Fluid Therapy in Septic Shock

CE: Namrta; MCC/534; Total nos of Pages: 12;
MCC 534
Fluid therapy i n septicshock
a
b
Emanuel P. Rivera s, ,bAnja Kathrin Ja e hne
, Laura Eichhorn-Wharry
,
a
a
Samantha Brown and David Amponsah
a
Department of Emergency Medicine and

Purpose of review
Department of Surgery, Henry Ford Hospital, Wayne
To examine the role
State University, Detroit, Michigan, USA
b
of uid therapy in the pathogenesis of severe sepsis and septic

shock. The type, composition, titration, management strategies and complications of
Correspondence toEmanuelP.Rivers,MD,MPH,IOM,
uid
Vice Chairman and Research Director, Department
of administration will be examined in respect to outcomes.
Emergency Medicine, Attending Staff, Emergency
Recent ndings
Medicine and Surgical Critical Care, Henry Ford
Fluids have a critical role in the pathogenesis and treatment of early resuscitation of
Hospital, Clinical Professor, Wayne State University,
Detroit, MI, USA
severe sepsis and septic shock.
Tel: +1 313 916 1801; e-mail: erivers1@hfhs.org
Summary
Current Opinion in Critical Care2010,
Although this pathogenesis is evolving, early titrated uid administration modulates
16:000000
inammation,improvesmicrovascularperfusion,impactsorganfunctionandoutcome.
Fluid administration has limited impact on tissue perfusion during the later stages of
sepsisandexcess uidisdeleterious to outcome. Thetype ofuidsolution doesnot
seem to inuence these observations.
Keywords
colloid therapy, crystalloid therapy, uid therapy, sepsis, septic shock, severe sepsis
Curr Opin Crit Care 16:000000
2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
1070-5295
permeability.Allofthesemechanismsresultinadecrease
in intravascular volume which gives rise to a critical
reductioninventricularpreload,ventriculardiastolicpresIn 1942, Cuthbertson [1] described the metabolicsure,strokevolume,
CO,andsystemicoxygendelivery.
responsetoinammation,injuryandshockintheebb
andowphase.Duringtheebbphaseorresuscitation Compensatory responses as a reaction to decreased cirphase, there is low cardiac output
CO),
( poor tissue culatingbloodvolumearemediatedbytheactivationof
perfusion and a cold and clammy patient. During the
the sympathetic nervous system and include:
owphasewhichisastaccatoaffair,thepatientstruggles
to break from the grip of the ebb phase which lasts(1) A redistribution of blood ow away from skeletal
about3days.Uponenteringtheowphase,theswollen
muscle beds and the splanchnic viscera to support
patient has an increased
CO, normal tissue perfusion
vitalorganbloodowtotheheartandbrain [2,3] .The
whendiuresisoccursandbodyweightfallssteady.This movement of uid into or out of the intravascular
eloquent description serves as the framework for the compartment is determined by the hydrostatic and
clinical principles of uid management in sepsis. This oncoticpressuregradientsbetweenthemicrovascular
review will examine the role of uid therapy in the
andtheinterstitial spaces.Precapillary vasoconstricpathogenesis of sepsis. The timing, type, composition,tiondecreasesmicrovascularbloodpressurepromottitration, management strategies and complications ofing the net movement of uid from the interstitial
uid administration will be examined in respect to
compartment into the vascular compartment [4] .
outcome.
Because of these factors, the type of uid administered(crystalloidversuscolloid)becomesanimportant and controversial component of the initial
The pathogenesis of hypovolemia in sepsis
resuscitation.
Sepsis-inducedhypovolemiacanbearesultofvomiting,(2) An augmentationof myocardial contractility
diarrhea,sweating,edema,peritonitisorotherexogenous increasesstrokevolume [2] .Pre-existingcardiacdislosses. Further contributions to hypovolemia may result
easemayalterthisresponseandtheclinicalpicture.
from a maldistributivedefect with vasodilatation, (3) Thereisaconstrictionofarterialandvenouscapaciperipheral blood pooling, and extravasation of uid into
tance vessels, particularly in the splanchnic bed,
the interstitial space and increased capillary endothelial
augmenting venous return [2,3] . The use of antihy-
Introduction:Theebbandowphaseofuid
management
1070-5295
2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
DOI: 10.1097/MCC.0b013e32833be8b3
Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
MCC 534
2 Intravenous uids
pertensive medications and diuretics may alter Fluidtherapymodulatesearlyinammation.Inthehuman

