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Hypertonic saline in the traumatic hypovolemic

shock: meta-analysis

Jia-Wei Wang, MD, PhD, Jin-Ping Li, MD, PhD, Ying-lun Song, MD,
Ke Tan, MD, PhD, Yu Wang, MD, Tao Li, MD, Peng Guo, MD,
Xiong Li, MD, PhD, Yan Wang, MD, and Qi-Huang Zhao, MD, PhD*
Department of Neurosurgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, P.R. China

article info abstract

Article history: Background: A wealth of evidence from animal experiments has indicated that hypertonic
Received 13 December 2013 saline (HS) maybe a better choice for fluid resuscitation in traumatic hypovolemic shock in
Received in revised form comparison with conventional isotonic saline. However, the results of several clinical trials
16 March 2014 raised controversies on the superiority of fluid resuscitation with HS. This meta-analysis
Accepted 15 April 2014 was performed to better understand the efficacy of HS in patients with traumatic hypo-
Available online xxx volemic shock comparing with isotonic saline.
Materials and methods: According to the search strategy, we searched the PubMed, EMBASE,
Keywords: and the Cochrane Central Register of Controlled Trials, which was completed on October
Hypertonic saline 2013. After literature searching, two investigators independently performed the literature
Traumatic hypovolemic shock screening, assessment of quality of the included trials, and data extraction. Disagreements
Meta-analysis were resolved by consensus or by a third investigator if needed. The outcomes included
Randomized controlled trial mortality, blood pressure, fluid requirement, and serum sodium.
Results: Six randomized controlled trials were included in the meta-analysis. The pooled
risk ratio for mortality at discharge was 0.96 (95% confidence interval [CI], 0.82e1.14),
whereas the pooled mean difference for the change in systolic blood pressure from base-
line and the level of serum sodium after infusion was 6.47 (95% CI, 1.31e11.63) and 7.94
(95% CI, 7.38e8.51), respectively. Current data were insufficient to evaluate the effect of HS
on the fluid requirement for the resuscitation.
Conclusions: The present meta-analysis was unable to demonstrate a clinically important
improvement in mortality after the HS administration. Moreover, we observed HS
administration maybe accompanied with significant increase in blood pressure and
serum sodium.
2014 Elsevier Inc. All rights reserved.

1. Introduction hypovolemic shock have long been recognized and intensive

As a leading cause of death and morbidity worldwide,
hypovolemic shock resulting from traumatic injury has
received considerable attention in the clinical practice [1].
Unfortunately, although the deleterious effects of traumatic
researches have been carried out in the area, the strategies of
fluid resuscitation in the patients with traumatic hypovolemic
shock remain controversial [2].
It is well known that conventional fluid resuscitation
protocols posit an important role of isotonic saline such as

