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KEYWORDS
Endothelial glycocalyx Hypovolemia Dehydration Crystalloid Colloid
End points of resuscitation
KEY POINTS
The discovery of endothelial glycocalyx has dramatically changed the understanding of
vascular permeability, and should be considered when developing fluid therapy plans.
Dehydration and hypovolemia are terms to describe fluid derangements, and each must
be addressed uniquely to maximally benefit patients.
Synthetic colloids have many potential benefits but appropriate patient selection is vital for
maximizing patient safety while using them.
INTRODUCTION
Total body water (TBW) comprises 60% of body weight.1 The 2 main fluid compart-
ments in the body are the intracellular fluid (ICF) and extracellular fluid (ECF). The ICF
compartment comprises approximately 60% of TBW, and the ECF compartment
makes up the other 40%.1 ICF is found inside the bilayered cell plasma membrane,
and is in osmotic equilibrium with the ECF. The ECF is divided into 3 components:
the interstitial compartment, the intravascular compartment, and the third space.1
The interstitial compartment is the fluid space that surrounds cells and allows move-
ment of ions, proteins, and nutrients across cell membranes. Approximately 75% of
ECF is located in the interstitial compartment and is continuously turned over and recol-
lected by the lymphatic vessels. The intravascular compartment comprises approxi-
mately 25% of the ECF, and fluids do not normally accumulate in the third space.1
Movement of fluid across capillary walls is essential for maintaining a continuous ex-
change of oxygen and carbon dioxide between the bodys cells and the blood supply.
There is a continual exchange between fluid compartments in the body, which
provides nourishment to cells and removes waste products. Hydrostatic pressure and
oncotic pressure work against each other to produce this fluid movement. Hydrostatic
pressure is the pressure exerted by any fluid in a confined space. If fluid is in a
container, there will be some pressure applied to the wall of that container. Picture
a column-shaped container. The pressure pushing against its wall is greater at the bot-
tom than at the top partly because of the force of gravity. Capillaries are the equivalent
of a column-shaped container turned on its side. As fluid moves through a capillary,
hydrostatic pressure causes fluid to move into the interstitial compartment. This
movement also means that the hydrostatic pressure decreases as the blood moves
from the arteriolar to the venous end of the capillary. The fluid pushed out through
the capillary wall by hydrostatic pressure is called filtrate.
Blood contains plasma proteins that displace some water in blood, and less water in
the intravascular compartment creates a concentration gradient between the intravas-
cular and interstitial spaces. The osmotic pressure generated by plasma proteins is
called oncotic pressure or colloid osmotic pressure (COP). Plasma proteins pull water
into the intravascular compartment, whereas the force of osmosis equalizes the
amount of water in the intravascular compartments and the interstitial fluid.
ENDOTHELIAL GLYCOCALYX
Extracellular edema forms when excess fluid accumulates in the interstitial compart-
ment; this accumulation occurs as a result of either abnormal leakage from the intra-
vascular compartment to the interstitial compartment or a failure of the lymphatics to
return fluid from the interstitium to the intravascular compartment, or both. Altered
capillary filtration occurs because of an increased capillary filtration coefficient,
Fluid Therapy 3
CRYSTALLOIDS
Crystalloids contain variable amounts of electrolytes, water, and dextrose, and may be
characterized by tonicity and their effect on acid-base status. Crystalloids are used
either to replace sodium loss or maintain the status quo. Replacement fluids contain
sodium at concentrations similar to normal plasma (approximately 140 mmol/L),
whereas maintenance fluids have sodium concentrations similar to normal total
body concentration (70 mmol/L). Replacement crystalloids and maintenance crystal-
loids may also be classified as isotonic or hypotonic, respectively. Approximately one-
third of administered isotonic replacement fluid remains in the intravascular space and
two-thirds enters the interstitial space.
Common examples of replacement fluids are lactated Ringer solution (LRS),
Plasma-Lyte, Normosol-R, and 0.9% sodium chloride. The first 3 have potassium con-
centrations similar to plasma and contain a lactate, acetate, or gluconate buffer,
respectively, to maintain a physiologic pH. Animals normally lose potassium through
urine, and this loss is augmented during aldosterone release and sodium conserva-
tion. Accordingly, replacement fluids should be supplemented with potassium when
used long term. Normal saline contains no potassium or buffers, and is the fluid of
choice for hypercalcemia given that it contains no calcium. Normal saline may exac-
erbate volume overload, metabolic acidosis, heart disease, and hypertension.
