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INTRODUCTION — Sepsis is a clinical syndrome characterized by systemic inflammation due to
infection. There is a continuum of severity ranging from sepsis to severe sepsis and septic shock. Over
1,66,!!! cases of sepsis occur in the "nited States each year, #ith a mortality rate up to ! percent $ 1%.
&ven #ith optimal treatment, mortality due to severe sepsis or septic shock is appro'imately (! percent
and can e'ceed ! percent in the sickest patients $)*%.
+n this topic revie#, the management of severe sepsis and septic shock is discussed. efinitions,
diagnosis, pathophysiology, and investigational therapies for sepsis, as #ell as management of sepsis in
the asplenic patient are revie#ed separately. -See Sepsis and the systemic inflammatory response
syndrome/ efinitions, epidemiology, and prognosis and 0athophysiology of sepsis and +nvestigational
and ineffective therapies for sepsis and linical features and management of sepsis in the asplenic
patient.2
THERAPEUTIC PRIORITIES — The early administration of fluids and antibiotics is the cornerstone of
management for patients #ith severe sepsis and septic shock.
Therapeutic priorities for patients #ith severe sepsis or septic shock include/
3&arly initiation of supportive care to correct physiologic abnormalities, such as hypo'emia and
hypotension $6*4%.
3istinguishing sepsis from systemic inflammatory response syndrome -S+5S2 - table 12 because, if
an infection e'ists, it must be identified and treated as soon as possible -table )2. This may reuire
appropriate antibiotics as #ell as a surgical procedure -eg, drainage2.
EARLY MANAGEMENT — The first priority in any patient #ith severe sepsis or septic shock is
stabilization of their air#ay and breathing. 7e't, perfusion to the peripheral tissues should be restored and
antibiotics administered $4,1!%.
Stabilize respiration — Supplemental o'ygen should be supplied to all patients #ith sepsis and
o'ygenation should be monitored continuously #ith pulse o'imetry. +ntubation and mechanical ventilationmay be reuired to support the increased #ork of breathing that typically accompanies sepsis, or for
air#ay protection since encephalopathy and a depressed level of consciousness freuently complicate
sepsis $11,1)%.
The choice and use of sedative and induction agents -eg, etomidate, ketamine2 used to intubate patients
#ith severe sepsis or septic shock are discussed separately. Other aspects of intubation and mechanical
ventilation are similarly described else#here. -See Sedation or induction agents for rapid seuence
intubation in adults and 8dvanced emergency air#ay management in adults and 5apid seuence
intubation in adults and The decision to intubate and The difficult air#ay in adults.2
hest radiographs and arterial blood gas analysis should be obtained follo#ing initial stabilization. These
studies are used in combination #ith other clinical parameters to diagnose acute respiratory distress
syndrome -85S2, #hich freuently complicates sepsis. -See 8cute respiratory distress syndrome/
linical features and diagnosis in adults and 9echanical ventilation of adults in acute respiratory
distress syndrome.2
Assess per!sion — Once the patient:s respiratory status has been stabilized, the adeuacy of perfusion
should be assessed. ;ypotension is the most common sign but critical hypoperfusion can also occur in
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the absence of hypotension, especially during early sepsis. linical signs of impaired perfusion include
the follo#ing/
3Hypotension < ;ypotension is the most common indicator that perfusion is inadeuate -eg,
systolic blood pressure $S=0% >4! mm;g, mean arterial pressure >?! mm;g, decrease in S=0 @(!
mm;g2. Therefore, it is important that the blood pressure be assessed early and often. =ecause a
sphygmomanometer may be unreliable in hypotensive patients, an arterial catheter may be inserted
if blood pressure is labile or restoration of arterial perfusion pressures is e'pected to be a protracted
process $A%. 8ttempts to insert an arterial line should not delay the prompt management of shock.
-See8rterial catheterization techniues for invasive monitoring.2
3Si"ns o poor en#$or"an per!sion < Barm, flushed skin may be present in the early phases of
sepsis. 8s sepsis progresses to shock, the skin may become cool due to redirection of blood flo# to
core organs. 8dditional signs of hypoperfusion include tachycardia @4! per min, obtundation or
restlessness, and oliguria or anuria.
