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Resusitacion Con Liquidos en La Sepsis PDF
Resusitacion Con Liquidos en La Sepsis PDF
KEYWORDS
Fluid resuscitation Sepsis Crystalloids Colloids Albumin Early goal-directed therapy
KEY POINTS
Fluid resuscitation to correct hypovolemia and support organ perfusion is central to current
management of severe sepsis and septic shock.
Recent randomized trials have not confirmed a benefit for targeting invasive physiologic parame-
ters; the ideal fluid volume and end points in sepsis resuscitation remain unknown.
Increased fluid balance is associated with increased mortality in early and late sepsis; whether con-
servative fluid management can improve sepsis outcomes requires further study.
Hydroxyethyl starch increases risk of acute kidney injury and may increase mortality in patients with
sepsis.
Whether albumin or physiologically balanced crystalloids improve clinical outcomes in sepsis
remains the focus of ongoing study.
Funding: When this review was prepared, Dr M.W. Semler was supported by a National Heart, Lung, and Blood
Institute T32 award (HL087738 09).
Conflicts of Interest: The authors have no potential conflicts of interest.
Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Medical
Center North, T-1218, Nashville, TN 37232-2650, USA
* Corresponding author.
E-mail address: matthew.semler@vanderbilt.edu
intended to optimize volume expansion through to fluid resuscitation. Although the clinical implica-
colloid retention in the intravascular space. tions of these findings are not yet fully understood,
It is increasingly clear, however, that the hemo- they argue against an overly simplified approach
dynamic response to fluid administration is deter- to fluid dose (fill the tank) and fluid choice
mined by an intricate interaction of mean systemic (colloids stay in the vasculature).
filling pressure, right atrial pressure, venous resis-
tance, and ventricular compliance, which makes
FLUID DOSE
predicting a critically ill patients response to fluid
Fluid Administration in Sepsis Resuscitation
challenging.7 Impaired oxygen use and nonhy-
poxemic causes of lactic acidosis may elevate Fluid resuscitation is currently considered an
lactate levels despite adequate perfusion. Perhaps essential component of early sepsis manage-
most importantly, the century-old Starling model ment.1 Prompt IV fluid administration for patients
conceptualizing maintenance of vascular volume with sepsis was advanced by a 2001 study of early
as the balance of hydrostatic and oncotic pressure goal-directed therapy (EGDT).5 In that landmark
gradients between the vessel lumen and interstitial trial, 263 patients with sepsis and hypoperfusion
space has been challenged by the recent recogni- were randomized to either standard therapy or
tion of the importance of the endothelial glycoca- EGDT. Standard therapy involved arterial and
lyx (Fig. 1).8 Because it is a primary determinant central venous catheterization and a protocol tar-
of membrane permeability, damage to the glyco- geting CVP of 8 to 12 mm Hg, mean arterial pres-
calyx during sepsis may alter patients response sure (MAP) at least 65 mm Hg, and urine output at
large pore
Jv - filtration rate protein
transport
Crystalloids distribute through the extracellular volume Colloids initially distribute through plasma volume,
crystalloids through intravascular volume
Fig. 1. Models of transvascular fluid exchange. In the original Starling model, the gradient of hydrostatic pressure
from the capillary (Pc) to the interstitium (Pi) is opposed by the gradient of oncotic pressure from the capillary (pc)
to the interstitium (pi), with filtration (Kf) and reflection (s) coefficients. Understanding the web of membrane-
bound glycoproteins and proteoglycans on the luminal side of endothelial cells (endothelial glycocalyx layer)
suggests the low oncotic pressure under this semipermeable membrane (psg) is a more important regulator of
transcapillary flow than the interstitial oncotic pressure.
Sepsis Resuscitation 3
least 0.5 mL/kg/h. EGDT included all elements pre-enrollment fluids were similar to the 20 to
of standard therapy in addition to a catheter 30 mL/kg required before inclusion in the original
measuring central venous oxygen saturation trial. Patients in the modern trials were less severely
(SvO2), 6 hours of treatment in the emergency ill than patients in the original trial, potentially limiting
department before admission, and protocolized the impact of early intervention. Ultimately, ancillary
administration of 500 mL of IV crystalloid every aspects of critical care have changed so dramati-
30 minutes to achieve CVP goals, vasopressors cally in the decade between trials9 that comparing
and vasodilators to maintain MAP goals, and fluid management across EGDT studies may not
blood transfusion or dobutamine to achieve yield firm conclusions about the optimal approach
SvO2 at least 70%. During the 6 hours of to early fluid resuscitation.