this response.
modelofendotoxemiaisotonicprehydrationsignicantly
(4) A sustained release of adrenocortico-medullary horattenuates the concentrations of proinammatory cytomones including cortisol, aldosterone and catecholkines(TNF-a,IL-8andIL-1 b),whereastheconcentration
amines such as epinephrine occurs [5] . Congestive
of the anti-inammatory cytokine IL-10 demonstrates a
heart failure, renal failure, liver disease and adrenal
trendtowardshigherconcentrations.Prehydrationresults
dysfunction may modify this salt and water homeoina shifttowardsananti-inammatorycytokinepattern.
stasis which will alter both requirements and elimThis effect is associated with a reduction of endotoxinination of uid.
induced symptoms and fever, whereas the endotoxin(5) Theactivationoftherenin-angiotensinaxisreleasesinduced changes in hemodynamic parameters remain
aldosterone from the adrenal cortex. Changes inunchanged. More importantly, the peak activity of the
serum osmolarity lead to arginine-vasopressin inammatoryresponseisbetween1and6hafterintroduc(AVP) release from the posterior pituitary. Both tionoftheinsult,whichgivesrisetotheconceptofearlyand
enhances uid retention [3,68] .
lateresuscitationasdistincttherapeuticentities [10] .
(6) Microcirculatory changes such as acidosis, pyrexia,
andincreased redblood cell 2,3-diphosphoglycerate
Fluidsmayincreasemicrovascularperfusionbyincreasing
occur,creatingalocaltissueenvironmenttoenhance
thedrivingpressureorbydecreasingbloodviscosity(hemothe unloading of oxygen to tissues. Multiple factors
dilution)andmodulatinginteractionsbetweentheendomay contribute to microvascular alterations, includtheliumandcirculatingcells.AngiotensinIIisbelievedto
ing driving pressure, alterations in red blood cellplayaroleintheinductiononammation.Mildhypovorheology and viscosity (local hematocrit) and leukolemiaactivatesthesympatheticnervoussystemleadingto
cyte adhesion to endothelial cells, endothelial dysincreased concentrations of circulating catecholamines
function and interstitial edema.
which activates cytokine-producing cells containing
a
andb-adrenoreceptors.Duringadrenalineinfusion,endotoxininduceslessTNF-a andmoreIL-10,indicatingthat
The magnitude of compensatory mechanisms is depenb-adrenergicstimulationexertsanti-inammatoryeffects.
dent on the timing, severity of insults and the baseline
In-vitrostudiesdemonstratedthatnoradrenalineexhibits
organfunctionstatusofthepatient.Compensatorymechproinammatoryproperties.Bystimulatingthe
a-adrenoranisms are effective at restoring tissue perfusion for
a
periodduringshock;however,iftheinitiatingprocessis eceptors of macrophages and lung mononuclear cells,
noradrenaline augments TNFa secretion in various
not reversed the non-compensatory pathogenesis coninammation-inducing models. Because uid infusion
tinues and leads to downstream complications. These
decreasesthestimulusforactivationofvasoactiveagents,
pathogenic mechanisms include endothelial disruption,
the generation of proinammation and anti-inam- itinuencesinammation [11] .
mation, microcirculatorycompromise,global tissue
hypoxia, organ dysfunction and death ( Fig. 1 ).
Clinical manifestations of hypovolemia
When a clinician is confronted with a profoundly hypotensivepatientandasourceonfection,thediagnosisof

septicshockisstraightforward.Althoughhypovolemiais
In animal models, uid therapy has been shown to present in virtually all patients ranging from sepsis to
improve outcome. Natanson
et al. [9] compared the septic shock, quantitating volume status is one of the
efcacy of antibiotics, cardiovascular support (uidsmostdifcultmanagementsteps.Theclinicalassessment
and dopamine titrated by intravascular monitoring of
to hypovolemia is historically nonsensitive and nonspecic. In a post-hoc analysis of Fluids and Catheters
hemodynamic endpoints) and a combination of these
Treatment Trial in acute lung injury (FACTT) this
two therapies in dogs with septic shock. Survival rates
hypothesis was examined. When physical examination
were 0, 13, 13, and 43% in groups receiving no therapy
(controls),antibiotics alone, cardiovascularsupport ndingsofanineffectivecirculation(capillaryrelltime
>2s,skinmottling,andcoolextremities)werecompared
alone, or combined therapy [9] . The improved survival
to parameters obtained from a pulmonary artery catherobserved in the group receiving combined therapy conter, it was found that they are not useful predictors of a
siderably exceeded that in the groups receiving either
low cardiac index
CI)
( or low SvO
therapyalone.Althoughsurvivorsandnonsurvivorsinthe
2 [12 ,13 ] .
combined therapy group required similar quantities of
uid therapy, nonsurvivors gained signicantly more
uidtherapy
weight, suggesting abnormal vascular permeabilityTitrating
with
extravascularretentionofuidsinthenonsurvivorsindi-Optimizing uid therapy not only modulates inammation,italsodecreasestheneedforvasopressortherapy,
cating a more pronounced ebb phase.
Fluid therapyeffects on the pathogenesis of

severe sepsis and septicshock
MCC 534
Fluid therapy in septic shock

Riverset al. 3
Figure 1 Compensatory and non-compensatory responses to shock
Compensatory
Infection and volume loss

