HYPERTONIC SALINE RESUSCITATION
Shock 1998: Oxígeno, Oxido Nítrico y
Simposio Internacional, Academia Nacional de Medicina
Buenos Aires, 30 abril 1998
HYPERTONIC SALINE RESUSCITATION
MAURICIO ROCHA e SILVA
Research Division, Heart
Institute, Faculty of Medicine, University of São Paulo, São Paulo,
Key words: hemorrhage, hypertonic saline, shock, leukocyte
adhesion, blood flow, oxygen consumption
of severe hemorrhage offers few theoretical problems, but in practice,
severe blood loss usually occurs out of hospital, often in more or
less inaccessible scenarios. Controversy rages over ideal fluid, ideal
volume, and minimum O2 carrying capacity, but all agree that
pre-hospital, isotonic resuscitation is unfeasible. The effects of
highly hypertonic 7.5% NaCI (HS) was first described in 1980, when we
showed that it induced immediate and long lasting hemodynamic
restoration. The addition of 6% dextran-70 to (HSD) significantly
enhances the duration and intensity of volume expansion, with no loss
of hemodynamic effects. HS/HSD restores cardiac output, arterial
pressure, base excess and oxygen availability, induce pre-capillary
vasodialtion, moderate hyperosmolarity and hypernatremia, reversal of
high glucose and lactate. It interferes with endocrine secretions when
administered to animals in hemorrhagic hypotension. HS acts through
transient plasma volume expansion, positive inotropic effect on
cardiac contractility, precapillary vasodilation through a direct
action on vascular smooth muscle. Expansion of circulating volume is
part of the mechanism, the extra volume coming from the intracellular
compartment fluid, especially from endothelial and red blood cells,
which facilitate microcirculatory flow. The new field of interactions
of hypertonicity with the immune mechanisms may provide insight into
the long lasting effects of hypertonic solutions. Randomized double
blind prospective studies on the effects of HS, or HSD, used as first
treatment of shock show that both are safe and free from collateral,
toxic effects. These studies show an early significant rise in
arterial blood pressure and a non-significant trend towards higher
levels of survival. HSD administration to patients about to undergo
cardiopulmonary bypass for cardiac surgery results in higher cardiac
output before, and immediately following cardiopulmonary bypass, as
well as zero fluid balance.
con solución salina hipertónica. El tratamiento de una hemorragia
severa presenta pocos problemas teóricos, pero en la práctica, la
pérdida abundante de sangre se presenta generalmente lejos del
hospital y a menudo en escenarios poco accesibles. Hay mucha
controversia en cuanto al fluido de reposición ideal, al volumen
ideal y a la capacidad mínima de transporte de O2, pero hay un
acuerdo tácito en que la resucitación isotónica pre-hospitalaria no
es factible. Los efectos de la solución salina hipertónica (HS) al
7.5% fueron descriptos inicialmente en 1980 cuando demostramos que es
capaz de conducir a una restauración hemodinámica inmediata y de
larga duración. La adición de dextran 70 al 6% a la solución
hipertónica (HSD) aumenta significativamente la duración y la
intensidad del volumen de expansión, sin pérdida de los efectos
hemodinámicos. HS/HSD restaura el volumen mínimo, aumenta la
presión arterial, corrige el exceso de bases y aumenta la
dispo-nibilidad de oxígeno además de inducir vasodilatación
precapilar, hiperosmolaridad moderada e hipernatremia, disminuyendo
los altos niveles de glucosa y de lactato. Administrado a animales en
hipotensión hemorrágica, HS/HSD interfiere también con las
secreciones endocrinas. HS actúa a través de la expansión del
volumen plasmático con un efecto inotrópico positivo sobre la
contractilidad cardíaca, y sobre la vasodilatación precapilar
mediante una acción directa sobre el músculo liso vascular. La
expansión del volumen circulante es parte del mecanismo a expensas
del fluido de los compartimientos intracelulares en especial de las
células endoteliales y de los glóbulos rojos, lo que facilita el
flujo microcirculatorio. El reciente campo de interacciones de la
hipertonicidad con los mecanismos inmunes abre horizontes nuevos en el
estudio de los efectos a largo plazo de las soluciones hipertónicas.