* Corresponding author. Department of Neurosurgery, Beijing Chao-Yang Hospital, Capital Medical University, 8 South Gongti Road,
Beijing 100020, P.R. China. Tel.: 86 10 85231761; fax: 86 10 85231761.
E-mail address: chaoyanghospital@126.com (Q.-H. Zhao).
0022-4804/$ e see front matter 2014 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.jss.2014.04.027
2 j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 4 ) 1 e7
normal saline and lactated ringers in the treatment of patients
with traumatic hypovolemic shock [3]. According to the
Advanced Trauma Life Support guidelines, aggressive fluid
resuscitation with up to two or more liters of isotonic saline is
suggested [4]. However, the side effects of large-volume
isotonic saline are also concerned. Since the intravascular
fluid can leak into the interstitial space because of the
increased capillary permeability in the setting of trauma,
large-volume resuscitation may cause water-logging effects
and cell swelling, which can result in organ dysfunction and
ultimate death [5]. Furthermore, it is reported that the
administration of large-volume isotonic saline is associated
with significantly increased inflammatory response [6],
whereas the latter also can exaggerate the water-logging
effects. These issues have led to increasing enthusiasm about
the development of alternative approaches in fluid resusci-
tation [7].
In recent years, hypertonic saline (HS) has emerged as an
attractive alternative in fluid management in a variety of
clinical practices including traumatic hypovolemic shock [8].
A wealth of evidence from animal experiments has indicated
that treatment with small volume of HS is able to effectively
restore the hemodynamic stability and decrease the mortality
in the models of traumatic hypovolemic shock [9]. The pro-
tective mechanism of HS may mainly involve its ability to shift
fluid from interstitial and intracellular space to intravascular
space by establishing the osmotic gradient across the vessel
and cell [10]. Moreover, HS can modulate the overwhelming
inflammatory response after trauma, which contributes to
disturb the vicious inflammation cascades [11]. Previous
several clinical trials have also shown that small-volume
resuscitation with HS maybe superior to conventional fluid
resuscitation with isotonic saline [8,9]. However, the impact of
these trials on clinical practices has been limited because of
various reasons such as small sample size and different
research endpoints. Therefore, to better understand the effi-
cacy of HS in patients with traumatic hypovolemic shock, we
performed this meta-analysis of randomized controlled trials
(RCTs) in the area.
2. Materials and methods
2.1. Study identification
We performed a systematic review of the published literature
to identify all randomized controlled clinical trials in which
HS has been used for the treatment of patients with traumatic
hypovolemic shock in comparison with isotonic saline.
Studies that were either not RCTs or that did not directly
involve the effects of HS on the treatment of patients with
traumatic hypovolemic shock were eliminated.
2.2. Search strategy
Based on the text words or MeSH terms such as saline solu-
tion, hypertonic, hypertonic saline, wounds and injuries,
trauma, hypovolemia, and shock, an electronic search
for relevant articles was conducted on PubMed, EMBASE, and
the Cochrane Central Register of Controlled Trials (CENTRAL)
without language limitation. We also complemented this by
using the Related Articles function on PubMed and searching
the reference lists of relevant articles. For full details of the
search strategy, see Supplementary Data File 1. The search
was performed independently by two investigators and was
completed on October 2013.
2.3. Literature screening
After literature search, two investigators independently
reviewed the titles and abstracts of all studies identified and
excluded those that were obviously irrelevant. The trials that
totally did not involve the clinical practice of HS alone were
excluded in the final analysis. The full articles of the
remaining studies were then retrieved and independently
reviewed by them using a structured form to determine
eligibility and extract data. When the trials included multiple
arms of patients with the treatment of HS alone or HS with
colloids, the data from the patients with the treatment of HS
alone without colloids were extracted. Disagreements were
resolved by consensus or by a third investigator if needed. We
contacted study authors for clarifications and further infor-
mation as necessary.
2.4. Quality assessment
The quality of eligible studies was formally evaluated by using
the Cochrane Collaborations tool for assessing the risk of bias
in RCTs. Specifically, studies were judged on (1) the adequacy
of the random sequence generation, allocation concealment,
and blinding; (2) the completeness of outcome data; (3) the
possibility of selective outcome reporting; and (4) the exis-
tence of other potential sources of bias.
2.5. Data extraction
We extracted the following data from each study: its design,
objective, number of patients, method of delivery, timing of
measurements, main results of the study, and follow-up re-
sults. The primary outcome assessed was mortality at
discharge. The secondary outcomes included changes of the
systolic blood pressure after the HS administration from
baseline, fluid requirements in the research period scheduled
for each trial, and the level of serum sodium after the
administration of HS.
2.6. Statistical analysis
A homogeneity-based method of meta-analysis was per-
formed using Review Manager for Windows(version 5.2, The
Cochrane Collaboration and Update Software) for prospective
RCTs. Homogeneity between studies was assessed by means
of standard Cochran Q and I2 statistics. Homogeneity was
prespecified as P > 0.10 or I2 < 50%. A fixed-effect model was
used to merge the values of relative risk and mean difference
and to estimate the overall effect size when the homogeneity
between studies was reached. Otherwise, a random-effect
model was used in the statistics. Overall effect, risk ratio,
mean difference, and 95% confidence interval (CI) were pre-
sented in the present systematic review.
 j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 4 ) 1 e7 3

Table e The baseline characteristics of the six included trials.

Study and year Groups Study characteristics

Number of Age (y, Study fluid Treating Outcome measures

patients mean) (250 mL) place

Vassar 1990 [17] Experimental 32 32 HS ER Mortality, SBP, serum sodium

Control 27 38 LR
Younes 1992 [16] Experimental 35 31 HS ER Mortality, MAP, serum sodium, fluid
Control 35 31 NS requirement
Vassar 1993a [15] Experimental 85 32 HS PH Mortality, SBP, serum sodium
Control 84 31 NS
Vassar 1993b [14] Experimental 50 31 HS PH Mortality, SBP, serum sodium
Control 45 37 LR
Cooper 2004 [13] Experimental 114 38 HS PH Mortality, SBP, serum sodium
Control 115 37 LR
Bulger 2011 [12] Experimental 256 36.8 HS PH Mortality, SBP, serum sodium, fluid
Control 376 36.2 NS requirement

ER emergency room; LR lactated ringers; MAP mean arterial pressure; NS normal saline; PH prehospital; SBP systolic blood pressure.

