Trauma Inflamatie Terapie Volemica F Bun

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v1
Review
Update on Current Concepts in Management of Severe

Hemorrhagic Shock and Optimal Individualized Fluid
Therapy in Critically Ill Polytrauma Patients
Alexandru Florin Rogobete 1,2,3 $, Stelian Adrian Ritiu 1,2,3$, Ovidiu Horea Bedreag 1,2,3 , Marius Papurica 1,2,3 , Sonia
Elena Popovici 1,2,3 , Daiana Toma 1,2,3 , Maria Alina Lupu 2,4, Diana Loreta Paun 5,*, Nicolae Dragos Garofil 5, Dan
Corneci 5, Adriana Pistol5#, Elena Mihaela Pahontu 6, Liana Valeanu 5 and Dorel Sandesc1,2,3#
1 Clinic of Anaesthesia and Intensive Care, Emergency County Hospital ”Pius Brinzeu„ , Timisoara, Romania.
stelian.ritiu@umft.ro (S.A.R.), alexandru.rogobete@umft.ro (A.F.R.), bedreag.ovidiu@umft.ro (O.H.B.), mar-
ius.papurica@gmail.com (M.P.), popovici.sonia@yahoo.com (S.E.P.), daiana.toma@yahoo.com (D.T.), dsan-
desc@yahoo.com (D.S.)
2 Faculty of Medicine, „Victor Babes„ University of Medicine and Pharmacy, Timisoara, Romania;
lupu.alina@umft.ro (M.A.L.)
3 Anaesthesia and Intensive Care Research Center Timisoara, „Victor Babes„ University of Medicine and Phar-
macy, Timisoara, Romania

4 Center for Diagnosis and Study of Parasitic Disease, Department of Infectious Disease, „Victor Babes„ Uni-
versity of Medicine and Pharmacy, Timisoara, Romania

5 Faculty of Medicine, „Carol Davila„ University of Medicine and Pharmacy, Bucharest, Romania .
dragosgarofil@gmail.com (D.N.G.), dan.corneci@umfcd.ro (D.C.), dianaloreta_paun@yahoo.com (D.L.P.); adri-

ana.pistol@insp.gov.ro (A.P.); liana.valeanu@yahoo.com (L.V.).
6 Faculty of Pharmacy, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania;
elena.pahontu@umfcd.ro (E.M.P.)
* Correspondence: dianaloreta_paun@yahoo.com (D.L.P.) +40 759 852 479
# A.P. and D.S. These authors contributed equally to this work.
$ A.F.R. and A.S.R. These authors contributed equally to this work.
Abstract: Worldwide, one of the main causes of death among young adults is multiple trauma. In
these patients hemorrhagic shock represents the leading cause for worsening of the clinical status
and for increased morbidity and mortality. This is due to a multifactorial complex involving cellular,
biological, and biophysical mechanisms. The most important mechanisms affecting clinical outcome
are oxidative stress, the augmentation of pro-inflammatory status, immune deficiency, disruptions
in the coagulation cascade, imbalances in electrolyte and acid-base homeostasis. Polytrauma pa-
tients in hemorrhagic shock need adequate fluid management to ensure hemodynamic stability that
must consider not only the maintenance of adequate blood pressure, but also the adequate oxygen-
ation of tissues for optimal cellular function. In the current clinical practice, fluid resuscitation in
polytrauma patients uses a variety of widely studied pharmacological products, such as crystal-
loids, colloids, blood transfusions, and the infusion of other blood products. Although these prod-
ucts exist, an agreement was not reached on a standard administration protocol that could be gen-
erally applied for all patients. Moreover, numerous studies have reported a series of adverse events
related to fluid resuscitation and to the inadequate use of these products. This review aims at de-
scribing the impact the administration of all the solutions used in fluid resuscitation might have on
the cellular and pathophysiological mechanisms in the case of polytrauma patients suffering from
hemorrhagic shock.
Keywords: hemorrhagic shock; multimodal monitoring; individualized therapy; fluid therapy; crit-
ical care; trauma
1. Introduction
Multiple trauma is one of the main causes for disability in patients under 40 years of
age. A recent study has reported that in the United States of America, over 150.000 of
© 2022 by the author(s). Distributed under a Creative Commons CC BY license.

Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 8 August 2022 doi:10.20944/preprints202208.0141.v1
persons die because of multiple trauma with a significant social impact. The main causes
of death in the case of polytrauma patients are represented by the organic injuries includ-
ing cerebral trauma, spinal trauma, injuries to other vital organs, as well as indirect causes
that refer to secondary injuries related to the multiple trauma constellation. Among these
secondary injuries, the most important seems to be circulatory failure due to hemorrhagic
shock, as it has multifactorial implications at cellular and tissue level, and it is responsible
for augmenting the inflammatory response, for generating the systemic inflammatory re-
sponse syndrome (SIRS) , oxidative stress (OS), severe coagulopathy, ventilatory dysfunc-
tion, multiple organ dysfunction syndrome (MODS), and finally leading to death [1–7].
During a recent consensus meeting that has analyzed over 28000 patients from
trauma registries, the mean age was 42,9 years, 72% of patients were male, mean injury
severity score (ISS) was 30,5, mean mortality rate 18,7%, the participants have drawn con-
clusions towards the definition of the polytrauma patient that has to include not only an
ISS score > 16 and AIS > 2 for at least one of the following variables: hypotension (systolic
blood pressure <90 mmHg), level of consciousness ( Glasgow Coma Scale <8), acidosis
(base excess >=6), coagulopathy ( International normalized ratio 1.4/ partial thromboplas-
tin time >40 s) and age ( >70 years) [8,9]. Hemorrhagic shock in patients with severe mul-
tiple trauma and the fluid resuscitation management applied, as well as the ICU length of
stay are directly correlated with the mortality rate due to their multifactorial impact. The
main challenges in fluid resuscitation remain the ability to appreciate the volume of blood
lost, the ability to correctly choose one or more solutions for infusion, but also the volume
to infuse and the appropriate infusion timeline [10]. Therefore, a series of guidelines and
protocols have been developed that include the optimization of fluid management in pol-
ytrauma patients with hemorrhagic shock. These include permissive hypotension, hemo-
static resuscitation, making adequate use of blood transfusion and of other blood prod-
ucts, as well as individualizing fluid management for each patient [11].
2. Pathophysiology pathways in hemorrhagic shock