intervention, EGDT patients received more IV fluid Although broad adoption of EGDT in devel-
(5.0 vs 3.5 L; P<.001), red-cell transfusions (64.1% oped countries complicates the study of sepsis
vs 18.5%; P<.001), and dobutamine (13.7% vs resuscitation, provocative data have emerged
0.8%; P<.001). In-hospital mortality was 16% elsewhere. The Fluid Expansion as Supportive
lower with EGDT compared with standard therapy Therapy (FEAST) study10 randomized 3170
(46.5% vs 30.5%; P 5 .009). African children with sepsis to weight-based fluid
The remarkable improvement in mortality pro- boluses with 0.9% saline, 5% albumin, or no
pelled early, protocolized fluid resuscitation to bolus. The median volume of fluid received by 1
the forefront of sepsis management. Based on and 8 hours was 20.0 and 40.0 mL/kg for
the 2001 EGDT study, an EGDT trial at eight the bolus groups compared with 1.2 and
Chinese centers, and dozens of before-after 10.1 mL/kg in the no bolus group. By 48 hours,
studies of EGDT implementation, the Surviving 10.5% of children in the fluid bolus groups had
Sepsis Campaign (SSC) promoted incorporation died compared with 7.3% in the no bolus group
of goal-directed fluid resuscitation into early (P 5 .003). Receipt of fluid was harmful in all sub-
sepsis management globally.6 The most recent groups. Although shock resolved more frequently
version of the SSC guidelines recommends pro- in the bolus groups, excess mortality was evident
tocolized, quantitative resuscitation of patients regardless of blood pressure response.11 Simi-
with sepsis-induced tissue hypoperfusion begin- larly, the Simplified Severe Sepsis Protocol
ning with an initial fluid challenge.to achieve a (SSSP) trial12 randomized 112 African adults
minimum of 30 mL/kg of crystalloids targeting with sepsis and organ dysfunction to usual care
CVP, blood pressure, urine output, and venous ox- or an algorithm of simplified, goal-directed resus-
ygen saturation goals outlined in the 2001 EGDT citation. Patients in the intervention arm received
trial.6 1.3 L more fluid in the first 6 hours (2.9 vs 1.6 L;
More than a decade after the original EGDT study, P<.001) with no differences in vasopressors,
three large, multicenter trials attempted to confirm transfusions, or antibiotics. In-hospital mortality
the benefit of EGDT. The ProCESS,2 ARISE,3 and was 64.2% with fluid resuscitation compared
ProMISe4 trials all compared EGDT with usual with 60.7% without when the study was
care in which invasive management was optional stopped early for high mortality among patients
(eg, central venous access in ProCESS) or with baseline respiratory failure randomized to
forbidden (eg, SvO2 measurement in ARISE). Fluid the intervention.12 The Simplified Severe
resuscitation in the first 6 hours of each EGDT trial Sepsis Protocol-2 (SSSP-2) trial currently
is shown in Fig. 2. There were no differences in enrolling patients with septic shock in Zambia
any clinical outcome between EGDT and usual (NCT01663701) may provide more definitive
care among the 4201 patients in these trials. Under- data on the impact of fluid compared with little
standing the implications of these new EGDT trials or no resuscitation for early sepsis in this
for fluid resuscitation presents several challenges. population.
First, the largest separation between arms in fluid
administration in the first 6 hours was a 1-L differ-
Recommendation for clinical practice
ence between modified protocol-based standard
therapy (3.3 L) and usual care (2.2 L), less than the For patients with severe sepsis and septic shock,
1.5-L difference in the original trial. Advocates of early administration of IV fluids to correct hypo-
EGDT would suggest that routine sepsis care has volemia and potentially improve blood pressure
and tissue perfusion remains standard of care.
shifted to resemble the intervention arm of the orig-
The optimal amount, rate, and end point
inal trial, but patients in both arms of the modern for fluid administration in early sepsis are
trials actually received less IV fluid than either arm unknown. Fluid resuscitation beyond euvole-
of the original trial (see Fig. 2). Although the modern mia may be detrimental.
trials enrolled patients later after presentation, the
4 Semler & Rice
8000 50
Mortality (%)
40
30
2000
0
control EGDT control EGDT PST control EGDT control EGDT
Rivers et al ProCESS ARISE ProMISe
Fig. 2. Fluid administration in EGDT trials. Volume of IV fluid during the first 6 hours in each EGDT trial. Volume
of fluid (black) is mean and standard deviation for all trials except ProMISe, which is median and interquartile
range. Mortality (gray X) is through 60 days in ProCESS and 28 days in all other trials. PST, protocol-based
standard therapy.
