See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/14708078

Hypovolemic shock.

Article  in  Critical Care Clinics · May 1993

DOI: 10.1016/S0749-0704(18)30195-7 · Source: PubMed

CITATIONS READS

13 3,613

4 authors, including:

Lakshman Sehgal
University of Illinois at Chicago
92 PUBLICATIONS   1,870 CITATIONS   

SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Use of a gutless adenoviral vector in cardiovascular , peripheral vascular occlusion, renal transplantation and cancer treatment. Looking for clinical collaborators. View
project

All content following this page was uploaded by Lakshman Sehgal on 03 June 2014.

The user has requested enhancement of the downloaded file.

 CIRCULATORY SHOCK 0749-0104/!3 w.00 ;.26

HYPOVOLEMIC SHOCK
Steven A. Gould, MD, Lakshman R. Sehgal, PhD,
Hansa L. Sehgal, BS, and Gerald S. Moss, MD

- PHASE 1: INTRAVASCULAR VOLUME EXPANSION

The infusion of fluid is the fundamental treatment of acute hypo-

volemia. All commercially available intravenous fluids (Table 1)have in
common the ability to replenish the circulation once appropriate in-
travenous access is established. The challenge inherent in the use of
these solutions is to promote the prompt and adequate restoration of
cardiac filling pressures to optimum values without compromising
ventilation secondary to fluid overload. Regardless of the fluid used for
resuscitation, it therefore is imperative to use physiologic endpoints to
gauge the initial response to treatment and to adjust the therapy to meet
the individual needs of the patient.
Controversy surrounding the appropriate intravenous solution to
use in the management of hemorrhagic shock centers on their ultimate
distribution following intravenous administration, which, in turn, de-
pends on their composition. In order to understand their fate, it is
necessary to review the physiology of normal fluid exchange.

Normal Fluid Dynamics

On examination of the fluid distribution in adults, approximately

two thirds of the total body water is intracellular; the remaining one-
third in the extracelluIar compartment is distributed between the in-
terstitial and intravascular spaces at a ratio of 3: 1. The movement of

From the Department of Surgery (SAG) and Surgical Research (LRS, HLS), Michael Reese
Hospital and Medical Center; and University of Illinois and College of Medicine (SAG
and GSM), Chicago, Illinois

CRITICAL CARE CLINICS

VOLUME 9 NUMBER 2 . APRIL 1993 239
Table 1. CHARACTERISTICS OF FLUIDS USED FOR RESUSCITATION
Sodium Hypertonic
Chloride Ringer's Saline Solution Albumin Hetastarch Dextran-70 Fresh Frozen
(0.9%) Lactate (3%) (5%) (6%) (6%) Plasma

Sodium (mEqlL) 154 130 513 1 30-1 60 1 54 154 1 70

Chloride (mEq/L) 154 109 513 130-160 154 154 100
Osmolarity 310 275 1025 310 310 310 300
(mOsrn1L)
Oncotic pressure 0 0 0 20 30 60 20
(mm Hg)
Lactate (rnEqlL) 0 28 0 0 0 0 4
PH 5.0 6.5 5.0 6.9 5.5 3.0-7.0 Variable
Cost' (liter) $ 0.60 $ 0.75 $ 0.84 $80.0 $ 76.0 $ 25.0 $120.0
'Prices reflect costs charged to our hospital, as of 1990. Patient charges vary from institution to institution.
 HYPOVOLEMIC SHOCK 241

fluids between the major compartments of the body is governed by the

number of particles, or osmoles, in solution.
Under steady-state conditions, the osmolality of the intracellular
and extracellular compartments is maintained between 280 and 300
mOsm by the sodium-potassium adenosine triphosphatase pump. In
contrast, the distribution of fluid between the intravascular and ex-
travascular spaces, as defined by the Starling equation, depends on the
transcapillary hydrostatic and oncotic pressures, and the relative per-
meability of the capillary membranes that separate these spaces.
Although controversy exists regarding the absolute values of these
forces, the net effect is a small efflux of fluid into the interstitium that is
returned to the circulation via the lymphatics.

- Crystalloid Solutions

The osmolality of a solution depends on the number of particles in

solution. The functional osmolality, or tonicity, of a solution is defined
by the ability of the particles in solution to permeate cell membranes.
Accordingly, isotonic solutions such as 0.9% sodium chloride and h n g -
er's lactate freely equilibrate between the intravascular and interstitial
spaces but will not promote intracellular fluid shifts. In contrast, the
osmotic pressure exerted at the cell membrane by the infusion of
hypertonic saline solutions leads to the redistribution of intracellular
fluid into the extracellular compartment.
Isotonic crystalloid solutions are recognized universally as the pri-
mary fluid for acute intravascular volume expansion. When care is taken
to titrate total infusion volume to physiologic endpoints, resuscitation
usually is successful, without the development of pulmonary edema. A
concern with isotonic fluids is the large volume often required for
resuscitation. This usually results in peripheral edema, which clears
within several days. The large volume requirements also may represent
a logistic problem in some settings. For these reasons, hypertonic saline
solution has been studied.
- The theoretic advantage of hypertonic saline solution relates to the
total infusion volume required for adequate resuscitation. The greater
the sodium concentration, the less total volume is necessary for satis-
factory resuscitation when compared with isotonic saline solution. & I
addition to the osmotic effects, hypertonic solutions are believed to exert
/d
vasodilation effe~t.""~""~""
The principal disadvantage of hypertomi
saline infusion is the danger of hypernatremia. Serum sodium levels
above 170 mEq/L produce extreme brain dehydration and can be fatal."
The primary mechanism for the maintenance of relatively constant
serum sodium levels in the face of hypertonic infusions involves the
movement of intracellular water into the extracellular compartment.
Thus, the infusion of exogenous hypertonic saline solution is always
accompanied by an endogenous infusion of free water into the ex-
tracellular space. A simple method of calculating the expected endog-
242 GOULD et a1

enous infusion is to examine the ratio of the infused fluid to the normal
serum sodium concentration. A solution containing 300 mEq/L of
sodium, for example, would produce a 2 : l endogenous infusion,
whereas a solution containing 1200 mEq/L of sodium would produce a
7 : l infusion volume. The safety of hypertonic solutions depends on
how much of the intracellular volume can be transferred safely to the
extracellular compartment without injuring cell function or leading to
hypernatremia in a given clinical situation.