The severity of the injuries and its impact on the survival rate are both associated
with acute blood loss, that leads to hypoperfusion and tissue injury, responsible for the
activation of the immune response and of the coagulation cascade. This in turn will lead
to an accelerated biosynthesis of the pro-inflammatory and pro-oxidative molecules, and
to an imbalance in the aerobic biochemical pathways with severe increase in lactate levels.
This multifactorial phenomenon was initially described by Denver and was named the
lethal triad – hemorrhage, acidosis, and coagulopathy [12–15].
The main mechanisms underlying the physiology of hemorrhagic shock is a decrease
in the delivery of oxygen needed by the cells to sustain molecular mechanisms involved
in vital functions, leading to anaerobic mechanisms and dangerous increases in lactate
levels. Under normal conditions, the oxygen delivery (DO2), is 1000-1250 ml O2/ minute
in males and 925-1100 ml O2/minute in females. Biophysically, DO2 is characterized by the
rate of blood flow that is the equivalent of cardiac output multiplied by the oxygen bound
to hemoglobin in a known blood volume. An important aspect regarding tissue oxygena-
tion is the oxy-hemoglobin dissociation (OHD) curve and the oxygen binding affinity of
hemoglobin. Both mechanisms can be significantly influenced by a series of variables that
are often seen in critically ill polytrauma patients, among which pH values and tempera-
ture. An increase in the concentration of H+ ions shifts the OHD curve to the right, leading
to an increased unload of oxygen to the tissues, while a decrease in temperature shifts the
curve to the left, leading to a decreased oxygen delivery to the tissues. Moreover, tissues
that had been affected by the multiple trauma have a different behavior regarding oxygen
extraction. Under normal conditions, the systemic oxygen consumption (VO2) is 250 mL
O2 / minute. The oxygen extraction ratio (O2ER) represents ratio of the body's oxygen con-
sumption (VO2) compared to the systemic oxygen delivery (O2ER= VO2/DO2). Physiolog-
ically, oxygen consumption is different for each organ, which can increase the imbalance
between delivery and consumption especially in critically ill polytrauma patients. For ex-
ample, renal O2ER is 15%, liver O2ER is 45%, while for the heart it is 60%.
During hemodynamic instability due to massive blood loss with implicit oxygen de-
livery and consumption imbalance, there is a compensatory mechanisms mediated by
O2ER. Up to a loss of 30% blood volume VO2 stays constant and is independent from the
flow because a drop in DO2 leads to an increase in O2ER. In case DO2 continues to drop,
O2ER can be increased compensatory up to 60-70%. After this threshold the O2ER reaches
a plateau. If blood loss continues the compensatory mechanism will be overcome and VO2
will be dependent on flow [16–19]. Depending on the amount of blood lost, there are four
stages of hemorrhagic shock and fluid resuscitation is based on these 4 stages.
Shortly after the traumatic injury, a series of molecular mechanisms are activated,
either self-induced or through external, non-self involvement. Both are capable of aug-
menting the biochemical pathways responsible for inflammation and injury at tissue level
and cellular level [8]. An important link in the systemic inflammation mechanism is neu-
trophile activation and their invasion in the tissues [20–24].
The activation of the complement system is another pathological mechanism acti-
vated after a traumatic injury. This will lead to the production of highly reactive molecules
that are involved in the transmission and alteration of intercellular signaling. Among
these molecules recent studies have highlighted the importance of the under expression
of C1qrs and C3b opsonin responsible to the excessive bioproduction of C3a and C5a.
Complement activation leads to an augmentation in the pro-inflammatory status through
the production of excessive amounts of cytokines. These cytokines will further be in-
volved in mitochondrial dysfunction, impairing the mitochondrial respiratory chain, as
well as the cellular respiration, increasing systemic inflammation and generalized capil-
lary leakage. All the aforementioned dysfunctions are in the first phase restricted to a cel-
lular level, but as the trauma advances they affect all body tissues, leading in the end to
multiorgan dysfunction, worse clinical outcomes, and increased death rates [25,26].
Bogner-Flatz et al., have analyzed the role played by neutrophiles in post-traumatic pro-
inflammatory activity at 6, 12, 24, 48 and 72 hours after trauma. To identify correlations
between the neutrophile expression and pro-inflammatory activity, they have quantified
the expression of IL-1, and of the c-JUN, BCL2a, c-FOS, TIMP-1, MMP-9, ETS-2 and MIP-
1 genes. The samples from 40 patients with a mean ISS of 3614 have been included in
the study; the study revealed a significant correlation between the expression of BCL2a,
MMP-9, TIMP-1 and ETS-2 and 90 days survival rates. Another important issue high-
lighted by this study are the significant correlation observed between the expression of
IL-1, MIP1, MMP-9 and BCL2a and the need for blood transfusion [27].
The redox balance is also affected in patients with hemorrhagic shock, leading to an
overexpression of oxidative stress [28]. The superoxide ion (O2-) will be produced in this
situation especially by the activation through the complement factors of the arachidonic
acid pathways and of other pro-inflammatory cytokines in the nicotinamide adenine di-
nucleotide phosphate (NADPH-oxidase) membrane. The body’s enzymatic antioxidant
activity will intervene in order to block the oxidative reactions induced by the reactive
oxygen species, reducing it to hydrogen peroxide after catalyzing the superoxide dis-
mutase in the cytosol (SOD1), the superoxide dismutase in the membrane (SOD3), and the
mitochondrial superoxide dismutase (SOD2). Once the enzymatic resources of the body
have been exhausted, the reactive oxygen species tend to accumulate and to interact with
the myeloperoxidase to form new reactive oxygen species, such as the hydroxyl radical
(OH-). They will also attach lipids and proteins leading to a destruction of endothelial and
parenchymal cells. These reactions will interfere with the NO biochemical pathways, ac-
tivate specific enzymes, and generate increased nitrogen free radical species. All these cel-
lular events will increase the general pro-inflammatory status and will negatively impact
the clinical outcome of the patients due to microvascular injury, increased capillary leak-
age, as well as impacting the hemodynamic stability [29].
Numerous studies have shown that pro-oxidative activity is directly related to an
augmentation in the inflammatory status. The imbalance in the mechanisms and
biochemical pathways leads to the production of a series of mediators that are further
responsible for the biosynthesis of pro-inflammatory cytokines and chemokines. Two
hours after the traumatic injury the first species that show an aggressive increase in ex-
pression are IL-1 and TNF-. Their biosynthesis will afterwards lead to the production
of impressive amounts od IL-6 and IL-8 that will be responsible for the activation of neu-
trophiles and for a disruption in the function of macrophages. Moreover, shortly after they
had been synthetized, IL-12 and IL-8 will be involved in modulating interferon- and high
motility group protein-1 (HMG-1). Different studies have shown an increase in serum
TNF-, IL-1 and IL-8 in patients with systemic inflammation, thoracic trauma, or acute
respiratory distress syndrome. Claude et al., have carried out a study on the activity of
TNF- and IL-6 in two categories of patients suffering form a systemic inflammatory re-
sponse – polytrauma patients with hemorrhagic shock and patients suffering from septic
shock. Their prospective study included 24 patients with septic shock and 60 patients with
trauma. From the trauma group 8 patients also presented with hemorrhagic shock, while
8 did not. The septic patients showed increased expressions only for IL-6. Interestingly
enough, in the case of patients suffering from septic shock, increased values of TNF- and
IL-6 corelated with higher mortality rates. Furthermore, the authors have identified a
strong and statistically significant correlation between the expression of IL-6 and the inci-
dence of hospital-acquired infections. IL-6 concentration before the diagnosis of pneumo-
nia was made was 433  385 pg/ml, with a maximum peak of 3970  1478 pg/ml on day 7
and a reduction to 219  58 pg/ml on day 11. Following this study the authors concluded
that IL-6 can be useful as an indicator for the development of infections in trauma patients,
and that it directly correlates with clinical outcome.
3. Updates – in fluid resuscitation formulas