Los estudios prospectivos doble ciego randomizados de los efectos de
HS o de HSD empleados como primer tratamiento del shock muestran que
ambas soluciones son seguras y sin efectos tóxicos colaterales. Se
obtuvo un aumento temprano y significativo de la presión arterial y
una tendencia no significativa hacia mayores niveles de sobrevida. La
administración de HSD a pacientes en cirugía cardíaca antes de un
by-pass cardiovascular resultó en un aumento del volumen mínimo,
antes e inmediatamente después del by-pass cardiopulmonar alcanzando
un perfecto equilibrio de los fluidos orgánicos.
Postal address: Dr. Mauricio Rocha e Silva, Instituto del
Corazón, Av. Enéas de Carvalho Aguiar 44, São Paulo, SP, CEP
Fax: 55-11-853-7887; E-mail: firstname.lastname@example.org
The early treatment of severe hemorrhagic hypotension offers few
theoretical problems, simply a matter of blood loss control, general
care and replacement of losses, specially losses of volume and O2
carrying capacity. In practice, however the problem is more complex:
in the overwhelming majority of cases, severe blood loss occurs out of
hospital, often in more or less inaccessible scenarios. In most cases,
hemorrhage control can only be ensured in a hospital setting and in
some cases not even then, while volume replacement is torn between the
conflicting concepts of crystalloid vs. colloid fluid. O2 carrying
capacity is in turn subject to debate concerning the minimal
acceptable levels of hemoglobin coupled to the shadow of transmission
of infectious diseases. In urban settings, large accidents may result
in large blood loss, in a large number of patients. Rural settings may
impose long travelling times, whereas military settings require
consideration with respect to distance, terrain, and availability of
personnel, and degree of hostility from enemy action. Thus, it may be
safely stated that the extra-hospital setting in conjunction with very
urgent therapeutic requirements imposes severe limitations to
applicable procedures. Another important issue refers to the duration
of this pre-hospital stage of care, which is also variabe, on account
of distance to hospital, quality of ambulance/helicopter service,
level of prevailing urban traffic, eventual need of extricating the
patient from a severely distorted vehicle. It is therefore not
surprising that transport time, counting from the start of bleeding to
entry into hospital may range from a very few min. (e.g., when a
person is injured in front of the hospital) to many hours (e.g. when a
patient has to be extricated from a crashed vehicle and transported
during rush hours through a large, traffic-congested city). Other fast
or slow scenarios may be envisaged.
Arguments abound, concerning ideal fluid, ideal volume replacement,
minimum O2 carrying capacity, but one point draws agreement from all
parties. The logistics of pre-hospital management of severe blood loss
all but precludes the administration of ideal volumes of crystalloid
or colloid solutions. In the most favorable scenarios, it is difficult
to infuse much more than 800-1000 mL, during the pre-hospital stage of
trauma patient management. This is clearly insufficient to replace
lost circulating volume in the face of class III or class IV
hemorrhage (blood loss greater than 30% of blood volume, ~ 1.5 L).
These are, of course, the conditions which normally require most
urgent treatment. Replacement of O2 carrying capacity remains
virtually impossible. These shortcomings led to the concept of the
scoop-and-run strategy, on the grounds that, since it is impossible to
provide even token volume replacement en route to hospital, no time
should be wasted in securing an intravenous line on the site of the
occurrence. More recently a new and potentially explosive concept has
been proposed by the Houston Trauma Center14: volume replacement prior
to full control of bleeding is dangerous, because it is may increase
blood loss. This bold suggestion was made after comparison between two
groups of patients: in one, treatment was withheld until hemorrhage
had been controlled, while in the other standard of care ATLS
procedures were instituted. This of course transcends the mere domain
of therapeutic strategy and overflows into the field of ethics of
patients management. It should be noted that the study on which this
concept was based was seriously flawed: on one hand, it did show a
significant advantage in favor of withholding treatment, but on the
other it violated its own protocol in circa 20% of patient entries,
all belonging to the withhold-treatment group, who received
significant amounts of volume in spite of being attended on “withhold-treatment”
days. In the absence of any rational expla-nation, the obvious
assumption must be that in a number of these so called “mistakes”,
ethical considerations forced field workers, on the site of the
occurrence, to violate the protocol in respect to hierarchically
superior values of life protection.