(decrease in DO
2 )
Renin-angiotensin,
vasopressin and ADH
Splanchnic viscera, skin,

kidneys and skeletal muscle
Non-compensatory
Endothelial cells
Complement
kinins
endorphins
ICAM-1
ELAM-1
oxidants
Cortisol
and catecholamines
CNS stimulation
Redistribution of blood volume to

heart and brain (hypovolemia)
Arterio-venous
constriction
Peripheral vasodilation and

vasoconstriction (tissue hypoxia)
Gut hypoperfusion and

mucosal breakdown
Activation of inammation and

panendothelial dysruption
Endotoxin release
Leukocytes
Platelets
Monocytes/macrophages
Adherence
proteases
oxidants
Arachidonic acid
metabolites
platelet activating
factor
Coagulation
cascade
Pro and
anti-inammatory
mediators and
apoptotic proteins
Cellular and organ dysfunction

necrosis and/or apoptosis
(myocardial suppression)
Impaired uptake and utilization:

microcirculatory alterations
increased diffusion distance
Local and global tissue hypoxia
Oxygen debt
Reversible or irreversible
organ dysfunction
steroiduseandmoreinvasivemonitoringwithpulmonary
vasopressorsusetoincreasedmortality [15,16] .Thegoal
arteryandarteriallinecatheterization [10,14] .Decreasing
ofuidresuscitationinseveresepsisandsepticshockis
vasopressorusewhichcausesafalseelevationincardiac
not merely achieving a predetermined value, but rather
llingpressureseliminatespressurevolumemisinterpreoptimizing systemic oxygen delivery (cardiac preload,
tations. It is these mulifactorial reasons which associate
afterload, arterial oxygen content, contractility or stroke
MCC 534
4 Intravenous uids
Figure 2 The hemodynamic, oxygen transport and utilization components of tissue perfusion
Systemic oxygen delivery Systemic oxygen extraction
=
(OER-%) = (1-SvO2 )
(DO 2)
Arterial oxygen
Cardiac output
heart rate stroke volume content (CaO2 )
Stroke volume (SV)

cardiac output/heart rate
Heart rate
Hemoglobin
Pulmonary
gas
exchange
(PaO 2, SaO2)
Systemic oxygen
consumption (VO2 )
Systemic oxygen demands:

stress
pain
hyperthermia
shivering
work of breathing
Microcirculation
Contractility
Preload
(CVP, PAOP,
SVV, PPV, FTc)
Systemic vascular
resistance (SVR)
MAP-CVP or PAOP 80
CO
Metabolic endpoints
SvO2 > 65%
ScvO2 > 70%
lactate < 2 mM/l
base decit < 5 mEq/l
pH > 7.3
(a-v)CO2 < 5mmHg
pHi > 7.31
urine output > 0.5 cc/kg/h
volume), and ultimately balancing tissue oxygen order to assess uid responsiveness, the uid challenge
demands ( Fig. 2 ) [17] . The goal is to infuse adequate
has been the traditional method for decades. In the
volumetorestoreperfusionbeforetheonsetorrevers-volume-responsive phase, a change in CVP of 2 mmHg
ibletissuedamagewithoutraisingcardiacllingpressure
willproduceaneasilymeasurablechangein
CO,whereas
to a level that produces hydrostatic pulmonary edema.
in the plateau phase there is no changeCO
inwith a
change in CVP [21] .
Hemodynamicmonitoringusedtoaccomplishthesegoals
EchocardiographycanbeusedtoestimateLVEDV,but
is noted in Table 1 [18] . Thus, it is important to have
a
commandofphysiologicvariablesthatareresponsiblefor
thisapproachisverydependentontheskillandtraining
tissueperfusion.Thesevariablesfurtherserveasdiagnosoftheindividualusingit [22] .Isolatedmeasurementsof
tictoolsandtherapeuticroadmapsforcharacterizationand
LVEDV fail to predict the hemodynamic response to
managementofthepatientpresentingwithshock.
alterationsinpreload [23] .Pulsepressurevariation(PPV)
during apositivepressurebreathcanbeusedtopredict
Commonly used methods to assess the adequacy oftheresponsivenessof
COtochangesinpreload [24] .PPV
volumestatusorcardiacpreloadincludebloodpressure,is dened as the difference between themaximal pulse
heartrate,urineoutput,centralvenouspressure(CVP)or
pressureandtheminimumpulsepressuredividedbythe
pulmonary artery occlusion pressure (PAOP). Multicenaverageofthesetwopressures [24] .PPVhasbeencomteroutcomestudieshaveshownthatthecentralvenouspared to CVP, PAOP, and systolic pressure variation as
catheter measurements are equal to the volume assesspredictorsofpreloadresponsiveness.Patientswereclassiments via pulmonary artery catheter in uid manageedaspreloadresponsiveiftheir
CI increasedbyatleast
ment. However, neither CVP nor PAOP correlates well
1015%afterrapidinfusionofstandardvolumeontrawiththetrueparameteronterest,left-ventricularend-venousuid [25] .Receiveroperatorcurvecharacteristics
diastolicvolume(LVEDV) [19] .Thus,measuringanor-(ROC)demonstratedthatPPVwasthebestpredictorof
malCVPorPAOPmaynotruleoutinadequatepreload. preload responsiveness. Atrial arrhythmias and sponExtremely high or low CVP or PAOP values are infor-taneous breathing can interfere with the usefulness of
mative;however,intermediatereadingsarenotclinically
this technique [23] . PPV in mechanically ventilated
useful. Furthermore, changes in CVP or PAOP fail to patientsremainsauseful approachforassessingpreload
correlate well with changes in stroke volume [20] . responsiveness
In
[23] .
MCC 534

