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REVIEW

URRENT
C
OPINION

Fluid choices impact outcome in septic shock


James J. Douglas and Keith R. Walley

Purpose of review
We discuss the goals of resuscitation, in both the early and the later phases, measures of organ perfusion,
fluid responsiveness and the consequences of tissue edema.
Recent findings
The cost of over-aggressive fluid resuscitation is increased organ failure and mortality. In anticipation of the
upcoming trials on early goal-directed therapy, we explore strategies to maximize effectiveness of
resuscitation. Furthermore, we review recent data on the choice of fluid therapy.
Summary
Rapid diagnosis and early fluid resuscitation are crucial to patients with septic shock, initially with the
primary goal to relieve the overt tissue hypoxia. Early fluid therapy is important with the caveat that
patients must show an increase in their cardiac output. Beyond 612 h further positive fluid balance may
not usefully improve tissue oxygenation and may be counterproductive.
Keywords
albumin, early goal-directed therapy, edemagenesis, perfusion, resuscitation

INTRODUCTION
Early goal-directed therapy (EGDT) has profound
effects on clinical outcomes in septic shock patients
[1,2,3]. Targeted fluid resuscitation relieves overt
tissue hypoxia; however, over-aggressive fluid
therapy has deleterious effects on patient outcomes.
We discuss goals of resuscitation, both in the early
(first 6 h) and in the later phases (672 h), measures
of organ perfusion, fluid responsiveness and the
consequences of tissue edema. Furthermore, we
explore new directions in early goal-directed
therapy and the choice of fluid therapy.
Fluid resuscitation has vexed intensivists for
many generations and until recently was guided
by expert opinion [4] and loosely based on the
1983 Packman and Rackow article [5] that explored
increases in pulmonary artery wedge pressure leading to an increase in stroke volume index and cardiac index. Ironically, the authors also found a very
poor correlation with wedge pressure and central
venous pressure (CVP); a debate that persists today.

EARLY GOAL-DIRECTED THERAPY HAS


DRIVEN INTEREST IN FLUID
RESUSCITATION
The Rivers et al. 2001 EGDT landmark trial [1] compared therapy driven to achieve hemodynamic end
points versus standard therapy of the late 20th
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century. Therapy was divided into two periods,


the initial 6 h and 672 h. In the initial 6 h, more
patients in the EGDT groups achieved CVP, mean
arterial pressure (MAP) and urine output goals. The
patients in the EGDT group had higher central
venous oxygen saturation (ScvO2) and lower base
deficit at 6 h, implying improved oxygen delivery
and extraction. During the period from 6 to 72 h, the
standard therapy group had a higher heart rate,
lactate and base deficit, lower MAP, and a similar
CVP. Consequently, the standard therapy group
received more fluids, red blood cell transfusions,
vasopressors and inotropic support during the 6
72-h period. Overall, from baseline to 72 h, both
groups received the same total amount of fluids and
inotropic support, whereas the standard group
required more vasopressors and mechanical ventilation. The EGDT group showed a 16% absolute risk
reduction of mortality compared with the standard
therapy group at 28 days mainly from improved
Centre for Heart Lung Innovation, St. Pauls Hospital, University of British
Columbia, Vancouver, British Columbia, Canada
Correspondence to James J. Douglas, MD, Centre for Heart Lung
Innovation, 1081 Burrard Street, Vancouver, BC, Canada V6Z1Y6.
Tel: +1 604 806 8346; fax: +1 604 806 8351; e-mail: josh.douglas
@hli.ubc.ca
Curr Opin Crit Care 2014, 20:378384
DOI:10.1097/MCC.0000000000000116
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Fluid choices impact outcome in septic shock Douglas and Walley

KEY POINTS
 Early identification and fluid resuscitation of septic
shock patients improves inadequate oxygen delivery
and mortality.
 Fluid resuscitation should be aimed at the least amount
of fluid and lowest CVP to achieve an improvement in
end organ perfusion (improved ScvO2, lactate or urine
output).
 Dynamic measure of fluid responsiveness should be
used prior to any volume resuscitation.
 Fluid restrictive strategies have shown improved
outcomes in acute lung injury, kidney injury and
survival in septic shock patients.
 Albumin provides a higher CVP, MAP with a lower
overall fluid balance in patients with sepsis and
improved survival in those patients with septic shock.