3.2. Risk of bias in included studies

3. Results
3.1. Characteristics of included studies
In total, 66 articles were initially identified, of which 60 articles
were excluded, leaving six studies for final analysis. Figure 1
described the flow diagram of search results and study selection.
All the six included studies were prospective RCTs [12e17].
A total of 1254 participants were enrolled in the six trials,
among which 567 patients (45.2%) were included in the group
with HS treatment. The average age of participants in the
included studies ranged from 31e38 y. All the included trials
had distinct inclusion and exclusion criteria. Each trial
described the baseline characteristics of the enrolled partici-
pants, and there were no significant differences in the baseline
characteristics of participants between groups in these trials.
Table summarized the baseline data of the six included trials.
The concentration and volume of HS used in the six
included trials was 7.5% and 250 mL, whereas the control
groups were treated with 250 mL of normal saline in the three
trials [12,15,16] or 250 mL of lactated Ringer solution in the
three trials [13,14,17].
Each trial reported that the study fluid was provided in the
identical containers, and all the investigators were blinded
to the treatment assignment. Five trials [12e15,17] had
adequate description of allocation concealment while the
allocation concealment is unclear in one trial [16]. There
was no loss to follow-up in four trials [14e17]and the other
two trials reported loss to follow-up [12,13]. The intention-
to-treat analysis was used to treat the missing data in the
two trials with a total of five participants lost to follow-up
[12,13].
3.3. Effect of HS on the mortality at discharge
As shown in Figure 2, each included trial reported the
effect of HS on the mortality at discharge in patients with
traumatic hypovolemic shock. The pooled risk ratio of
mortality at discharge using HS compared with isotonic
saline was 0.96 (95% CI, 0.82e1.14, P 0.66), indicating that
there was no significant difference in mortality between
the groups treated with either hypertonic or isotonic
saline.

Fig. 1 e Flow chart of study inclusion in the present meta-analysis.

4 j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 4 ) 1 e7

Fig. 2 e Forest plot comparing the mortality at hospital discharge between the groups treated with either HS or isotonic
saline. M-H [ ManteleHaenszel. (For interpretation of the references to color in this figure, the reader is referred to the web
version of this article).

3.4. Effect of HS on the change in systolic blood pressure 3.5. Effect of HS on the fluid requirement

In the six included studies, five trials investigated the systolic
blood pressure [12e15,17], whereas one trial studied the mean
arterial pressure [16] before and after the administration of
either hypertonic or isotonic saline. Furthermore, the change
from baseline in systolic blood pressure was recorded directly
in two studies [14,15]. The additional three studies [12,13,17]
recorded the systolic blood pressure before and after the
treatment of study fluid, in which the data presented in the
primary studies were translated into change from baseline in
the final meta-analysis according to the Cochrane Handbook
for Systematic Reviews of Interventions.
As indicated in Figure 3, the pooled mean difference of
change in systolic blood pressure using HS compared with
isotonic saline in five included studies was 6.47 (95% CI,
1.31e11.63, P 0.01), which suggested that HS could signifi-
cantly increase the systolic blood pressure in patients with
traumatic hypovolemic shock. After the exclusion of the
three studies with translating data [12,13,17], the sensitivity
analysis was done, which indicated the increase in systolic
blood pressure by the treatment of HS remained significant
(mean difference: 11.62, 95% CI, 1.32e21.92, P 0.03). In
addition, mean arterial pressure in the study conducted by
Younes et al. [16] showed significant increase in HS-treated
patients comparing with the one treated with normal saline
(P < 0.01).
There were two trials reported fluid requirement in the six
included studies. Considering the clinical heterogeneity of
different research protocols, the two studies were just
described as followed. In a prospective double-blind study,
Younes et al. [16] studied the effect of 250 mL of HS treatment
on the fluid requirement to maintain systolic blood pressure
reached 100 mm Hg in patients with severe hypovolemia. They
found that significantly less volume of fluids were required to
restore systolic pressure in the group treated with HS than the
one given isotonic saline during the resuscitation process
(median: 1000 mL versus 2000 mL, P < 0.01), which suggested
fluid resuscitation with HS was beneficial in reducing the fluid
requirement in shock. In another RCT conducted by Bulger et al.
[12], the researchers investigated the effects of HS in patients
after the severe injury with hemorrhagic shock. Initial resus-
citation with 250 mL of HS was followed with additional fluids
guided by local emergency medical services protocols. They
found that the total fluids requirement during the first 24 h in
the group treated with HS was similar to the one with isotonic
saline treatment (11.6  10.4 versus 12.3  12.1 L, P > 0.05).
3.6. Effect of HS on the serum sodium after infusion
Each included trial investigated the serum sodium after the
infusion of HS in patients with traumatic hypovolemic shock,

