October, 1969
357
Blood Volume and Extracellular Fluid Volume
in Anesthesia
Solomon N. Albert, M.D.*
Washington, D. C.
The art of treating cardiovascular
insufficiency, "shock," is to prevent
it. One of the basic parameters that
plays a major role in maintaining
homeostasis and tissue perfusion is
the amount of blood that fills the
vascular tree.
From every day experience we find
that the accepted standards and indices for the quantitative adequacy
of the circulating blood, such as hemoglobin-gms and hematocrit percents, are not adequate and do not
reflect volume or mass. The laboratory tests that we have habitually
adopted as guidelines denote percentage concentration per unit volume
and not absolute amounts. There is
all the difference in the world between an actual available volume and
just a concentration. A patient may
bleed to death, and yet, the hematocrit will show no changes; in fact,
in some instances, it may rise, which
would normally indicate improvement.
The extracellular fluid volume
(EFC) comprises two fluid spaces
the intravascular and interstitial fluid
*Director, Anesthesiology Research Laboratory,
Washington Hospital Center, Washington, D. C.
Presented at the annual meeting, American
Association of Nurse Anesthetists,
gust 18, 1969.
Chicago, Au-
volume. These two fluid spaces are
in constant equilibrium and are measured simultaneously as one compartment. It is important to differentiate
between the intravascular fluid volume and the interstitial fluid volume
(IFV). The interstitial fluid volume
is a buffer zone through which all
metabolic elements have to cross
either to reach or to leave the cell
and at the same time acts as a reservoir of fluid to back up changes in
the intravascular fluid volume in order to maintain an adequate venous
return and cardiac output.
In recent years several papers have
appeared in the literature advocating
infusion of large quantities of crystalloid solutions, balanced salt solutions,
to replace deficits in blood volume. 1 2
Some investigators prefer infusions of
colloids or macromolecules to sustain
intravascular volume. Specific regimen of replacement has been suggested-replace each ml of blood
with 3-4 ml of crystalloid infusion.
In most instances, these reports have
been established by experiments conducted on animals and the information transposed to humans, regardless
of the physiological age or systemic
conditions of the patient.
Such physiological trespasses have
led Moore and Shires s to publish an
editorial entitled Moderation, which
J. Am. A. Nurse Anesthetists
358
summarizes their concern, as investigators and clinicians, and calls to the
attention of practicing physicians
about judicious fluid and blood replacement in the surgical patient. The
following is the closing paragraph of
this editorial: "Instead of any such
rule of thumb, the surgeon should
carry on with his established habits
of careful assessment of the patient's
situation, the losses incurred, and the
physiological needs in replacement.
The objective of care is restoration
to normal function of organs, with a
normal blood volume, functional body
water and electrolytes. This can never
be accomplished by inundation."
With the patient's physiologic
needs as guidelines in fluid therapy,
actual measurements are necessary to
determine the amount of blood or
fluid the patient needs to reestablish
a normal physiological state, red cells,
Dilution Volume-
tillation counter.* Blood samples
drawn in plastic syringes serve as the
counting container and are inserted
into two geometrically related openings in the counter for radioanalysis. 4
Extracellular fluid volume is measured in a separate system as a sulfate (3"S) space. Sulfur-35, a weak
beta-emitting nuclide, was prepared
in a protein-free filtrate from plasma
samples and measured in a liquid
scintillation system. 5 6
Four 10 ml blood samples were
drawn in heparinized syringes. A premix sample was drawn prior to the
administration of the tracers and
three postmix samples were drawn
following the administration of the
tracers at 15, 30 and 60 minute intervals.
Red cell, plasma volume and extracellular fluid volume are calculated according to the basic equation:
Quanitity of Tracer Administered
Net Final Concentration of Tracer in Sample
plasma, crystalloids, colloids
fluids. This report summarizes
observations on blood volume
ECF measurements in surgical
tients.
and
our
and
pa-
METHOD
A technique was developed whereby plasma, red cell and ECF volume
were measured simultaneously utilizing three radioactive tracers.