The concept of small volume hypertonic resuscitation
The effects of moderately hypertonic solutions were sporadically
described in medical literature since the latter years of World War
I6, 103, 104, 118, 177, 179. Effects were generally described as
vasodilator, positive inotropic and transiently beneficial in
hemorrhagic hypotension. The highly hypertonic (7.5%, 2.400 mOsm/L)
NaCI solution (HS) first appeared in 1980, when it was shown that,
given in a relatively small volume (4 mL/kg)165, HS induced immediate
and long lasting recovery of arterial pressure, cardiac output,
vasodilation. It also induced moderate hyperosmolarity and
hypernatremia, and restored base excess levels.
The addition of 6% dextran-70 to HS, first described in 1985149, and
exhaustively tested thereafter62, 76, 94, 107, 117, 120, 131, 149,
150, 152, 162, 164, 168, 169, 173 significantly enhances the duration
and intensity of volume expansion, with no loss of hemodynamic
effects. This HSD solution: (NaCI at 7.5% + dextra-70 at 6%)
accelerates volemic expansion, and converts the mere pressor effect of
pure dextran to a nutritionally effective increase in blood pressure
and cardiac output164. Toxicity evaluation showed that up to five
times (20 mL/kg) the usually prescribed doses of HSD are free of toxic
or collateral effects40, 42, 43, 44, 153. Consequently, this
hyperosmotic-hyperoncotic crystalloid-colloid combination has become a
standard small volume resuscitation solution. Two different colloids
(dextran and hydroxyethylstarch) are used in preference to any
others76. The total therapeutic dose for the average human adult is
only 250 mL, a volume which is well within the logistic restrictions
of pre-hospital care.
Experimental data on the effects of HS/HSD show an early recovery of
cardiac output, arterial pressure, base excess and oxygen
availability2, 3, 35, 56, 59, 60, 74, 112, 125, 134, 139, 148, 165, a
widespread pre-capillary vasodilator response31, 80, 81, 82, 107,130,
144, moderate hyperosmolarity and hyperna-tremia74, 134, 143, reversal
of high glucose and lactate blood levels86, improved renal
function144, 151, unaltered pulmo-nary gas exchange138 and transient
circulating volume expansion73, 74, 143, 165, 167. In the original
study165, when compared to an equal volume of isotonic saline, used as
placebo, hypertonic NaCI was found to increase survival, from
virtually zero to nearly 100%. Other studies, perfor-med in dogs or in
different animal species produced sur-vival data which are somewhat
less encouraging155, 156.
HS/HSD interferes with endocrine secretions, when administered to
animals in hemorrhagic hypotension: it decreases circulating levels of
vasopressin, renin, and angiotensin171, probably on account of the
correction of hypotension and hypovolemia. Particularly interesting is
the reduction of vasopressin circulating levels170, 171, since this
hormone is normally secreted in response to hyperosmolarity. In this
situation, however the removal of the more powerful secretory drive
induced by blood loss overrides the osmotic drive. HS does not
interfere with atrial natriuretic factor1.