sudden cardiovascular collapse, whereas death from


multiorgan failure was similar.
Criticism of the EGDT trial centered on the
unblinded protocol of the study, its small size and
single institution nature, the high mortality in the
standard therapy group (46.5%) and abundance of
red blood cell transfusions. However, the results
were still impressive and upon review are likely
explained by a couple of simple, yet powerful, facts.
First, care began in the emergency department (ED)
and emphasized the early identification of high-risk
patients based on blood pressure and lactate. Second, hemodynamic monitoring is feasible and
improves diagnostic accuracy, rapid access and
monitoring of critically ill patients. Finally, the
EGDT group received on average 1500 ml more total
fluid in the first 6 h of treatment, achieving a higher
CVP, MAP and urine output. Follow-up metaanalyses of the many subsequent observational
studies confirmed that early goal-directed resuscitation imparted a significant reduction in mortality
[odds ratio (OR) 0.64, 95% confidence interval (CI)
0.430.96] [6]. Moreover, it emphasized the critical
role in identifying sepsis and septic shock, and
rapidly initiating antibiotic and fluid resuscitation.
Sepsis is a form of distributive shock in which
tissue metabolism is impaired by a number of mechanisms. First, patients present acutely hypovolemic
and early fluid resuscitation serves to improve overt
tissue hypoxia from critical decreases in oxygen
delivery. Second, tissue dysoxia may exist after
fluid resuscitation due to inflammation-induced
disruption of oxygen extraction either from oxygen
diffusion abnormalities or from mitochondrial dysfunction. EGDT studies support the vital need to

correct the initial phase of intravascular hypovolemia and inadequate oxygen delivery; however, care
has to be taken not to aggravate the second phase of
tissue injury by excessive fluid administration.

ENDPOINTS OF RESUSCITATION
A common fallacy in septic patients is the notion that
fluid resuscitation has succeeded when a number
is reached. The Rivers et al. trial taught us that a timesensitive protocolized approach based on numerical
goals improves outcomes. Yet, this approach bypasses crucial questions that must be addressed
during fluid resuscitation. First, is end organ perfusion adequate (so that additional fluid may not
be necessary)? Second, is the patient fluid responsive?
Third, what is the cost of giving additional fluids?
Fluid resuscitation early in the management of
septic shock is aimed at improving cardiac output.
Although much maligned over its poor correlation
with fluid responsiveness, central venous access and
its transduced pressure still exist as part of the initial
resuscitation [7]. The EGDT trial used a CVP of
8 mmHg or less to trigger an additional volume bolus
during the initial 6 h. The Surviving Sepsis Campaign
(SSC) guidelines propose a goal CVP of 812 mmHg
and further suggest consideration of a CVP of
1215 mmHg in patients who are mechanically
ventilated, or have known preexisting decreased
ventricular compliance, increased abdominal pressure or pulmonary arterial hypertension [7]. But this
higher CVP comes at the cost of increased tissue
edemagenesis, as described by the Starling equation,
so confirmation that a higher CVP increases oxygen
delivery and improves organ perfusion and function
is required.

Organ perfusion
The initial profile of sepsis has components of all
varieties of shock, but is often dominated by a
picture of a hypodynamic state with low stroke
volume. Only after adequate volume resuscitation,
does a vasodilatory state with low vascular resistance
emerge. The change also may include macrovascular-to-microvascular shunting and can be associated
with a histotoxic hypoxia component, elements of
which are difficult to identify.
The mean arterial pressure is the driving pressure for perfusion for most organs and, although
autoregulated in tissues such as brain and kidney,
when it declines below a lower limit, flow becomes
dependent on the MAP [8]. Small studies found no
benefit to higher MAP goals in terms of arterial
lactate, urinary output or splanchnic perfusion
[9]. The sepsis and mean arterial pressure trial