Plasma volume is determined by
the extent of dilution of 125I labeled
albumin in plasma and red cell volume with 51Cr labeled red cells.
These two nuclides have different
gamma energies and are measured
simultaneously on whole blood samples by a dual channel scaled analyzer
in a specially designed well-type scin-
NORMAL VALUES
Blood volume varies with metabolic
needs and tissue requirements. Normal values based on body weight do
not reflect accurately predicted red
cell or plasma volume for a particular
individual. Norms calculated as a ratio to body surface are more realistic
and are adaptable to various clinical
conditions. For this purpose the
values established by Hidalgo, Nadler, and Block for blood volume have
been utilized as predicted values. 86
To compute red cell and plasma
volume, a corrected average 40 percent hematocrit has been adopted to
represent the normal distribution of
*Omniwell-Picker-Nuclear
Corp.
359
October, 1969
the red cell volume in the body as a
whole.
B.V. = 0.0234H0.725 MO.423 _ 1.229
(MALES)
B.V. = 0.0248H0.725 MO.425
-
1.954
(FEMALES)
H = Height in centimeters.
M = Body weight in kilograms.*
Since the extracellular fluid compartment comprises both plasma and
interstitial fluid volume, we found
that there is closer correlation between the ECF volume as a ratio to
plasma volume, rather than an arbitrary value equivalent to 20 percent
of body weight. 7 The difference between ECF and plasma volume represents interstitial fluid volume.
FLUID THERAPY
Crystalloid and macromolecular
solutions, when administered intravenously, alter fluid volume in the
two compartments differently - interstitial and intravascular. Onethousand ml of a test solution was administered and the distribution of
fluid between the interstitial and
plasma compartments was compared
before and one hour after the volume
of fluid was administered by measuring plasma and ECF volume.
Balanced salt solution (Ringer's),
when administered intravenously, followed a normal distribution pattern
between the interstitial fluid space
(IF) and intravascular space (IV)
in a 3:1 ratio. From these observations one can infer that to raise intravascular volume by one unit volume,
four units of balanced salt solution
should be given.
Six percent Dextran '75,' a macromolecular solution, when adminis*Tables for male and female values have been
established and are available from Picker-Nuclear
Corp., Publ. No. 60-30.
tered intravenously, was retained in
the intravascular space. In fact, there
was a slight increase in intravascular
volume beyond the amount of Dextran administered. The normal ratio
of distribution of IF:IV did not remain in effect. The difference in response lies in the fact that the oncotic pressure exerted by the macromolecular polysaccharide solution
tends to pull in fluid from the interstitial to the intravascular space;
moreover, the Dextran molecule seems
to bind water. 37
EFFECT OF RESTRICTING
FLUID AND FOOD INTAKE
Control measurements were effected the night before and kept
N.P.O. for 12-18 hours. The following morning and just prior to surgery
measurements were repeated. The patients in this study received no preoperative enemas the night before
or premedication. In all instances
there was a loss of 1000 - 1300 mls
of fluid.
HEMATOCRIT
The hematocrit percent denotes the
volume that red cells occupy in a
unit volume of blood. In effect it is
an index equivalent to concentration
and does not reflect intravascular
volume.
CASE PRESENTATIONS
Two patients with fractured hips developed hypotension upon induction of anesthesia. Case (A) went into mild pulmonary
edema; Case (B) needed blood to re-establish an adequate circulation.
CASE (A): F. V., an 84-year-old female,
5'8", 120 Ibs., B.P. 190/100, P. 76, CVP 9
cms water.
The patient went into hypotension upon
induction of anesthesia with signs and
symptoms of cardiac decompensation.
CASE (B): B. B., a 92-year-old female,
5'4", 121 lbs., B.P. 160/100, P. 80, CVP 11
cms water.