These findings may be modified by pree'isting disease or medications. 8s e'amples, older patients,
diabetic patients, and patients #ho take beta*blockers may not e'hibit an appropriate tachycardia asblood pressure falls. +n contrast, younger patients freuently develop a severe and prolonged
tachycardia and fail to become hypotensive until acute decompensation later occurs, often suddenly.
0atients #ith chronic hypertension may develop critical hypoperfusion at a higher blood pressure
than healthy patients -ie, relative hypotension2.
3Ele%ate# la&tate < 8n elevated serum lactate -eg, @) mmolCD2 can be a manifestation of organ
hypoperfusion in the presence or absence of hypotension and is an important component of the
initial evaluation $4,1E,1(%. 8 serum lactate level F( mmolCD is consistent #ith, but not diagnostic of,
severe sepsis. 8dditional laboratory studies that help characterize the severity of sepsis include a
lo# platelet count, and elevated international normalized ratio, creatinine, and bilirubin. Galues for
laboratory parameters that suggest severe sepsis are described separately. -See Sepsis and the
systemic inflammatory response syndrome/ efinitions, epidemiology, and prognosis, section on:Severe sepsis:.2
3Ot'er < Tests that combine output from many organs -eg, arterial lactate2 may obscure the
presence of significant ischemia in an individual organ $1%. Hastric tonometry indirectly measures
perfusion to the gut by estimating the gastric mucosal 0O). +t can be used to detect gut hypo'ia by
calculating the gastric to arterial 0O) gap $1*1?%. =ut, gastric tonometry is not #idely available and
it is uncertain #hether it can successfully guide therapy. 8dditional studies and clinical e'perience
are needed.
Establis' %eno!s a&&ess — Genous access should be established as soon as possible in patients #ith
suspected sepsis. Bhile peripheral venous access may be sufficient in some patients, particularly for
initial resuscitation, the maIority #ill reuire central venous access at some point during their course. 8central venous catheter -G2 can be used to infuse intravenous fluids, medications -particularly
vasopressors2, and blood products, as #ell as to dra# blood for freuent laboratory studies. +n addition,
this access can be used for hemodynamic monitoring by measuring the central venous pressure -G02
and the central venous o'yhemoglobin saturation -ScvO)2. Bhile in the past, a maIor purpose of a G
#as the measurement of ScGO) and G0, evidence from randomized trials on the value these targets to
follo# therapeutic effect is conflicting $1A*)!%. -See :Hoals of initial resuscitation: belo#
and omplications of central venous catheters and their prevention.2
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Be believe that pulmonary artery catheters -08s2 should not be used in the routine management of
patients #ith severe sepsis or septic shock. 08s can measure the pulmonary artery occlusion pressure
-08O02 and mi'ed venous o'yhemoglobin saturation -SvO)2. +n theory, this may be helpful to guide
circulatory resuscitation. ;o#ever, the 08O0 has proven to be a poor predictor of fluid responsiveness in
sepsis and the SvO) is similar to the ScvO), #hich can be obtained from a G $)1,))%. 08s increase
complications and have not been sho#n to improve outcome $)E*)%. -See 0ulmonary arterycatheterization/ +ndications, contraindications, and complications in adults.2
Inter%entions to restore per!sion — The rapid restoration of perfusion is predominantly achieved by
the administration of intravenous fluids, usually crystalloids. 9odalities such as vasopressor therapy,
inotropic therapy, and blood transfusion are added, depending on the response to fluid resuscitation,
evidence for myocardial dysfunction, and presence of anemia. -See Treatment of severe hypovolemia or
hypovolemic shock in adults.2
Intra%eno!s l!i#s — +n patients #ith sepsis, intravascular hypovolemia is typical and may be severe,
reuiring rapid fluid resuscitation.