Fluid Management in Sepsis After Historically, patients with sepsis have received
Resuscitation significant volumes of fluid throughout their ICU
stay. Observational studies report positive fluid
In contrast to the intense focus on fluid in the first
balances of 5 to 11 L in the week after presenta-
6 to 12 hours of sepsis, little attention has been
tion.17,18 After resuscitation, potential benefits of
dedicated to optimal fluid management after
fluid are balanced against risks of pulmonary
resuscitation. There is broad agreement that fluid
edema, renal parenchymal edema, and effects of
management may differ between different phases
the IV fluid constituents themselves. Observational
of sepsis, but the factors delineating each phase
studies have associated fluid receipt and positive
and the optimal fluid strategy for each phase
fluid balance with mortality. Among 778 patients
remain largely undefined. The 2012 SSC guide-
with septic shock in the Vasopressin in Septic
lines recommend a fluid challenge approach for
Shock Trial (VASST), odds of mortality doubled
patients requiring hemodynamic support wherein
for patients with the highest cumulative fluid
fluid boluses are continued as long as there is
balance.17 For 1177 patients with sepsis in the
hemodynamic improvement.6 Frequently in clin-
Sepsis Occurrence in Acutely Ill Patients (SOAP)
ical practice this has meant administering IV fluids
study, each additional liter of fluid balance at
to patients for changes in heart rate, blood pres-
72 hours was associated with a 10% increase in
sure, or urine output. Recognizing the limitations
the odds of death.19 These observational studies
of these traditional indices in assessing intravas-
are inherently limited by the indication bias that pa-
cular volume status and fluid responsiveness, re-
tients with higher severity of illness may be more
searchers and clinicians have sought dynamic
likely to die and have fluid administered by pro-
predictors of response to fluid administration.13,14
viders. The Fluid and Catheter Treatment Trial
Cardiac output monitoring,15 pulse pressure and
(FACTT) controlled postresuscitation fluid man-
stroke volume variation,16 and interior vena cava
agement for 1000 patients with acute respiratory
diameter and stroke volume assessment by echo-
distress syndrome (ARDS), of whom 70% had
cardiography13 have all been advocated to guide
underlying infection. Fluid management empha-
fluid administration. However, many dynamic
sizing diuretics and limiting fluid administration
measures cannot be used for patients who are
increased ventilator-free days and ICU-free days
spontaneously breathing or receiving low tidal-
without precipitating cardiovascular or renal
volume ventilation. Moreover, no clear evidence
dysfunction.20 The 2012 SSC recommends con-
yet correlates improvement in short-term physio-
servative fluid management for patients with
logic parameters with improvements in longer-
sepsis and ARDS after the resolution of shock.6
term clinical outcomes.
Sepsis Resuscitation 5
Colloid
Crystalloid Human Hydroxyethyl Starch Gelatin
4% 3.5%
0.9% 10% 6% 6% 6% 6% 6% Succinylated Urea-Linked
Sodium Ringer Hartmann Plasma- 4% 20% (200/0.5) (450/0.7) (130/0.4) (130/0.4) (130/0.42) (130/0.42) Gelatin Gelatin
Plasma Chloride Lactate Solution Lyte Albumin Albumin (Hemohes) (Hextend) (Voluven) (Volulyte) (Venofundin) (Tetraspan) (Gelofusine) (Maemaccel)
Sodium 135145 154 130 131 140 130160 48100 154 143 154 137 154 140 154 145
Potassium 4.55.0 4.0 5.4 5.0 3.0 4.0 4.0 5.1
Calcium 2.22.6 1.5 1.8 5.0 2.5
Magnesium 0.81.0 1.5 0.9 1.5 1.0
Chloride 94111 154 109 112 98 128 19 154 124 154 110 154 118 120 145
Acetate 27 34 24
Lactate 12 28 28 28
Malate 5.0
Gluconate 23
Bicarbonate 2327
Octanoate 6.4 32.0
Osmolarity 291 308 273 277 294 250 210260 308 304 308 286 308 296 274 301
All values are given in mmol/L except osmolarity, which is in mOsm/L. Electrolyte concentrations of intravenous fluid preparations may differ by manufacturer: information is given for Hart-
mann solution (B. Braun Melsungen AG, Melsungen, Germany), Plasma-Lyte 148 (Baxter, Deerfield, IL, USA), and Albumex 20 (CSL Behring, King of Prussia, PA, USA). HES solutions
are described with regard to their concentration (6%10%), mean molecular weight (70480 kDa), and degree of molar substitution (range, 01; tetrastarch 0.4, pentastarch 0.5,
hexastrach 0.6).