Maintenance fluids are simply designed to replace daily sodium losses, and are
appropriate for long-term administration. Dextrose is commonly supplemented to
approximate plasma tonicity and prevent hemolysis. These lower-sodium fluids do
not stay in the intravascular space, do not meaningfully expand blood volume, and
should not be used for volume resuscitation.
Hypertonic saline may be used for rapid intravascular volume expansion, because it
pulls fluid primarily from the interstitial compartment. Volume expansion is short lived,
because the sodium redistributes throughout the extracellular compartment quickly.
Hypertonic saline is available as both 7% to 7.5% and 23% solutions; the 23% solu-
tion must be diluted before administration. Do not administer hypertonic saline faster
than 1 mL/kg/min to avoid vagally mediated bradycardia and potential cardiopulmo-
nary arrest.
COLLOIDS
Colloids are large molecules that remain in the intravascular space because of the
Gibbs-Donnan equilibrium. Smaller volumes compared with crystalloids are required
to achieve intravascular expansion. When used appropriately, these fluids are less likely
to induce hemodilution, hypoproteinemia, extracellular edema, and fluid overload.8
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so 1-time use is recommended because of the potential for antibody formation and
subsequent immunologic reactions. The HBOCs cause the patients mucous mem-
branes, sclera, and urine to turn red or yellow, and affect colorimetric diagnostic blood
and urine tests. The availability of HBOCs is currently extremely limited because of
decreased commercial production.
With progressive hypoalbuminemia, COP decreases, which allows fluid to shift from
the intravascular space into the interstitial space and potentially cause edema if tissue
safety factors are overwhelmed. Serum albumin has been used in critically ill patients
to help support blood pressure and to aid in the treatment of significant hypoalbumi-
nemia. At present, 2 types of serum albumin are available for administration: human
serum albumin (HSA) and canine serum albumin (CSA). HSA has been used success-
fully in both dogs and cats, but both acute and delayed immunologic reactions have
been documented.11,12 This product is available as a solution, and may be infused
in 4-hour aliquots over 4 to 72 hours. CSA is available as a lyophilized powder for
reconstitution with sterile saline. Concentrations currently range from 4% to 25%
and do not contain any preservatives. Thus CSA must be administered within 6 hours.
Infused albumin remains in the intravascular space for 24 hours, and close monitoring
for fluid overload is recommended. The reported doses for both HSA and CSA range
from 100 mg/kg to 6.3 g/kg.
ROUTE OF ADMINISTRATION
Common routes of fluid administration in dogs and cats include intravenous (periph-
eral, central, or peripherally inserted central catheters), subcutaneous, enteral, intra-
osseous, and intraperitoneal. For patients with hypovolemia, an intravenous
catheter with short length and large bore diameter is recommended. If venous access
is not immediately possible, the intraosseous route may be used until vascular access
is achieved. The subcutaneous route is not appropriate for hypovolemic patients
because peripheral vasoconstriction severely limits absorption. With mild dehydra-
tion, the subcutaneous route may suffice. Dextrose should not be delivered
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subcutaneously, and potassium delivered via this route may cause discomfort. Sub-
cutaneous fluids are frequently administered at 10 to 20 mL/kg per site. Enteral water
supplementation is commonly used in the intensive care unit.
When determining the appropriate fluid volume and rate of administration, the
following questions should be asked:
Is the patient hypovolemic?
Is the patient dehydrated?
What are the patients daily physiologic requirements?
Are there any ongoing losses? If yes, how much?
By answering these questions, the clinician is addressing the 3 major components
of fluid administration: resuscitation, replacement, and maintenance. During fluid
resuscitation, intravascular volume is restored with intravenous fluid administration.
Hypovolemic patients require fluid resuscitation, and the volume infused depends
on the stage of shock (Table 1).