Riverset al. 5
Table 1 Tools for assessing volume status
Static measures of uid responsiveness CVP or right atrial pressure, PAOP or PAWP, right-ventricular end-diastolic volume index,
left-ventricular end-diastolic area, global end-diastolic volume and intrathoracic blood
volume index [26] . May not reliably reect the left-ventricular lling pressure in clinical states
that produce pulmonary hypertension or compliance changes in the right or left heart.
Common iliac venous pressure can approximate CVP [17,27,28 ]. If cardiac output increases
after a uid challenge and stroke volume variation decreases, this can be a sign of resolving
hypovolemia.
Dynamic measures of uid responsiveness
Fall in systolic pressure compared with end-expiratory baseline or inspiratory decrement in
PPV, peak aortic blood ow velocity variation, respiratory variation in vena cava diameter,
passive leg raising and plethysmographic pulse wave variation [29] . In ventilated patients,
measures of SVV using arterial pulse contour analysis estimates
CO and can demonstrate
uid responsiveness. A pulse pressure variation of 13% is highly sensitive and specic
for detecting preload responsiveness [26] .
Noninvasive cardiac output
CO can be measured by PPV, pulse contour analysis, transesophageal Doppler, thoracic
cutaneous bioimpedance, lithium dilution or transpulmonary thermodilution [30] .
difference
Increased arterial-mixed venous carbon dioxide gradients 2or (a-v)CO are seen in acute
Systemic arterial-venous2CO
circulatory failure, and inversely correlate with
CI. Central
the
venous and pulmonary
artery CO
CI [31] . Measuring PCO
has been
2 values can be interchanged to determine
2
advocated as a way to monitor perfusion of the gastrointestinal tract. Small increases
(515mm Hg) in the difference between arterial and gastric mucosal
PCO become
2
apparent before other signs of hemodynamic instability [32,33] .
Ultrasound and echocardiography
Intracardiac, vena caval diameters, left-ventricular end-diastolic area after a uid challenge
or passive leg raising may be used to asses volume status. Controlled compression
sonography is a valuable tool for measuring venous pressure in peripheral veins and allows
reliable indirect assessment of CVP. Ultrasound can also be used to assist in-line placement
and cardiac output measurement [34] . It can also be a diagnostic tool to detect
myocardial dysfunction, pericardial disease, aortic disease, intraperitoneal blood and
pneumothoraces [35] .
Circulating blood volume measurement There is astatistically signicant, but weak, correlation between blood volume results and PAOP,
but no correlation with CVP,
CI, and stroke volume index. Circulating blood volume
measurements may be useful in critically ill patients when clinical appraisal of intravascular
volume is uncertain. This remains to be validated in a larger, prospective randomized trial [36 ].
CI, cardiac index;
CO, cardiac output; CVP, central venous pressure; PAOP, pulmonary artery occlusion pressure; PPV, pulse pressure variation.
dextrans, and gelatins). Colloids include the starches,