J. Am. A. Nurse Anesthetists
360
(CASE A)
Expected
Normals
Measured
Differences
1464
2016
3480
1750
2600
4350
44.2
+286
Measured
Differences
Red Cell Volume
Plasma Volume
Total Blood Volume
Hematocrit % (Corrected)
+584
+870
(CASE B)
Expected
Normals
Red Cell Volume
Plasma Volume
Total Blood Volume
Hematocrit % (Corrected)
1460
2015
3475
The patient went into hypotension upon
induction of anesthesia with signs of inadequate cardiac output.
HEMOCONCENTRATION
AND DEHYDRATION
PREOPERATIVELY
Patients with a deficit in ECF have
no reserves to hemodilute or compen-
1000
1900
2900
38.4
-460
-115
-575
WATER-LOGGING THE PATIENT
POSTOPERATIVELY
With the liberal use of balanced
salt solutions there is a tendency to
overload the patient with fluid with
no apparent reflection of overload on
the CVP.
CASE (D): A female, 36-year-old, 5'6",
sate in the event of vasodilation or
272 lbs., B.P. 180/110, P. 130, underwent
blood loss.
surgery for lysis of abdominal adhesions.
Three days postoperatively she developed
tachycardia, dyspnea and looked distressed.
Her CVP was 3 cms water and x-ray of the
chest was negative. She gained 6 pounds
during the three days in the hospital while
on fluid therapy.
CASE (C): J. B., a 63-year-old male, 6',
185 lbs., developed hypotension upon induction of anesthesia. As a result, surgery
was postponed until a later date. After
proper hydration over a period of two days,
he was again anesthetized and his blood
pressure remained stable throughout the induction period of anesthesia and during the
whole surgical procedure.
This patient, although normovolemic, had
a 2.3 liter deficit in ECF.
Table 1 presents her findings. Column A
presents expected values according to body
weight, corrected by a 10 percent reduction
for obesity. Column C presents expected
values obtained according to body surface,
as a 4.5:1 ratio for females. Column B pre-
(CASE C)
Red Cell Volume
Plasma Volume
Total Blood Volume
Hematocrit % (Corrected)
Plasma Protein (gms%)
Plasma Osmolality (mOs/Kg)
Extracellular Fluid Volume
Total ECF (Equilibrated-60-min-Urine)
Expected
Normals
Measured
2220
3330
5550
2350
2620
4970
48.8
16.0 L
7.3
294
13.7 L
13.6 L
361
October, 1969
TABLE I (CASE D)
TWO DAYS POSTOPERATIVE LYSIS OF ADHESIONS
(FEMALE, 272 lbs.)
Pulse Rate 130, B.P. 180/110, C.V.P. 3 cms. H 2 O, Urine Output 50 ml/hr
*
**
Values For
250 Ibs.
(A)
2750
4125
6875
44.0
40.0
0.91
290-300
7-8
22.7
Re d Cell Volume (ml)
Plaasma Volume (ml)
To tal Blood Volume (ml)
Hematocrit %
Hematocrit % (Body)
Fcell Ratio
Plasma Osmolality (mOs/Kg)
Protein (gms %)
E.C.F. Volume (Liters)
Total Available E.C.F.
*Weight corrected for obesity.
**Values calculated according to body surface.
E.C.F. = 4.5 X expected Plasma Volume (Females).
sents measured values. One can note the
marked measured overload in extracellular
fluid volume (25 L - Column B) compared
to expected values based on body surface
(Column C - 16.2 L).
In this patient an infusion of 6 percent
Dextran '75' was considered and following
the administration of 500 ml her general
condition improved. Her pulse rate dropped
to 90 beats per minute, her dusky cyanotic
color disappeared, venous pressure rose to
8 cms water and her urine output increased
from 50 ml per hour to 150-200 ml per hour.
DISCUSSION
One is often confronted by a divergence of opinion when reviewing the
literature and finding continuous
changes in attitudes, concepts and
even "revolutions" in fluid therapy.