(ol!)e — The optimal volume of resuscitative fluid is unkno#n. Several studies of early goal directedtherapy reported intravenous fluid infusions targeted to physiologic endpoints and resulted in volumes
ranging from E to liters $1A*)!%. The volume of fluid that #as administered #ithin the initial si' hours of
presentation #as targeted to set physiologic endpoints -eg, mean arterial pressure2. Bhile an early study
of early goal*directed therapy -&HT2 reported mean infusion volume in the first si' hours of E to liters
$1A%, later trials reporting mean infusion volumes of ) to E liters $ 14,)!%. Thus, rapid, large volume
infusions of intravenous fluids are indicated as initial therapy for severe sepsis or septic shock, unless
there is coe'isting clinical or radiographic evidence of heart failure. Suggested targets for fluid
resuscitation are discussed separately. -See :Hoals of initial resuscitation: belo#.2
Jluid therapy should be administered in #ell*defined -eg, !! mD2, rapidly infused boluses $ 4%. Golume
status, tissue perfusion, blood pressure, and the presence or absence of pulmonary edema must be
assessed before and after each bolus. +ntravenous fluid challenges can be repeated until blood pressure
and tissue perfusion are acceptable, pulmonary edema ensues, or fluid fails to augment perfusion.
areful monitoring is essential because patients #ith sepsis may develop noncardiogenic pulmonary
edema -ie, 85S2. Once patients #ith 85S have been fluid resuscitated a liberal approach to
intravenous fluid administration has been sho#n to prolong the duration of mechanical ventilation,
compared to a more restrictive approach that also typically reuires large doses of furosemide $)6%. +n
addition, small retrospective studies have reported that fluid overload is common in patients #ith sepsis
and is associated #ith the increased performance of medical interventions -eg, diuresis, thoracentesis2K
the effect of fluid overload and such interventions on mortality is unclear $)?,)A%. Thus, #hile the early,
aggressive fluid therapy is appropriate in severe sepsis and septic shock, fluids may be unhelpful or
harmful #hen the circulation is no longer fluid*responsive. -See 8cute respiratory distress syndrome/Supportive care and o'ygenation in adults, section on :Jluid management:.2
C'oi&e o l!i# — &vidence from randomized trials and meta*analyses have found no convincing
difference bet#een using albumin solutions and crystalloid solutions -eg, normal saline, 5ingerLs lactate2
in the treatment of severe sepsis or septic shock, but they have identified potential harm from
usingpentastarch or hydro'yethyl starch rather than a crystalloid solution $)4*E%/
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3Crystalloi# %ers!s alb!)in* +n the Saline versus 8lbumin Jluid &valuation -S8J&2 trial, 644?
critically ill patients #ere randomly assigned to receive ( percent albumin solution or normal saline
for up to )A days $)4%. There #ere no differences bet#een groups for any endpoint, including the
primary endpoint, mortality. 8mong the patients #ith severe sepsis -1A percent of the total group2,
there #ere also no differences in outcome. +n another multicenter open*label randomized trial of
patients #ith severe sepsis or septic shock, the addition of albumin to crystalloid did not improvesurvival compared to crystalloid alone -E1 versus E) percent2 $E!%.
3Crystalloi# %ers!s 'y#ro+yet'yl star&'* +n the Scandinavian Starch for Severe Sepsis and
Septic Shock -6S2 trial, A!( patients #ith severe sepsis #ere randomly assigned to receive either 6
percent hydro'yethyl starch or 5ingerLs acetate at a volume of up to EE mDCkg of ideal body #eight
per day $E1%. Bhen assessed 4! days after randomization, mortality #as increased in the
hydro'yethyl starch group -1 versus (E percent2 and more patients in the hydro'yethyl starch
group had reuired renal replacement therapy at some time during their illness -)) versus 16
percent2.
3Crystalloi# %ers!s pentastarch* The &fficacy of Golume Substitution and +nsulin Therapy in
Severe Sepsis -G+S&02 trial compared pentastarch to modified 5inger:s lactate in patients #ith
severe sepsis and found no difference in )A*day mortality $E)%. The trial #as stopped early because
there #as a trend to#ard increased 4!*day mortality among patients #ho received pentastarch.