Sepsis Resuscitation 7
Recommendation for clinical practice: rate and MAP. Overall there was no difference
in 28-day mortality between albumin and saline.
For patients with sepsis, administration of However, analysis of a prespecified subgroup of
normal saline contributes to metabolic acidosis
patients with severe sepsis (N 5 1218) suggested
and may increase the risk of AKI. Whether use
of balanced crystalloids can prevent AKI and reduced in-hospital mortality with albumin
decrease mortality remains unknown. (relative risk, 0.87; 95% confidence interval,
0.741.02).36 In contrast to the SAFE study of
4% albumin for fluid resuscitation, the Albumin
Italian Outcome Sepsis (ALBIOS) study examined
Colloids daily administration of 20% albumin targeting a
serum albumin level of 3 g/L.37 Among 1818
Colloids are suspensions of molecules in a carrier
ICU patients with sepsis, albumin administration
fluid with high enough molecular weight to prevent
resulted in higher serum albumin levels, lower
crossing of healthy capillary membranes. Available
net fluid balance, lower heart rate, higher MAP,
colloids include derivatives of human plasma
and more rapid freedom from vasopressors. The
(albumin solutions) and semisynthetic colloids
28-day mortality was identical in the two groups
(gelatins, dextrans, and hydroxyethyl starches
but a post hoc subgroup analysis suggested
[HES]). The physiologic rationale favoring colloids
fewer deaths with albumin among patients in
over crystalloids is that colloids may more effec-
shock (relative risk, 0.87; 95% confidence inter-
tively expand intravascular volume by remaining
val, 0.770.99; P interaction 5 .03). The third trial,
in the intravascular space and maintaining colloid
Early Albumin Resuscitation during Septic Shock
oncotic pressure.
(EARSS; available only in abstract form), random-
ized patients with septic shock within 6 hours of
Albumin vasopressor initiation to receive 100 mL of 20%
Human serum albumin is a small protein synthe- albumin or 100 mL of 0.9% saline every 8 hours
sized by the liver and maintained in the vasculature for 3 days. Among 798 patients, vasopressor-
through a dynamic equilibrium of leak into the free days were higher with albumin without
interstitium matched by lymphatic return. Beyond improvement in 28-day mortality (24.1% vs
providing 75% of plasma colloid oncotic pressure, 26.3%).38 (Although the Colloids vs Crystalloids
albumin binds nitric oxide, protects against lipid for the Resuscitation of the Critically Ill (CRISTAL)
peroxidation, and regulates inflammation, leading trial allowed use of 4% or 20% albumin, albumin
to the enticing proposition that albumin solutions administration was too similar between the
might expand intravascular volume and directly colloid and crystalloid arms (20.4% vs 16.5%) to
mediate sepsis pathogenesis. allow inferences about the relative effects of
Administration of human albumin was intro- albumin39).
duced in World War II for victims of traumatic Despite no overall benefit in each of the individ-
and thermal injury. Commercial preparations of ual trials, multiple meta-analyses33,4042 have
isotonic 4% to 5% albumin solution for fluid suggested improved mortality with albumin
replacement and hyperoncotic 20% to 25% administration in sepsis (Fig. 3). The SCC in 2012
albumin solution to support colloidal pressure continued to recommend crystalloids as the initial
led to expanded use in civilian operating rooms, sepsis resuscitation fluid, but advised consider-
emergency departments, and ICUs. Fifty years ation of albumin when patients require substantial
after the introduction of albumin into clinical amounts of crystalloids.6 Given albumins cost
practice, the first systematic evaluation of albu- and a more recent meta-analysis showing no
mins effect on clinical outcomes reported an impact on sepsis mortality,43 ongoing trials
alarming 6% increase in the risk of death with al- evaluating earlier albumin administration
bumin use35 and calls were made for large, rigor- (NCT01337934, NCT00819416) need to demon-
ously conducted trials of albumin administration strate clear mortality benefit for albumin to replace
in critical illness. crystalloids as the gold standard fluid for sepsis
Three large trials now inform the utility of albu- resuscitation.