hetastarchandpentastarch,humanserumalbumin,gelaThe two most commonly used crystalloid solutions are
tin,anddextran.Colloidsaredissolvedineithernormal
0.9% sodium chloride solution (normal saline or NaCl)
salineorabalancedsaltsolution.Recentreviewssuggest
and Ringers lactate solution. The composition of these
thattherearenoclinicallysignicantdifferencesamong
two uids is shown in Table 2 . Although normal saline
thevariouscolloid solutionswhen usedforshock resusandRingerslactatesolutionhavebeenregardedbymany
citation [38] . When compared to saline-based solutions,
clinicians as being essentially interchangeable, accumuhetastarchdissolvedinacalcium-containinglow-chloride
latingdatasupporttheviewthattheuseoargevolumesbalancedsaltsolutionmaybeassociatedwithlessacidosis
of normal saline, but not Ringers lactate solution, proand use of blood products [39] ( Table 3 ).
motes the development of hyperchloremic metabolic
acidosis [37] .
Duetotheirhighermolecularweight,colloidsstayinthe
intravascular space signicantly longer than crystalloids
Colloids are higher-molecular-weight
solutions that with anintravascularhalf-lifeforalbumin of16hversus
increaseplasmaoncoticpressure.Colloidscanbeclassi-3060min for normal saline and lactated Ringers
ed as either natural (albumin) or articial (starches,
solution [41,42] . When titrated to the same PAOP,
Crystalloid therapy
Normasol contains acetate 27mmol/l and gluconate 23mmol/l.
CE:
Namrta;
MCC/534;
Intravenou
Total
s
uids
nos
of
Pages:
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MCC
534
Table
Solution
NaCl
Ringers
Plasmalyte
Normasol
Hartmanns
0.9%
and
2 Composition
glucose
B asolutionOsmolarity
and
(mOsm/l)
or
308
264
275
298.5
280
lactated
osmolarity
Ringers
(mmol/l)
Na
154
130
140
of31
crystalloid
solution.
(mmol/l)
154
110
Cl98
31
solutions(mmol/l)
[11]
K
4
5
a
b
blactate
(mmol/l)
Ca32
Glucose
(mg/l)
40
(mmol/l)
HCO
503-
(mmol/l)
Lactate
28
Energy
(kcal/l)
320
MCC 534
Expressed as percentage of administered volume.

Riverset al. 7
Table 4 Descriptions of uid therapy
Normal saline
Normal saline is a slightly hyperosmolar solution containing 154 mEq/l of both sodium and chloride.
Due to the relatively high chloride concentration, normal saline carries a risk of inducing hyperchloremic
metabolic acidiosis when given in large amounts [42] .
Lactated Ringers
LR results in a buffering of the acidemia which is advantageous over normal saline. Due to the fact that
LR contains potassium, albeit avery small amount, there is a small risk of inducing hyperkalemia in patients
with renal insufciency or renal failure. There is a theoretic issue of using LR because of the signicant immune
activation and induction of cellular injury caused by the D-isomer of lactated Ringers.
Hypertonic saline
Hypertonic saline exerts immunomodulatory effects through suppression of neutrophil activation and modulation
of and proinammatory and anti-inammatory cytokines. In-vitro experiments demonstrate that hypertonic
saline reduces endotoxin-inducedaTNFproduction, whereas IL-10 production is augmented and, therefore,
Table 3 Physiological characteristics
and the
clinical
effects of commonly used intravenous
solutions
[11,40]
(table
from
publication)
helps to restore
proinammatory/anti-inammatory
balance.
Hypertonic
saline
hasobtained
led to rapid
plasma
volume expansion, improvement in myocardial contractility and performance, reduction in endothelial and
Available formulations
myocardial edema, and enhancement of immune function in experimental models of sepsis. Human data
are lacking
[46] .
Albumin
solutions
Starches
Dextrans
Gelatins Crystalloids
Albumin [47]
Albumin is a protein derived from human plasma. It is available in varying strengths from 4 to 25%. The Saline
versus Albumin Fluid
Evaluation
(SAFE)
study
compared
uid
resuscitation
with
albumin
or
saline
mortality
3%, 6%, 10%
3% Dextran-60, Succinylatedon
and
cross-linked;
Ringers
Normal
similar
mortalities
and secondary
outcomes
in each
arm [48] . However,
a subset
analysislactate
of
4%,and
5% found
20%,
25% 28-day
Hetastarch
10% Pentastarch
10%
Dextran-40
6% Dextran-70
2.5%, 3%,
4% urea-linked:
saline
3.5%
patients with sepsis and acute lung injury resuscitated with albumin showed a decrease in mortality, although
statistically
There280
was a signicant40
increase in mortality
particularly
Molecular weight,
69
69it was insignicant.
4 50
70 in trauma patients3035
0
with head injury [42] .
average (kD)
Hydroxyethyl
starch
Hydroxyethyl
starch
(HES)
is
asynthetic
colloid
derived
from
hydrolyzed
amylopectin,
which
has
been
found
Osmolality, mOim/l
290
310
300310
326
280-324
280324
300350
308
273
285
250
to be harmful,
renal impairment
at recommended
long-term survival
at high
COP, mmHg
2030
70100causing
2350
2350
2060 doses and impairing
2060
2542
0
doses [49]
. HES can
also cause coagulopathy
and 100200
bleeding complications
from reduced factor7080
VIII and von
Maximum volume 70100
300500
100200
100200
80140
25
20
0
2
a
Willebrand factor levels, as well as impaired platelet function. HES increases the risk of acute renal failure
expansion,
%
among
patients
with
sepsis
and
reduces
the
probability
of
survival.
HES
should
be
avoided
in
sepsis
[4951]
.
Duration of volume 1224
1224
836
1224
12
824
46
14
4
1
Dextrans
Dextrans are not frequently used for rapid plasma expansion, but rather to lower blood viscosity. This class can
expansion, h
cause renal
dysfunction,
reactions.
Plasmatic half-life, h 1624
1624
50as well as anaphylactoid
2 12
46
12
29
0.5
Gelatins
are
produced from
molecular weight, they
are not
bovine collagen.
Because they
have a much smaller
Potential to adverse Gelatins

