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Perioperative Fluids:
An Evidence-Based Review
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ELIZABETH A. M. FROST, MD

Professor of Anesthesia
Icahn School of Medicine at Mount Sinai
New York, New York

The author reports no relevant financial conflicts of interest.

any questions have arisen and

much controversy has emerged

regarding how much fluid

should be given perioperatively, which

fluids should be given, when they should

be given, and whether outcomes can be
influenced. Its been called the Great
Fluid Debate. In fact, one might ask

Background

whether the anesthesiologist can even

make a difference in the long run. Several

identified: Tissue perfusion should be
optimized; and heart rate, stroke volume,
should be appropriately manipulated.

Galen was among the first to appreciate the circulation of the blood in the second century A.D., recognizing
a difference between venous (dark) and arterial (bright)
blood.5 He posited 2 circulations, venous through the
liver and arterial via the heart. It was not until 1628 when
the role of the heart as a pump was described by Harvey in de Motu Cordis.6 Sir Christopher Wren along with
Robert Boyle are credited with being the first to propose and demonstrate IV administration of medications
(wine and opium) into dogs, using an animal bladder and quills.7 OShaughnessy, an Irish physician who
trained in Edinburgh and then moved to London, examined the blood in a healthy state and in cases of cholera,

d.

goals of fluid administration have been

hemoglobin, and oxygen saturation

But just how to achieve these end points, and

whether they can be done by fluid administration,
remains unclear. Our current standard therapycannulate a vein, give fluids to maintain blood pressure, and
make up for supposed losseshas been challenged for
almost a century. Canon noted that fluids administered
before operative control of an injury were ineffective,1
an observation emphasized by Bickell and others some
70 years later.2,3 Nevertheless, standard U.S. Army protocols called for massive crystalloid resuscitation in the
arena of warespecially in Vietnamto preserve the
kidneys. Thus, the Da Nang lung, or adult respiratory
distress syndrome, was born.4

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noting a deficiency in salt in the latter samples.8 He recommended the injection of aqueous fluid into the veins.
Building on these observations, Thomas Latta, during
the cholera epidemic of Scotland in 1831-1832, decided
to throw the fluid immediately into the circulation.9
He described inserting a tube into a basilica vein and
injecting ounce after ounce of a solution containing two
to three drachms of muriate of soda and two scruples
of the subcarbonate of soda in six pints of water.9 He
used a pump that had been patented in 1830 by Reid
to remove stomach contents. Francis Rynd, another Irish
physician, is credited with the introduction of the hypodermic syringe during the 1840s.10 Some 10 years later,
Alexander Wood produced the first hypodermic syringe
that had a hollow needle attached.11
IV infusion of anesthetic agents, first chloral hydrate
and later hedonal, became popular during the latter part
of the 19th century.12 For a brief period, both ether and
chloroform were administered in saline solutions.12 By the
middle of the 20th century, short-acting agents, especially pentothal and amytal, were used for minor and
major surgeries, administered as infusions, and often
combined with local infiltration and nitrous oxide.12
A more routine use of continuous fluid infusion during
surgery was introduced by Hirshfeld, Hyman, and Wang
in 1931, but they also noted that too rapid administration
could cause speed shock.13 Nevertheless, by the mid1950s, various solutions were available and were administered using glass bottles and red rubber resterilizable
infusion sets. In Europe, however, many centers continued the practice of securing a vein preoperatively with
a metal needle, the end of which was then closed with
a moveable external rubber stopper. Induction agents
were given, but fluids only if deemed necessary.

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the literature, with both sides ultimately calling for moderation in fluid replacement.16
However, the idea of a mysterious third space took
hold; protocols were developed to compensate for it
and for other supposed intraoperative requirements. The
4:2:1 or 100-50-20 rule was developed and has remained
in general practice, despite its lack of relevance to anesthesia today.17 Basically, depending on weight, the rule
calls for 4 mL/kg/h for the first 10 kg to be followed by
2 mL/kg/h for the next 10 kg and finally 1 mL/kg/h thereafter; or, in daily replacement, 100 mL/kg for the first
10 kg, 50 mL/kg for the next 10 kg, and 20 mL/kg for
any weight over that. In other words, a 70-kg patient
should receive 110 mL/h replacement, or around
2,500 mL fluid/d. What should be realized is that Hollidays article was intended for pediatric application and
not specifically for intraoperative application. It was
based on 3 theories from earlier work:
Surface area can estimate water expenditure.18
Caloric needs depend on age, weight, activity, and
food (a comparison was made between a steer and
a rat).19
Urinary output and insensible losses correspond
to age (but only up to age 20 and weight <60 kg,
based on the theory that caloric need/kg =
100 3 age).20
These papers were founded on even earlier studies,
some from as few as 2 patients and using gasometer
estimates of body surface area from the 1920s.
The relevance of these rules must be considered in
light of present-day practice. They were developed
without scientific evidence, much of which was supposition based on unpublished data; the anesthetic and
surgical techniques since have changed drastically; the
application of the rules was intended for children on a
daily basis; and, at the very least, they were meant only
as a very rough guide. Nevertheless, we continue to
fluid load.

