Hindawi Publishing Corporation

BioMed Research International

Volume 2014, Article ID 421291, 9
pages
http://dx.doi.org/10.1155/2014/421291

Review Article
Vasopressin in Hemorrhagic Shock:
A Systematic Review and Meta-Analysis of Randomized
Animal Trials

Andrea Pasquale Cossu,1 Paolo Mura,1 Lorenzo Matteo De Giudici,1

Daniela Puddu,1 Laura Pasin,2 Maurizio Evangelista,3 Theodoros Xanthos,4
Mario Musu,1 and Gabriele Finco1
1
Department of Medical Sciences “M. Aresu”, University of Cagliari, SS.554 Bivio per Sestu, 09042 Monserrato,
Italy
2
Department of Anesthesia and Intensive Care, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milano,
Italy
3
Department of Anesthesia and Intensive Care, Catholic University, Via Giuseppe Moscati 31, 00198 Roma,
Italy
4
MSc Program “Cardiopulmonary Resuscitation”, University of Athens, Medical School, Hellenic Society
of
Cardiopulmonary Resuscitation, 75 Mikras Asias Street, 11527 Athens, Greece

Correspondence should be addressed to Andrea Pasquale Cossu;

[email protected] Received 8 May 2014; Accepted 28 July 2014; Published 1

September 2014

Academic Editor: Ahmed Abdel-

Latif

Copyright © 2014 Andrea Pasquale Cossu et al. This is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original
work is properly cited.

Objective. The latest European guidelines for the management of hemorrhagic shock suggest the use of vasopressors (nore-
pinephrine) in order to restore an adequate mean arterial pressure when fluid resuscitation therapy fails to restore blood
pressure. The administration of arginine vasopressin (AVP), or its analogue terlipressin, has been proposed as an alternative
treatment in the early stages of hypovolemic shock. Design. A meta-analysis of randomized controlled animal trials.
Participants. A total of 433 animals from 15 studies were included. Interventions. The ability of AVP and terlipressin to reduce
mortality when compared with fluid resuscitation therapy, other vasopressors (norepinephrine or epinephrine), or placebo was
investigated. Measurements and Main Results. Pooled estimates showed that AVP and terlipressin consistently and significantly
improve survival in hemorrhagic shock (mortality: 26/174 (15%) in the AVP group versus 164/259 (63%) in the control arms;
OR = 0.09; 95% CI 0.05 to 0.15; � for effect < 0.001; � for heterogeneity = 0.30; ��2 = 14%). Conclusions. Results suggest that
AVP and terlipressin improve survival in the early phases of animal models of hemorrhagic shock. Vasopressin seems to be
more effective than all other treatments, including other vasopressor drugs. These results need to be confirmed by human
clinical trials.