Fig. 3 e Forest plot comparing the change in systolic blood pressure after the infusion of study fluid from baseline between
the groups treated with either HS or isotonic saline. IV [ inverse variance. (For interpretation of the references to color in
this figure, the reader is referred to the web version of this article).
 j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 4 ) 1 e7
Fig. 4 e Forest plot comparing the level of serum sodium after the infusion of study fluid at emergence admission between
the groups treated with either HS or isotonic saline. IV [ inverse variance. (For interpretation of the references to color in
this figure, the reader is referred to the web version of this article).
among which four studies [12e15] reported the level of serum
sodium after infusion of HS when arriving at emergency
department. As shown in Figure 4, the pooled mean difference
of serum sodium at arrival in emergency department in the
four trials using HS compared with isotonic saline was 7.94
(95% CI, 7.38e8.51, P < 0.00001), indicating that infusion of HS
could significantly increase the serum sodium. In the study
conducted by Younes et al. [16], they found that the serum
sodium in the group with HS treatment was significantly
increased at 15 min after infusion (158  17.7 versus 143  23.7,
P < 0.01) and retuned to pretreatment levels 30 min later
(146  17.7 versus 141  29.6, P > 0.05) compared with the one
in the group treated with isotonic saline. However, Vassar
et al. [17] found that there was no significant difference in
serum sodium at 4, 8, and 24 h after infusion of study fluid
between the groups treated with either HS or isotonic saline
(P > 0.05).
4. Discussion
In the present meta-analysis of six randomized controlled
clinical trials, we investigated the effects of HS administration
on the mortality, blood pressure response, fluid requirement,
and serum sodium in patients with traumatic hypovolemic
shock. The main findings are as follows: (1) there was no sig-
nificant difference in mortality at discharge in the group with
HS treatment comparing with the one treated with isotonic
saline; (2) HS was more effective than isotonic saline in the
blood pressure restoration; (3) current data were insufficient
to evaluate whether HS can reduce the fluid requirement in
the resuscitation process; and (4) compared with isotonic sa-
line treatment, HS administration may tend to significantly
increase the level of serum sodium early after infusion.
In the present meta-analysis, trials from before 2000 and
trials from 2000 and after were combined for two reasons
despite that there was improvement in the treatment of
traumatic hypovolemic shock around about the year of 2000.
On the one hand, considering that the patients in the sub-
groups in each trial included in the present meta-analysis
were subjected to the same management criteria except for
the study fluid; the effects of the variance within the treat-
ment of traumatic hypovolemic shock that might affect the
outcome were probably randomly allocated to the subgroups.
On the other hand, all the therapeutic strategies in each trial
5
were performed according to the protocols on fluid resusci-
tation issued at the corresponding years, which would
contribute to minimize the effects of confounding parameters
in administration. In addition, as we all know, the prehospital
interventions and emergency department care are the two
main important aspects involved in the management and
treatment of traumatic hypovolemic shock [3]. Mortality at
discharge was selected as the primary outcome in the present
meta-analysis, whereas HS used either out-of-hospital or in
emergency room are considered to have potential effects on
the mortality at discharge. Thus, it maybe appropriate to
combine trials that administered the resuscitation fluid pre-
hospital or on hospital arrival.
In recent years, great interest has been focused on
searching an ideal solution for the fluid resuscitation in
patients with traumatic hypovolemic shock [8,9]. Because a
series of animal experiments supported that the use of HS was
beneficial in improving outcomes in animals with shock
states, HS was widely used in clinic and considered as an
alternative choice for the conventional isotonic fluid. How-
ever, our meta-analysis failed to show that HS could signifi-
cantly improve mortality at discharge in patients with
traumatic hypovolemic shock compared with isotonic saline.
The possibility that we did not detect significant difference
may result from the following causes. On the one hand, all the
six included studies in the present meta-analysis, especially
the early clinical trials [14e17], are limited by sample size and
statistical power. As describe in Table, the largest trial
included in our meta-analysis was the research conducted by
Bulger et al. in 2011 [12], of which the number of final enrolled
patients were only 23% of the proposed sample size because of
the early stopping of the trial. On the other hand, in this meta-
analysis, the mortality in groups was mainly investigated at
hospital discharge in the included trials. Only one in six
studies reported the survival rate at 6 months after trauma
[13]. Previous studies have indicated that follow-up up to