The Third Space?

32

A N E ST H E S I O LO GY N E WS .CO M

The Case For and Against Fluid Loading

Clinicians have presented cases for and against perioperative fluid administration for decades.

FOR

Several assumptions are made to explain why fluids

should and indeed must be given perioperatively:
The patient is fasted preoperatively and is thus
hypovolemic.
Insensible losses continue during surgery and must
be accounted for.
Fluid shifts to the third space must be replaced.
Blood must be replaced at 3 or 4:1 crystalloid.
Hypotension following induction is due to vasodilation and the vascular space must be filled.
Urine output must be taken into consideration and
replaced.
Even if the patient is overloaded, the kidneys will
regulate.
We have always done it that way.

d.

Traditionally, we have been taught that there are

3 spacesintravascular, extravascular, and a space that
appears during surgery or trauma. The origin of this
third space came about some 60 years ago in Texas.14
Using 2 groups of patients, 5 undergoing minor surgery (group 1) and 13 having major procedures such as
cholecystectomy, gastrectomy, or colectomy (group 2),
Shires and colleagues measured plasma volume, red
blood cell mass, and extracellular volumes on 2 occasions using tagged substances. No IV fluids were given.
They found a decrease in functional extracellular fluid in
group 2 and thus determined that fluid (up to 28% of
the extracellular water) was redistributed due to the surgery and needed to be replaced. Two years previously,
Moore, a Boston surgeon, had suggested that there was
a metabolic response to surgical stress and the release
of antidiuretic hormone (ADH) that caused the retention of sodium and water and that, therefore, perioperative fluids should be restricted.15 He also emphasized
that the type of anesthesia (in the Texas studies, cyclopropane and ether were used), the complexity of the surgery, the time involved, and other comorbidities should
all be taken into consideration. A debate developed in

Each of these arguments can be examined and found

flawed, resulting in a case for at least a review of this line
of thinking.

AGAINST

ll

A patients preoperative hydration state is largely

unknown and the target is unclear. Pulmonary artery
wedge pressures and central venous pressures do not
indicate volume responsiveness. Preoperative fasting for
8 to 10 hours results in a slight decrease in extravascular
fluid. However, intravascular volume is maintained. Putting it in perspective, 1 L crystalloid is the approximate
volume of 4 cups of coffee, an amount that rarely has to
be consumed before 8 AM to avoid dehydration. Also, the
recommendations for fasting guidelines from the American Society of Anesthesiologists now advocate water or
clear fluid intake 2 hours preoperatively.21 Bowel preparation, also targeted as a cause of hypovolemia, is undertaken less frequently. The effenescent drugs used today
mean that the patient is awake and able to take fluids
much sooner. Combinations of antiemetics and better
pain control also have hastened the patients return to
the preoperative state. Hypotension following induction
is more likely related to administration of the anesthetic
drug or to other comorbidities.
Much surgery today is performed using laparoscopic,
robotic, or minimally invasive techniques. Even in the
case of open approaches, irrigation is constant. Temperature control and humidification systems further reduce
insensible losses. Urinary output is frequently low during
periods of stress due to ADH release; giving fluid boluses
is more likely to result in fluid overload than in diuresis.
This begs the question: If the kidneys are already under
stress can they compensate, and if so during what time
period? Preexisting renal problems or administration
of drugs that hamper kidney function may further delay
diuresis, resulting in greater weight gain.
Regarding the argument concerning the third space,
we might ask, if it exists, how do we measure it? There
are ongoing fluid shifts that may peak around 5 hours,
persisting for days.22 Infused fluids may take up to
3 weeks to be excreted. Indeed, the very existence of a
third space has been emphatically rejected.23 The rationale of replacement of blood by 3 or 4 times as much
crystalloid stems from the fast movement of the latter
out of the vascular space, leaving less than one-third to
actually replace the blood. This extravasated fluid moves
rapidly to dependent and soft tissue areas such as the
lungs and gut, with the end result of weight gain.
The argument that we have always done it this way
may be the most difficult to refute. Generally, a minimum
of 20 years is required for proven measures to become
universally adopted, or as Boswell remarked in 1770,
That fellow seems to me to possess but one idea, and
that is a wrong one.