Colloid Solutions

Intravenous colloidal solutions have in common the Presence of

large molecules that are relatively impermeable to the capillary mem- -
branes. These oncotically active particles produce an effective volume
expansion with little loss into the interstitial space, as occurs with simple
salt solutions. In addition, the intravascular persistence of these mole-
cules increases their duration of action. The net effect of colloid adminis-
tration is a marked reduction in the volume of infusate necessary to
expand the intravascular space compared with isotonic saline solutions.
One of the most commonly used colloid preparations is 5% albumin
(see Table 1). It is prepared from normal donor plasma that is heat-
treated to eliminate the votential for disease transmission. Once admin-
istered, it leads to an iffective intravascular volume expansion of ap-
proximately one-half the volume infused, with a duration of action of 24
hours. Side effects include the rare occurrence of anaphylactic reactions
(0.5%) and inhibition of h e m o s t a ~ i s . ~ ~
The high cost and limited availability of albumin solutions led to the
development of synthetic colloid preparations such as 6% hetastarch
and 6% dextran solutions (see Table 1). Hetastarch is an amylopectin-
derived polymer with an average molecular weight of 450,000 D. Dex-
tran-70 is a'polysaccharide formed by bacterial growth and digestion in
sucrose media. Administration of these solutions leads to a vlasma
volume expansion and duration of action approximately 50% greater
than 5% albumin. Side effects of these solutions are similar to albumin,
with the excevtion of dextran-70's documented inhibition of vlatelet
-
aggregation ahd interference with red blood cell cross-match?mg. In
addition, concern has been raised over the long-term effects that these
svnthetic macromolecules mieht have on immune function secondarv ' to
their incomplete e~irninationvb~ the reticuloendothelial system.
Theoretically, fresh frozen plasma also can be used as a volume
expander. It is similar to 5% albumin in electrolyte concentration and
oncotic pressure. In addition, it contains all the naturally occurring
immunoglobulins and all the clotting proteins except platelets. At first
glance, it appears to be an ideal volume expander. Unfortunately, as is
the case with all currently used blood components, the risk of hepatitis
and acquired immunodeficiency syndrome is real, and neither risk can
be totally eliminated by current screening techniques. Accordingly, its
use following acute blood loss should be limited to the treatment of
 HYPOVOLEMIC SHOCK 243

clinically significant coagulopathies following large volume resuscita-

tion, as discussed later in this article.

Experimental Comparisons of Intravenous Solutions

Laboratory Studies
There has been considerable controversy over the role of resuscita-
tion with crystalloid or colloid solutions in the subsequent development
of deranged pulmonary function after major nonthoracic trauma. Pro-
ponents of colloid therapy cite the following points derived from labora-
tory studies:
1. Resuscitation with colloid leads to a more rapid and effective
correction of the intravascular volume deficits that follow acute
hemorrhage .'
2. Colloid resuscitation prevents pulmonary edema formation
through maintenance of the intravascular colloid osmotic pres-
sure.54
3. Crystalloid resuscitation dilutes the plasma protein pool, thereby
reducing plasma oncotic pressure and setting the stage for the
development of pulmonary
4. The peripheral edema that follows large volume crystalloid in-
fusions may impair wound healing and nutrient transport.23

Crystalloid proponents cite the following:

1. Crystalloid administration most effectively replaces the in-
terstitial fluid deficits that follow hemorrhagic shock.50
2. The rapid intravascular-extravascu1ar fluid equilibrium that fol-
lows crystalloid resuscitation may reduce the incidence of pul-
monary edema by promoting a less rapid rise in the pulmonary
artery occlusion pressure.59
3. Albumin normally enters the pulmonary interstitium relatively
freely and is returned to the circulation via the lymphatic system.
The exogenous administration of colloid solutions increases the
albumin pool in the pulmonary interstitium, promoting the
accumulation of interstitial

It is evident from this discussion that the arguments supporting

either treatment regimen are in direct conflict with respect to the
physiologic changes that are believed to follow resuscitation with either
crystalloid or colloid solutions. Much of this conflict stems from the
divergent study conditions employed to answer these questions in the
laboratory setting. Nevertheless, numerous clinical studies designed to
compare the efficacy and safety of these resuscitation regimens follow-
ing acute blood loss have failed to demonstrate a clear advantage of
colloid administration to justify its cost. The following section reviews
244 GOULD et a1

these clinical trials, with particular emphasis on the resuscitation from

hemorrhagic shock.

Randomized Trials in Human Subjects

Crystalloid Versus Colloid. One of the first trials comparing crys-
talloid and colloid resuscitation was revorted bv Skillman and col-
l e a g u e ~Sixteen
. ~ ~ patients undergoing elictive abdbminal aortic surgery
were administered either colloid or crystalloid solutions in the perioper-
ative period. The researchers noted a significant difference during the
immediate postoperative period in plasma colloid oncotic pressure be-
tween the Ringer's lactate-treated group (22 mm Hg) and the colloid-
treated group (27 mm Hg), but no alveolar-arterial oxygen difference.
They also reported a significant correlation between the amount of
infused sodium and the alveolar-arterial oxygen difference in the Ring-
er's lactate-treated group but not in the albumin-treated group. It was
concluded that albumin-rich fluid was preferable because it reduced the
amount of sodium-containing fluid required for adequate resuscitation.
This study does not represent a strong argument for albumin-rich fluids,
given that both groups received albumin in the form of whole blood
administered intraoperatively. Furthermore, the test fluid was given by
formula rather than by titration to physiologic endpoints. The positive
correlation between infused sodium and vulmonarv function was not
I J

confirmed in several subsequent studies by other investigators.

Another study involving patients undergoing elective vascular sur-
gery was published in 1979 by Virgilio and coworkers.59During surgery,
patients received either Ringer's lactate (14 patients) or 5% albumin in
Ringer's lactate (15 patients) in order to maintain preoperative filling
pressures, cardiac output, and urine output. Lost blood was replaced by
packed cells. Patients assigned to the Ringer's lactate-treated group
received approximately 11 L test fluid on the day of operation; those in
the albumin-treated group received 6 L. Both groups required approx-
imately 6.5 U packed red blood cells. Patients receiving Ringer's lactate
gained 10% of their original body weight and had a 40% reduction in
plasma colloid oncotic pressure.
During the study, no deaths occurred in either group. No difference
was noted between groups in regard to intrapulmonary shunt on any
day of the study. Furthermore, no correlation was found between the
intrapulmonary shunt and the plasma colloid oncotic pressure-hydro-
static pressure gradient. Mean postoperative ventilator time was 23
hours in both groups. Pulmonary edema developed in two patients
receiving albumin. No patient treated with Ringer's lactate showed the
development of pulmonary edema, despite reduced colloid oncotic pres-
sures. It was concluded that safe resuscitation without albumin could be
achieved in patients undergoing elective vascular surgery.
Numerous clinical trials have compared the effects of crystalloid or
colloid administration in the resuscitation of trauma patients. In 1977,
Lowe et a13' reported a clinical trial involving 141 trauma victims from
 HYPOVOLEMIC SHOCK 245