HS appears to interfere significantly with the immune response, both
in vivo and in vitro. It has been shown to reduce adherence of
leukocytes to capillary endothelium7, and to enhance proliferation of
T-cells (obtained from peripheral blood of normal human volunteers),
at NaCI concentrations normally encountered following hypertonic
resuscitation28. It was also shown that the addition of prostaglandin
E2 (PGE2) to isotonic culture media inhibits human peripheral blood
T-cell proliferation by circa 30%, but has virtually no inhibiting
effect in hypertonic media28. In a murine model of hemorrhagic shock,
it has been shown26, 27 that T-cell proliferation remained inhibited
up to 24 hr after shock and lactated ringer’s resuscitation, and
that this immunosuppressive response is associated with high levels of
Interleukin-4 (IL-4) and prostaglandin E2 (PGE2). In contrast,
similarly shocked animals treated with HS exhibited normal T-cell
proliferation and IL-4 and PGE2 levels comparable to those of
unshocked controls. In a two-hit model of aggression, hemorrhagic
shock followed 24 hr later by a septic aggression induced by cecal
ligation and puncture, HS (which had been used to resuscitate from the
initial hemorrhagic shock) significantly enhanced survival, in
comparison to Lactated Ringer’s (LR) treated animals. The latter
group also exhibited significant pulmonary lesions identified as early
ARDS25. In recently performed experiments4 LR treated animals
exhibited significant elevation of neutrophils in broncho-alveolar
lavage, and high myeloperoxidase levels, when compared to HS treated
mice, leading to the conclusion that HS prevents the pulmonary lesion
normally encountered following hemorrhagic shock.
Suggested mechanisms of action included, from the early days,
transient plasma volume expansion73, 74, 143, 164, 167 a positive
inotropic effect on cardiac contractility22, 68, 69, 70, 71, 106,
precapillary vasodilation through a direct action on vascular smooth
muscle31, 80, 81, 82, 130, 165, and venoconstriction, through a neural
reflex, the afferent leg of which would lie in pulmonary vagal
afferents, with an efferent limb via sympathetic venomotor fibers87,
88, 89, 181. The latter hypothesis has so far remained unconfirmed3,
132, 163, 166. A central action for hypertonic saline (HS)166 has been
suggested, but this also remains unconfirmed. Expansion of circulating
volume is certainly part of the mechanism and the extra volume comes
from the intracellular compartment fluid, which normally expands
during hemorrhagic shock because of cell swelling. Cell types found to
be the major volume contributors are endothelial and red blood cells,
on account of their immediate contact with the hypertonic circulating
fluid. This represents, of course, an additional bonus, because at
capillary level, endothelial and erythrocyte swelling induce a very
significant restriction to free flow of red cells99, 100, 101, 102. It
has also been shown that HS restores resting action potential of
excitatory cells, which are depolarized through hemorrhage97, 111.
Although more research is certainly required in the field of the
interactions of hypertonicity with the immune mechanisms, this may be
the first convincing insight into the possible mechanism of the long
lasting effects of hypertonic solutions after a single bolus
HS reduces intracranial hypertension, (induced by balloon inflation or
localized brain injury), with a resulting increase in cerebral blood
flow8, 9, 32, 37, 38, 45, 46, 52, 53, 57, 58, 61, 90, 105, 122, 123,
142, 146, 174, 175, 176, 178,185, 186. The effects of HS on
experimental burn injuries are usually described as variable and
transient, and tend to disappear by the end of the first 24 hours48,
65, 66, 67, 116, 183. Effects of HS on endotoxemia, or endotoxic shock
have been described. In general they appear to be transient and
partial29, 30, 64, 68, 82, 124. These scenarios should be re-evaluated
in the light of recently described interferences of HS/HSD with immune
responses. The use of HS for the treatment of shock in previously
dehydrated animals has produced conflicting results79, 92, 119, 172.
Hypertonic solutions are normally injected slowly, over 3-5 min by
peripheral or central intravenous route, with no adverse effects to
the histological structure of venous walls55. Intraosseous injections
have been proved to be safe and efficacious23, 41, 54, 75, 91, 114,
135, 136, 137, 140.
Simulations of clinical use of hypertonic solutions resulted in a
certain amount of conflicting evidence. Kramer and his co-workers
developed a protocol72 in which unanesthetized sheep were bled to 50
mm Hg and kept at this pressure for 3 hr. This was followed by
treatment with 200 mL HSD or lactated Ringer’s solution (LR). After
30 more min of “no-treatment”, all animals were resuscitated to
their own pre-hemorrhage levels of cardiac output with isotonic fluid.