+n our clinical practice, #e generally use a crystalloid solution instead of albumin solution because of the
lack of clear benefit and higher cost of albumin. Be believe that giving a sufficient uantity of intravenous
fluids rapidly and targeting appropriate goals is more important than the type of fluid chosen. Be do not
use hydro'yethyl starch or pentastarch. These choices are consistent #ith the Society of ritical are
9edicineguidelines $4%. -See Treatment of severe hypovolemia or hypovolemic shock in adults, section
on :hoice of replacement fluid:.2
(asopressors — Gasopressors are second line agents in the treatment of severe sepsis and septic
shockK #e prefer intravenous fluids as long as they increase perfusion #ithout seriously impairing gas
e'change $E6%. ;o#ever, intravenous vasopressors are useful in patients #ho remain hypotensive despite
adeuate fluid resuscitation or #ho develop cardiogenic pulmonary edema.
+n most patients #ith severe septic shock, #e prefer to use norepinephrine -table E2 $?,4,E?%. ;o#ever, #e
find phenylephrine -a pure alpha*adrenergic agonist2 to be useful #hen tachycardia or arrhythmias
preclude the use of agents #ith beta*adrenergic activity -eg, norepinephrine2. hoosing a vasopressor
agent is discussed in greater detail else#here. -See "se of vasopressors and inotropes, section on
:hoice of agent in septic shock:.2
A##itional t'erapies — There is conflicting evidence on the use of additional therapies, such as
inotropic therapy or red blood cell transfusion. Such therapies are targeted at increasing the cardiac
output to improve tissue perfusion and thereby raise the central venous -superior vena cava2o'yhemoglobin saturation to#ard normal -ScvO) F?! percent2. Be prefer that their use be limited to those
#ith refractory shock in #hom the ScvO) remains >?! percent after optimization of intravenous fluid and
vasopressor therapy.
Inotropi& t'erapy — 8 trial of inotropic therapy may be #arranted in patients #ho have refractory shock
#ho also have diminished cardiac output $?,A,1A,EA,E4%. +notropic therapy should not be used to increase
the cardiac inde' to supranormal levels $?%. obutamine is the usual inotropic agent $4%. 8t lo# doses,
dobutamine may cause the blood pressure to decrease because its peripheral effects can dilate the
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systemic arteries. ;o#ever, as the dose is increased, blood pressure usually rises because cardiac
output increases out of proportion to the fall in peripheral vascular resistance. -See "se of vasopressors
and inotropes, section on :obutamine:.2
Re# bloo# &ell trans!sions — =ased upon clinical e'perience, randomized studies, and guidelines on
transfusion of blood products in critically ill patients, #e typically reserve red blood cell transfusion for
patients #ith a hemoglobin level M? g per deciliter. &'ceptions include suspicion of concurrent
hemorrhagic shock or active myocardial ischemia.
Support for a restrictive transfusion strategy -goal hemoglobin @? gCdD2 is derived from direct and
indirect evidence from randomized studies of patients #ith septic shock/
NOne multicenter randomized study of 44A patients #ith septic shock reported no difference in
)A day mortality bet#een patients #ho #ere transfused #hen the hemoglobin #as
M? gCdD-restrictive strategy2 and patients #ho #ere transfused #hen the hemoglobin #as
M4 gCdD -liberal strategy2 $(!%. The restrictive strategy resulted in ! percent fe#er red blood
cell transfusions -1( versus E!AA transfusions2 and did not have any adverse effect on the
rate of ischemic events -? versus A percent2.
Nata from randomized studies of early goal directed therapy -&HT2 that use red blood cell
transfusion as part of the protocol for treating patients #ith sepsis are conflicting. Bhile one
trial initially reported a mortality benefit from &HT that included transfusing patients to a goal
hematocrit @E! -hemoglobin level 1! gCdD2 $1A%, t#o similarly designed studies published since
then reported no benefit to this strategy $14,)!%. These studies are discussed belo#.
-See:0rotocol*directed therapy: belo#.2
+n further support of a restrictive approach to transfusion in patients #ith septic shock is the
consensus among e'perts that transfusing to a goal of @? gCdD is also preferred in critically ill
patients #ithout sepsis $(1*(E%. The use of blood transfusions in critically*ill patients is discussed in
detail separately. -See "se of blood products in the critically ill, section on :5ed blood cells: .2
Goals o initial res!s&itation — The goal of fluid resuscitation is early restoration of perfusion to preventor limit multiple organ dysfunction, as #ell as to reduce mortality.