as effective expanding plasma volume; however, they cost less [52] . They too have been reported to cause
reactions
renal impairment,
as allergic reactions
ranging
from pruritusAnaphylactoid
to anaphylaxis. GelatinsHigh
are not
currently
Possible side effects Allergic
Allergic as well
Renal
Renal
Anaphylactoid
calcium
Hyperchloremic
Hyperkalemia
available
in North America.
Because
of the signicant
calcium contentreactions
of Hemaccel, blood should
not(ureabe
reactions
reactions
dysfunction
dysfunction
reactions
content
metabolic
acidosis
infused through tubing previously used for this product.
linked forms)
Transmitted TransmittedCoagulopathy Coagulopathy
Allergic
Allergic
Anaphylactoid
infection infection
reactions
reactions
reactions
Pruritus
Pruritus
Interference
Interference with
with blood blood cross-matching
cross-matching
Anaphylactaid
colloids and crystalloids restore tissueAnaphylactoid
perfusion to
improveinthelatephaseeveninpatientswiththeworst
the
reactions
reactions
samemagnitude,althoughtwotofourtimesmorevolume
microvascular perfusion at baseline [53 ] .
COP, colloid osmotic
pressure.
of crystalloids
is
required
to
achieve
the
same
endpoint
a
[43] . This obviously depends on the stage of shock and
The optimal hemoglobin(macrovascular and
capillary permeability.
microvascular hematocrit)
The outcome advantagesbetween crystalloidand Appropriate hemoglobin levels in shock remain controversialbecausethereisapaucityoiteratureforpatients
colloids continue to remain unresolved in septic shock
septic shock. The controversy is largely based on a
[40] . Table 4 compares the most commonly used in
uid
studybyHebert
etal.[54] whichfoundtolerancetolower
therapies. Meta-analyses of the results from trials comhemoglobin
levels
in stable ICU patients. Hemoglobin
paringcrystalloidsversuscolloidssuggestthatoutcomeis
concentrations
may
vary in the central, peripheral and
not affected by the choice of uid [44,45] .
microvascular circulations.
Fluidtherapy and the microcirculation
The combination of anemia and global tissue hypoxia

Microvascular alterations are frequent in patients with
provides the physiologic rationale for transfusion of red
septic shock, even when global oxygen delivery seems
blood cells (RBCs) during this delivery-dependent
adequate.Commonndingsincludeadecreaseinfunc-(increased lactate and low ScvO
) phase. Anemia may
2
tional capillary density and heterogeneity of blood ow
also result from hemodilution. Itis this particular phase
withperfusedcapillariesinclosevicinitytononperfusedthathasgoneunstudiedinprevioustrialsofhemoglobin
capillaries.Thesealterationsaremoresevereinnonsur-maintenancestrategies.Whereastransfusiontherapyhas
vivors than in survivors, and their persistence is associreceivedincreasingscrutinyincriticalillness,recentdata
ated with organ failure and death [53 ] . Fluids improve
areconicting [55] .Furthermore,therearendingsthat
themicrocirculationinearlybutnotinlatesepsis.These suggest that the sublingual microcirculation is globally
effects are independent ofthesystemic effects ofuids
unalteredbyRBCtransfusioninsepticpatientsandcan
andareobservedwithcrystalloidaswellaswithalbuminimprove in patients with altered capillary perfusion at
solutions. In addition, microvascular perfusion failedbaseline
to
[56] .TherisksandbenetsofRBCtransfusion
MCC 534
8 Intravenous uids
should be assessed in every patient before transfusion.