12 mo or even longer seem to be appropriate to precisely
evaluate the outcome in patients with trauma [18,19]. The
short period of follow-up maybe not enough to assess the
long-term effect of HS administration.
Despite no significant difference in mortality found in both
groups, present meta-analysis has demonstrated that HS
treatment contributed to significant increase in blood pres-
sure in the group compared with the one with isotonic saline.
Rapid restoration of circulating volume in shock states has
6 j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 4 ) 1 e7
been shown theoretically to improve survival. Nevertheless,
we recognize that the increase of blood pressure is merely a
practical goal but maybe a moot point if not accompanied by
improved patient functional outcomes. Furthermore, suc-
cessful resuscitation from shock states does not guarantee an
improved outcome as demonstrated in our meta-analysis and
various previous studies. Notwithstanding this crucial limi-
tation, we believe that data on the effective restoration of
hypotension are valuable to practicing clinicians in the daily
management of patients with traumatic hypovolemic shock,
as blood pressure is undoubtedly included in the goal-directed
therapy guideline for the fluid resuscitation in patients with
shock [20,21].
As we all know, the fluid overload accompanied with fluid
resuscitation in patients with shock is a critical issue
deserving attention because it can lead to vicious conse-
quences such as cell swelling and organ dysfunction. Thus,
fluid requirement is chosen as the secondary outcome in the
present meta-analysis. In the six included studies, only one
study clearly reported that the fluids were administered ac-
cording to the blood pressure goal, and its results indicated
that HS could significantly reduce the total volume of fluid
required for resuscitation in patients with shock in compari-
son with the isotonic solution [16]. The other studies just
described additional fluid followed by the initial study fluid
such as HS was given as guided by local protocols, which re-
ported no significant difference in the total fluid requirement
during the first 24 h after injury between the HS group and
the isotonic saline group [12]. Therefore, although numerous
animal experiments have already confirmed the effect of
small-volume resuscitation arising from HS administration
[22,23], current clinical data are insufficient to evaluate
whether HS can reduce the fluid requirement in the resusci-
tation process.
It is also important to consider any direct negative effects
such as hypernatremia associated with the administration
of HS. In the present meta-analysis, the effect of HS on serum
sodium was also studied. Our study indicated that the
administration of HS may tend to increase the level of serum
sodium early after infusion, which is consistent with previ-
ous researches [8]. A wealth of previous data has suggested
the hypernatremia after the infusion of HS is transient and
will not last beyond 24 h, especially after single dose of
infusion. Furthermore, a recent review has confirmed that
the transient hypernatremia after doses administered in the
study does not have any adverse consequences [24]. In
addition, we should note that the study performed by Bulger
et al. [12] was stopped early for futility and potential safety
concern and post hoc analysis showed that there was an in-
crease in mortality among those patients who did not receive
any blood transfusion. The authors considered that mortality
was higher in the group not receiving blood transfusion
because of a shift toward earlier mortality in the hypertonic-
treated arms such that some patients died before blood
transfusions were available or administered [12]. To date, no
neurologic deficits or central pontine myelinolysis that may
occur theoretically during the infusion of HS has been re-
ported in any patient [8,9,17]. More studies in the future
maybe beneficial to understand the potential side effects of
HS treatment.
5. Conclusions
In summary, the present meta-analysis was unable to
demonstrate a clinically important improvement in mortality
as a result of administration of HS. Moreover, we observed
administration of HS maybe accompanied with significant
increase in blood pressure and serum sodium. Further pro-
spective RCTs with larger sample size and enough statistical
power are needed to clarify current issues regarding the use of
HS in patient with traumatic hypovolemic shock.
Acknowledgment
This work was supported by the grant from Youth Fundation
of Beijing Chao-Yang Hospital, Capital Medical University
(No.YQ201314).
Authors contributions: J.-W.W., J.-P.L., Y.-l.S., K.T., Y.W.,
T.L., P.G., X.L., and Y.W. contributed to analysis and inter-
pretation of data. J.-P.L., Y.-l.S., K.T., Y.W., T.L., P.G., X.L., and
Y.W. collected the data. J.-W.W. wrote the article and was in
charge of obtaining funding. Q.-H.Z. was responsible for
conception and design and critical revision of the article.
Disclosure
The authors reported no proprietary or commercial interest in
any product mentioned or concept discussed in the article.
Supplementary data
Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.jss.2014.04.027
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