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Intravenous fluids

compared a MAP target of 8085 mmHg to


6570 mmHg in septic shock patients and found
no difference in mortality at 28 and 90 days [10 ].
Newer trials using transcutaneous oxygen saturation
in septic patients have shown that increasing MAP
can increase cutaneous microvascular flow and tissue
oxygenation, yet prospective trials need to show an
outcome benefit [11].
&&

Surrogate measures of organ perfusion


The Rivers et al. trial [1] emphasized the measurement and response to ScvO2 monitoring to detect
imbalances between oxygen delivery and oxygen
consumption. Manuevers to increase ScvO2 included increasing oxygen delivery by inspired oxygen
concentration, red blood cell transfusion and inotropic support or decreasing oxygen consumption
using mechanical ventilation, sedation and even
paralysis. A number of trials have shown a correlation between mixed venous oxygen saturation
measured in the pulmonary artery (SvO2) and ScvO2
with a difference of approximately 5% between
them [1]. A meta-analysis of 21 sepsis bundle studies
found that achievement of a ScvO2 greater than 70%
as part of the 6-h resuscitation bundle was associated
with greater than two times likelihood of survival
[2]. Lactate at 6 h, ScvO2 at 48 h and MAP at both
time points were independently associated with
mortality and ScvO2 and MAP less than 65 had
the highest predictive value as measured by area
under a receiver operating characteristic curve. Pope
et al. [12] performed a secondary analysis of four
prospective studies of EGDT and found low ScvO2
(suggesting inadequate oxygen delivery relative to
demand) and excessively high ScvO2 (> 90%,
suggesting histoxic hypoxia) recorded in the ED
were associated with increased mortality.
Elevated lactate is associated with early mortality in critically ill patients [13,14]. In severe sepsis
patients the reported prevalence of elevated lactate
alone upon admission is 5.4% which increases to
16.6% in the presence of hypotension [15].
Mortality in these two groups was 30% and
46.1%, respectively. Addition of lactate clearance
to the primary SSC bundle observed improved outcomes when lactate was 1 mmol/l or less or when
lactate decreased significantly within 12 h [16].
Despite the prevalence of elevated lactate in septic
patients, it is the acidosis and not the hyperlactatemia that predicts mortality [17]. Jones et al. [18]
performed a noninferiority study comparing severe
sepsis and septic shock patients with one of two
resuscitation strategies after normalization of MAP
and CVP: ScvO2 at least 70% or lactate clearance
greater than 10% over 6 h [18]. Interestingly, there
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was no observed difference in the treatments in the


initial 72 h and no difference in mortality.
Although there is significant overlap in the utility of both ScvO2 and lactate measures, certain
features of each provide bedside assistance. ScvO2
provides immediate feedback on the oxygen consumption or oxygen delivery relationship; however,
interpretation may be required depending on the
phase of sepsis. ScvO2 levels below 5060% are
interpreted as evidence of inadequate oxygen delivery with respect to oxygen demand. However, high
ScvO2 levels (> 8090%) may indicate adequate
oxygen delivery, but may also indicate histotoxic
hypoxia and impaired tissue-oxygen extraction
capacity. Furthermore, high ScvO2 (> 90%) is associated with increased mortality [12] and is currently
without a known effective therapy. Lactate levels
and metabolism involve complex kinetics and
reflect whole body metabolism. As such the sensitivity to regional insults may be poor, resulting in
delayed or missed diagnosis [19]. There is only a
modest correlation between a ScvO2 at least 70%
goal and a lactate clearance at least 10% goal, with
the later more strongly associated with survival [20].
Although the Jones trial declared noninferiority of a
lactate clearance goal compared with a ScvO2 goal,
certain points need to be remembered. The patients
in the Jones trial were less sick, with lower lactate and
higher ScvO2 at baseline, and required less therapeutic intervention compared with the original
EGDT trial. We conclude that measurement and
trending of ScvO2 and lactate are complementary
and not mutually exclusive. Future studies targeting microcirculatory perfusion derangements may
improve understanding and treatment of other
cryptic changes that can accompany sepsis.