In the daily practice more than one type of fluid is used for the volemic resuscitation,
among which crystalloids, colloids, and blood products. From a chemical point of view,
crystalloids are aqueous solutions to which inorganic ions are addes, as well as organic
molecules with low molecular weights. During the last decades new formulas for crystal-
loid solutions have been developed, with different concentrations of potassium, magne-
sium, calcium, and other inorganic ions such as lactate and acetate. The composition of
these solutions is extremely important, as it has a direct impact on cell and tissue function,
as well as an indirect impact on the functionality of certain organs, as well as of certain
physiological pathways such as the coagulation cascade [30].
After administering normal saline, it is redistributed in a short period of time be-
tween the compartments of the extracellular space, and it stays in the body for a long time.
Greenfield et al., have evaluated the effects intravenous normal saline administration has
on hematocrit levels in 28 healthy volunteers. The participants in the study received 10,
20 si 30 ml/kg NaCl 0,9% as bolus, at a rate of 115  4 ml/min, followed by a continuous
infusion at 1-5 ml/kg/h. immediately after the bolus administration they determined the
blood hematocrit and compared it to the stating value, with the measurements showing
statistically significant differences. The administration of 10 ml/kg bolus of normal saline
led to a decrease in hematocrit with 4,5  0,6 (p<0,001), 20 ml/kg bolus led to a decrease
with 6,1  0,4 (p<0,01), while in the group that received 30 ml/kg bolus of normal saline
the hematocrit dropped with 6,3  0,6 (p<0,01). Twenty minutes after the infusion was
started hematocrit was measured again and compared to the value after the bolus dose,
showing an increase in all three patient groups with 1,5  0,8 (p=0,03), 2,4  0,4 (p=0,004),
and 2,3  0,7 (p=0,005) respectively. This study demonstrated that normal saline solution
will diffuse in less than 20 minutes in the extravascular space when administered as intra-
venous bolus [31]. A similar study was carried out by Mullins et al., in 126 patents that
were administered 2 L of normal saline over 2 hours, one day before surgery. They com-
pared hemoglobin before and after the infusion and have calculated the change in blood
volume. The differences before and after the infusion were 1,06  0,06 which shows a 18-
24% retention of the infused solution [32]. Other studies have shown that up to 60% from
the volume of the administered fluid will stay in the body even longer than 6 hours, and
approximately 13% will stay in the intravascular space [33].
For a long time, fluid resuscitation was based on high amounts of normal saline
(NaCl 0,9%), but numerous studies concluded that it leads to hyperchloremic metabolic
acidosis. Waters et al., carried out a prospective study on the impact of normal saline ad-
ministration on the acid-base balance in non-cardiac/non-vascular surgery, which in-
cluded 12 patients undergoing surgical procedures with a duration longer than 4 hours.
They have analyzed arterial blood gas parameters and serum and urinary electrolyte val-
ues, preoperatively and postoperatively. The statistical analysis has shown a significant
increase in lactate from 1,1 0,6 in the preoperative period to la 1,8  1 postoperatively,
and a change in base excess from 0,8  2,3 to -2,7  2,9. Serum chloride concentrations also
increased significantly form 106 3 to 110  5 (p<0,001, r2=0,92) [34]. These findings can be
explained by the fact that the intravenous administration of normal saline increases the
extracellular volume which in turn will dilute the buffer systems, especially the bicar-
bonate buffer system, this phenomenon being called dilution acidosis. Gattinoni et al.,
have simulated this dilution phenomenon by infusion hydrogen peroxide, normal saline,
and Lactated Ringer’s solution. After this study they concluded that the pH of the system
is only modified when CO2 is infused in the solution, which in turn will change the pK
constant following the dissociation of CO2 and bicarbonate [35].
Cervera et al., in an experimental animal study divided the subjects in two groups -
one receiving intravenous normal saline, and the other intravenous lactated Ringer’s.
They have identified statistically significant differences between the groups, with a drop
in pH from 7,4  0,7 to 7,36  0,6 in the normal saline group, in comparison to the lactated
Ringer’s group where no significant change in pH was noticed, from 7,4  0,7 to 7,4  0,9
[36].
Scheingraber et al., carried out a randomized study on 12 patients that were allocated
to two study groups – one receiving normal saline and the other Ringer’s lactate with
equivalent doses of 30 ml/kg/h. They have measured pH, serum sodium, potassium, chlo-
ride, and lactate, as well as the partial pressure of carbon dioxide. In the case of patients
receiving normal saline a hyperchloremic metabolic acidosis could be seen (104 mmol/L
vs 115 mmol/L, pH 7,4 vs pH 7,2), as well as a decrease in base excess [37].
Recent studies have shown that the acidosis induced by the administration of crys-
talloids can be avoided by using solutions that contain anions that the body is able to
metabolize, such as lactate, acetate, citrate, and malate. These are termed balanced crys-
talloids and a few examples of widely used balanced solutions are Sterofundine, Plasma-
Lyte, Hartmann Solution, Lactated Ringer’s, and Acetated Ringer’s. One side effect of ad-
ministering these solutions is the slight decrease in plasma osmolarity, as Lactated
Ringer’s osmolarity is 273 mOsmol/L while measured osmolarity is 254 mOsmol/kg. In-
travenous administration of hypotonic solutions can lead to an increase in cerebral edema
or an increased diuresis.
In polytrauma patients one of the main organs affected by the metabolic imbalances
is the kidney. The kidney can suffer from a direct traumatic injury or can be injured indi-
rectly through massive blood loss leading to hypoperfusion, through delayed resuscita-
tion or rhabdomyolysis. Up to 40% of trauma patients can develop acute kidney injury in
the first phase of treatment, but in this case, it is a reversible dysfunction if correct and
optimal hemodynamic management and fluid resuscitation occur [38,39]. However, kid-
ney injury can also be precipitated by the type and volume of solutions used for fluid
resuscitation.
Feinman et al., in a study on fluid resuscitation in trauma, concluded that the admin-
istration of a high volume of fluids can be associated with the development of hypoxia,
acidosis, coagulopathy, dilution induced hyperfibrinolysis, and multiple organ failure.
Recent guidelines recommend adopting a restrictive fluid management in the first phase
of treatment and avoiding using lactated Ringer’s solution in traumatic brain injury, es-
pecially because of the correlations reported between increased incidence of cerebral
edema and the infusion of large volumes of lactated Ringer’s [40]. Young et al., in their
study on the initial resuscitation in trauma have highlighted the increased capacity of ac-
etate Ringer’s to maintain a better acid-base balance compared to normal saline. Regard-
ing the use of artificial colloids, European guidelines suggest a restrictive use especially
due to their adverse effects on homeostatic mechanisms. On the other hand, Weiskopf and
the Trauma Hemostasis and Oxygenation Research Network (THOR) have reported that
using hydroxy-etyl-starches (HES) products can lead to an adequate fluid resuscitation in
trauma patients, reducing the need for crystalloids and blood products, and without a
negative impact on the kidney [41]. A similar study was carried out by Qureshi et al.,
showing that colloid administration does not increase mortality rates compared to crys-
talloid administration in trauma patients [42].
Another serious complication associated with normal saline administration is due to