During initial treatment, HSD restored cardiac output and arterial
pressure to normal, and raised plasma Na+ to 155 mEq/L. During
isotonic resuscitation, only 500 mL of fluid was required to retain
normal cardiac output for 2 hr. LR treated animals, in contrast,
exhibited no significant effects on pressure, output, or plasma Na+,
on initial treatment. Moreover, they required 2.5 L of isotonic fluid
to recover to, and maintain a normal cardiac output for 2 hr. This is
of course a typical model of controlled hemorrhage. However, it may be
relevant to clinical situations, because similar findings, concerning
rapid hemodynamic recovery and reduced fluid requirements are normally
observed in human trauma patients. Bickell et al. developed a porcine
model of uncontrolled bleeding11, 12, 13, in which a standardized
aortic lesion induced severe hypotension within 5 min. Given
immediately after the initial fall of pressure, HSD intensified the
shock condition and caused early death. In contrast, given 20-30 min
after the initial hypotension, HSD restored stable hemodynamic
conditions. This is also a clinically relevant model, in that it
sounds a note of caution against ultra-early use of hypertonic
solutions. Krausz and co-workers49, 50, 51, 77, 126 described
different protocols of uncontrolled arterial hemorrhagic shock in
rats. In all of these, HS was given immediately after the initial fall
of arterial blood pressure leading to severe hypotension and short
survival times as the outcome. Animals treated with isotonic solutions
did better with stable, albeit low levels of arterial pressure.
Untreated animals had the best evolution, with highest levels of
arterial pressure, longer and better overall survival. Authors
attributed these results to renewed bleeding in HS treated rats, due
to an intense initial pressor response, and to arterial vasodilation.
These results reiterate the caution against ultra-early use of
hypertonic solutions, but otherwise appear to have little clinical
relevance, since no clinical data so far described (see below) show
this pattern of evolution. Moreover, an independent duplication of one
of these protocols (bleeding caused by total transection of the rat
tail)15 under 4 different anesthetic regimens (droperidol-ketamine, as
used by Krausz et al., pentobarbitone, chloralorse and urethane)
brought out an interesting fact: only under droperidol-ketamine, which
incidentally is a very powerful arterial vasodilator, could the
results described by Krausz et al. be partially reproduced: untreated
and HS treated rats bled abundantly and died in similar proportions.
In contrast, under all other anesthetic procedures, very little
occurred. Yet another model of uncontrolled hemorrhage with severe
blood loss (50% of total blood volume) into an artificially produced
retroperitoneal hematoma has been recently described133, 146. Shock
develops in less than 5 min and stabilizes at a blood pressure of 40
mm Hg, with cardiac output reduced to 25% of control. Treatment, 30
min after the start of bleeding, with 4 mL/Kg HSD, or with a volume of
LR sufficient to restore mean arterial pressure to 90 mm Hg reverts
the shock condition, with no indications of renewed bleeding as
measured through the loss of marked red blood cells147. Therefore, and
even though no attempt was made to control this bleeding, it appears
to have tamponaded itself quite effectively. A number of clinical
trauma situations in all likelihood follow this pattern. Other risks
involved in the use of hypertonic solutions in uncontrolled hemorrhage
are discussed in a number of reports33, 34, 39.
Clinical studies on the use of hypertonic solutions in hypovolemic
shock began with a sequential study36 of 12 shocked patients
pronounced to be in refractory hypovolemic shock by the ICU medical
staff in charge (persistence of critical hypotension for at least 4
hr, with no response to 5 L of crystalloids and/or blood, and absence
of response to vasoactive therapy. HS was administered in 50 mL
aliquots, at 15 min intervals, to an end point of recovery of mean
arterial pressure to 80 mm Hg, or to a maximum of 200 mL. Fluid/blood
replacement followed, in adherences to the Institution’s routine
procedures. A significant pressor response with recovery of
consciousness, and of urine flow was observed in 11 out of these 12
patients. Fluid requirements, over the next 24 hr were reduced by 90%
with respect to initial volumes. Nine of these patients were
ultimately discharged from hospital. This study suffers, of course,
from the lack of an adequate control group, but it appeared to be
justified, on account of the “in-extremis” condition of the
patients. Dosing of HS was deliberately fractionated into 50 mL
aliquots, to ensure interruption of treatment if required. In no case
was this necessary.