FLUID RESPONSIVENESS
Now well documented is the inability of the CVP
to predict volume responsiveness. CVP is often
thought of as a surrogate for right ventricular enddiastolic volume which, in turn, is an indicator of
preload responsiveness. The flaw lies not only in the
curvilinear shape of the ventricular diastolic pressurevolume curve, but also in alterations in ventricular compliance that occur during critical illness
due to pressures transmitted from adjacent compartments. Mark and Cavallazzi [21] performed a metaanalysis of 43 studies from the ICU and operating
room and found a correlation coefficient between
baseline CVP and change in stroke volume index
and cardiac index of 0.18, indicating essentially
no relationship.
A common approach in the ICU is a fluid challenge. Osman et al. [22] evaluated 150 fluid
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Fluid choices impact outcome in septic shock Douglas and Walley

challenges among 96 patients and found that the


cardiac index improved in only 65 cases. The CVP
was similar in responders and nonresponders in
whom a CVP less than 8 and pulmonary artery
occlusion pressure less than 14 predicted volume
responsiveness of only 47% and 54%, respectively,
similar to flipping a coin.
Cyclic changes in intrathoracic pressure during
mechanical ventilation change ventricular preload
and, to a lesser extent, afterload. Higher intrathoracic pressure during ventilator inspiration impedes
venous return with a corresponding decrease in
stroke volume and pulse pressure [23]. Studies examining these dynamic ventilation-induced changes
found that pulse pressure variation and stroke
volume variation are useful in predicting responsiveness to volume administration (sensitivity,
specificity and diagnostic OR 0.89, 0.88 and 59.9
for pulse pressure variation and 0.82, 0.86 and
27.3 for stroke volume variation, respectively)
[24]. As an extension, use of the pulse oximeter
plethysmographic waveform has been used to predict fluid responsiveness with good correlation and
agreement with the pulse pressure variation [25].
Drawbacks of these strategies include the need for
absence of significant arrhythmias and mechanical
ventilation using tidal volumes of 810 ml/kg in
patients without spontaneous breathing, which
conflicts with lung protective ventilation and strategies at minimizing sedation.
Doppler echocardiography assessment of the
aortic blood velocity over the respiratory cycle follows the same principle as arterial waveform analysis.
Using either esophageal Doppler monitoring or
transesophageal echocardiography of ventilatorinduced variation in aortic blood flow has been used
to predict fluid responsiveness [26,27]. Similar to
arterial changes during positive pressure ventilation,
superior and inferior vena cava diameter has been
used to predict fluid responsiveness. Using focused
echocardiography, inspiratory increases in inferior
vena cava diameter greater than 12% in one study
and 18% in another had greater than a 90% sensitivity and specificity for fluid responsiveness [28,29].
A recent study looking at end-expiratory occlusion
during mechanical ventilation showed that an
increase in cardiac output or arterial pulse pressure
by more than 5% predicted fluid responsiveness with
good accuracy [30].
Spontaneously breathing patients can be
assessed using a passive leg raise. Lifting the legs
passively to a 458 angle has been shown to predict
changes in aortic blood flow to the same extent as a
500 ml bolus even in patients with cardiac arrhythmias and spontaneous ventilation. It is important
to assess this method with real-time evaluation

of cardiac output or stroke volume. Newer techniques including transpulmonary thermodulition


to measure the stroke volume (PiCCO, FloTrac-Vigileo) allow this assessment, and increases in pulse
contour cardiac output at least 10% predict volume
responsiveness. Other techniques to assess the response to a passive leg raise can use bioimpedancebased systems (e.g., noninvasive cardiac output
monitoring measuring changes in signal amplitude
[31]).