1. Introduction leading causes of cardiac arrest [3, 4]. Appropriate

management and treatment are necessary to prevent
Trauma is the principal cause of death for people under 35 adverse events and outcomes [5–7]. The early phase of
years of age, with more than 5 million injury-related hemorrhagic shock is characterized by a vasoconstrictive
deaths every year in the world. Approximately 30% of response and if the shock is left untreated it can lead to
these deaths can be attributed to hemorrhagic shock [1, vasodilation that does not respond to conventional
2]. Untreated prehospital hemorrhagic shock is one of the
resuscitation strategies [8, 9]. Prehospital hemorrhagic
shock treatment should be focused on maintaining
adequate mean arterial pressure (MAP) along with organ
perfusion up until arrival at the hospital [10, 11].
Small volume resuscitation with colloids or
hyperoncotic fluids may be useful during early phases of
uncontrolled bleeding [12–14]. Recent international
guidelines suggest that vasopressors may also be required
to maintain tissue perfusion where fluid resuscitation itself
does not achieve the expected goal [15].
Arginine vasopressin (AVP) is an endogenous neuro-
hypophysial hormone with an antidiuretic function.
The
2 BioMed Research International
BioMed Research International 3
most important AVP pulmonary flow [30]. e title/abstract level by two
release stimulus is the Recent animal studies have t investigators, with
plasma osmo- lality shown that AVP treatment divergences resolved by
variation followed by can achieve hemodynamic
h consensus and then, if
blood pressure variations optimization during o potentially pertinent,
[16– prehospital hemorrhagic d retrieved as a complete
18]. AVP also suppresses shock, while fluids and s article.
nitric oxide (NO) catecholamines showed Inclusion criteria for
production [19]. The AVP neither improvement of 2.1. Search Strategy. All potentially relevant studies
release may also be hemodynamic parameters randomized animal trials were random allocation to
suppressed by increased nor sur- vival [1, 31, 32]. using AVP or terlipressin treatment; animal
levels of norepinephrine AVP use is associated in hypovolemic shock were experimental design;
and the increased release with some adverse effects identified. Relevant studies comparison of AVP or
of NO from vascular such as ischemic were independently terlipressin (with or
endothelium of the complications especially in searched by two trained without fluid
posterior pituitary gland cardiac, splanchnic, and investi- gators in Google administration) versus
[20, 21]. Terlipressin is a skin circulation [33]. The Scholar and PubMed placebo or fluids or
long-acting synthetic decreased gut perfusion (updated November 4, catecholamines or both
analogue of AVP, may determine tissue 2013). The full PubMed fluids plus catecholamines.
proposed in the septic necrosis with subsequent search strategy, including Exclusion criteria were
shock management as a translocation of bacteria keywords AVP, arginine duplicate publications,
rescue therapy, when that promotes the vasopressin, terlipressin, human trials, and studies
adequate MAP values are development of sepsis in and hemorrhagic and with no data on survival.
difficult to reach with the postresuscitation phase hypovolemic shock, was Two investigators selected
standard therapy. It is [34]. The increased developed according to studies for the final
characterized by a longer expression of the V1 Biondi- Zoccai et al. and is analysis by independently
duration of action and a receptor subtype in trauma available in the Appendix assessing compliance to