overalluidvolumeintherst72hwasessentiallyequal
Althoughmaintainingstablepatientsarbitrarilyathemoinbothgroups.Inasubsetanalysis,patientswhowereon
globinof10isnotsupported,forhemodynamicallycom-hemodialysis at enrollment had a more pronounced
promised patients, especially those with coronary artery
mortality reduction and decrease in mechanical ventidisease, transfusion may be warranted.
lation despite similar volume administration [62] .
The FACTT isolated the manipulation of volume
Fluidoverloadandpositiveuidbalancehasbeenassocitherapy as a controlled intervention which began an
atedwithworseoutcomesincriticallyillpatients [5759]
average
.
of 43h after ICU admission and 24h after the
In the setting of sepsis, edema is attributed to a combiestablishmentofacute lung injury (ALI) [63] .Although
nationoncreasedcapillarypermeabilitytoproteinsand
there was no difference in 60-day mortality, patients in
increased net transcapillary hydrostatic pressure through
the conservativestrategy group had signicantly
reducedprecapillaryvasoconstriction.Theuseofpositive
improved lung and central nervous system function
end-expiratorypressure(PEEP)inthesepatientscanalso
and a decreased need for sedation, mechanical ventiexacerbateuidandsaltretentionanddecreaselymphatic
lation, and ICU care. However, there was a statistically
drainage. In addition, several studies have shown that
signicant0.3-dayincreaseincardiovascular failure free
mechanical ventilation and PEEP reduce urine output;
days in the liberal compared to the conservative uid
however, their effects on glomerular ltration rate and
group,suggestingthatcautionshouldbeusedinapplying
renal blood ow are inconsistent and may reect differa conservative uid strategy during the resuscitation
encesinhydrationstatusandlunginjury.Fluidaccumu- phase. When liberal uid management strategies are
lationcancontributetoimpairorganfunctionbydifferent
utilized early, there were no differences in pulmonary
mechanisms. Tissue edema can impair gut absorption,
function and the use of mechanical ventilation. In fact,
kidney excretion, increased abdominal pressure leading
this early liberal strategy decreases the incidence of
to abdominal compartment syndrome [60] . High-risk
mechanical ventilation over the rst 72h of hospitalizpatients are the elderly, renal failure, malnutrition and
ation.ThismaybeduetothemodulatingeffectsonIL-8,
mechanicalventilation [18] .Weshouldnotonlyfocuson
whichhasbeenidentiedasaculpritwithintherst72h
daily uid balances but also on the cumulative uidof presentation [64,65] .
balance,asdurationofuidaccumulationmightinuence
outcomes.
The ndings of the FACTT trial are not at odds with
EGDT.Thisstudyhasbroughtattentiontothenegative
Liberal or conservative uid management strategies or consequences of overzealous uid administration. The
is it timing?
protocol used in FACTT is not identical to standard
The concept of early goal-directed therapy (EGDT), practice. In order to generalize these results and avoid
basedonastudybyRiversandcolleagues [61] ,notonlymitigatingthesalutaryndings, multiplevariables must
changedthelandscapeofsepsismanagementbutalsorebe considered when applying a conservative uid maninvigoratedthedebatesregardingresuscitationanduid
agement approach [11] . The exclusion of patients on
management in sepsis. High-risk sepsis patients were
hemodialysis, overt renal insufciency, heart failure
randomized to conventional therapy or goal-directed
and the relatively young age of the patients studied
resuscitation to normal physiologic endpoints during
(about 50 years of age) make FACTT a departure from
the rst 6h after presentation. EGDT is a stepwise therealitythatmanyclinicianswillfaceinthetreatment
physiologic approach that includes optimization of preof ALI or sepsis.
load,afterload,arterialoxygencontent,contractilityand
theminimizationofoxygendemands.RatherthantargetAs Cuthbertson decribed in 1942, the clinician must
also make an accurate clinical assessment of the ow
ingspecicvaluesfor
CO,systemicDO2 orsystemicVO
,
2
EGDTtargetstheachievementofanScvO
greaterthan
phase while paying particular attention to the untoward
2
70% as an additional endpoint rather than only an complications upon instituting conservative uid stratoptimized CVP.
egies and active diuresis. Although pathogenically well
described, the clinical landmark that separates the ebb
Using this carefully planned algorithm for resuscitation
from ow phase is frequently indistinct and complex.
( Fig.3 ),EGDTimproved30-daymortalityfrom46.5to In ALI theebbphase ischaracterized byanincreasein
30.5%.Theoutcomendingsofthisstudyanditssocio- lung water due to direct permeability changes on lung
economicimpacthavebeenconrmedextensivelysince
capillaries and systemic inuences on water balance
this seminal publication. However, because the treat[8,9] . In the absence of manipulating uid balance in
ment arm received an average of 2l more uid thanthis phase of ALI, pulmonary edema, myocardial comthe control arm in the rst 6h, the uid therapy hasplications, respiratory insufciency and the continued
receivedthemostattention.Itshouldbenotedthatthe need for ventilator support result. Thus, conservative
Negative consequences of uid therapy
MCC 534