Cook County Hospital in Chicago. Thirty-six of these patients were in

shock on admission. Patients received, in random sequence, either
Ringer's lactate (84 patients) or 4% albumin solution (55 patients) in
volumes sufficient to restore normal vital signs and urine output. This
was the first report in the literature of a group of human subjects
resuscitated without any albumin. Red blood cell losses were replaced
with washed red blood cells. These patients received an average of 5.5 L
test fluid and 2 U red blood cells before surgery.
Three deaths occurred in each group. Eight patients (14%) in the
albumin-treated group required ventilatory support after operation;
three (3.6%)treated with Ringer's lactate required ventilatory support.
There were no changes in the results of a battery of pulmonary function
tests, including intrapulmonary shunt pressure and alveolar-arterial
oxygen difference. In addition, no correlation was found between the
amount of sodium infused and any pulmonary function test result in
either test group. Lowe et a132concluded that adding albumin to Ring-
er's lactate was unnecessary to achieve successful resuscitation in this
group of patients. A criticism of this study was that too few patients
were in shock on admission, so the failure to find differences in mortal-
ity or pulmonary function with either test fluid was not ~urprising.~'
In 1981, further findings in the 36 patients at Cook County Hospital
who were in shock on admission were published by Moss et al?'
Twenty patients were assigned to the Ringer's lactate-treated group and
16 received albumin. These patients received an average of 8 U packed
red blood cells and 9 L test fluid, indicating severe injury and blood loss.
Only one death occurred. Two patients in each group required ventila-
tory support, and no differences were noted in the pulmonary function
test results. Once again, no evidence could be found that albumin added
to Ringefs lactate was necessary to prevent adult respiratory distress
syndrome.
In an effort to determine the relative mortality following resuscita-
tion with either crystalloid or colloid solutions, ~ e l a n o v i c hpooled
~ ~ the
results of these and other clinical trials and compared the mortality rates
by meta-analysis. On examination of results from clinical trials derived
from trauma patients, the mortality rate was 12% lower for those that
received crystalloid. In contrast, the relative difference in mortality from
studies performed on nontrauma patients was 8% in favor of colloid
treatment. Based on these results, it was concluded that crystalloid
administration may be more efficacious than colloids in the trauma
setting.
Hypertonic Saline Solutions. Hypertonic saline solution is an
attractive fluid in the treatment of burn resuscitation because peripheral
edema frequently is seen after conventional resuscitation and may com-
plicate local burn tissue management. If resuscitation with hypertonic
saline solution results in a smaller infusion volume and less peripheral
edema, it would constitute an argument in favor of its use in burns. The
effect of varying the concentration of sodium in resuscitative fluids for
burn victims has been r e p ~ r t e d . ~Three
' groups of patients were stud-
246 GOULD et a1

ied: One group was given saline solution with sodium concentrations of
116 to 149 mEq/L; the second group, 150 to 199 mEq/L; and the third
group, 200 to 250 mEq/L. The total volume infused decreased as the
sodium concentration in the infusate increased. No increase was seen in
sodium loading. In two instances, however, the serum sodium concen-
tration increased to above 170 mEq/L. Similar results with hypertonic
saline solution have been reported in young and aged burn victims.283
Weight gain was noted to be minimal in children treated with hyperton-
ic saline solution, and the problem of hypernatremia was avoided by
serial monitoring of serum sodium levels. Hypertonic saline solution has
become an acceptable form of therapy in burn resuscitation.
Hemorrhage studies using hypertonic saline solutions have been
reported. In a study of 58 patients undergoing vascular surgery, Shack-
ford et a149showed that the hypertonic saline solution group required
less fluid during operation than the isotonic saline solution group (4.5 L
-
and 9.5 L, respectively)and gained less weight. They concluded that the
use of hypertonic saline solution during surgery resulted in a reduction
in infusion volume but demanded careful monitoring of serum osmolar-
ity to avoid hypernatremia. In a clinical study in trauma victims, one
group of 10 patients received 3% saline solution at a volume of 4 mL/kg
for no more than 3 hours and the control group received isotonic saline
solution.24The hypertonic saline solution group required less fluid and
produced more urine than the control group.

Summary of Clinical Studies

1. Isotonic solutions are effective plasma expanders. There is no

good evidence that resuscitation with these fluids in the treat-
ment of hemorrhagic shock produces increased pulmonary in-
terstitial water.
2. There is some evidence that albumin resuscitation may result in
albumin accumulation in the lung interstitium. The clinical sig-
nificance of this observation is not clear. d
3. A major increase in pulmonary microvascular pressure is the
most important determinant of transvascular movement of water
into the pulmonary interstitium. The clinical implication of this
observation is that careful monitoring of pulmonary hydrostatic
pressure is crucial during resuscitation.
4. Most clinical studies suggest that there is no advantage to the
administration of colloid solution rather than crystalloid in the
treatment of hemorrhagic shock.
5. Preliminary studies with hypertonic saline solutions suggest that
effective resuscitation can be achieved using relatively small
volumes of fluid. Further clinical studies are necessary to verify
the safety and efficacy of this therapy following hemorrhagic
shock.
 HYPOVOLEMIC SHOCK 247

PHASE II: RESTORATION OF THE OXYGEN-CARRYING

CAPACITY

The traditional approach to transfusion of the critically ill patient is

to maintain the hemoglobin concentration above 10 g/dL by transfusion
of homologous blood. This dogma rarely was questioned in the past
because a patient is unlikely to die of anemia at this level. However,
recent concern over the safety of all blood components as related to
disease transmission, blood compatibility, and immunogenicity has led
to a reassessment of traditional transfusion practices.
It is clear that following acute massive blood loss, red cell transfu-
sions are indicated for the restoration of the blood's oxygen-carrying
capacity. Nevertheless, the use of hemoglobin concentration as the sole
indicator of the need for red blood cell replacement, the so-called
"transfusion trigger,"12 may lead to the unnecessary administration of
homologous blood products. Indeed, clinical and laboratory studies
have clearly demonstrated that hemoglobin concentrations far below 10
g/dL may be well tolerated following acute normovolemic anemia.5,18,36
Accordingly, transfusion therapy should be instituted based on the
patient's physiologic needs, as determined by his or her oxygen de-
mand, rather than by any arbitrary hemoglobin value. In order to un-
derstand the appropriate indications for a blood transfusion, the basic
principles of oxygen transport should be reviewed briefly.