higher selectivity on the brain injury might [36]. the selection criteria.
V1 receptors that limits promote the development Divergences from the
the edemigenous effect of cerebral edema [8, 35]. 2.2. Study Selection. selection criteria were
mediated by the V2 To evaluate the impact References obtained from resolved by consensus.
receptors differently from on survival of V1 receptor databases and literature
what its native counterpart agonists in hypovolemic searches were first
does [22]. AVP and refractory shock, we 2.3. Data Abstraction and
examined independently at Study Characteristics. Two
terlipressin can be both conducted a systematic the
used with the aim of review and meta-analysis inves- tigators
reaching the desired MAP of data pooled from independently extracted
target or reducing the existing trials comparing data on the study design,
norepinephrine dosage AVP or terlipressin and experimental setting,
[23, 24]. conventional shock man- dosages of AVP or
In animal models in agement in mammals. terlipressin, and
which severe uncontrolled experimental duration,
blood loss has been with divergences resolved
induced, the administration 2 by con- sensus. If the
of AVP has shown . required data could not be
improvement in survival, retrieved from the
neurologic outcome, and published report, at least
M two separate attempts to
enhanced hemodynamic
performance [25–27].
a contact the original authors
During the irreversible t were made.
phase of hemorrhagic e The primary end-point
shock, unresponsive to was mortality at the longest
r avail- able follow-up. In
fluids and catecholamines i
administration, AVP can addition, we performed
mediate peripheral a further subanalysis
vasoconstriction through l comparing animals treated
V1 receptors [13, 28, 29]. s with AVP (or terlipressin)
AVP works primarily on with those treated,
arterioles in extracerebral respectively, with placebo,
a fluid resuscitation, and
tissues, with less
constriction action on n other vasoconstrictive
coronary and renal vessels d drugs.
with potential vasodilatory
effect on cerebral and M 2.4. Data Analysis and
 4
Synthesis. Computations performed by sequentially BioMed Research International
were per- formed with removing each study and
RevMan 4.2 [35]. Binary reanalysing the remaining
outcomes from individ- ual dataset (producing a new
studies were analyzed to analysis for each study
compute individual odds removed) and by
ratios (ORs) with analysing only data from
pertinent 95% confidence studies with low risk of
intervals (CIs), and a bias.
pooled summary effect
estimate was calculated by
means of the Mantel- 3
Haenszel method and the .
fixed effect model
in case of low statistical R
2
inconsistency (� < 25%)
or the e
random-effect model in s
case of moderate or high u
2
statistical inconsistency (� l
> 25%) [37]. Statistical t
heterogeneity and
inconsistency were s
measured using Cochran
� tests and 3.1. Study Characteristics.
2 Database searches,
� (by Higgins and
backwards snowballing,
Thompson), respectively and contacts with experts
[38]. Statistical yielded a total of
significance was set at 2- 246 citations. After
tailed 0.05 for hypothesis excluding nonpertinent
testing and at 0.10 for
titles or abstracts,
heterogeneity testing.
According to Higgins et 22 studies were retrieved
2 in complete form and
al., the � values around assessed according to the
25%, 50%, and 75% were selection criteria (Figure
considered to represent, 1). Seven studies
respectively, low,
moderate, and severe
statistical
i
n
c
o
n
s
i
s
t
e
n
c
y