Stabilizing interventions for patients with shock should target EOR, particularly:
Restoration of normal vital signs
Normalization of abnormal mentation
Restoration of normal blood pressure (systolic >8090 mm Hg)
Normal serum lactate concentration (<2.5 mmol/L)
Central venous oxygen saturation (ScvO2) greater than 70%
Packed cell volume (PCV) greater than 25%
Urine output (UOP) greater than 1 mL/kg/h
Pulse oximetry greater than 93% at a fraction of inspired oxygen of 21%
Central venous pressure (CVP) of 5 to 10 cm H2o
Initially, for hypovolemia, an isotonic crystalloid should be administered at a shock
rate (dogs, 20 mL/kg, up to 90 mL/kg; cats, 10 mL/kg, up to 4050 mL/kg) over 15 mi-
nutes, and then EOR should be reassessed.13 With hypoproteinemic hypovolemia,
administration of a synthetic colloid may be appropriate; these fluids should be deliv-
ered over 20 to 30 minutes (dogs, 5 mL/kg, up to 20 mL/kg; cats, 25 mL/kg, up to
10 mL/kg) and EOR should be reassessed after each bolus.13
After effectively addressing hypovolemia, an appropriate fluid therapy plan must
address dehydration, daily physiologic requirements, and ongoing losses. Isotonic
crystalloids should be used for fluid replacement (correcting dehydration and replen-
ishing ongoing losses). Clinical signs of dehydration include tacky mucous mem-
branes, decreased skin turgor, enophthalmia, and prolonged capillary refill time.
The volume required to correct dehydration is the product of the estimated percentage
of dehydration and body weight in kilograms, and should be delivered over
Table 1
Clinical signs associated with stages of shock
80 BW0.75 5 mL/d
where BW is body weight. Both isotonic and hypotonic crystalloids may be appro-
priate and the ultimate choice of crystalloid type should be determined based on
the patients volume status and serum electrolyte concentrations. Fluids should al-
ways be titrated to effect. Fluid therapy is commonly used during the perianesthetic
period. Potential benefits of providing fluids to healthy patients during the perianes-
thetic period include cardiovascular support, the ability to counter potential
anesthesia-induced adverse reactions (eg,: vasodilatation), and the correction of
normal ongoing losses.
HYPOTENSIVE RESUSCITATION
The profound inflammation associated with SIRS and sepsis induces vascular leakage
secondary to endothelial dysfunction. Subsequently, fluid extravasation results in
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relative and absolute hypovolemia, hypoperfusion, and possibly septic shock. Fluid
therapy is the mainstay of resuscitation of patients with SIRS, sepsis, severe sepsis,
and septic shock. In 2001 the concept of early goal-directed therapy (EGDT) was intro-
duced, which is a specific algorithm for managing patients presenting with septic
shock.18 Aggressive fluid resuscitation to achieve specific end points was recommen-
ded. In-hospital mortality was 30.5% in the EGDT group and 46.5% in the standard
therapy group, a finding that was statistically significant.18 Patients in the EGDT group
also had significantly higher mean ScvO2, lower lactate concentration, lower base
deficit, and higher pH than patients assigned to standard therapy.18 Subsequently,
clinical guidelines, the Surviving Sepsis Campaign (SSC) guidelines, for the manage-
ment of human patients with severe sepsis and septic shock were developed and are
routinely updated.19,20
Aggressive initial fluid resuscitation is considered the cornerstone of initial therapy
for human and veterinary patients with severe sepsis and septic shock. The SSC
guidelines recommend immediately instituting volume resuscitation in affected people
according to a specific protocol. Within 3 hours of presentation, clinicians should:
Measure lactate concentration
Obtain blood cultures before administration of antibiotics
Administer broad-spectrum antibiotics
Administer a crystalloid (30 mL/kg) for hypotension or hyperlactatemia
(4.0 mmol/L)
If patients have persistent hypotension (MAP <65 mm Hg) after initial fluid resusci-
tation or if they had an initial lactate concentration greater than or equal to 4.0 mmol/L,
further assessment is warranted. Clinicians may either repeat a focused examination
or evaluate 2 of the following:
CVP
ScvO2
Dynamic assessment of fluid responsiveness (ie, passive leg raise test)
Bedside cardiovascular ultrasonography
Vasopressors should be used within 6 hours for those patients with persistent hypo-
tension despite aggressive initial fluid resuscitation. Transfusion with packed red
blood cells to maintain PCV greater than 30% and vasopressor therapy may also
be helpful. Serial monitoring of perfusion parameters, particularly lactate, should be
pursued, and lactate concentrations should be normalized as rapidly as possible.