Normal Oxygen Transport

Oxygen delivery is defined as the product of blood flow (cardiac

output) and arterial oxygen content ([02]a):
O2 delivery = CO x [02]a
Although [02]a depends on several variables, hemoglobin is the
principal determinant. A drop in hemoglobin and, therefore, [02]a will
lead to one of two outcomes-a drop in oxygen delivery if CO does not
change, or an increase in CO to maintain oxygen delivery. For anemic
patients with good cardiac function, this increased CO does occur, and
is the justification used by advocates of purposeful hemodilution. This
response has been observed during normovolemic hemodilution in
baboons.40Other authors have also documented this ability of the car-
diovascular system to compensate for significant reductions in hemoglo-
bin.4,'3,22Tissue oxygenation is well maintained at hematocrit levels as
low as 20% to 25% as long as blood volume remains These
observations are further evidence that hemoglobin alone is not an
adequate parameter for determining whether a red cell transfusion is
required.
The important issue then becomes the adequacy of oxygen supply
at any given hemoglobin measurement. The actual utilization of oxygen
248 GOULD et a1

by the tissues is the oxygen consumption, which can be calculated as the

product of CO and the difference in oxygen between the arterial and
venous blood:
O2 consumption = CO X ([02]a - [02]V)
Tissue oxygen tension is the appropriate monitor of oxygen supply.''
The mixed venous Po2 (Pvo2)is the oxygen tension of the venous blood
when oxygen unloading has been completed, and is the best indication
of mean tissue oxygen tension. Mixed venous Po2 therefore becomes a
key measurement for assessing the adequacy of oxygen transport, and
determining whether an anemic patient requires red cells. The normal
value for Pvo2 is 40 mm Hg.
The authors have evaluated the oxygen extraction ratio (ER) as
another physiologic indication of transfusion need. The oxygen ER is the
ratio of oxygen consumption to oxygen delivery:
O2 consumption
ER =
O2 delivery

Because normal [02]a = 20 vol percent and normal AVD02 = 5 vol

percent, the normal ER = 25%. In other words, available oxygen is four
times the oxygen normally consumed, leaving a large oxygen reserve.
The authors have performed an analysis of changes in Pvo2 and ER
in extreme normovolemic anemia.61Animals survive normovolemic ex-
change transfusion to hematocrit levels of 5%. Mixed venous Po2 falls
and ER increases as soon as hematocrit begins to fall, but no
hemodynamic instability is evident until hematocrit is below 10% or
hemoglobin is 3.5 g/dL. At this point, Pvo2 is less than 25 mm Hg, and
the ER is greater than 50%. The Pvo2 and ER therefore may represent
indicators of the compensation for any level of hemoglobin.

Clinical Implications

Patients with a low Pvo2can be categorized as being in a stable or an

unstable condition based on the adequacy of their hemodynamics,
ventilation, urine output, and acid-base status. If a patient's condition is
stable with a low Pvo2, no therapy is indicated unless a true critical value
is reached (5 25 mm Hg). If a patient is unstable with a low Pvo2,
therapeutic intervention is indicated.
In practical terms, we consider a patient with a changing Pvo2
value to be undergoing significant alterations of the oxygen transport
system, which may be explained by many different conditions, only a
 HYPOVOLEMIC SHOCK 249

few of which may actually be manipulated. A patient with normal lungs

will have a normal saturation, and a patient with significant pulmonary
disease may be quite refractory to attempts to improve his or her hypox-
ia. Likewise, a healthy person can easily compensate for a drop in
hemoglobin by an increase in CO. It is the cardiac patient with a CO
level that cannot be augmented who might benefit from a blood transfu-
sion when Pvo2 is reduced or ER is increased, despite an "acceptable"
hemoglobin concentration. In effect, life-threatening anemia may exist
despite only a modest reduction in hemoglobin mass.
In sum, we believe the hemodynamic stability of the patient, the
Pvo2, and the ER may be more appropriate indicators of red blood cell
transfusion need than hemoglobin concentration alone. Conversely, use
of this analysis may lead to a reduction in the transfusion trigger, thus
.. contributing to a reduction in exposure to homologous blood.
The current recommendation set forth by the National Institute of
Health Consensus Conference on Perioperative Red Cell ~ransfusions'
reflects these changing attitudes toward red cell need, as follows:
1. If the hemoglobin is greater than 10 g/dL, transfusion rarely is
indicated.
2. If the hemoglobin is less than 7 g/dL, transfusion usually is
indicated.
3. If the hemoglobin is greater than 7 g/dL, but less than 10 g/dL,
the clinical status, Pvo2, and ER will be helpful in assessing
transfusion need.

Transfusion

Once a need for restoration of the oxygen-carrying capacity of the

~ l o o dhas been established, a number of alternative interventions exist.
The most common method employed to increase red blood cell mass is
the administration of homologous blood. Autologous blood represents a
viable alternative to homologous transfusions, when applicable. A third
alternative undergoing laboratory and clinical evaluation is the use of
red blood cell substitutes.

Homologous Blood
The identification of the major isoagglutinins of human blood by
Landsteiner made safe transfusions possible via the development of
principles of blood grouping and compatibility. With the evaluation of
blood component therapy, the number of transfusions given in the form
of whole blood has declined steadily. Whereas as much as, 30% of
homologous blood administered in the United States a decade ago was
in the form of whole blood,26the theoretical and practical advantages of
component therapy have made whole blood's use and availability lim-
ited at the present time.
Component therapy consists of fractionation of whole blood at the
250 GOULD et al

time of collection into red blood cells, platelets, and plasma. The use of
packed cells rather than whole blood to restore oxygen-carrying capacity
is specific treatment, allows more efficient use of the other limited
commodities (platelets and plasma), and avoids the undesirable effects
often seen after the administration of platelet and white blood cell
debris6 The argument that a patient bleeding whole blood must un-
dergo blood replacement with whole blood no longer is acceptable.
After separating the red blood cells from the other blood com-
ponents, they may be stored and used in three separate ways:
Packed Red Blood Cells. A concentrated suspension of red blood
cells is obtained by removing the supernatant plasma from the whole
blood after settling or centrifugation. The red blood cell mass is the same
as in 1U whole blood. The plasma citrate level and volume of plasma are
reduced substantially.
Washed Red Blood Cells. After the red blood cells have been
obtained by settling or centrifugation, they are washed with sterile
isotonic saline solution. This process results in a still lower plasma
citrate level than found in a unit of nonwashed cells. The only disadvan-
tage is the additional time and possibility of bacterial contamination.
Frozen Red Blood Cells. The use of frozen red blood cells has been
an important addition to blood component therapy. A major concern
with the use of liquid preserved blood has been the outdating of blood
because of its limited shelf-life (21-28 days). Despite progress in the
development of better preservatives, 28 days is still a relatively brief
period. Frozen red blood cells can be stored indefinitely, with no appar-
ent loss of safety or efficacy after thawing and administration. In addi-
tion to providing an indefinite shelf-life, frozen blood facilitates auto-
logous blood usage, permits stockpiling of all blood groups, particularly
those that are difficult to obtain, maintains normal levels of 2,3-
diphosphoglycerate (2,3-DPG) and oxygen half-saturation pressure of
hemoglobin (P-50), and may be associated with a lower risk of hepatitis
transmi~sion,~'although the latter issue remains unsettled.