[
3
8
]
.
The risk of
publication bias was
assessed by visual
inspection of the funnel
plot for mortality.
Sensitivity analyses were
BioMed Research International 5
6were further excluded for BioMed Research International
magnitude of statistical i adequate mean arterial
the absence of survival findings. Sensitivity o pressure when fluid
data. Fifteen eligible trials analyses carried out with therapy gives no positive
were included in the final studies with low risk of
n results [15, 41]. Guidelines
analysis. bias (eliminating the The most important recommend the use of
The 15 included studies studies responsible for the finding of this meta- norepinephrine as the
randomized 433 animals, asymmetry of the funnel analysis is that the use of vasopressor of choice,
174 to AVP (14 trials) or plot) confirmed the overall AVP in the hypovolemic whilst the use of
terlipressin (one trial) and results of our work shock increases survival in terlipressin or AVP is not
259 to control (placebo, showing a reduction in animal studies. All studies mentioned.
vasopressors, or fluid mortality in included were randomized The use of AVP and its
resuscitation). The AVP/terlipressin animals (AVP or terlipressin synthetic analog
included trials were versus controls (OR = versus placebo, other terlipressin has received
conducted on pigs (12 0.13 (95% CI 0.08–0.24); vasopressors or fluid significant attention in
studies) and on rats (three � for effect < 0.001, � administration), were clinical practice, especially
studies). All manuscripts for heterogeneity conducted on animal in septic shock and cardiac
2
were published in indexed 0.99, � = 0% with 10 models (pig and rats), and arrest [43–46]. AVP was
journals. Detailed study studies and 329 animals were published in peer- discovered in 1895 from
characteristics are included) reviewed journals. the extract of the posterior
summarized in Table 1. (Figures 4 and 5). Data The use of pituitary gland and named
of mortality are vasopressors in after its vasoconstrictive
3.2. Quantitative Data summarized in hypovolemic shock might properties [16, 42].
Synthesis. The overall T contradict the Landry et al. reported,
analysis showed that a conventional knowledge for the first time, the
AVP/terlipressin were b of how to treat this successful administration
associated with a l condition. Nevertheless of exogenous AVP in
reduction in animal e their use in late phases patients with septic shock
mortality (26/174 (15%) in of hem- orrhagic shock is [43]. Russell et al.
the AVP/terlipressin group 2 a common practice. compared the use of AVP
versus 164/259 (63%) in . Vasopressors have versus norepinephrine in
the control arms; OR = In the majority of the recently been suggested in patients with septic shock
0.09 (95% CI 0.05–0.15); studies included in this the European guidelines in the “Vaso- pressin and
� for effect < 0.001; � meta- analysis, AVP has for the management of Septic Shock Trial.”
for heterogeneity = been administered with hemorrhagic shock in In 779 patients the
2 an initial bolus followed order to maintain an
0.30; � = 14%) (Figure adverse effects were
by continuous infusion. similar in both groups,
2). When studies were
Bolus doses ranged from with no differences in 28-
grouped to
0.1 U/kg to 0.4 U/kg day mortality and major
either fluid resuscitation,
while continuous organ dysfunction [44].
placebo, norepinephrine,
infusion dosages ranged Another potential use of
or other vasoconstrictive
from 0.04 U/kg/min to AVP is in the
drugs as a comparator,
0.08 U/kg/min. Other pharmacological treatment
administration of
studies report AVP of cardiac arrest [45, 46].
AVP/terlipressin was still
infusion dosages in U/kg/h AVP followed by
associated with a
that range from 0.1 [21] to epinephrine may be more
reduction in mortality.
2 U/kg/h [39, 40]. In the effective than epinephrine
(see Supplementary
study of Bayram et al., alone in the treatment of
Figures 6(b)–6(e) available
terlipressin was refractory cardiac arrest,
online at
administered at the dose of especially in patients with
http://dx.doi.org/10.1155/20
50 mcg/kg [3]. asystole [29].
14/421291).
Visual inspection of In recent years, several
funnel plot identified an 4 animal studies have shown
asym- metrical shape, that the administration of
. AVP in patients with
suggesting the presence of
publication bias (Figure uncontrolled hemor-
3). Sensitivity analyses D rhagic shock is a
performed by i promising treatment [10].
sequentially removing s Our systematic analysis of
each study and reanalysing literature has evaluated
c several clinical studies on
the remaining dataset
(producing a new analysis u animals. Morales et al.
for each study removed) s were the first ones to study
did not lead to major s the effects of the
changes in direction or administration of different
 BioMed
doses Research
of AVP (fromInternational
1 to the volemic status where 7
4 mU/kg) in seven dogs hypovolemic patients are
undergoing prolonged those with values of
hemorrhagic shock and central venous pressure ≤
concluded that AVP is an 8 mmHg. In this
effective agent in the retrospective study,
irreversible phase of vasopressor exposure was
hemorrhagic shock associated with death
unresponsive to volume independent of injury
replacement and severity. Vasopressor-
catecholamines [28]. treated patients had lower
For a long time the arterial pressure, required
use of vasopressors in more fluids and
hemorrhagic shock was transfusions, and had a
considered a debatable higher serum creatine [50].
topic. During the early
phases of hemorrhagic
shock arterial pressure is
main- tained as adequate
through the activation of
compensatory
vasoconstrictive
mechanisms guaranteed by
the sympathetic system
that produces a venous
and arterial compensatory
vasoconstriction [41].
When blood loss is
abundant and this
mechanism is no longer
efficient to maintain an
adequate organ perfusion,
the sympathetic system
becomes inhibited with
subsequent reduction of
peripheral resistance and
bradycardia. Hemor-
rhagic shock is also
responsible for an
abnormal vascular bed
reaction mediated by nitric
oxide that reduces the
response to endogenous
and exogenous
norephineprine [47]. The
trauma and organ damage
developing from the
shock- induced
hypoperfusion bring
about the activation of
the inflammatory cascade
with subsequent vasoplegia
[48, 49].
The use of
vasopressors may be
helpful in these cases. In
their retrospective study
Plurad et al. determined
that an early vasopressor
exposure after a critical
injury is independently
associated with an
increased mortality rate
and this is not related to
8 BioMed Research International