The term early goal*directed therapy -&HT2 refers to the administration of intravenous fluids #ithin t'e
irst si+ 'o!rs o presentation using physiologic targets to guide fluid management. &HT has gained
#idespread acceptance in clinical practice but the optimal targets are unkno#n.
Early "oal$#ire&te# t'erapy tar"ets — 8lthough evidence is conflicting regarding the routine
measurement of early goal*directed therapy targets, #e suggest measuring the follo#ing targets for fluid
management in patients #ith sepsis/
39ean arterial pressure -9802 F6 mm;g -980 $-) ' diastolic2 P systolic%CE2 -calculator 12
3"rine output F!. mDCkgChour 3Static or dynamic predictors of fluid responsiveness, eg, central venous pressure -G02 A to 1)
mm;g #hen central access is available -static measurement2 or respiratory changes in the radial
artery pulse pressure -dynamic measurement2.
3entral venous -superior vena cava2 o'yhemoglobin saturation -ScvO)2 F?! percent -#hen central
access is available2 or mi'ed venous o'yhemoglobin saturation -SvO )2 F6 percent -if a pulmonary
artery catheter is being used2.
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Dactate clearance is not readily available at the bedside, making it a less useful target to follo# acutely in
&HT. 7onetheless, it should be follo#ed as a target in patients #ith sepsis to ensure a trend that
demonstrates adeuate clearance #ith therapy.
The optimal physiologic target-s2 of &HT is unkno#n. There is also conflicting evidence on the value of
measuring such targets, particularly G0 and ScGO), #hich reuire central catheter placement $1A*
)!,((%. +n addition, the generalizability of a standard targeted approach to both resource*poor and
resource*rich facilities is unkno#n. Be prefer measuring 980 and urine output as universal targets that
can be readily measured in all patients #ith sepsis, #ith the addition of G0 andCor ScGO) in those in
#hom central access is other#ise reuired. This approach differs slightly from that of The Surviving
Sepsis ampaignguidelines that recommend central venous access for G0CScvO) measurement
together #ith 980 and urine output in all patients #ith severe sepsis $ 4%. ;o#ever, these guidelines #ere
created before the results of three maIor randomized trials -0ro&SS, 85+S&, 0ro9+Se2, that sho#ed no
mortality benefit to an &HT*based approach, #ere published $14,)!,((,(%.
&vidence that supports the use of &HT targets is described belo#/
3C(P, MAP an# !rine o!tp!t < G0 A to 1) mm;g, 980 F6 mm;g - calculator 12, and urineoutput F!. mDCkg per hour are common &HT targets used in clinical practice. Support for their use
is derived from clinical e'perience and their use in the single randomized trial that studied them #ith
and #ithout ScvO) $1A%. They have not been compared to each other nor have they been proven to
be superior to any other target or to clinical assessment.
The ideal targets for 980, G0, and urine output are unkno#n. One trial that randomized patients to
a target 980 of 6 to ?! mm;g -lo# target 9802 or A! to A mm;g -high target 9802 reported no
mortality benefit to targeting a higher 980 $(6%. 0atients #ith a higher 980 had a greater incidence
of atrial fibrillation -? versus E percent2, suggesting that targeting a 980 @A! mm;g is potentially
harmful.
3S&%O- < &vidence from randomized trials that study the value of central venous o'yhemoglobin
saturation -ScvO)2 report mi'ed results. Bhile one early trial of patients #ith septic shock reported amortality benefit to targeting ScvO) F?! percent in a protocol*based therapy, trials published since
then -0ro&SS, 85+S&, 0ro9+Se2 have reported no mortality benefit $1A*)!,((%. -See :0rotocol*
directed therapy: belo#.2
3La&tate &learan&e < 8lthough the optimal freuency is unkno#n, #e follo# serum lactate -eg,
every si' hours2, as an additional &HT target in patients #ith sepsis until the lactate value has
clearly fallen.