In some instances, such reports eminate from the same authors at different time intervals or from rival institutions. For example, we find that in
one paper the authors have no use
for blood volume measurements."3 A
few years later, the same senior author changes his mind to state that
the only rational way to follow replacement therapy is by blood volume measurements.89 Most of the
changing patterns are basically due
Measured
Values
(B)
2306
3877
6183
45.3
37.3
0.823
272
5.7
18.0
25.0
Values For
Ht. & Wt.
(C)'
2300
3600
5900
16.2
to two factors: (1) poor methodology
and understanding of what and how
measurements are performed and (2)
applying physiological concepts and
interpretation to measured values.
From continued experience with
blood volume measurements over the
n t 14 years and ECF measurements
for the past 4 years, we have come
to report on numerous occasions two
important observations: (1) results
of experiments conducted in lower
animals are not necessarily applicable
to all species8 and specifically to man
and (2) whenever volume measurements are performed, applying the
dilution principle, blood sampling
should be drawn at the time the tracer has been thoroughly mixed with
the volume or medium being measured and corrections should be allowed for the quantity of tracer that
is eliminated from the space being
measured during the period denoted
as mixing or equilibration period.
This applies to all dilution-measuring
techniques, and in this instance, when
measuring red cell, plasma and extra.
cellular fluid volume. 10, 11
362
What is a normal value? This is a
debatable question and, here again,
sound judgement is important. Physiological needs are the basis for determining values; nevertheless, guidelines are needed. Different body parameters have been utilized as a basis
to establish normal expected values
for blood volume. 12 Norms based on
body weight alone presume that body
composition of the patient is within
normal limits
the distribution of
the elements that constitute body
1 2 13
mass - fat and lean body mass. ,
This is far from being so: wide variations in fatty tissue will affect expected values. For this purpose, normal expected values for blood volume
determined on the basis of body surface and ECF volume, as a function
of plasma volume, seem to be realistic
and fit the wide variations one meets
in a hospital population.
Although the relationship of plasma volume to ECF volume seems to
remain fairly constant under normal
physiological conditions, in our
studies, we were unable to predict
the ECF volume from the measured
plasma volume nor could we reconcile
the figures by introducing correction
factors to account for deviations in
osmolality or protein content of plasma to equate the actual measured
values. We have observed that in
some patients with a normal blood
volume that the ECF volume was
contracted, while in others the reverse situation prevailed.
The normal transfer of fluid from
the interstitial space to the intravascular space, following loss of vascular
tone or hemorrhage, takes effect in a
matter of seconds. These physiological
responses tend to maintain intravascular blood volume and adequate venous return. When the interstitial
J. Am. A. Nurse Anesthetists
fluid volume is contracted, this response is greatly delayed, or even fails
to take effect. There must be a sufficient quantity of free interstitial fluid
and patent capillaries in the circulatory circuit to permit fluid transfer.
It is important to realize that some
patients may reach the operating
table in a state of dehydration with
a normal hematocrit and blood volume and respond adversely to anesthesia and blood loss. Proper preoperative hydration, 14' 1 especially in
the chronically ill and geriatric patient, is important. An adequate ECF
volume will act as a safeguard for
maintaining intravascular volume in
case of blood loss or vasodilation resulting from induced depression of the
sympathetic autonomic nervous system and central nervous system.
We find in the literature that we
are going through a period of massive
fluid replacement for the purpose of
circumventing the use of blood. We
read that an emperic hematocrit
range is the determining factor as to
when blood should be given and gradually the term "octane" is added to
the "gallons""' of fluid given, indirectly inferring that the red cell mass
should be respected. The real crux
of the discussion appears in a final
statement: "..