Autologous Blood
u
The risks inherent in the use of homologous blood products have
led to the evaluation of numerous strategies designed to limit exposure
to homologous blood. The reinfusion of the patients' own blood, auto-
logous blood transfusion, clearly represents the safest form of transfu-
sion therapy. Three established methods are available for the use of
autologous blood-preoperative autologous blood donation (ABD) pro-
grams, immediate preoperative collection and hemodilution, and intra-
operative autotransfusion. A fourth method that is under laboratory and
clinical investigation is the pharmacologic acceleration of endogenous
erythropoiesis with hematopoietic growth factors.
Preoperative Autologous Blood Donation Programs. This tech-
nique was developed in the 1960s as a means of obtaining blood for
patients with rare antibodies that were difficult to cross-match. The real
and perceived risks of blood-borne infection transmission from homo-
 HYPOVOLEMIC SHOCK 251

logous transfusions has led to an exponential rise in the use of ABD

- programs prior to elective operations. In a recent national survey of
transfusion practices in the United States during the 1980s, autologous
blood donations increased from 30,000 U in 1982 to 397,000 in 1 9 8 7 . ~ ~
Nevertheless, the application of this procedure to the treatment of
hemorrhagic shock is limited to situations where acute blood loss is
anticipated.
The criteria used for donor acceptability for ABD programs vary
from institution to institution. The American Association of Blood Banks
recommends a minimum hematocrit value of 34% and a hemoglobin of
11 g/dL for autologous d~nation.'~Donations most commonly are
scheduled 7 days apart.9 A recent review has shown that following
those criteria, 96% of patients could donate at least 3 U blood prior to
operative intervention.15The most common reasons cited for the limita-
- - tion of this procedure in the elective surgical setting are physician
underutilization, insufficient time intervals for collection prior to sur-
gery, and the limited erythropoietic reserve of patients subjected to
repeated phlebotomy.17
Immediate Preoperative Collection and Hernodilution. This tech-
nique is based on the cardiovascular changes that occur during the
induction of normovolemic anemia. Blood is withdrawn to reduce acute-
ly the hematocrit reading to 30% and blood volume is maintained with
Ringer's lactate, dextran, or other volume expanders. A healthy in-
dividual maintains oxygen delivery during this period of normovolemic
anemia with an increase in CO. Messmer et a136 showed that tissue
oxygenation remains normal, and advocates of purposeful hemodilution
actually believe that a hematocrit reading of 30% is optimal.
This method can provide approximately 3 U whole blood for in-
traoperative use. Although the technique has been used widely in Eu-
rope, it primarily has been limited to patients undergoing open heart
operations in the United States. Because open heart operations are
responsible for a large proportion of our homologous blood demand,#
wider use of this method could have a substantial influence on the
availability of blood.
Intraoperative Autotransfusion. Autotransfusion represents an
efficient means of reducing homologous blood requirements through
the recycling of red cells lost during intraoperative hemorrhage.
Although the potential of autotransfusion is appealing, there are certain
practical limitations to its use. The theoretical problem of bacterial con-
tamination limits its use in a variety of settings in which it might be most
helpful, such as major trauma. A second concern is the required logistic
support necessary to implement this expensive technique on a 24-hour
basis. Finally, air embolism during readmission is a rare but troublesome
complication.
Acceleration of Erythropoiesis. Approximately two thirds of all red
cell transfusions are administered in the perioperative period.* Loss of
blood is the most common cause of anemia in the surgical patient and
occurs in one of two s e t t i n g ~ l e c t i v esurgery (planned blood loss) or
emergency surgery (unplanned blood loss). Effective preoperative auto-
252 GOULD et a1

logous donation and rapid postoperative recovery both depend on brisk

erythropoietic responses. The pharmacologic stimulation of erythro-
poiesis therefore represents an attractive means of increasing red cell
recovery following acute blood loss.
The advent of recombinant DNA technology has led to the isolation
and cloning of numerous hematopoietic growth factors that promote
bone marrow cellular proliferation. Erythropoietin, a glycoprotein nor-
mally released by the kidney in response to tissue hypoxia, is known to
r
be the rimary regulator of bone marrow red cell proliferation. Pre-
clinical2 ,30 and clinical16studies with exogenously administered recom-
binant human erythropoietin (rHuEPO) have demonstrated its efficacy
in increasing the number of autologous units collected prior to elective
operations and enhancing erythropoietic recovery when given prior to
acute blood loss. When rHuEPO is administered following acute blood
loss, however, clinically significant effects are not evident until 1 week
after therapy is ir~itiated.~'Accordingly, rHuEPO's therapeutic potential
-
is limited in the setting of nonanticipated blood loss. Laboratory studies
are underway investigating the application of other erythropoietic
growth factors that may further accelerate the endogenous response
following acute blood loss.

Red Blood Cell Substitutes

Efforts to develop a safe and effective red cell substitute have
continued for many decades. The goal has been to obtain a product that
would transport oxygen and carbon dioxide adequately enough to re-
place the primary function of the red cell in the setting of temporary
unavailability of blood. The recent focus on the risks associated with
homologous transfusion has stepped up efforts to develop a sterile red
cell substitute as an alternative to homologous blood. Perfluorochemical
emulsions and hemoglobin solutions are the two potential products that
have been evaluated most extensively.
Perfluorochemical Emulsions. Considerable progress has been
made in research with perfluorochemicals since they were first de-
scribed by Clark and Gollan in 1966.~Perfluorochemicals are organic
liquids that have the unique property of carrying large amounts of "
oxygen in physically dissolved form. The solubility for oxygen in the
pure perfluorochemicals is actually 10- to 20-fold greater than in water. It
was Clark and Gollan's liquid breathing experiment with mice that so
vividly demonstrated this remarkable property and led to the potential
application of perfluorochemicals as clinically useful ox gen carriers.
The next important event was the report by Geyer et a112'who demon-
strated that rats could survive a total exchange transfusion with per-
fluorochemicals to a zero hematocrit reading. The important stipulation,
however, was that the rats breathe supplemental oxygen, because the
perfluorocarbons required a high partial pressure of oxygen to carry
adequate amounts of oxygen. This requirement continues to be a limit-
ing factor with all perfluorochemicals.
 HYPOVOLEMIC SHOCK 253