the over-physiological chloride concentration that leads to renal vasoconstriction and a
decrease in glomerular filtration rate. Wilcox et al., carried out an experimental study on
the impact of crystalloids on the glomerular filtration rate. They have infused intrarenal
hypertonic saline, Na acetate, dextrose, NaHCO3, NH4Cl, and NH4 acetate. Following the
administration renal blood flow increased abruptly with 10-30% for all types of hypertonic
solutions, which demonstrates that a rapid increase in plasma tonicity leads to renal vas-
odilation. After the renal infusion of NaHCO3, , NH4 acetate and Dextrose the glomerular
filtration rate stayed the same, while in the case of hypertonic saline and NH4Cl renal
blood flow and the glomerular filtration rate decreased after 1-5 minutes to values lower
than those measured before the infusion (p<0,01) due to a severe vasoconstriction. There-
fore, they concluded that glomerular filtration rate and blood flow are both directly af-
fected by the increased reabsorption of chloride following the administration of crystal-
loids with high chloride concentrations [43].
Modifying the Ca2+ plasma concentration through an inadequate fluid resuscitation
can have a direct negative impact on coagulation by the changes in induces in cell polari-
zation, leading to changes in the expression of coagulation factors and in the acid-base
balance. Crowell et al., studied the impact that changes in pH have on coagulation and
reported that a decrease in pH will lead to disturbances in the coagulation factors activity
[44].
Meng et al., have analyzed the impact of pH and temperature on coagulation factor
VIIa (FVIIa) proving a 20% decrease in activity with a decrease in temperature from 37 C
to 33 C and up to 90% decrease in activity was associated with a decrease in pH from 7,4
to 7 [45]. Engstrom et al., after a similar study have shown that a pH decreases from 7,4 to
6,8 will determine an 158% prolongation of the coagulation time [46].
Laszlo et al., have compared the impact of normal saline fluid resuscitation with that
of lactated Ringer’s fluid resuscitation in animal models. They have studied the impact on
coagulation status by analyzing the values of prothrombin time (PT), fibrinogen, and par-
tial thromboplastin time (PTT). At baseline there were no significant differences between
the two groups. After 30 minutes of fluid resuscitation no significant differences were seen
compared to baseline values in the normal saline group (p=0,17), while in the lactated
Ringer’s group significant differences were observed (p=0,02). At the end of the study,
when comparing the two groups, statistically significant differences were seen in PT and
PTT values (p<0.05), while in the normal saline group increased blood loss was observed.
The conclusion of the study was that using lactated Ringer’s for fluid resuscitation de-
creases blood loss and increases hypercoagulability [47].
Another important element in fluid resuscitation is the distribution of the infused
fluids between the intracellular and extracellular compartments, a distribution that is
modulated by the osmotic pressure in different biological compartments. Based on the
osmolarity theory, osmotic pressure is characterized by the quantity of solute and it os-
molarity coefficient. Physiologically, measured osmolarity of plasma is 288mOsmol/kg
H2O, which is equivalent with the calculated plasma osmolarity of 291 mOsmol/L [48].
Jeffrey et al., in a metanalysis compares the clinical effects different balanced crystal-
loid solutions. The metanalysis included 24 trials comparing lactated Ringer’s, Hart-
mann’s solutions, bicarbonate Ringer’s, Normosol, Ringerfundin, Sterofundin, Kabilyte
and Plasmalyte. One o the conclusion was the Plasmalyte determines the lowest increase
in chloride concentration in plasma after infusion (mean difference 0,83 mmol/L, 95%CI
0,03 to 1,64 mmol/L) and the lowest increase in serum lactate (mean difference 0,46
mmol/L, 95% CI 0,05 to 0,87 mmol/L) compared to any other balanced crystalloid. No
statistically significant differences were reported for the serum potassium levels or the pH
values for the solutions included in the study [49].
Ramanathan et al., studied the impact preloading with crystalloid solutions before
cesarean section has on the lactate and pyruvate concentrations and on the base excess
levels. The study was carried out on 4 groups of patients that received normal saline 0,9%,
lactated Ringer’s, lactated Ringer’s with 20 g glucose and Plasmalyte. A significant in-
crease in lactate concentration could be seen in all four groups, while pyruvate concentra-
tion only increased significantly in the group receiving lactated Ringer’s and lactated
Ringer’s with 20 g glucose. No significant differences have been shown for base excess
and the conclusion of the study was that there was no significant differences between the
four solutions in this scenario [50].
Pfortmueller et al., have studied the impact of fluid resuscitation with lactated
Ringer’s vs acetated Ringer’s on the clinical prognosis of patients undergoing major car-
diac surgery. Two groups of patients were included in the study, 73 receiving lactated
Ringer’s, while 75 acetated Ringer’s. No statistically significant differences were found
following the study regarding acid-base balance or hemodynamic status. Both balances
solutions bring about the same benefits [51]. Bradley et al., compared in their study the
impact the administration of colloid vs the administration of crystalloid has on blood vol-
ume, kidney function, and cardiac output. The study included healthy volunteer men that
received 1,5 L Sterofundin Iso, 0,5 L 4% Gelaspan, 0,5 L 4% Gelaspan + 1 L Sterofundin
Iso. The changes in blood volume were calculated by analyzing weight and hematocrit.
Cardiac index, renal cortex perfusion, renal cortex diffusion, renal volume and renal ar-
tery blood flown have been then analyzed by magnetic resonance imaging. Following the
analysis the authors have found an increase in weight and extracellular volume in patients
receiving 1,5 L Sterofundin Iso and 0,5 L 4% Gelaspan + 1L Sterofundin Iso compared to
the volunteers receiving 0,5 L 4% Gelaspan, but no differences in blood volume could be
proven. Renal volume was increased in all groups, but without statistically significant
differences. Furthermore, no significant differences were found regarding cardiac index,
renal cortex perfusion, or renal cortex diffusion [52].
Rajan et al., have studied the impact of intraoperative administration of lactated
Ringer’s on the serum lactate concentrations in patients with no hepatic dysfunction un-
dergoing long surgeries. There were two study groups that received either lactated
Ringer’s or Sterofundin. They concluded that patients receiving lactated Ringer’s had sig-
nificantly higher serum lactate levels at 2, 4, 6, and 8 hours. The pH was comparable be-
tween the two groups, except from the 8-hour analysis when the pH was statistically
lower in patients receiving lactated Ringer’s (7,42  0,1 vs 7,4  0,1). No significant differ-
ences were shown on the bicarbonate, chloride, sodium, potassium, and pCO2 values. The
authors concluded that in the case of longer surgical interventions it is recommended to
administered balanced solutions with acetate rather than lactate [53]. Hassan et al., stud-
ied the changes in acid-base balance and plasma electrolyte concentration after the admin-
istration of normal saline 0.9% compared to Sterofundin Iso in patients with severe trau-
matic brain injury. The study included 66 patients that were randomized in two groups
receiving one of the solutions. After 24 hours in the normal saline group the authors iden-
tified a significant decrease in base excess (-3,2 vs -1,35, p=0,0049), a decrease in plasma
bicarbonate (22,03 vs 23,48 mmol/L, p=0,031), and an increase in serum chloride (115,12 vs
111,74 mmol/L, p< 0,001). In the Sterofundin Iso group they have noted an increase in
serum calcium levels (1,97 vs 1,79 mmol/L, p=0,03) and an increase in serum magnesium