arisen. First, there has been little consensus as to what represents liberal (20 mL/kg/h), standard (5-10 mL/kg/h),
or restrictive (2-5 mL/kg/h) replacement. Most studies have not been standardized for reasonable comparison. Study targets also are open to speculation (Table 1).
Many clinicians are unwilling to change established
protocols. Clear differentiation between major and minor
surgery does not exist.
Perhaps the target that has been most closely associated with adverse outcome is that of weight gain.
Lowell found that several parameters were improved
with reduced crystalloid infusion (Table 2).22

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Study Targets
Weight gain

Postoperative nausea and vomiting

Pain

Tissue oxygenation
Postoperative ileus
Pneumonia

Revision surgery
Wound healing
Infection

Cardiovascular diseases
Hospital stay

Coagulopathies

Table 2. Outcomes With Low Versus

Aggressive Crystalloid Infusion
Crystalloid Infusion

Low: 4 L

Aggressive: 12 L

Weight gain, %

4.7

32

Postoperative
ventilation, d

1.7

Vasopressors, d

2.8

26

ARF, %

17

33

Mortality,%

10

100

d.

Problems With Study Designs

Table 1. Targets Used Without

Standardization

ARF, acute renal failure

Although it might seem simple to arrive at a formula

that could be applied universally, many difficulties have

From reference 22.

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Conflicting data surround the effect of fluid administration on postoperative nausea and vomiting. Liberal
fluid administration especially appears to be beneficial for younger women undergoing short gynecologic
procedures.23
Time to wound healing has been used as a study target. Oxidative killing by neutrophils is essential to tissue repair. Mild hypothermia reduces tissue oxygenation
by a factor of 3. Although supplemental oxygen can
increase availability, this effect is not seen in hypoperfused areas that may be edematous from extravasated
fluid. In patients receiving liberal fluid replacement, the
infection rate and time of hospitalization increased.24-26
Major surgery is not well defined, whether it be by
length or complexity of the procedure. Also, the experience and level of training of the surgeon and the identification of the hospital center as a tertiary care center
are unknown factors.

CARDIAC EFFECTS

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Fluid overload, especially in patients with underlying cardiac disease, may result in congestive heart failure. In 4,059 patients undergoing major noncardiac
surgery, cardiac events occurred 3 times more often
in those with a positive fluid balance exceeding 3.2 L
compared with those with a balance less than 2 L.32
Vretzakis et al studied 192 patients undergoing cardiac
surgery. In group 1 (100 patients), fluids were turned
off after induction.33 Fluids were unrestricted in group
2 (92 patients). Sixty-two patients in group 1 required
blood transfusions compared with 76 in group 2. Also,
the total number of units given in group 1 was 113 and in
group 2 was 176 (P<0.001). The researchers concluded
that hemodilution increased transfusion needs.

Fluids and Body Systems

Due to the rapid rate at which crystalloids leave the

vascular compartment, effects are seen in most body
systems, especially when the fluid balance is markedly
positive. Swelling of the face and neck is often marked
after hours in the prone position, delaying time to safe
extubation.