. or whatever appears
a reasonable physiological level."' 7
Balanced salt solution tends to
equilibrate between the interstitial
and intravascular compartments in a
3 or 3.5:1 ratio. To raise the intravascular volume by one unit volume,
one should administer approximately
4 unit volumes of fluid. This is where
the magic figures of 3-4 ml replacement for each ml of blood loss came
about. It is obvious that such a regimen of replacement will result in
overhydration without any visible
signs of overload or edema.18
363
October, 1969
The deleterious effects of overhydration are quite apparent when one
takes into consideration the basic
principles that govern diffusion and
exchange of nutrients, gases and metabolites to and from the bloodstream
with the tissues. It takes longer for
matter to diffuse between two points
when the distance between the cells
and the nutrient vessel is increased 19
due to accumulation of fluid in the
interstitial space, and as a result, tissues may be damaged. 20 Takaori, et
al, 21 noted, at autopsy, that following
infusion of large volumes of crystalloid solutions to dogs in hemorrhagic
shock, there was effusion of fluid within body cavities. It is interesting to
note that the proponents of fluid therapy now are starting to think in terms
of diffusion and the effect overhydration may have on metabolic processes. 16
22
8
In view of these observations, ' 2 '
expanding intravascular volume
and improving venous return by administering large volumes of balanced
salt solution would not seem to be
totally justified. Humans who survived surgery with a 3-4 gms percent
hemoglobin or a 10 percent hematocrit and animals that have survived
experiments whereby all the blood
was replaced by various fluids have
been reported in the literature. One
should realize that these physiological
trespasses are only possible at the
expense of an increase in cardiac output to compensate for a deficit in
oxygen carrying capacity of blood 26
with a steady accumulation of acidosis. The red cell is responsible for
almost 85 percent of the carbon dioxide transport.
24,25
It is questionable whether the average hospital patient can tolerate the
stress of surgery, the depressant ef-
fects of anesthetic agents on the central nervous system and myocardium
and still be able to maintain an accelerated cardiac output for an appreciable extent of time. Hardaway, et
al,2 7 in their studies on shock recommended that the red cell mass should
be maintained within normal limits
at all times while trying to re-establish venous return and circulatory
dynamics.
Two recent cases were presented
to prove that we could "almost live
without red cells" by citing a case
which survived. 16'2 8 Needless to say,
the cases cited were young individuals
and in one case, an auxiliary measure
(hyperbaric oxygen) was employed to
achieve this miracle.
It is important to remember that
the ideal hematocrit, with which nature has provided us, is between 35-45
percent. This ratio of red cells to
plasma should be respected. The Iationale for maintaining a near-normal
hematocrit is based on numerous
physical and physiological considerations. Oxygen delivery per unit of
time and volume is maximal when the
hematocrit is 40 percent. Animals
with a normal hematocrit survive
longer when subjected to traumatic
shock. 2 0 ' 0,31,32 The hematocrit is
responsible to a great extent for the
viscosity of blood and the rheology
of blood is altered with a low or high
hematocrit. 8s
Under anesthesia, the signs and
symptoms of overload and underload
are difficult to determine. Figures 1
and 2 illustrate the vicious cycle encountered in both situations.
Central venous pressure, a physiological monitor for venous return,
measures intracardiac resting pressure
and, according to Starling's Law, 84
there is a direct response curve: CVP
J. Am. A. Nurse Anesthetists
364
versus cardiac output. This response
curve does not always hold true and
is shifted to the right with age, myocardial depression and sympathetic
blockade. It is important to realize
that central venous pressure, as a
monitor, is a combination of three
major factors and can be expressed
in its most simple form by the following equation:
Effective Blood Volume
Central Venous Pressure =---
Cardiac Function + Vascular Capacity
Incomplete Emptying
TACHYCARDIA --
Cardiac Chambers
Venous Return -- > Cardiac Volume -> Cardiac Output
>Increased
Reduced--
Increased
MYOCARDIAL
FAILURE
HYPERVOLEMIA -
and
Stagnant Hypoxia --
- Reflex Arteriolar -
Venous
CEREBRAL
EDEMA
Constriction
Engorgement
> Pulmonary -- Gaseous Exchange -- Hypoxemia
Reduced
Congestion
Negative Pressure -*PULMONARY
EDEMA
Intrapulmonary
Figure 1. Cycle of events in hypervolemia.