levels (0,94 vs 0,80 mmol/L, p<0,001) compared to the other study group [54].
Lu et al., studied the impact these solutions have on the immune system on animal
models. They analyzed changes in the expression of T-lymphocytes following the admin-
istration of normal saline vs hypertonic saline in 18 Sprague-Dawley hemorrhagic shock
rats. After fluid resuscitation CD4+ lymphocytes in peripheral blood had an increased ex-
pression in both study groups, but the immunological disorders were less severe in the
group receiving hypertonic saline [55].
Wu et al., evaluated the use of the Na+/H+ exchanger inhibitor (NHE-1) on cardiac
protection during fluid resuscitation in hemorrhagic shock. This prospective experimental
study included three groups: one control group, one group that received 15 ml/kg HES
and one that received 3mg/kg benzamide, N-(aminoiminomethyl)-4-[4-(2-furanylcar-
bonyl)-1-piperazinyl]-3-(methylsulphonyl), methanesulfonate (BIIB513) (NHE1-inhibi-
tor) + 15 ml/kg HES. In both study groups the infusion time was 40 minutes. In the group
receiving NHE-1-inhibitor the authors reported a decrease in TNF-, C-reactive protein,
intracellular adhesion mollecule-1 and a decrease in neutrophile infiltrate in the liver tis-
sue. Moreover, using NHE-1 decreases the concentration of alanine aminotransferase in
plasma 24 hours after the resuscitation [56].
More recently it was observed that one of the main adverse reactions that should be
minimized during fluid resuscitation is metabolic acidosis due to its negative impact on
multiple organ systems. Yu et al., carried out a prospective study including 96 patients
with hemorrhagic shock that were divided in two study groups – one control group re-
ceiving normal saline 0.9% and one study group receiving bicarbonate Ringer’s solution.
Shortly after the administration of bicarbonate Ringer’s a decrease in heart rate, lactate,
chloride and sodium concentration was observed. Regarding pH and base excess they
have shown a significant differences between the two groups (p<0,05). The patients in the
bicarbonate Ringer’s group have undergone shorter mechanical ventilation time (2,3 vs
3,5, p<0,05) and have shorter stays in the intensive care unit (3,8 vs 4,1, p<0,05) with a
lower incidence of acute respiratory distress syndrome (8,3% vs 22,9%, p<0,05). No statis-
tically significant differences have been seen regarding 28 day survival [57].
Hafizah et el., in their prospective, randomized trial, compared the changes in acid-
base balance and serum electrolyte concentrations in patients undergoing elective neuro-
surgical procedures depending on the type of solution that was used as maintenance fluid
intraoperatively. There were 2 study groups with 15 patients each, which received either
normal saline 0.9% or Sterofundin ISO. Statistically significant differences were seen in
the group receiving normal saline as a maintenance fluid regarding base excess, bicar-
bonate levels and pH (p<0,01). Four of the patients in this group presented with a drop in
pH under 7,35 and 5 patients with a decrease in base excess value under -4 at the end of
surgery. Serum sodium concentration was significantly higher in this group at the end of
surgery (142,6 2,4 vs 138  2,7 mmol/L, p<0,01), as well as serum chloride levels (105,7 
4,1 vs 113,2 3 mmol/L, p<0,01). The authors concluded that by using Sterofundin ISO a
significantly better control of the acid-base status and ion homeostasis can be attained [58].
Colloids were designed to maintain the infused volume for a longer time in the in-
travascular space through their increased oncotic pressure. Colloids can contain blood
components such as human albumin or can be synthetic or semi-synthetic such as Dex-
trans, Hydroxyethylstarch (HES) and Gelatines. Their main characteristic is that of plasma
volume expansion and this process depends on and is directly influenced by the oncotic
pressure, molecular weight, and half-life of the product [59].
In clinical practice human albumin is used under its iso-oncotic formulation (4-5%
concentration) or hyper-oncotic (concentration 20-25%). Administering human albumin
for volume replacement and fluid resuscitation in critical patients have proven advanta-
geous when compared to crystalloids or other colloidal solutions, but until now the cost-
efficiency benefit has not been proven. Finfer et al., have carried out a randomized multi-
center study on the impact of fluid resuscitation with human albumin compared to crys-
talloids. 6977 patients were included in the study that were randomized in two groups.
The first group included 3497 patients that received human albumin, and the second
group included 3500 patients that received normal saline. The two groups were statisti-
cally homogenous regarding their baseline characteristics. No statistically significant dif-
ferences have been reported between the two study groups regarding number of days on
mechanical ventilation (4,5  6,1 vs 4,3  5,7, p=0,74), length of stay in the ICU (6,5  6,6 vs
6,2  6,2, p=0,44), length of hospital stay (15,3  9,6 vs 15,6  9,6, p=0,30), number of days
on renal replacement therapy (0,5  2,3 vs 0,4  2, p=0,41). The two groups were similar
also regarding de incidence of multiple organ failure (p=0.85) and mortality rates were
similar (726 vs 729, relative risk of death 0,99, 95CI 0,91 to 1,09, p=0,87). Following this
study, the authors came to the conclusion that in the case of critically ill patients using
normal saline or human albumin 4% for fluid resuscitation returns similar results with no
impact on 28-day mortality [60]. Ernest et al., designed a study on the distribution of fluid
in the extracellular space and its impact on oxygen delivery following the administration
of 5% albumin or 0.9% normal saline in patients undergoing cardiac surgery. This ran-
domized prospective study included 40 patients. For data analysis the authors monitored
cardiac index, plasma volume, extracellular fluid volume, and arterial oxygen concentra-
tion at T0, as well as after each fluid infusion. At T0 there were no statistically significant
differences between the two groups. Following study analysis significant differences have
been observed regarding the increase in plasma volume in the group receiving albumin
5% (52  84% vs 9  23%, p<0,05). No significant differences were seen for fluid volume or
DO2. The authors therefore concluded that in the case of cardiac surgery the infusion of
albumin 5% does not bring any benefit over the administration of normal saline when
considering DO2 or interstitial fluid volume, but it can increase up to 5 times the plasma
volume acting as a plasma expander [61]. Horstick et al., studied the impact of early ad-
ministration of albumin on the hemodynamic status and mesenteric microcirculation in
patients suffering from hemorrhagic shock. This was an experimental study on 17 labor-
atory animals that undergone controlled hemorrhagic shock by losing 2,5 ml/kg body
weight of blood in 60 minutes. The animals were assigned to two groups, one group re-
ceiving 20% Albumin as a continuous infusion in 30 minutes and the other group 0.9%
normal saline. They concluded that the administration of Albumin increases mesenteric
microcirculation by significantly decreasing leukocyte adhesion [62]. One of the largest
trials on Albumin administration in fluid resuscitation in patients with traumatic brain
injury included 460 patients, divided in two groups. 231 received Albumin, while 229 re-
ceived normal saline. After 24 months, 71 of the patients in the Albumin group did not
survive, compared to 42 patients in the normal saline group (relative risk 1,63, 95%CI 1,17
to 2,26, p=0,003). Out of the patients with severe TBI (Glasgow Coma Scale, GCS 3-8), 61
of the Albumin group died, compared to 31 receiving normal saline (relative risk 0,74,
95% CI 0,31 to 1,79, p=0,50). This trial has shown that fluid resuscitation with Albumin is
associated with higher mortality rates compared with resuscitation with normal saline
[63].