GASTROINTESTINAL FUNCTION

As fluid accumulates in the gut wall, intraabdominal pressure (IAP) increases, especially in obese individuals in whom resting IAP is elevated. This rise in IAP
results in impaired pulmonary function and decreased
renal perfusion, especially when mean arterial pressure
also is decreased. Increased IAP also stimulates the production of ADH, also contributing to oliguria. As fluid
overload increases, gut wall edema allows the translocation of endotoxins and/or bacteria, leading eventually
to sepsis and multiple organ failure.
Postoperative ileus remains a major problem following abdominal surgery. Several studies have indicated
that fluid reduction and limiting positive fluid balance
to 1 to 2 L contributes significantly to decreased severity and duration of this debilitating complication and
reduces hospital length of stay.27,28

RENAL SYSTEM

Renal demands increase with fluid overload. The

secretion of ADH, aldosterone, and renin after injury or
stress decrease water and sodium excretion, delaying
excretion of an acute saline load by days or weeks. Historically, fluids have been given to prevent renal failure,
although there is no evidence of an association between
oliguria and later renal failure. Moreover, oliguria intraoperatively often does not respond to fluid loading, and
preloading may not prevent later renal failure.34
Chronic kidney disease often is associated with cardiovascular problems. Fluid and electrolyte balance is
deregulated in patients with chronic kidney disease
and excess fluid therapy contributes to postoperative
morbidity and mortality.35 Diuresis forced through fluid
overload does not offer any renoprotection; rather, the
opposite. A rationale for fluid replacement involving
the endocrine system (reninangiotensinaldosterone
vasopressin) may be appropriate with the concept of
a zero-fluid balance policy, according to some recent
studies.35
Although an older concept advised anesthesiologists
to administer large amounts of fluid after kidney transplant to force the new organ to function, recent studies indicate that graft survival was better in patients
in whom the mean arterial pressure was greater than
93 mm Hg and less than 2.5 L fluid was infused.36
Extremity reimplantation and flap survival also are
improved when less fluids are given.37

PULMONARY EFFECTS

34

A N E ST H E S I O LO GY N E WS .CO M

POSTOPERATIVE VISUAL LOSS

Postoperative visual loss after long back surgery and

robotic procedures performed in a steep Trendelenburg
position has been linked with a compartment syndrome
caused by excessive intraoperative fluid administration.
Guidelines advise combining crystalloids and colloids,
giving both in reduced amounts.38

d.

Direct correlation had been shown between the

development of postoperative acute lung injury (adult
respiratory distress syndrome [ARDS]) and liberal fluid
administration.29 Fluid balance is best kept at no more
than +1.5 L. In a study of patients undergoing vascular surgery, respiratory failure occurred in 10% of those
who received more than 6 L of fluid in 24 hours.30 Of
89 patients who had respiratory failure postoperatively,
25 developed ARDS. Intraoperative fluid administration
of 20 mL/kg/h was associated with a 3.8 times higher
adjusted odds ratio of developing ARDS. The ratio was
2.4 times at 10 to 20 mL compared with patients who
received less than 10 mL/kg.31

What To Infuse:
Blood, Crystalloids, or Colloids?
Blood transfusions are rarely indicated in elective
procedures. The American Society of Anesthesiologists
noted that blood should rarely be given if hemoglobin

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is greater than 10 g and almost always when hemoglobin is less than 6 g.39 As such, it is clear that blood
transfusion must be individualized. Rate of loss must
be considered, as should hemodynamic status and
comorbidities.
The most commonly administered crystalloid is
normal saline. However, in a study of nearly 23,000
patients, hyperchloremic metabolic acidosis occurred
in 22% of patients and was independently associated
with increased morbidity and mortality.40 Mortality at
30 days was 3% versus 1.9% in patients who did not have
metabolic acidosis. Hospital lengths of stay increased
by almost 1 day.
Hydroxyethyl starch (HES) is available in several
preparations (Hespan, B.Braun; Voluven, Hospira; Volulyte, Fresenius Kabi). It is subclassified according to
molecular weight and presence of electrolytes. In 2013,
the FDA issued a black box warning that HES was not
to be used in ICUs.41 A Cochrane review of colloid solutions and crystalloid fluids in 78 trials concluded that
resuscitation with colloids did not reduce the risk for
death and that HES increased mortality if the liver or
kidneys were injured.42 Another Cochrane review examined the effects on kidney function in more than 11,000
patients. HES increased the need for renal replacement therapy43; however, a safe volume of HES was not
defined.
The Surviving Sepsis Campaign issued several
guidelines regarding management of patients in sepsis.44 Several trials were reviewedincluding the VISEP
(Efficacy of Volume Substitution and Insulin Therapy
in Severe Sepsis), CRYSTMAS (Effects of Voluven on
Hemodynamics and Tolerability of Enteral Nutrition
in Patients With Severe Sepsis), SAFE (Saline versus
Albumin Fluid Evaluation), and CHEST (Crystalloid
versus Hydroxyethyl Starch Trial) studieswhich did
not show any difference in survival between patients
administered colloids and saline resuscitation.45
However, the conclusions drawn were that although
colloid might increase renal damage in patients with
preexisting kidney failure, extra fluid increased mortality and conservative fluid replacement was indicated. Further recommendations included the use of
vasopressors (norepinephrine, then epinephrine, then
vasopressin) to restore blood pressure rather than fluids and the use of stroke volume to guide therapy.