Randomized double blind prospective studies on the effects of HS, or
HSD, used as first treatment of shock have been performed, involving a
total of approximately 1.500 patients63, 98, 157, 158, 159, 160, 161,
180, 181, 182. These studies have shown that HS and HSD are safe and
free from collateral, toxic, or undesirable side effects. No clotting,
renal, neural, cardiopulmonary, or septic complications were noted;
signs of renewed bleeding were conspi-cuously absent. In terms of
efficacy, a majority of these studies show an early significant rise
in arterial blood pressure and a non significant trend towards higher
le-vels of survival. The University of California studies63, 145, 158,
159, 160, 161 showed a significant difference in outcome for cranial
trauma, in favor of HSD; the USA multicenter trial98 showed a
significant difference in favor of HSD in the subpopulation arriving
alive at the Hospital and requiring surgical intervention.The
intra-hospital São Paulo trial, which detected a significant overall
difference in survival indicated that a mean arterial presure below 50
mm Hg is a prognostic index for survival which distinguishes
positively in favor of HSD. A metanalysis of the individual patient
files entered into all published studies conforming to a uniform
protocol, show a significant (p < 0.005) diference in survival, to
favor HSD (Wade et al., in press). The use of HSD for primary care in
shock and trauma is further discussed in a number of different
papers83, 84, 85, 95, 96. The use of HS/HSD in current veterinary
practice, mainly associated with hypovolemic shock has also been
repeatedly reported10, 47, 93, 107, 108, 109, 110, 139, 184.
HSD or HSS (7.5% NaCI - 6% hydroxyethylstarch - 200 kDalton)
administration to patients about to undergo cardiopulmonary bypass for
cardiac surgery results in higher cardiac output before, and
immediately following cardiopulmonary bypass, as well as zero fluid
balance, in contrast to a positive balance in control, HSD/HSS
untreated patients16, 17, 18, 19, 20, 21, 115. However, acutely
adverse effects have been described121 in patients with significant
cardiac deficit. Reduction in gut tissue water, but no improvements in
intestinal mucosal perfusion, under cardiac bypass have also been
The effects of hypertonicity upon the aortic declamping hypotension
have been described5, 143, 145. Given immediately after declamping,
hypertonic solutions induce partial restoration of arterial pressure;
given immediately before declamping, hypertonicity partially prevents
HS given to patients following right ventricular acute infarct induce
a lasting restoration of arterial pressure and cardiac output127, 141,
and an early reduction of enzymes associated to myocardial lesion24.
New concepts in the field refer to the experimental use of hypertonic
solutions in which CI- is partly replaced by acetate, in order to
induce an isochloremic resuscitation127, 128, 129. These HA (2.500
mOsm/L sodium acetate) or HAD (2.500 mOsm/L sodium acetate, plus 6%
dextran-70) solutions have been found to induce a low pressure high
cardiac output type of response78, 113, 127, 128, with no significant
elevation of blood CI- levels, and early corection of blood pH. They
should not, however, be attempted in clinical situations, until more
work has been done to determine their safety. The combination of HS
with a-a-hemoglobin, as an oxygen carrying oncotic factor is also
under current study, in experimental conditions (Figueiredo et al., in
In conclusion, hypertonic solutions appear to have multiple
physiological effects in severe hypotensive shock or in hypotensive
like situations, many of which require further research. It also
appears to have potential clinical applications in the primary
treatment of hypovolemic shock, in cardiac surgery with
cardiopulmonary bypass and in myocardial infarct. The interaction of
hypertonic solutions with pro-inflammatory mediators has barely been
scratched, and may induce a critical review of many concepts.
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