246 citations retrieved from database

searches

228 titles/abstracts excluded

as being irrelevant

18 studies assessed according to the

selection criteria
4 more additional studies were found
in references

7 studies excluded according to

explicit exclusion criteria

15 randomized controlled trials

finally included in the systematic
review

Figure 1: Flow diagram of the systematic review process.

BioMed Research International
Experimental Control 9
Odds ratio Odds ratio
Study or subgroup Weight
Events Total Events Total M-H, fixed, 95% CI M-H, fixed, 95% CI
Bayram et al. [3] 2 7 10 14 4.5% 0.16 [0.02, 1.19]
Cavus et al. [31] 0 8 8 16 5.2% 0.06 [0.00, 1.19]
Cavus et al. [55] 0 8 2 8 2.2% 0.15 [0.01, 3.77]
Dudkiewicz and Proctor [56] 0 10 0 10 Not estimable
Feinstein et al. [8] 0 14 1 23 1.0% 0.52 [0.02, 13.58]
Feinstein et al. [32] 2 13 10 14 7.6% 0.07 [0.01, 0.49]
Li et al. [11] 10 30 31 40 16.6% 0.15 [0.05, 0.42]
Liu et al. [39] 11 32 36 48 17.7% 0.17 [0.07, 0.46]
Meybohm et al. [13] 0 7 3 7 3.1% 0.09 [0.00, 2.07]
Meybohm et al. [57] 0 10 7 20 4.6% 0.09 [0.00, 1.68]
Raedler et al. [10] 0 7 14 14 8.8% 0.00 [0.00, 0.13]
Sanui et al. [21] 0 5 3 5 3.0% 0.06 [0.00, 1.79]
Stadlbauer et al. [30] 1 9 14 14 9.2% 0.01 [0.00, 0.17]
Stadlbauer et al. [40] 0 7 11 12 7.7% 0.01 [0.00, 0.24]
Voelckel et al. [1] 0 7 14 14 8.8% 0.00 [0.00, 0.13]

Total (95% CI) 174 259 100.0% 0.09 [0.05, 0.15]

Total events 26 164
Heterogeneity: ��2 = 15.08, df = 13 (P = 0.30); I2 =
14% 0.01 0.1 1 10 100
Test for overall effect: Z = 9.22 (P < 0.00001) Favours [experimental] Favours [control]

Figure 2: AVP or terlipressin versus all other strategies (fluid resuscitation, vasoconstrictors, and placebo).

However the update of the European guidelines has At present, a multicenter, randomized controlled trial
recently considered the use of norepinephrine for (Vasopressin in Traumatic Hemorrhagic Shock—VITRIS
irreversible hemorrhagic shock. There are several human study) is being organized in Europe to evaluate the effects
case reports that have supported the use of AVP as an of AVP in prehospital management of hemorrhagic shock
optimizing measure capable of supporting arterial pressure [52]. Unfortunately, as of now, we only have the results of
during the triage of trauma victims [27, 51]. retrospective studies on humans. Collier et al. conducted
 Table 1: Studies included in the meta-analysis.

1st author Journal Year Number of AVP (V) or terlipressin (T) Number of Controls Control
Animal
 Placebo (7);
Bayram [3] Am J Emerg Med 2012 7 (T) 14 Rats
Ringer lactate (7)
Cavus [31] Resuscitation 2009 8 (V) 8 Fluid resuscitation (8) Pigs
Fluid resuscitation (8);
Cavus [55] Resuscitation 2010 8 (V) 16 Pigs
noradrenaline + HS (8)
Dudkiewicz [56] Crit Care Med 2008 10 (V) 10 Phenylephrine (10) Pigs
Crystalloid (9);
Feinstein [8] J Am Coll Surg 2005 14 (V) phenylephrine (5); Pigs
23 crystalloid +
phenylephrine (9)
Feinstein [32] J Trauma 2005 8 (V) 9 NS (9) Pigs
Placebo (10); Ringer
Li [11] J Surg Res 2011 30 (V) 40 lactate (10); whole blood Rats
(10); NE (10)
Hypotensive
resuscitation (16);
Liu [39] Shock 2013 32 (V) 48 Rats
Ringer lactate (16); NE
(16)
Meybohm [13] J Trauma 2007 7 (V) 7 HHS + NE (7) Pigs
Fluid (10); HHS + NS
Meybohm [57] Resuscitation 2008 10 (V) 20 Pigs
(10)
Raedler [10] Anesth Analg 2004 7 (V) 14 Saline placebo (7); Pigs
fluid resuscitation (7)
Sanui [21] Crit Care Med 2006 5 (V) 5 Placebo (5) Pigs