The lactate clearance is defined by the euation $-initial lactate * lactate @) hours later2Cinitial lactate%
' 1!!. The lactate clearance and interval change in lactate over the first 1) hours of resuscitation
has been evaluated as a potential marker for effective resuscitation $ (?,(A%. One trial randomly
assigned E!! patients #ith severe sepsis to undergo resuscitation targeting either a lactate
clearance F1! percent or an ScvO) F?! percent -other than these targets, the resuscitation protocols
that included 980, G0, and urine output targets #ere identical2 $(?%. There #as no difference in
hospital mortality, length of stay, ventilator*free days, or incidence of multiorgan failure, suggesting
that lactate clearance criteria may be an acceptable alternative to ScvO) criteria.
8fter the restoration of perfusion, lactate is a poor marker of tissue perfusion $(4%. 8s a result, lactate
values are generally unhelpful follo#ing restoration of perfusion, #ith one e'ception < a rising lactate
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level should prompt reevaluation of perfusion -see Genous blood gases and other alternatives to
arterial blood gases2.
3Ot'er < ynamic indices have been studied as a potential target to guide fluid management in
sepsis. 5espiratory changes in the vena caval diameter, radial artery pulse pressure, aortic blood
flo# peak velocity, and brachial artery blood flo# velocity are considered dynamic hemodynamic
measures, #hereas G0, 980, ScvO) and pulmonary artery occlusion pressure are consideredstatic hemodynamic measures $!,1%. There is increasing evidence that dynamic measures are
more accurate predictors of fluid responsiveness than static measures, as long as the patients are in
sinus rhythm and passively ventilated #ith a sufficient tidal volume $)1,),E%. Jor actively breathing
patients or those #ith irregular cardiac rhythms, an increase in the cardiac output in response to a
passive leg*raising maneuver -measured by echocardiography, arterial pulse #aveform analysis, or
pulmonary artery catheterization2 is a sensitive and specific predictor of fluid responsiveness $ (%.
Darge randomized studies #ill be needed proving the efficacy of assessing dynamic measurement in
response to intravenous fluids before they can be routinely applied to patients for the management
of sepsis.
Proto&ol$#ire&te# t'erapy — 0rotocols targeted at the use of a combination of physiologic endpoints toguide fluid management in patients #ith severe sepsis and septic shock are common practice $ 1A*
)!,((,(,*?%. Typically, they combine the &HT targets -ScvO), G0, 980 -calculator 12 and urine
output, lactate2 for fluid management #ith early administration of antibiotics, both #ithin the first si' hours
of presentation.
There is conflicting evidence regarding the value of protocol*based therapy for sepsis $1A*)!,((,(,?*
4%/
3One single center randomized trial of )6E patients #ith severe sepsis or septic shock compared a
protocol that included targeting ScvO) F?! percent, G0 A to 1) mm;g, 980 F6 mm;g, and urine
output F!. mDCkgChour to conventional therapy that targeted G0, 980, and urine output only $1A%.
=oth groups initiated therapy -including antibiotics2 #ithin si' hours of presentation. 9ortality #aslo#er in the group #here all four targets #ere used -E1 versus (? percent2, suggesting that targeting
ScvO), G0, 980, and urine output #as a superior strategy. There #as a heavy emphasis on the
use of red cell transfusion -for a hematocrit @E!2 and dobutamine in order to reach the ScvO) target
in this trial. +n addition, the results of this trial may not be generalizable due to the inclusion of a
significant number of sick patients #ith liver and heart disease that may have potentially biased the
outcome favorably.
38 multicenter randomized trial -0ro&SS2 of 1E(1 patients #ith septic shock reported no mortality
benefit #ith protocol*based therapies $14%. 8 protocol*based therapy that used all of the &HT
targets -ScvO), G0, 980 and urine outputK protocol*based &HTK central access reuired2 #as
compared to a protocol that used some of the &HT targets -980 and urine outputK protocol*based
standard therapyK central access not reuired2 and to usual care -no protocol used to direct fluid
management2. There #ere no differences in 6!*day mortality bet#een the groups -)1 versus 1A
versus 14 percent2.