Considerable efforts were then devoted to developing a product

- that would be suitable for clinical testing. The commercially prepared
product, Fluosol-DA, 20% (Green Cross Corporation, Japan) was the
first to be introduced into clinical testing. Several brief studies eventual-
, ly led to clinical studies with Fluosol in the United States, including the
trial at Michael Reese Hospital and Medical Center.18
The trial assessed the safety and efficacy of Fluosol-DA as a red cell
substitute in acute anemia. Twenty-three surgical patients with blood
loss and religious objections to receiving blood transfusions were evalu-
ated. Fifteen moderately anemic patients with a mean hemoglobin level
(+ S.E.) of 7.2 + 0.5 g/dL had no evidence of a physiologic need for
increased arterial oxygen content and did not receive Fluosol-DA. Eight
severely anemic patients with a mean hemoglobin level of 3.0 + 0.4 g/dL
- met our criteria of need and received the drug until the physiologic need
disappeared or a maximal dose of 40 mL/kg body weight was reached.
All patients breathed supplemental oxygen. No adverse reactions to
Fluosol-DA were observed. The average peak increment in arterial
oxygen content with the drug was only 0.7 + 0.1 mL/dL. This is equiv-
alent to an increase in hemoglobin concentration of only 0.5 g/dL. There
were no appreciable beneficial effects of Fluosol-DA, perhaps because
of the small increase in arterial oxygen content, the brief half-life of
the drug (24.3 + 4.3 hours), and the limited total dose. Six of the
eight patients receiving Fluosol-DA died. One of the survivors received
red cell transfusions against his wishes, under a court order, after
his total Fluosol-DA dose. Fourteen of the 15 moderately anemic pa-
tients lived.
These data suggest that after blood loss, Fluosol-DA is unnecessary
in moderate anemia and ineffective in severe anemia.
Efforts are continuing to develop other modifications that would
have higher concentrations of perfluorochemicals and a longer in-
travascular biologic half-life. In the near future, however, there does not
appear to be any perfluorochemical that will be an effective red cell
substitute.
Hemoglobin Solutions. Hemoglobin solutions are prepared from
. outdated blood. Various techniques have been used to separate the
hemoglobin from the red cell membrane to prepare this stroma-free
hemoglobin (SFH) solution. The first generation of this unmodified
tetrameric form or "stripped" hemoglobin solution had a hemoglobin
concentration of only 7 g/dL, and a P-50 of 12 to 14 mm Hg, about half
the normal 26 mm Hg. Although SFH can be prepared with a hemoglo-
bin level of 14 g/dL, the solution has a colloid osmotic pressure (COP) of
greater than 60 mm Hg. This hyperoncotic solution would not be accept-
able for clinical use. The hemoglobin of 7 g/dL therefore is required to
maintain an iso-oncotic product. The low P-50 is caused by the loss of
2,3-DPG from the solution. Despite these limitations, SFH supports life
in primates at a zero hematocrit reading, documenting effective oxygen
transport in the absence of red cells.40
Subsequent efforts have attempted to develop a product with a
254 GOULD et a1

normal oxygen-carrying ~apacity.~' The P-50 issue was the first problem
to be corrected. Pyridoxal phosphate is an alternative organic phosphate
ligand that can be permanently bound to the hemoglobin molecule. The
resulting pyridoxylated hemoglobin or SFH-P has a P-50 of 20 to 22 mm
Hg. Although this was an improvement compared with the stripped
hemoglobin, the product still had a low hemoglobin concentration.
The authors' approach to the problem of the hemoglobin concentra-
tion was to use a polymerized product that would permit a normal
hemoglobin concentration and a normal COP. First, SFH-P is prepared
with a hemoglobin of 14 g/dL. Polymerization of this hyperoncotic
product reduces the total number of molecules and increases the aver-
age molecular size without losing any hemoglobin mass. The COP is
lowered to an iso-oncotic range (20 mm Hg) because the COP is pro-
portional only to the actual number of particles (molecules). Polymer-
ized pyridoxylated hemoglobin solution, or Poly SFH-PI therefore
achieves the goal of both a normal hemoglobin concentration of 15 g/dL
and a normal COP of 20 mm Hg. The P-50 is 20 to 22 mm Hg. We
therefore have a product that has virtually the same properties as a bag
of red cells that has been stored for approximately 2 weeks. In addition
to these physiologic improvements, the product has a half-life of 24 to 48
hours.48
The authors have evaluated the efficacy of Poly SFH-P. The results
document that Poly SFH-P supports life in a primate at a zero hematocrit
reading.l9r2' Furthermore, observations indicate that this product is
more effective in maintaining hemodynamic and oxygen transport val-
ues than any of our earlier hemoglobin modification^.^^ We believe that
Poly SFH-P is indeed an effective oxygen carrier and, therefore, are
enthusiastic about its potential clinical applications.
The limiting factor before clinical testing is concern about the safety
of Poly SFH-P. The main uncertainty is the effect of this product on renal
function. The key observation was a 1978 study by Savitsky et alr4' in
which tetrameric hemoglobin solution was given to human volunteers.
The study showed that small infusions of hemoglobin solution pro-
duced transient, but significant, changes in renal function. The authors
have developed a sensitive and reproducible animal model that virtual-
ly duplicates these findings.46Infusion of tetrameric hemoglobin solu-
tion into unanesthetized primates produced the same changes in hemo-
dynamics and renal function that were observed in humans. It is our
hypothesis that because the polymerized hemoglobin molecule
does not traverse the renal tubules, it may not produce these same
effects.
We recently completed the first clinical evaluation of Poly SFH-P in
healthy human volunteers. In this study, no significant differences
between pre- and postinfusion measures of renal function occurred.
There were no clinically significant abnormalities in routine chemical
and hematologic variables throughout a 6-week follow-up. Although
these results are encouraging, the efficacy of this therapy depends on
future studies in anemic patients.
 HYPOVOLEMlC SHOCK 255

Summary of Phase II

In conclusion, the restoration of the oxygen-carrying capacity of the

circulation is a fundamental adjunct to volume expansion in the treat-
ment of hemorrhagc shock. The risks associated with homologous
transfusion necessitate the adoption of a multi-tiered approach to red
cell replacement, encompassing both reductions in the transfusion trig-
ger and increased use of various autologous techniques, so as to reduce
homologous blood exposure. Finally, further developments in red cell
substitutes hold promise that exposure to homologous transfusions may
be avoided altogether.