FLUID CONSEQUENCES
Recent evidence is emerging, suggesting that overexuberant fluid resuscitation is detrimental. Boyd
et al. [14] demonstrated higher mortality with a
more positive fluid balance at 12 h and day 4. Lowest
mortality at 12 h was observed in those with a CVP
less than 8 mmHg, followed by 812 mmHg and
lastly greater than 12 mmHg had the highest
mortality. No correlation between CVP and fluid
balance was seen on days 14. The fluid expansion
as supportive therapy trial group explored fluid
bolus therapy versus no fluid bolus therapy in
African children admitted to hospitals with severe
febrile illness and impaired perfusion. The trial [32]
was stopped early after preliminary results showed
an increased 48-h and 4-week mortality in the fluid
bolus group. Post-trial exploration revealed that
despite a greater perfusion increase at 1 h in the
bolus arm, a higher proportion of terminal events
were caused by cardiovascular collapse at 48 h [33].
Retrospective review of the Acute Respiratory
Distress Syndrome Network ventilator-tidal volume
trial revealed that negative cumulative fluid balance
at 4 days was associated with more ventilator and
ICU free days and lower odds ratio of mortality [34].
Another prospective trial in patients with acute lung
injury found a conservative strategy of fluid management improved oxygenation and shortened
mechanical ventilation and ICU care [35]. A number
of studies looking at restrictive versus liberal strategies of fluid administration perioperatively have
shown lower rates of postoperative complications
and mortality in the former [36,37].
Sepsis-induced acute kidney injury (AKI) is not
only the result of hypoperfusion, but the interaction
between inflammation and oxidative stress, microvascular dysfunction and adaptive changes in tubular
epithelium [38]. A recent retrospective study looking
at kidney injury and hemodynamics found that a
higher CVP was associated with risk of developing
new or persistent AKI [39 ,40]. Analysis of the Sepsis
Occurrence in Acutely Ill Patients trial showed that in
patients with AKI, mean fluid balance remained
an independent risk factor for mortality [41]. In

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Intravenous fluids

the Randomized Evaluation of Normal vs. Augmented Level study in critically ill patients, a negative
mean daily fluid balance was associated with
increased renal replacement free days, ICU free days
and survival [42].
In summation, we are left with the need for
rapid diagnosis and early fluid resuscitation,
possibly primarily to relieve overt tissue hypoxia.
Beyond the initial fluid loading during the first
612 h, further positive fluid balance may be counterproductive. EGDT, now in its teenage years, is still
being questioned; however, there can be no doubt
that an imperative to diagnose and respond quickly
to septic patients is vital to their survival. Perhaps, it
is necessary to make a clear distinction between
fluid resuscitation during the first 6 h and the following 672 h in which the end-point goals are very
different and are based on clear evidence that further fluids will improve organ function.

FUTURE TRIALS OF GOAL-DIRECTED


THERAPY
Despite widespread acceptance and early implementation into the Surviving Sepsis Campaign
guidelines, aspects of EGDT are debated. For these
reasons, three separate groups designed and finished
or are near completion of multicenter randomized
controlled trials of EGDT; the UK ProMISe, Australasia ARISE and USA ProCESS trials. These studies
presented a number of interesting questions. First,
sites were selected on the basis of an absence of
routine protocolized ED sepsis care. All three studies
are superiority trials, enrolled from the ED within
2 h of meeting criteria. Trained teams are activated
to deliver the EGDT on the basis of the original
EGDT trial with two arms (usual versus EGDT) in
the ARISE and ProMISe and three arms [usual, EGDT
and protocolized standard care (PSC)] in the ProCESS trial. The trials are powered to detect at 68%
absolute risk reduction in hospitals or 90-day
mortality, which will be challenging because of a
baseline mortality of septic shock of 2530% [43].
The only one released to date is the ProCESS trial in
which the protocol-based regimens (standard care
and EGDT) both received more fluids and had
higher MAPs and use of vasopressors at the end of
the 6-h resuscitation periods compared with usual
care [44]. Interestingly, there was no difference in
60-day and 90-day mortality between the groups,
yet the usual care group had a lower incidence of
acute renal failure requiring renal replacement.
Publication of the other two control trials of
EGDT may shed even more light on what elements
and quantities of EGDT are crucial. Even more challenging is the observation that usual care is now
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quite different from the previous century (when


EGDT was conducted) and now incorporates many
elements of EGDT.