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Phenylephrine, low-dose dopamine, and steroids probably have a limited place in the care of these patients.44
Following these reviews, many hospital pharmacies
decided that based on the increased cost of synthetic
colloids, they should be banned.
However, a more rational view might be to use both
colloids and crystalloids but in reduced amounts. Colloids maintain vascular volume and maintain hemodynamic status better than crystalloids. A study of
damage-control resuscitation indicated that mortality
increased when greater than 6 L of crystalloids were
given and was reduced when 1 L of colloid was used.46
During normovolemic anemia, a third-generation
tetrastarch (Voluven) maintained tissue perfusion in
an animal model, whereas lung water increased and
oxygen saturation decreased with lactated Ringers
solution.47

GLYCOCALYX

The glycocalyx, a very fragile system, coats the vascular endothelium and acts like a filter. Glycocalyx is the
main constituent of the vascular barrier with selective
protein filtration.48 It can easily be destroyed by surgery,
trauma (central cannulation), ischemia/reperfusion,
sepsis, inflammatory mediators, hyperglycemia, and
acute hypervolemia. As the filter breaks down, destruction causes leukocyte adherence, platelet aggregation,
and edema. Maintaining a physiologic concentration of
plasma protein, particularly albumin, can prevent glycocalyx damage.

Monitoring Fluid Balance

Historically, anesthesiologists have cannulated a

vein, connected the cannula to a flow system, and
infused fluids hoping that the amount given will compensate for unknown losses and maintain hemodynamic stability. A more accurate means of assessing
need and volume responsiveness is based on pulse
pressure variation.49
By looking at arterial pressure waveforms and respiratory excursion, stroke volume and cardiac output
can be established by algorithm. Several commercial
monitors are available, including Vigileo and FloTrac
(Edwards Lifesciences) and LiDCO (LiDCO), among
others. Fluid monitoring has become less invasive with
innovation, such that invasive technologies of the past

Table 3. Comparisons Between Crystalloids and Colloids

d.

Crystalloids

Colloids

Distributed in entire extracellular compartment

Expands plasma volume by amount infused

80% leaves vasculature

More expensive

Infused amount correlates to weight gain

Infection and allergenic responses very low

Causes dilutional coagulopathies in large amounts

? coagulopathies in larger amounts

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have been replaced with less invasive and even noninvasive modalities.
Transesophageal echocardiography also is valuable
in measuring cardiac output and guiding fluid therapy. Real-time direct visualization of cardiac motion is
possible, and allows preemptive maintenance of fluid
requirements. Other monitors incorporate sensors on
endotracheal tubes, again measuring pulse pressure
variation.
For a prompt bedside evaluation, lung ultrasound
may assess pulmonary congestion through the evaluation of vertical reverberation artifacts, known as B-lines.
These handheld devices can easily indicate accumulation of extravascular lung water.50 A study of 55 patients
in septic shock indicated that extravascular lung water
was significantly higher by day 3 in nonsurvivors, as
capillary permeability increased with a higher positive
fluid balance.51
Although central venous pressure continues to be
used as a monitor, it does not indicate circulating blood
volume or vascular responsiveness to a fluid challenge.52 It should not be used to make clinical decisions
regarding fluid administration.

Crystalloids in moderate amounts should be used to

replace urine and insensible losses, the latter usually not
more than 0.5 mL/kg/h. Colloids can replace plasma
deficits, acute blood loss, and protein-rich fluids. The
amount of colloid given should be approximately 1 to 2 L
but should not be administered to patients with kidney
or liver disease. There is no rationale for substituting 1 L
blood loss with 3 to 4 times crystalloid infusion. Blood
should be used sparingly.47 Overnight fasting does not
deplete the vascular space, and the third space does not
exist. The aim is to preserve normovolemia in all body
compartments with a fluid balance as close to zero as
possible.

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What To Infuse

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Conclusion

After decades of research it is clear that current

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