PHASE THREE: COMPONENT THERAPY OF

HEMOSTATIC DEFECTS

The components most frequently used are platelets and fresh-

frozen plasma (FFP). This section reviews the indications for the use of
these two components in massive transfusion.
In most patients with acute reduction in circulating volume, treat-
ment with crystalloid solutions followed by red blood cell transfusions,
when indicated, achieve successful resuscitation. In the case of massive
transfusion, defined as blood volume replacement greater than 1.5 times
the recipient volume, abnormal bleeding may occur. This hemostatic
defect is characterized by oozing from the operative wound, mucous
membranes, and intravenous puncture sites. The probability of develop-
ing a hemostatic defect is roughly related to the volume of infused blood
and fluids.
Investigations of massively transfused patients with a hemostatic
defect usually demonstrate the following changes in the coagulation
profile: (1) reduced platelet count, (2) increased bleeding time, (3) in-
creased prothrombin time (PT), (4) increased activated partial thrombo-
plastin time (PTT), and (5) decreased fibrinogen levels. In addition,
- studies of the coagulation profile following a 3-L plasma exchange in
normal apheresis donors demonstrate similar changes.
For these reasons, the traditional explanation for the hemostatic
defect following massive transfusion has been dilution of the various
clotting elements. Recommendations for coagulopathy prophylaxis in-
clude administration of platelet concentrates and FFP during resuscita-
tion and before the onset of oozing. An established coagulopathy is
treated with either platelet concentrates, FFP, or both, depending on the
coagulation profile. This approach is logical but should be re-examined
for several reasons.
First, both platelets and FFP may transmit non-A, non-B hepatitis.
Exposure to more than 2 U carries an estimated 10% risk of hepatitis.' It
is important to emphasize that this often takes the form of chronic liver
inflammation. The risk is likely to be the same as for whole blood. These
components therefore should be used with the same precautions used
for any other blood components.
Second, in the case of FFP, the observation that PT and activated
MT is abnormal in the presence of a coagulopathy is not, in itself,
evidence that administration of FFP will correct the hemostatic defect. It
is well known that normal clotting can still occur when the various
clotting protein concentrations are reduced substantially. Furthermore,
the infusion of FFP in patients who are oozing after massive transfusion
and who have abnormal PT and MT frequently fails to stop the bleed-
ing, despite normalized60PT and PTT. Finally, prophylactic use of FFP
(and platelets) has failed to reduce the incidence of coagulopathy after
massive transfusion.1°
Third, regarding platelets, there is no doubt that after the loss of
more than one blood volume, platelet counts of 100,000 or fewer may be
seen. In addition, bleeding time is abnormal in almost all massively -
transfused patients. In fact, bleeding time and platelet counts in such
patients without coagulopathy also may be abnormal and not different
from those in patients who do bleed. This is particularly evident in
patients with hypothermia, a known cause of elevated bleeding times.
Furthermore, spontaneous bleeding from thrombocytopenia rarely
occurs with a platelet count above 20,000, a level infrequently seen in
massive transfusion.
On the basis of these observations, we recommend the following
approach to component use in the third phase of resuscitation:
1. Platelet count, PT, and MT should be measured frequently dur-
ing massive resuscitation.
2. Bleeding times may not be useful, particularly in the hypother-
mic patient.
3. Administration of components prophylactically during resuscita-
tion is not helpful and exposes the patient unnecessarily to the
risk of hepatitis.
4. If a coagulopathy develops during massive resuscitation, platelet
infusions will be helpful if the patient's count is less than
100,000.
5. Fresh-frozen plasma is not helpful in most cases of coagulopa- "
thy. If the PT and M"T are substantially prolonged (> 1.5 times
control), however, FFP infusion may be helpful.
The clinical value of FFP has been summarized in a National In-
stitutes of Health consensus statement as follows.68
1. Approximately 90% of current FFP use is inappropriate.
2. The risk of hepatitis with FFP is similar to that associated with
any other blood component.
3. The use of FFP has risen 10-fold during the past decade for no
apparent reason.
4. Unacceptable indications for FFP use include as a volume ex-
 HYPOVOLEMIC SHOCK 257

pander; as a source of immunoglobulin, except in rare instances;

as a source of nutrition; or as a source of fibronectin.
5. Acceptable indications include treatment of postresuscitation
clotting defect when a major decrease in clotting problems can be
demonstrated, and treatment of life-threatening warfarin (Cou-
madin) intoxication.

SUMMARY

This article defines a rational approach to the treatment of

hemorrhagic shock. All patients that are hypovolemic following hemor-
rhage require fluid resuscitation. Some patients require red cell restora-
tion and very few require correction of any clotting deficiencies. A
physiologic approach to these problems will lead to optimal patient care
in these circumstances.

References

1. Alter JH: The dominant role of non-A, non-B in the pathogenesis of post-transfusion
hepatitis: A clinical assessment. Clin Gastroenterol 9:155, 1980
2. Bowser-Wallace B, Caldwell FT Jr: A prospective analysis of hypertonic lactated saline
vs. Ringer's lactate-colloid for the resuscitation of severely burned children. Burns
12:402, 1986
3. Bowser-Wallace B, Cone JB, Caldwell FT Jr: Hypertonic lactated saline resuscitation of
severely burned patients over 60 years of age. J Trauma 25:22, 1985
4. Carey JS: Determinants of cardiac output during experimental therapeutic hemodilu-
tion. Ann Surg 181:196, 1975
5. Carson JL, Spence RK,Poses RM, et al: Severity of anemia and operative mortality and
morbidity. Lancet 1:727, 1988
6. Chaplin H: Current concepts: Packed red blood cells. N Engl J Med 281:364, 1969
7. Clark LC, Gollan F: Survival of mammals breathing organic liquids equilibrated with
oxygen at atmospheric pressure. Science 152:1755, 1966
8. Consensus conference: Perioperative red blood cell transfusion. JAMA 260(18):2700,
1988
9. Council on Scientific Affairs: Autologous blood transfusions. JAMA 256:2378, 1986
10. Counts RB, Haisch C, Simon TL, et al: Hemostasis in massively transfused patients.
Ann Surg 190:91, 1979
11. Finch CA, Lenfant C: Oxygen transport in man. N Engl J Med 286:407, 1972
12. Friedman BA, Burns TL, Schork MA: An analysis of blood transfusion of surgical
patients by sex: A quest for the transfusion trigger. Transfusion 20:179, 1980
13. Geha AS: Coronary and cardiovascular dynamics and oxygen availability during acute
normovolemic anemia. Surgery 80:47, 1976
14. Geyer RP: Whole animal perfusion with fluorocarbon dispersions. Fed Proc 29:1758,
1970
15. Goodnough LT: Autologous blood donation. JAMA 259:2405, 1988
16. Goodnough LT, Rudnick S, Price TH, et al: Increased perioperative collection of
autologous blood with recombinant human erythropoietin therapy. N Engl J Med
321:1163, 1989
17. ~ o o d n o u ~ h Wasman J, Corlucci K, et al: Limitations to donating adequate auto-
LT,
logous blood prior to elective orthopedic surgery. Arch Surg 124494, 1989
18. Gould SA, Rosen AL, Sehgal LR, et al: Fluosol-DA as a red cell substitute in acute
anemia. N Engl J Med 314:1653, 1986
258 GOULD et a1