Riverset al. 9
Figure 3 Protocol for early goal-directed therapy in septic shock
Suspected infection and

document source
within 2 hours
The high risk patient:

blood pressure < 90 mmHg after
2040 cc/kg volume challenge or
lactic acid > 4 mmole/liter
Antibiotics within
hour and source
control
< 8 mmHg
Crystalloid
CVP
> 812 mmHg
Decrease
oxygen
consumption
MAP
< 65 or > 90 mmHg

Vasoactive agent (s)
90 mmHg
> 65
> 70%
ScvO2
< 70%
Packed red blood

cells to Hct > 30% < 70%
> 70%
Ionotrope (s)
No
Goals
achieved
Reproduced from [61] .
MCC 534
10 Intravenous uids
Figure 4 Fluid management strategies in sepsis
Fluid mobilization and

liberate from mechanical
ventilation
Severe sepsis and

septic shock
The Ebb phase:
Sodium and water conservation,

hypovolemia, vasodilation, myocardial
suppression, increase metabolic demands and
impaired tissue oxygen utilization
Compensated sepsis:
The flow phase:
Shock reversal and volume replete

avidity for water and sodium, low
plasma oncotic pressure, increased
lung water, generalized edema
Conservation of uids and/or

diuresis,
closely monitor electrolytes
and volume status
Co-morbidities and considerations:
Incomplete source control, ongoing inamation

complicated by:
renal failure
myocardial dysfunction
liver disease
endocrinopathies
-hypothyroidism
-adrenal dysfunction
Prolonged mechanical ventilation (increased anti-diuretic hormone)
Pre-existing hypertension (increased sodium and water retention)
Identify and treat:

Underlying disorder
Persistant Ebb phase:

Impaired uid mobilization
Reproduced from [63] .
uid strategies, perhaps even with a diuretic provocaand withdrawal of uid during appropriate phases of
tion, with appropriate cautions to preserve organ perinammation.
fusionandavoidmetabolicderangementsaretherapeutically sound ( Fig. 4 ).
Conclusion
Fluids are critical in the pathogenesis and treatment of

The FACTT trial and subsequent studies differentiate
early resuscitation of severe sepsis and septic shock.
adequateinitialuidresuscitationfromconservativelate
Althoughthispathogenesisisevolving,earlytitrateduid
uid management. Whereas appropriate uid resuscitaadministrationmodulatesinammation,improvesmicrotion based on the resuscitation or ebb phase leads to
vascularperfusion,impactsorganfunctionandoutcome.
improvedoutcomes,liberalandlateuidresuscitationis
Fluid administration has limited impact on tissue peranegativecontributortooutcome [66 ] .Thus,thereare
fusionduringthelaterstagesofsepsisandexcessuidis
signicantbenetstobothagoal-directedadministration
MCC 534
Fluid therapy inseptic shock

Riverset al. 11
20 Lichtwarck-Aschoff M, Zeravik J, Pfeiffer UJ. Intrathoracic blood volume
deleterious to outcome. The type of uid solution does
accurately reects circulatory volume status in critically ill patients with
notseem toinuencethese observations. Fluid therapy mechanical ventilation. Intensive Care Med 1992; 18:142147.
remainsaclinicaldecisionbasedontheunderstandingof
21 Magder S. Central venous pressure monitoring. Curr Opin Crit Care 2006;
12:219227.
the pathogenic landscape of the disease.
Acknowledgements
22 Smith MD, MacPhail B, Harrison MR,

et al.Value and limitations of transesophagealechocardiographyindeterminationoeftventricularvolumesand
ejection fraction. J Am Coll Cardiol 1992; 19:12131222.
Conicts of interests: None related to this publication. Dr Rivers 23

receivesresearchfundingfromtheNIH.Inthelast5yearshehasbeen
a consultant to Esai Pharmaceuticals, Agennix, Astra Zeneca and24
Idaho Technologies.
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CE: Namrta; MCC/534; Total nos of Pages: 12;