HES are produced under different concentrations based on the mean molecular
weight (MW), C2-C6 ratio and molar substitution (MS). Depending on their composition
the pharmacokinetics differ as follows: HES 670/0.75 (concentration 6% balanced solution,
MW 670 kDa, MS 0,75, C2-C6 ratio 4,5:1, maximum daily dose 20 ml/kg), HES 600/0.7 (con-
centration 6% saline, MW 600 kDa, MS 0,7, C2-C6 ratio 5:1, maximum daily dose 20 ml/kg),
HES 450/0.7 (concentration 6% saline, MW 480 kDa, MS 0,7, C2-C6 ratio 5:1, maximum
daily dose 20 ml/kg), HES 200/0.62 (concentration 6% saline, MW 200 kDa, MS 0,62, C2-C6
ratio 9:1, maximum daily dose 20 ml/kg), HES 200/05 (concentration 6% saline, MW 200
kDa, MS 0,5, C2-C6 ratio 5:1, maximum daily dose 33 ml/kg), HES 130/0.42 (concentration
6% saline, MW 130 kDa, MS 0,42, C2-C6 ratio 6:1, maximum daily dose 50 ml/kg), HES
130/0.4 (concentration 6% saline, MW 130 kDa, MS 0,4, C2-C6 ratio 9:1, maximum daily
dose 50 ml/kg), HES 70/0.5 (concentration 6% balanced solution, MW 70 kDa, MS 0,5, C2-
C6 ratio 3:1, maximum daily dose 20 ml/kg) [64,65].
From a biochemical point of view, the molecules are degraded intravascularly
through slow substitution of hydroxyl radicals in position C2, C3, and C6 with hydroxy-
ethyl radicals, that will lead to their accumulation in different tissues such as in the spleen,
liver, and kidney. It was proven in numerous studies that this can contribute to histolog-
ical changes such as osmotic necrosis. Most of the studies have reported a series of adverse
reactions to HES administration on the kidney function. Schortgen et al., led a study on
the impact of HES fluid resuscitation on kidney function in patients with severe sepsis.
The study time was 18 months and it included 129 patients, divided in 2 groups – one
group receiving HES and the other group Gelatine compounds. At the beginning of the
study baseline values for serum creatinine were similar in the two groups (143 vs 114
mol/L). For the patients in the group receiving HES the incidence of acute kidney failure
was higher than in the group receiving gelatins (27/65, 42% vs 15/64, 23%, p=0,028), and
incidence of oliguria was also higher (35/62, 56% vs 23/63, 37%, p=0,025). The highest cre-
atinine value was seen in the HES group (225 vs 169 mol/L, p=0,04). After a multivariate
statistical analysist the authors reported a strong correlation between the risk of renal fail-
ure and HES administration in patients with sepsis. (odds ratio 2,57, 95%CI 1,13-5,83,
p=0,026) [66].
A similar study was caried out by Brunkhorst et al., showing that using HES 10%
200/0,5 compared to lactated Ringer’s in patients with severe sepsis, leads to a significant
increase in the need for renal replacement therapy [67]. Huter et al., led an experimental
study including 24 animal kidneys with an experimental model of isolated kidney perfu-
sion over 6 hours. The animals were divided in 3 groups that received 10% HES 200/0,5,
6% HES 130/0,42 and lactated Ringer’s. Immediately after the infusions they observed a
decrease in diuresis in the two groups receiving HES (p<0,01). After analyzing the macro-
phage infiltrate, they have observed an increased macrophagic expression in the group
receiving HES 200/0,5 compared to the group receiving HES 130/0,42 (1,3 1 vs 0,2  0,04,
p=0,044). Osmotic nephron lesions were seen in the two groups receiving HES compared
to the group receiving lactated Ringer’s (p=0,002). Through their study the authors
demonstrated that the administration of 10% HES 200/0,5 solution has a more pronounced
proinflammatory effect compared to 6% HES 130/0,42 and it leads to significant tubular
injury compared to the lactated Ringer’s [68].
Verheij et al., investigated myocardial function in patients that had undergone major
cardiac or vascular surgery and received colloids or crystalloids for the treatment of
hypovolemic hypotension. The study was based on two groups of patients that received
either 0.9% normal saline, HES 6% or Albumin 5%. In the group receiving colloid solutions
the cardiac index increased with 22% compared to the normal saline group where CI in-
creased with only 13% (p<0,005).
Moreover, in the group receiving colloid solutions the left ventricular work index
was higher than in the controls. Plasma volume in the group receiving normal saline in-
creased with 3%, while in the groups receiving colloids it increased with 9% (p<0,001).
The authors concluded that fluid resuscitation for the treatment of hypovolemic hypoten-
sion in patients undergoing cardiac or vascular surgery is preferred to be achieved using
colloids as they significantly increase plasma volume and preload- recruitable cardiac and
left ventricular stroke work index [69]. Annane et al., presents in an international random-
ized trial on the fluid resuscitation in hypovolemic shock (The CRISTAL Randomized
Trial) that at 28 days there are no significant differences regarding mortality of hypovo-
lemic patients resuscitated with colloid vs those resuscitated with crystalloid. However,
the mortality rate at 90 days was lower for patients receiving colloids compared to those
receiving crystalloids for fluid resuscitation. In this trial the authors have highlighted the
fact that in the case of patients receiving colloid solution the mechanical ventilation free
days survival was higher (at 7 days, mean 2,1 vs 1,8 days, mean difference 0,30, 95%CI
0,09 to 0,48 days, p=0,01 and la 28 days, media 14,6 vs 13,5 days, mean difference 1,10,
95%CI 0,14 to 2,06 days, p=0,01). Furthermore, they found significant difference in vaso-
pressor requirements, with higher doses in patients receiving crystalloid solutions (at 7
days mean 5 vs 4,7 days, mean difference 0,30, 95%CI -0,03 to 0,50 days, p=0,04 and la 28
days mean 16,2 vs 15,2 days, mean difference 1,04, 95%CI -0,04 to 2,10 days, p=0,03) [70].
Tissue oxygenation can have a significant impact on clinical outcome in patients with
hemorrhagic shock, being directly related with hemodynamic status, and especially with
tissue perfusion pressure, blood flow, and cardiac output. Kurita et al., in an animal ex-
perimental study analyzed the impact hemorrhagic shock has on gas exchange. Hemor-
rhagic shock was induced through the aspiration of 600 ml of blood, followed by the in-
fusion of 600 ml of HES. After each blood aspiration apnea was induced and desaturation
time to SpO2 <70% measured. The difference in desaturation time between baseline and
the first blood loss was 11,2 seconds (p=0,0052), and 16 seconds after the second blood loss
(p<0,0001). Oxygen consumption decreased during hypovolemia and DO2 was recovered
following the normalization of perfusion pressure [71]. However, aggressive fluid resus-
citation in trauma is known to be associated with a series of complications that have a
significant impact on mortality. This is the reason why a new concept appeared, meaning
the maintenance of permissive hypotension that is able to reduce bleeding, maintain ade-
quate organ perfusion, and reduce mortality [72]. Tran et al., following a metanalysis in-
cluding 722 papers and 1158 patients concluded that permissive hypotension brings fur-
ther benefits in patient survival compared with conventional fluid resuscitation in the case
of hemorrhagic shock. Moreover, it reduces the need for blood transfusion and improves
coagulation status, decreasing bleeding [73]. Another metanalysis of Owattanapanich et
al., identified a decrease in mortality rates in patients in which fluid resuscitation was
carried out maintaining a degree of permissive hypotension. No significant differences
were identified between the study groups regarding incidence of AKI, but statistically
significant differences were shown for acute respiratory distress syndrome and multiple
organ dysfunction [74]. Albreiki et al., in a similar metanalysis on fluid resuscitation with
permissive hypotension in trauma patients with hemorrhagic shock, concluded that the
strategy has a favorable impact on both mortality and recovery [75].
4. Blood transfusion in hemorrhagic shock