CHOICE OF FLUIDS
Although the need for early fluid resuscitation in
septic patients is accepted, the choice of fluid therapy
remains controversial. Crystalloids include various
salt concentrations of isotonic saline (0.45%, 0.9%,
3%) and the balanced salt solutions (Hartmans,
Ringers lactate, PlasmaLyte). Crystalloids are inexpensive, rapidly expand the intra and extravascular
fluid compartments, improve end organ perfusion
and have minimal risks of anaphylactoid reactions
[45]. The colloids are a heterogeneous group of fluids,
including albumin, gelatins, hydroxyethyl starch
(HES) and dextran containing fluids. Colloids rapidly
improve intravascular volume and oncotic pressure;
thereby resuscitation may require less time and volume. Colloid resuscitation can improve oxgygen
transport, myocardial contractility and cardiac
output [46]; however, until recently no data have
clearly demonstrated their superiority in critically ill
patients in terms of pulmonary edema, length of stay
or mortality [47].
The Cochrane review [48] from 1998 compared
albumin to crystalloids in 30 randomized controlled
trials in critically ill patients with hypovolemia,
burns or hypoalbuminemia and found that the
pooled relative risk of death was significantly higher
with albumin. The crystalloid versus hydroxyethyl
starch trial compared crystalloid versus HES and
found no difference in 90-day mortality, but despite
an overall lower rate of AKI there was more need for
renal replacement therapy in the HES group [49].
The 6S trial group compared hydroxyethyl starch to
Ringers acetate in patients with severe sepsis for
ICU fluid resuscitation [50]. The group that received
HES had an increased risk of death at 90 days and
were more likely to require renal replacement
therapy.
The saline versus albumin fluid evaluation trial
compared albumin to saline for initial fluid resuscitation in ICU patients and showed no difference in
the rates of organ failure, ICU time, renal replacement or mortality [47]. However, when the investigators performed a subgroup analysis of patients
with severe sepsis the adjusted odds ratio for death
was 0.71 (95% CI: 0.520.97; P 0.03) for albumin
[51]. The CRISTAL trial compared a number of
colloids to crystalloids as part of a multicountry
collaboration to assess primarily death at 28 days
and a number of secondary outcomes [52]. Overall,
there was no difference at 28 days; however, 90-day
mortality was lower among patients receiving
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Fluid choices impact outcome in septic shock Douglas and Walley

colloids. Interestingly, the colloid group also had


significantly more days alive without mechanical
ventilation and alive without vasopressor therapy at
both 7 and 28 days. The recent Albumin Replacement in Patients with Severe Sepsis or Septic Shock
trial [53 ] randomized severe septic and septic
shock patients to albumin or crystalloids for early
fluid resuscitation (624 h) and to infusions of albumin to maintain levels of 30 g/l or less. Patients
receiving albumin had higher MAP and CVP and
a lower fluid balance with the same mortality. However, when only the patients with septic shock were
observed, the albumin patients had a 6.3% higher
probability of survival at 90 days (P 0.04) (website:
http://www.criticalcarecanada.com/presentations/
2013/albios_trial_%E2%80%93_albumin_in_sepsis.
pdf.).
One of the criticisms of the Rivers et al. trial
included the aggressive use of red blood cell transfusions for low ScvO2. Although packed red cells are
useful means of volume expansion, their use in
nonhemorrhagic patients is controversial. Restrictive strategies aimed at hemoglobin greater than
7.0 g/dl showed improved mortality in the less
acutely ill (APACHE II score  20) or less than
55 years of age and similar mortality to those with
significant cardiac disease compared with hemoglobins of 10 g/dl or less [54].
Currently, the data suggest that fluid resuscitation in septic shock patients with albumin provides
some improvement in survival and potentially
ventilator and vasopressor free days. With more
data soon to be available, the momentum may
shift again; however, the purpose will be the same:
early responsible fluid resuscitation improves outcomes.

REFERENCES AND RECOMMENDED


READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
&
of special interest
&& of outstanding interest

&&

CONCLUSION
Despite decades of research into mechanisms and
many failed trials of therapeutics, mortality from
septic shock still remains shockingly high. EDGT
was one of the first modalities to provide some
benefit, yet questions remain whether they are
the right goals. There can be no question that early
identification and adequate fluid resuscitation is
crucial and that over-aggressive fluid resuscitation
leads to complications; however, where that breaking point is remains unclear.
Acknowledgements
Support: Canadian Institutes of Health Research.
Conflicts of interest
Both authors state no conflict of interest.

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