T#o similarly designed multicenter randomized trials of 16!! -85+S&2 and )16! -0ro9+Se2 patients
#ith septic shock also reported no mortality benefit from &HT $ )!,((%. +n 85+S&, compared to
usual care, the 4! day mortality of 14 percent #as similar in patients #ho received &HT using the
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traditional targets outlined in prior studies $)!%. Similarly, in 0ro9+Se, the 4! day mortality #as no
different -)4 percent2 bet#een the &HT and usual care groups $((%.
One e'planation for the apparent negative results from these three trials may be that central line
placement #as common -@! percent2 in patients receiving protocol*based standard therapy and
usual careK it is likely that G0 and ScvO) #ere measured and targeted in these patients as #ell.
Dack of benefit may also be attributed to overall better outcomes in these studies, perhaps due toearly administration of antibiotics -?! to 1!! percent before randomization2 in all groups, and to
improved clinical performance by highly trained clinicians in academic centers during an era that
follo#s an aggressive sepsis education and management campaign.
Ti)in" an# #!ration — The early administration of fluid appears to be more important than volume or
type of fluid in reducing mortality associated #ith sepsis. =ased upon evidence from randomized studies
and meta*analyses, #e favor the initiation of fluid resuscitation #ithin si+ hours of presentation. Once the
targets of resuscitation are met and perfusion is restored, fluids can be reduced or stopped, and
occasionally patients can be diuresed, #hen necessary. 5esolution of severe sepsis and septic shock can
take as little as a fe# hours or can be protracted to days or #eeks.
8 )!!A meta*analysis of randomized trials that initiated resuscitation targeting specific physiologic
endpoints reported that compared to standard care, only trials that initiated resuscitation #ithin )( hours
of the onset of sepsis sho#ed a mortality benefit -E4 versus ? percent, odds ratio !.!, 4Q + !.E?*
!.642 $6!%. +n contrast, analysis of randomized trials that initiated therapy more than )( hours after the
onset of sepsis found no difference in mortality -6( versus A percent for standard resuscitation, odds
ratio 1.16, 4Q + !.6!*).))2.
There are t#o possible outcomes follo#ing the interventions described above/
3Ina#e.!ate per!sion < espite aggressive therapy, the patient may have persistent
hypoperfusion and progressive organ failure. This should prompt reassessment of the adeuacy of
the above therapies, antimicrobial regimen, and control of the septic focus, as #ell as the accuracy
of the diagnosis and the possibility that une'pected complications or coe'isting problems have
intervened -eg, pneumothora' follo#ing G insertion2.
3A#e.!ate per!sion < 0atients #ho respond to therapy should have the rate of fluid
administration reduced or stopped, and vasopressor support #eaned. 0atients should also continue
to have their clinical and laboratory parameters follo#ed closely. These include blood pressure,
arterial lactate, urine output, creatinine, platelet count, Hlasgo# coma scale score, serum bilirubin,
liver enzymes, o'ygenation -ie, arterial o'ygen tension or o'yhemoglobin saturation2, and gut
function -table (2. 5eevaluation is indicated if any of these parameters #orsen or fail to improve.
CONTROL O/ THE SEPTIC /OCUS — 0rompt identification and treatment of the primary site or sites of
infection are essential $61*6E%. This is the primary therapeutic intervention, #ith most other interventions
being purely supportive. 8ntibiotics should be administered #ithin the first si' hours of presentation or
earlier.
I#entii&ation o t'e septi& o&!s — 8 careful history and physical e'amination may yield clues to the
source of sepsis and help guide microbiologic evaluation - table 2. 8s an e'ample, sepsis arising after
trauma or surgery is often due to infection at the site of inIury or surgery. The presence of a urinary or
vascular catheter increases the chances that these are the source of sepsis.
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Hram stain of material from sites of possible infection may give early clues to the etiology of infection
#hile cultures are incubating. 8s e'amples, urine should be routinely analyzed via dipstick for leukocyte
esterase, Hram stained, and culturedK sputum should be e'amined in a patient #ith a productive coughK
and an intra*abdominal collection in a postoperative patient should be percutaneously sampled under
ultrasound or other radiologic guidance.