In the last decade, the transfusion of blood and blood products has been widely stud-
ied and, in many countries, it is considered one of the components of national security.
Blood and blood products that are currently used in clinical practice are red blood cells,
platelets, and plasma. From plasma fibrinogen concentrate and cryoprecipitate can be fur-
ther obtained [76]. In trauma patients with hemorrhagic shock, a series of studies and
guidelines recommend using red blood cells (RBC), platelets and plasma in different com-
binations and concentrations. The efficiency of RBC is given not only by the volume, but
also by their age and storage [77]. Chang et al., analyzed the quality of RBC depending on
the time and temperature of storage of the blood. They compared blood stored frozen to
fresh blood at 7, 14, 21, 28 and 42 days. Frozen blood in comparison with fresh blood after
7 days had a lower number of red blood cells (3,7 vs 5,3 x 106 cells/uL, p<0,01, hematocrit
33 vs 46,5%, p<0,01, hemoglobin 12 vs 16,5 gram/dL, p<0,01 and pH 6,27 vs 6,72, p<0,01).
The authors concluded that frozen blood loses efficiency in time and the cells become less
resistant to osmotic pressure [78]. Other complications and reactions associated with
transfusions have been described in the literature, such as increased systemic inflamma-
tion, risk of infection, transfusion lung injury (TRALI), and errors concerning administra-
tion [79]. An important trial was carried out by Holcomb et al., regarding the clinical prog-
nosis of the mixture plasma: platelets: red blood cells 1:1:1 vs 1:1:2 ratio in patients with
severe trauma. 338 patients received blood and blood products 1:1:1 during fluid resusci-
tation, and 342 patients received the blood products 1:1:2. Mortality rates did not differ
significantly between the two groups at 24 hours after resuscitation (12,7% vs 17%, differ-
ence -4,2, 95%CI -9,6% to 1,1%, p=0,12), and at 30 days after resuscitation (22,4% vs 26,1%,
difference -3,7%, 95%CI -10,2% to 2,7%, p=0,26). No statistically significant differences
were seen regarding secondary adverse effects associated to trauma such as multiple or-
gan failure, sepsis, venous thromboembolism, acute respiratory distress syndrome, or
other complications related to transfusion. However, the patients that received transfu-
sion based on the 1:1:1 protocol presented with better hemodynamic stability and shorter
bleeding times [80].
In a study carried out by Sohn et al. regarding statistical correlations between lactate
concentrations and shock index, 33,4% out of a total 302 patients in hemorrhagic shock
needed massive transfusion. Lactate concentration correlated positively with the need for
massive blood transfusion (86,1 specificity and 67,8% positive predictive value). By
combining lactate concentration (>4 mmol/L) and shock index >1, the specificity for mas-
sive transfusion requirements increases to 95,5% and positive predictive value to 82,4%
[81].
Many studies have identified the advantage of plasma administration in the initial
phases of fluid resuscitation in the case of hemorrhagic shock, although different meta-
nalysis also reported a higher incidence for multiple organ failure. D’Alessandro et al., in
an animal experimental study, showed the positive impact the administration of plasma
has in hypovolemic shock in lactate levels, on the mitochondrial metabolism, and on pro-
tein oxidation. The author group concluded that this also has a positive impact on coagu-
lation [82].
Makley et al., also carried out an experimental study on animal models with induced
hemorrhagic shock where they compared two groups of subjects, one receiving lactated
Ringer’s for fluid resuscitation, and the other fresh whole blood. The IL-6, IL-10 and mac-
rophage derived chemokines was significantly higher in the animals receiving lactated
Ringer’s compared with those in which resuscitation was based on fresh whole blood. The
group that received crystalloid solutions suffered lung injury, with increased pulmonary
capillary permeability. No significant differences have been noted between the study
groups regarding mortality rates [83].
Seheult et al., studied retrospectively the clinical impact of transfusion of less than 4
low titer group O whole blood (LTOWB) units in trauma patients. They included 135 pa-
tients receiving a mean of 2 units of LTOWB and 135 patients receiving conventional blood
products. The found significant differences of mortality between the groups (24,4% vs
18,5%, p=0,24), mortality at 24 hours (12,6% vs 8,9%, p=0,033%), length of ICU stay, and
length of hospital stay. The time passed until normalization of lactate levels was also dif-
ferent between the two study groups with median 8,1 hr. vs 13,2 hr., p=0,05 in patients
that received LTOWB [84]. A similar study was carried out by Zhu et al. on remote dam-
age resuscitation. They administered LTOWB during transport in the pre-hospital phase
and compared it with the administration of crystalloids. The study results showed a de-
crease in mortality for patients that benefited from the LTOWB resuscitation formula com-
pared to conventional crystalloid resuscitation [85].
In trauma patients one of the main complications refers to dysfunctions in the coag-
ulation cascade; these can also be influenced by the transfusion management [86]. Spinella
et al., studied the impact of warm fresh whole blood (WFWB) transfusion on acute coag-
ulopathy in trauma patients and compared it with the administration of stored compo-
nents (CT). There were two study groups; the first included 100 patients that received
WFWB, red blood cells, and plasma. The second group included 254 patients that received
red blood cells, plasma but no WFWB. Baseline values such as hemoglobin, international
normalized ratio, base deficit, systolic blood pressure, ISS and Glasgow Coma Scale were
comparable in both groups. An increased survival rate was seen in those patients who
received WFWB compared to those who received CT (96% vs 88%, p=0,018) [87].
A similar study was conducted by Sperry et al., with 501 participants with trauma
associated with a risk of hemorrhagic shock, on the efficacy and clinical impact of pre-
hospital administration of thawed plasma. Study participants were divided into two
groups, 230 patients receiving plasma, and 271 patients receiving conventional resuscita-
tion with crystalloid and colloid solutions. Mortality at 30 days was significantly lower in
patients receiving plasma during the fluid resuscitation (23,2% vs 33%, difference -9,8%,
95%CI -18,6 to -1%, p=0,03). No differences have been noted for acute respiratory distress
syndrome, nosocomial infections and multiorgan failure [88].
Adverse effects of hemorrhagic shock in trauma patients are related to a series of
multiorgan complications that are further associated with endothelial hyperpermeability.
Endothelial hyperpermeability is a consequence of apoptosis of endothelial cells. Yu et al.,
in an experimental study on the molecular pathways involved in endothelial dysfunction
associated with hemorrhagic shock have identified an increase in the expression of
CD146+ AnnexinV+ that further increases apoptosis of these cells. Animal models with
induced hemorrhagic shock received fresh frozen plasma (FFP) transfusion, and have
shown a decrease in the expression of pro-apoptotic cells, a decrease in vascular hyper-