To date, the optimal composition and volume of resuscitation fluid are not known in
human or veterinary patients. Since the EGDT study, subsequent investigations have
been conducted to document potential benefits. Results have been mixed depending
on the patient population studied. The Australasian Resuscitation in Sepsis Evaluation
(ARISE) study in 1600 human patients with early septic shock failed to show a reduc-
tion of all-cause mortality at 90 days despite using EGDT interventions.21 Prospective
randomized controlled trials have not been conducted in veterinary medicine. Thus,
the ideal guidelines for resuscitation of veterinary patients with SIRS, sepsis, severe
sepsis, and septic shock are similarly unknown at this time.
FLUID ADDITIVES
MONITORING
With the provision of fluid therapy comes the requirement to monitor the patients
response to that intervention. Multiple parameters may be readily evaluated to assess
the patients response to prescribed fluid therapy. Common physical variables are:
Body weight: the change in a patients body weight is a noninvasive method for
evaluating fluid gain or loss on a day-to-day basis. Because several variables
predispose this measurement to errors, clinicians are encouraged to measure
patients body weight at the same time of day using the same scale to minimize
variability.
Mucous membranes: dehydrated patients frequently have dry mucous mem-
branes. Thus, a change from tacky mucous membranes to moist ones commonly
indicates a positive response to fluid therapy.
Capillary refill time (CRT): patients with poor perfusion typically have prolonged
capillary refill times, and poor perfusion frequently arises from hypovolemia. An
improving CRT suggests improved perfusion.
Skin turgor: evaluation of the patients skin turgor or degree of skin tenting has
historically been used to assess various degrees of dehydration. Overhydrated
patients are commonly described as having a gelatinous feeling to their skin
and may readily develop gravity-dependent edema. Geriatric patients and under-
weight patients have decreased turgor normally and overweight or obese pa-
tients commonly have increased skin turgor. Thus, evaluation of skin turgor in
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CONTROVERSIES
Synthetic Colloids
Measurements of urine specific gravity should be made before administration of
certain HESs, particularly hetastarch. Hetastarch molecules less than 50 kD are freely
filtered by the glomerulus, and falsely cause high refractometer readings. Total solids
Fluid Therapy 11
(TS) measurements via refractometry are also affected, because hetastarch yields a
value of 4.5 g/dL alone and 3.0 g/dL when mixed 1:1 with a hypooncotic diluent.23
Thus, TS measurements in patients receiving a hetastarch as a constant-rate infusion
for more than 24 hours tend to trend toward a range of 3.0 to 4.5 g/dL. Thus, direct
measurement of serum albumin or COP in these patients provides a more accurate
assessment of oncotic status.
HESs have been recommended for resuscitation in patients with hypoalbuminemia
or sepsis given their ability to induce a more rapid and lasting circulatory stabilization
than crystalloids. The use of HES has been called into question and advised against in
some human patients considering various adverse reactions reported in randomized
clinical trials, most notably coagulation alterations, immunologic reactions, increased
incidence of acute kidney injury (AKI), and need for renal replacement therapy.24 An
increased incidence of adverse outcomes, including AKI and death, occurred in
dogs in the intensive care unit (ICU) that received 10% HES compared with a general
ICU population. Randomized controlled clinical trials evaluating the safety of HES in
both dogs and cats are needed, and clinicians should limit the use of HES in patients
with preexisting renal injury or those at risk for renal tubular injury.25
HESs have been implicated in inducing several coagulation abnormalities in various
patient populations, including dogs and cats. The potential to induce a coagulopathy
must be considered when contemplating the use of HES in septic patients. Both
in vitro and in vivo studies in dogs and cats have documented adverse effects on
platelet function and coagulation.2628 However, the clinical relevance of these studies
is not known, and clinical prospective investigation is warranted. At this time, use of
HES in patients with preexisting coagulation abnormalities is cautioned.
Although immediate and delayed immunologic reactions to HES have rarely been
documented in humans, only anecdotal reports of such reactions exist in veterinary
medicine to the authors knowledge.
Albumin
Although human and canine albumins have significant amino acid homology, some
important differences exist between the two molecules, thus raising concerns over an-
tigenicity. A recent retrospective study of 64 dogs that received HSA did not identify
any significant problems.29 Nevertheless, the current recommendation is that clini-
cians should not administer HSA again more than 1 week after the initial dosing
because of the risk of antigenicity. Both HSA and canine albumin are hyperoncotic so-
lutions, and thus fluid overload and overhydration are possible.
SUMMARY
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