min administration for patients with sepsis.3638
The Saline versus Albumin Fluid Evaluation Semisynthetic colloids
(SAFE) Study randomized nearly 7000 critically The expense and limited availability of human
ill adults to 4% albumin versus 0.9% sodium albumin has prompted the development of
chloride for fluid resuscitation throughout the semisynthetic colloid solutions (gelatins, dextrans,
ICU stay.36 The albumin group received slightly and HES) (see Table 1). Gelatins are prepared
less fluid input but demonstrated similar heart by hydrolysis of bovine collagen, dextrans
8 Semler & Rice
biosynthesized from sucrose by bacteria, and HES Hydroxyethyl Starch Trial (CHEST) trial, those ran-
synthesized from the maize-derived D-glucose domized to 6% HES 130/0.4 received more renal-
polymer amylopectin. Each colloids duration of replacement therapy (7.0% vs 5.8%; P 5 .04) with
volume expansion is governed by rate of loss similar 90-day mortality (18.0% vs 17.0%). A subse-
from the circulation (determined by molecular quent meta-analysis confirmed an association be-
weight) and metabolism (determined by chemical tween HES and both AKI and mortality.47 In
properties, such as molar substitution). Each contrast, the CRISTAL trial found similar short-
colloid has been linked to a unique profile of term mortality and improved ventilator-free days
adverse events: increased risk of AKI (HES, and long-term mortality with colloids compared
gelatin), allergic reactions (gelatins, dextrans), with crystalloids.39 The CRISTAL trial randomized
and bleeding (dextrans, HES). 2857 adult ICU patients (55% with sepsis) to resus-
HES is the only semisynthetic colloid for which citation with colloids or crystalloids. Patients in the
large trials enrolling patients with sepsis have colloid arm received less 0.9% saline and Ringer
been conducted. The 2004 Efficacy of Volume Sub- lactate, more gelatins and HES, and a similar
stitution and Insulin Therapy in Severe Sepsis amount of albumin to patients in the crystalloid
(VISEP) trial comparing Ringer lactate with 10% arm. The 28-day mortality was 25.4% with colloids
HES 200/0.5 among 537 patients with severe compared with 27.0% with crystalloids (P 5 .26), a
sepsis was stopped early for increased AKI difference that increased to favor colloids at
(34.9% vs 22.8%; P 5 .002) and a trend toward 90 days (30.7% vs 34.2%; P 5 .03). Given the pre-
increased 90-day mortality (41.0% vs 33.9%; ponderance of data linking HES to AKI and the rela-
P 5 .09) with HES.44 Based on a reportedly tively high use of albumin in both arms of the
improved safety profile for starches with lower mo- CRISTAL trial, unless the improvement in long-
lecular weight and molar substitution, 6% HES 130/ term mortality seen in CRISTAL is replicated, the
0.4 was compared with 0.9% sodium chloride cost and potential risks prevent colloids from
among 196 patients with sepsis in the CRYSTMAS replacing crystalloids as first-line fluid therapy in
study.45 Differences between HES and 0.9% so- sepsis.6
dium chloride in mortality (31.0% vs 25.3%) and
AKI (24.5% vs 20.0%) failed to reach statistical sig- Recommendation for clinical practice:
nificance. However, in the larger Scandinavian
Starch for Severe Sepsis/Septic Shock (6S) trial in Colloid solutions should not be used as first-line
fluid therapy for patients with sepsis. HES seems
which 804 patients with severe sepsis were resusci-
to increase AKI and potentially mortality; the
tated with 6% HES 130/4.2 or Ringer acetate, renal- safety of other semisynthetic colloids is not
replacement therapy (22% vs 16%; P 5 .04) and established. Unless the potential beneficial
90-day mortality (51% vs 43%; P 5 .03) were signif- effects of albumin infusion are confirmed by
icantly higher with HES.46 Among 7000 critically ill further trials, cost precludes its routine use.
adults (1937 with sepsis) in the Crystalloid versus
Sepsis Resuscitation 9
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