Stadlbauer [30] Anesthesiology 2003 9 (V) 14 Saline placebo (7); Pigs

fluid resuscitation (7)
Stadlbauer [40] Crit Care 2007 7 (V) 12 Saline placebo (5); Pigs
fluid resuscitation (7)
Epinephrine (7);
Voelckel [1] Crit Care Med 2003 7 (V) 14 Pigs
saline placebo (7)

0 AVP concluding that its administration is associated with

increased mortality in trauma patients with refractory
1 hypotension [53]. However patients treated with AVP in
this study have higher values of Trauma-Injury
SE(log[OR])

2 Severity Score (TRISS) and initial lactate levels.

Arterial blood pressure values of these two groups are
3 not reported. Grmec et al. performed a prehospital
prospective cohort study to assess the influence of
4 treatment with AVP and hydroxyethyl starch solution
(HHS) on outcome in resus- citated blunt trauma patients
5 with pulseless electrical activ- ity (PEA) cardiac arrest.
0.01 0.1 1 10 100 Thirty-one patients were stud- ied concluding that
OR victims of severe blunt trauma with PEA should be
initially treated with AVP in combination with HHS for
Figure 3: Funnel plot of comparison of AVP or terlipressin versus volume resuscitation followed by standard resuscitation
all other strategies (fluid resuscitation, vasoconstrictors, and
therapy and other procedures when needed [54].
placebo).
Studies conducted on animals have several limitations.
Survival times measured in the experiments are different.
The median value is 15.5 hours and the median is 1.5 hours.
a retrospective cohort analysis of trauma patients requiring Few studies keep observing animals after six hours [11, 30].
vasopressors within 72 hours of admission. They observed Those studies are performed with different protocols in
higher mortality (51% versus 41%) in patients treated with settings
 Experimental Control Odds ratio Odds ratio
Study or subgroup
Events Total Events Total M-H, fixed, 95% CI M-H, fixed, 95% CI
Weight

Bayram et al. [3] 2 7 10 14 6.8% 0.16 [0.02, 1.19]

Cavus et al. [31] 0 8 8 16 7.9% 0.06 [0.00, 1.19]
Cavus et al. [55] 0 8 2 8 3.4% 0.15 [0.01, 3.77]
Feinstein et al. [8] 0 14 1 23 1.6% 0.52 [0.02, 13.58]
Feinstein et al. [32] 2 13 10 14 11.6% 0.07 [0.01, 0.49]
Li et al. [11] 10 30 31 40 25.3% 0.15 [0.05, 0.42]
Liu et al. [39] 11 32 36 48 27.0% 0.17 [0.07, 0.46]
Meybohm et al. [13] 0 7 3 7 4.7% 0.09 [0.00, 2.07]
Meybohm et al. [57] 0 10 7 20 7.0% 0.09 [0.00, 1.68]
Sanui et al. [21] 0 5 3 5 4.6% 0.06 [0.00, 1.79]

Total (95% CI) 134 195 100.0% 0.13 [0.08, 0.24]

Total events 25 111
Heterogeneity: ��2 = 2.02, df = 9 (P = 0.99); I2 =
0% 0.01 0.1 1 10 100
Test for overall effect: Z = 6.90 (P < 0.00001) Favours [experimental] Favours [control]

Figure 4: Forest plot of comparison of AVP or terlipressin versus all other strategies including studies with low risk of
bias.