TACHYCARDIA
Venous Return
-4
Cardiac Filling -
Reduced
Cardiac Output -
Coronary Flow
Reduced
Reduced
Reduced
--
MYOCARDIAL
FAILURE
HYPOVOLEMIA -* Vasoconstriction -
Tissue Perfusion -
Anemic Hypoxia -
Pulmonary Circulating -* Pulmonary Dead Space Increased
Blood Volume Reduced
and
CEREBRAL
HYPOXIA
Reduced
Gas Exchange
Reduced
--
Hypoxemia
1
T
POSITIVE PRESSURE
INTRAPULMONARY
Figure 2.
Cycle of events in hypovolemia.
Thus, the value of the CVP is
affected by three major parameters.
Furthermore, other incidentals, which
may be in effect during anesthesia or
surgery, such as intra-abdominal
splinting, positive intrapulmonary
pressure, venous obstruction, etc., will
also affect CVP readings. Central ve-
October, 1969
nous pressure has much more significance if one parameter, blood volume,
is known and relative changes in the
other two parameters could, therefore,
be inferred.
Regarding the significance of the
volume of blood and toxicity of drugs,
it is appropriate to recall a comment
we made some twelve years ago about
the relationship of blood volume and
the action of drugs on various receptor organs. One of the many factors
that determines the action of the drug
on the receptor area is the concentration of the drug. The concentration
is inversely proportional to the volume of the solvent or vehicle, blood
and fluids in the extracellular fluid
space. Consequently, for a given dose
based on body weight, one may produce different effects in two individuals having the same weight but who
are of different body and fluid composition. Thus, the toxicity of drugs
should preferably be based on concentration which is dose and volume
related rather than on weight alone.
It is gratifying to note that Stone
and Brown of the National Institutes
of General Medical Sciences" 5 have
recently expressed similar views on
the toxicity of drugs.
In conclusion, we refer to the opening statements and the comments
made by Moore and Shires: ". .. re-
store physiologic needs." This entails
an understanding of physiological processes and methods in measurement.
In our present age of technology we
have graduated from emperic values
and relative values to actual quantitation. We no longer should be satisfied
by saying that ventilation is adequate
or circulation is sufficient unless they
can be substantiated by quantitative
measurement of specific parameters.
This should also apply to circulating
blood volume. And, "the art of treat-
365
ing shock is prevention" can only
be achieved by proper preparation of
the patient who is undergoing the
ordeal of anesthesia or surgery.
It is true that we can live with
marked deficits in red cell massprovided we are physiologically in
"balance." Anesthesia does put the
organism in a state of "off balance"
and it is wiser to know beforehand
what we are dealing with than to use
emperic trial methods and see if the
patient survives. The only rational
manner to determine the amount and
nature of fluid, for replacement purposes in a particular case, is by volume measurement, crystalloid solutions to correct a deficit in interstitial
fluid volume, colloidal or macromolecular solution to correct a deficit in
intravascular volume 7 ' 40 and packed
cells for a deficit in red cell volume.
SUMMARY
Proper hydration and blood replacement are important in the management of problem surgical patients.
Volume disorders are best monitored
by actual volume measurements
rather than by the concentration of
the various elements that constitute
blood or other indirect indices such
as blood pressure, heart rate, oxygen
tension, pH, urine output, etc., which
are often unpredictable.
Measuring blood volume and ECF
volume is important in determining
the quantity and nature of replacement necessary in the management
of the surgical patient.
The techniques for measuring plasma, red cell and ECF volume simultaneously by the dilution method,
utilizing three tracers, are practical
and applicable in clinical practice.
These measurements will reduce morbidity and mortality when performed
J. Am. A. Nurse Anesthetists
366
on the seriously ill, chronically ill,
geriatric and complicated surgical
patient.
Fasting deprives patients of a substantial volume of fluid. This loss of
fluid preoperatively may play an im-
portant role in maintaining an adequate circulation when the patient is
subjected to the insult of anesthesia,
surgery and blood loss.
ACKNOWLEDGEMENT
I am greatly indebted to Elenore Zekas and
John B. Mann, II, for compiling this material
and for their able technical assistance.
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