permeability, leading the authors to the conclusion that early plasma administration in
fluid management of trauma patient with hemorrhagic shock might be beneficial [89].
Curry et al., has led a randomized trial on the impact of cryoprecipitate administra-
tion in the early phases of resuscitation of trauma patients with hemorrhagic shock. There
were two study groups – one group received standard treatment, and the other received
cryoprecipitate in the early fluid resuscitation phase. 85% of the patients the study group
received cryoprecipitate in the first 90 minutes following hospital admission, and fibrino-
gen values were maintained in the higher range (approx. 1,8g/L) throughout the time of
active bleeding. No statistically significant differences have been shown regarding 28-day
mortality following this study [90].
A series of new components based on blood and blood products have recently been
developed in the attempt to minimize vascular hyperpermeability, to reduce endothelial
inflammation and edema following hemorrhagic shock. One of these components is the
prothrombin concentrate. Shibani et al., carried out an in vitro study on the protection of
endothelial cells derived from the prothrombin complex concentrate and compared it to
that given by fresh frozen plasma or albumin. In the same study the authors also designed
an in vivo component in hemorrhagic shock patients that also suffered from lung injury.
The in vitro analysis has reported a strong inhibition of the endothelial cell permeability
after the administration of FFP and prothrombin complex concentrate, as well as an in-
creased restoration on adherence junctions in endothelial cells. The in vivo results showed
significant protection again vascular permeability induced by FFP and prothrombin com-
plex concentrate [91].
5. Conclusions
In the last decade important progress has been made regarding the understanding of
mechanisms underlying hemorrhagic shock, but also of cellular and molecular mecha-
nisms involved in adverse effects of shock, but also of fluid resuscitation. Fluid resuscita-
tion management has changed considerably through the development of new colloid and
crystalloid solutions meant to counteract and minimize associated adverse effects. The
research focused on the most important pathological mechanisms associated with hemor-
rhagic shock, such as coagulopathy, inflammation, infection, and complications related to
massive transfusion. Nevertheless, currently there is no standard formula to be applied to
all patients. The key in the day-to-day practice regarding therapeutic management and
fluid resuscitation of these patients is in the optimization of therapeutic models and adapt-
ing these models based on the individual clinical features of each patient. Further studies
are needed in order to establish a therapeutic protocol and a combination of substances to
be standardly used in fluid resuscitation, that could minimize side effects and maximize
the efficacy of fluid resuscitation methods for trauma patients.
Author Contributions: Conceptualization, A.F.R. and S.A.R.; methodology, A.F.R. and A.S.R.; soft-
ware, D.T., M.P. and O.H.B; validation, A.P. and D.S.; formal analysis, S.E.P. and D.L.P.; investiga-
tion, D.N.G. and M.E.P.; resources, L.V. and A.F.R.; data curation, S.E.P., D.T., D.C. and M.A.L.;
writing—original draft preparation, A.F.R. and A.S.R.; writing—review and editing, S.E.P., D.L.P.
and A.P.; visualization, D.S. and D.T.; supervision, O.H.B., S.E.P. and M.P.; project administration,
O.H.B., D.T. and L.V.; funding acquisition, A.F.R. All authors have read and agreed to the published
version of the manuscript.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
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Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 8 August 2022 doi:10.20944/preprints202208.0141.

Update on Current Concepts in Management of Severe

macy, Timisoara, Romania

versity of Medicine and Pharmacy, Timisoara, Romania

dragosgarofil@gmail.com (D.N.G.), dan.corneci@umfcd.ro (D.C.), dianaloreta_paun@yahoo.com (D.L.P.); adri-

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2. Pathophysiology pathways in hemorrhagic shock

3. Updates – in fluid resuscitation formulas

4. Blood transfusion in hemorrhagic shock

shown a decrease in the expression of pro-apoptotic cells, a decrease in vascular hyper-

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