Table 2: Results for mortality.

Number of
AVP/terlipressin Control 2
Outcome included OR 95% CI � for effect � for heterogeneity � (%)
animals animals
trials
Overall trials 15 174 259 0.09 0.05–0.15 <0.001 0.30 14
Mortality 15% 63%
Placebo as comparator drug 7 72 48 0.03 0.01–0.09 <0.001 0.57 0
Mortality 18% 92%
Fluid resuscitation as 0.08 0.04–0.15 <0.001 0.75 0
11 114 117
comparator drug
Mortality 18% 67%
Vasopressors (NE or
epinephrine) as comparator 7 88 87 0.18 0.08–0.44 <0.001 0.96 0
drug
Mortality 18% 39%
NE as comparator drug 4 54 53 0.16 0.06–0.45 <0.001 0.97 0
Mortality 20% 47%
Sensitivity analysis
(including only low risk 10 134 195 0.13 0.08–0.24 <0.001 0.99 0
of bias studies)
Mortality 18% 57%

varying from head trauma [55, 56], thoracic trauma, and patients with shock refractory to the administration of
abdominal trauma [40] or after severe hepatic lesions [57]. fluids and catecholamines but the use of AVP alone cannot
Dosages used in animal trials are higher than dosages replace the use of fluids [61]. The AVP, as well as other
used in human studies. Humans have been successfully vasopressors, seems to be beneficial only when administered
treated with AVP infusion of 2–4 U/h in vasodilatory in association with fluids [62, 63].
shock [58, 59] and 10–20 UI boluses in patients with upper
intestinal bleeding [60]. Most of the studies favorably 5. Conclusions
estimate the impact of AVP to handle hemodynamic and
improve sur- vival. However it is recommended not to Data acquired from our meta-analysis suggest strong scien-
underestimate the possible adverse effects that might tific evidence for the efficacy of AVP for the early
derive from the use of AVP since its use is only indicated treatment of hemorrhagic shock in animal models. AVP
in irreversible shock no longer treatable with fluid has shown to be more effective than all other treatments,
resuscitation alone. Vasopressin could be considered as a including other vasopressors drugs. We are awaiting the
possible pharmacologic adjunct in results of the VITRIS
 ∗
0 heterogeneous, more than OR prospective [tw] OR (meta-analysis[pt] NOT
∗
the typical clinical trials. volunteer [tw]) OR clinical trial[pt]) OR
Successfully translating (animal[mh] practice- guideline[pt] OR
0 OR human[mh]) NOT review[pt]))).
.
findings to human diseases
depends largely upon (comment[pt] OR
5
understanding the sources editorial[pt] OR
Conflict of Interests
SE(log[OR])

of heterogeneity and their

1 impact on effect size [64]. The authors declare that
The study is conducted there is no conflict of
without randomized interests regarding the
1 controlled trials in humans, publication of this paper.
.
5 and our findings should
only be considered as a Acknowledgment
hypothetical suggestion for
2 further research, awaiting The authors are indebted
0.01 0.1 the results of randomized to Toby Schwartzbarth
1 10 controlled human trials.
100
for the revision of the
paper.
OR
A
Figure 5: Funnel plot of References
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n
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d epinephrine, improves
[50] study to confirm in i survival in uncontrolled
x hemorrhagic shock after
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ons randomized controlled R. Atilla, and S. Kalkan,
trials[mh] OR random “Effects of terlipressin in
The purposes, designs, and allocation[mh] OR double- a rat model of severe
conduct are different blind method[mh] OR uncontrolled hemorrhage
single-blind method[mh] via liver injury,” The
between sys- tematic
American Journal of
review and meta-analysis OR clinical trial[pt] OR
Emergency Medicine, vol.
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∗
are intrinsically ((singl [tw] OR [4] H. P. Santry and H. B.
∗ ∗
confirmatory and the aim doubl [tw] OR trebl [tw] Alam, “Fluid
∗
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