
for patients in the protocol group
. Indeed in one study the intervention group had a higher mortality.
Taken together the
perioperative trials present an interesting picture. Many of the studies were not designed with mortality as a primary outcome
goal and several of those that were did not have adequate statistical power to detect a mortality reduction. However if all the trials
are grouped together and the control group mortality compared with the intervention group the results are striking. The crude
death rates are 96/753 for the combined control groups and 36/814 for the combined protocol groups. In only two of 15 studies
was there greater mortality in the protocol group: in one study 5/72 patients died: 2/40 control and 3/32 protocol and in the other
4/120 patients died: 1/60 control and 3/60 protocol
. The accumulated body of evidence relating to goal directed hemodynamic
perioperative management now includes at least 15 RCTS (Table 2) and 2 supportive meta-analyses.

Table 2. Studies on perioperative goal directed hemodynamic management and outcome.
Year First Author n Surgery Tool Algorithm Outcome Result
1985 Schultz 70 Elective hip PAC Unclear Death Y
1988 Shoemaker 58 High risk major PAC DO2/VO2 Death Y
1991 Berlauk 89 Vascular PAC CI Cardiac Y
1992 Fleming 67 Trauma PAC CI/DO2/VO2 Death N
1993 Boyd 107 High risk major PAC DO2 Death Y
1995 Bishop 115 Trauma PAC CI/DO2/VO2 Death Y
1995 Mythen 60 Cardiac EDM SV LOS Y
1997 Bender 104 Vascular PAC CI/SVR Complications N
1997 Sinclair 40 Elective hip EDM SV/FT
1997 Ziegler 72 Vascular PAC SvO2 Cardiac N
1998 Ueno 34 Liver PAC CI/DO2/VO2 Liver failure N
1998 Valentine 120 Aortic PAC CI/SVR Complications N
1999 Wilson 138 High risk major PAC DO2 Death Y
2000 Polonen 393 Cardiac PAC SvO2/Lactate LOS Y
2002 Gan 100 Mod. risk major EDM SV/FT

PAC=pulmonary artery catheter; EDM=esophageal Doppler monitor; DO2=oxygen delivery; VO2=oxygen comsumption; CI-
cardiac index; SV=stroke volume; SVR=systemic vascular resistance; FTc=corrected flow time; SvO2=venous oxygen
saturation; LOS=length of stay; Y=positive outcome; N=negative outcome

Arguments over the best choice of fluid for volume resuscitation have been hotly debated for more than 30 years. While all sides
agree that fluid resuscitation is fundamental in the management of hypovolemia there is disagreement as to which solutions to

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use. Crystalloid proponents point to the haemostatic derangement, the increased incidence of adverse drug reaction and the
greater risk of fluid overload occurring with colloidal fluids. The colloid lobby focuses on the large volumes of crystalloid
required to achieve adequate resuscitation and on the resultant tissue edema and reduction in tissue oxygen delivery. There have
been three meta-analyses focusing specifically on this issue and with mortality as an endpoint.
The most recent of these
focused on 19 RCTs including 1315 patients and suggested an increase absolute risk of mortality of 4% with use of colloid for
volume replacement (95% confidence interval 0% to 8%). However these meta-analyses have been widely criticized for pulling
together a large number of studies comparing a number of different solutions amongst diverse patient populations, for varying
indications. None of the original studies used mortality as a primary end point, the vast majority of studies included are of
albumin or dextran solutions and these two colloids contribute all the excess mortality. At present there is a lack of adequate
studies upon which to base a judgement on this question.

However, a recent study suggests that the quality of recovery may be superior when colloid/crystalloid combination was used
compared with crystalloid alone in patients undergoing major non-cardiac surgery. Patients who received lactated Ringer’s alone
had higher incidence of nausea and use of rescue antiemetic, double vision, and complained of more severe pain

Perioperative fluid management has undergone significant advances over the past few decades. The choice of fluid and its
electrolyte composition are important considerations when replenishing plasma volume and other body fluid compartments. The
coming decade will see an expansion of knowledge defining the role of goal directed fluid therapy in clinical practice and subtle
differences between colloids and crystalloids when used in the perioperative period.

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