19. Gould SA, Rosen AL, Sehgal LR, et al: Is polyhemoglobin an effective O2 carrier? J
Trauma 26:903, 1986
20. Gould SA, Sehgal LR, Rosen AL, et al. Polyhemoglobii: An improved red cell
substitute. Surg Forum 36:30, 1985
21. Gould SA, Sehgal LR, Rosen AL, et al: The efficacy of polymerized pyridoxylated
hemoglobin solution as an O2 carrier. Ann Surg 211(4):394, 1990
22. Gump TE: Anemia in surgical patients. In Collins JA, Lundsgaard Hansen P (eds):
Surgical Hemotherapy. Basel, S Karger, 1980, p 105
23. Hauser CJ, Shoemaker WC, Turpin 1, et al: Oxygen transport responses to colloids and
crystalloids in critically ill surgical patients. Surg Gynecol Obstet 150:811, 1980
24. Holaoft JW, Vassar MJ, Blaisdell F W Resuscitation of severely injured patients with a
3% NaCl solution. Ann Surg 206:279, 1987
25. Holland PV, Schmidt PJ: Standards for blood banks and transfusion services, ed 12.
Arlington, VA, American Association of Blood Banks, 1987, p 38
26. Kahn RA, Staggs SD, Miller WV, et al: Use of plasma products with whole blood and
packed RBCs. JAMA 242.2087, 1979
27. Kleeman CR. CNS manifestations of disordered salt and water balance. Hosp Pract
May:59, 1979
28. Levine EA, Gould SA, Rosen AL, et al: Perioperative recombinant human erythro-
-
poietin. Surgery 106:432, 1989
29. Levine EA, Rosen AL, Sehgal LR, et al: Physiologic effects of acute anemia: Im-
plications for a reduced transfusion trigger. Transfusion 30:11, 1990
30. Levine EA, Rosen AL, Gould SA, et al: Recombinant human erythropoietin and
autologous blood donation. Surgery 104365, 1988
31. Levine EA, Rosen AL, Sehgal LR, et al: Treatment of acute postoperative anemia with
recombinant human erythrupoietin. J Trauma 193134, 1989
32. Lowe RJ, Moss GS, Jilek J, et al. Crystalloid vs. colloid in the etiology of pulmonary
failure after trauma. A randomized trial in man. Surgery 81:676, 1977
33. Lucas CE, Denis R, Ledgerwood AM, et al: The effects of hespan on serum and
lymphatic albumin, globulin and coagulant protein. Ann Surg 207(4):416, 1988
34. Lucas CE, Ledgerwood AM, Mammen EF: Altered coagulation protein content after
albumin resuscitation. Ann Surg 196198, 1982
35. Marshall RJ, Shepherd JT: Effect of injections of hypertonic solutions on blood flow
through the femoral artery of the dog. Am J Physiol 97:951, 1959
36. Messmer K, Sunder-Plassman L, Jesch F, et al: Oxygen supply to the tissues during
limited normovolemic hemodilution. Res Exp Med 159:152, 1973
37. Miller RD, Robbins TO, Tong MJ, et al: Coagulation defects assodated with massive
blood transfusions. Ann Surg 174794, 1971
38. Monafo WW, Halverson JD, Schechtman K: The role of concentrated sodium solutions
in the resuscitation of patients with severe bums. Surgery 95:129, 1984
39. Moore FD, Lyons JH, Pierce EC: Post Traumatic Pulmonary Insufficiency. Philadel-
phia, WB Saunders, 1969
40. Moss GS, DeWoskin R, Rosen AL, et al: Transport of oxygen and carbon dioxide by
hemoglobin-saline solution in the red cell-free primate. Surg Gynecol Obstet 142357,
1976
-
41. Moss GS, Gould SA, Sehgal LR, et al: Hemoglobin solution: From tetramer to poly-
mer. Surgery 95:249, 1984
42. Moss GS, Lowe RJ, Jilek J, et al: Colloid or crystalloid in the resuscitation of
hemorrhagic shock: A controlled clinical trial. Surgery 893434, 1981
43. National Institutes of Health, Consensus Conference: Fresh-frozen plasma: In-
dications and risks. JAMA 253:551, 1985
44. Rackow EC, Falk JL, Fein IA, et al: Fluid resuscitation in circulatory shock: A compari-
son of the cardiorespiratory effects of albumin, hetastarch, and saline solutions in
patients with hypovolemic and septic shock. G i t Care Med 11:839, 1983
45. Roche JK, Stengle JM: Open-heart surgery and the demand for blood. JAMA 2251516,
1973
46. Rosen AL, Sehgal LR, Gould SA, et al: Renal response to hemoglobin solutions
(abstract). Physiologist 29:161, 1986
 HYPOVOLEMIC SHOCK 259

47. Savitsky JP, Doczij J, Black J, et al: A clinical safety trial of stroma-free hemoglobin. J
- Clin Pharmacol Ther 23:73, 1978
48. Sehgal LR, Gould SA, Rosen AL, et al: Polymerized pyridoxylated hemoglobin: A red
cell substitute with normal O2capacity. Surgery 95:433, 1984
49. Shackford SR, Sise MJ, Fridlund PH, et al: Hypertonic sodium lactate versus lactated
Ringer's solution for intravenous fluid therapy in operations on the abdominal aorta.
Surgery 9441, 1983
50. Shires GT, Braun FT, Canizaro PC, et al: Distributional changes in extracellular fluid
during acute hemorrhagic shock. Surg Forum 11:115, 1960
51. Shoemaker WC, Hauser CJ: Critique of crystalloid vs. colloid therapy in shock and
shock lung. Crit Care Med 7:117, 1979
52. Shoemaker MC, Schluchter M, Hopkins JA, et al: Fluid therapy in emergency resusci-
tation; clinical evaluation of colloid and crystalloid regiments. G i t Care Med 9:367,
1981
53. Siege1 DC, Moss GS, Cochin A: Pulmonary changes following treatment for
hemorrhagic shock: Saline versus colloid infusion. Surg Forum 21:17, 1970
54. Skillman JJ, Restall DS, Salman EW: Randomized trial of albumin vs. electrolyte
solutions during abdominal aortic operations. Surgery 78:291, 1975
55. Surgenor DN, Wallace EL, Hao SHS, et al: Collection and transfusion of blood in the
United States, 1982-88. N Engl J Med 322646, 1990
56. Templeton GH, Mitchell JH, Wildenthal K: Influence of hyperosmolarity on left
ventricular stiffness. Am J Physiol 222:1406, 1972
57. Valeri CR:Viability and function of preserved red cells. N Engl J Med 2&4:81, 1971
58. Velanovich V: Crystalloid versus colloid fluid resuscitation: A meta-analysis of mortal-
ity. Surgery 105:65, 1989
59. Virgilio RW, Rice CL, Smith DE, et al: Crystalloid vs. colloid resuscitation: Is one
better? Surgery 85:129, 1979
60. Wildenthal KD,Mierzwiak DS, Mitchell JH: Acute effects of increased serum osmolal-
ity on left ventricular performance. Am J Physiol216:898-904, 1969
61. Wikerson DK, Rosen AL, Gould SA, et al: Oxygen extraction ratio: A valid indicator of
myocardial metabolism in anemia. J Surg Res 42(6):629, 1987
Address reprint requests to
Steven A. Gould, MD
Department of Surgery
Michael Reese Hospital and Medical Center
2929 South Ellis Avenue
Chicago, IL 60616

View publication stats