=lood should be dra#n from t#o distinct venipuncture sites and inoculated into standard blood culture
media -aerobic and anaerobic2. Jor patients #ith a vascular catheter, blood should be obtained both
through the catheter and from another site $4%. -See =lood cultures for the detection of bacteremia.2
+f invasive candida or aspergillus infection is suspected, serologic assays for 1,E beta**glucan,
galactomannan, and anti*mannan antibodies, if available, may provide early evidence of these fungal
infections $4%. The limitations of these assays and their role in the diagnosis of fungal infection are
discussed separately. -See linical manifestations and diagnosis of candidemia and invasive candidiasis
in adults, section on :7on*culture methods: and iagnosis of invasive aspergillosis, section on
:Halactomannan antigen detection: and iagnosis of invasive aspergillosis, section on :=eta**glucan
assay:.2
There is no single test that immediately confirms the diagnosis of severe sepsis or septic shock. ;o#ever,
several laboratory tests, all of #hich are still investigational, have been studied as diagnostic markers of
active bacterial infection $6%/
3&levated serum procalcitonin levels are associated #ith bacterial infection and sepsis $ 6(*66%.
espite this, a meta*analysis of 1A studies found that procalcitonin did not readily distinguish sepsis
from nonseptic systemic inflammation -sensitivity of ?1 percent and specificity of ?1 percent2 $6%. 8n
additional randomized trial and another meta*analysis found that using clinical algorithms based
upon procalcitonin levels did not affect mortality or duration of antibiotic treatment $6?,6A%.
3The plasma concentration of soluble T5&9*1 -triggering receptor e'pressed on myeloid cells2, a
member of the immunoglobulin superfamily that is specifically upregulated in the presence of
bacterial products, is increased in patients #ith sepsis $64*?1%. +n a small trial, increased T5&9*1
levels #ere both sensitive and specific for the diagnosis of bacterial sepsis -46 and A4 percent,
respectively2 $64%. ;o#ever, a subseuent prospective cohort study found that increased T5&9*1
levels predicted sepsis #ith a sensitivity and specificity of only E and A6 percent, respectively $?)%.
Serial monitoring of T5&9*1 may also provide prognostic information in patients #ith established
sepsis $?!,?1%.
3+ncreased e'pression of 6( on polymorphonuclear leukocytes indicates cellular activation and
has been sho#n to occur in patients #ith sepsis $ ?E,?(%. +n a prospective cohort study of E!!
consecutive critically ill patients, increased 6( e'pression predicted sepsis #ith a sensitivity of A(
percent and a specificity of 4 percent $?)%. +n this study, the sensitivity and specificity of increased
6( e'pression #ere superior to that of increased procalcitonin or T5&9*1 levels.
The combination of procalcitonin levels, T5&9*1 levels, and 6( e'pression appears to be superior to
the use of any of these markers alone. ;o#ever, evaluation of the clinical usefulness of such biomarkers
is still in its early stages and should be considered preliminary. "ntil additional clinical investigations have
been performed, #e do not suggest the routine use of such biomarkers to identify sepsis.
Era#i&ation o ine&tion — 0rompt and effective treatment of the active infection is essential to the
successful treatment of severe sepsis and septic shock $4%. Source control -physical measures
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undertaken to eradicate a focus of infection and eliminate or treat ongoing microbial proliferation and
infection2 should be undertaken since undrained foci of infection may not respond to antibiotics alone
-table )2. 8s e'amples, potentially infected foreign bodies -eg, vascular access devices2 should be
removed #hen possible, and abscesses should undergo percutaneous or surgical drainage. Some
patients reuire e'tensive soft tissue debridement or amputationK in severe cases, fulminant lostridium
difficile*associated colitis may necessitate colectomy $?%.
Anti)i&robial re"i)en — +ntravenous antibiotic therapy should be initiated #ithin the first si' hours or
earlier -eg, #ithin one hour2, after obtaining appropriate cultures, since early initiation of antibiotic therapy
is associated #ith lo#er mortality $?,?6%. The choice of antibiotics can be comple' and should consider the
patient:s history -eg, recent antibiotics received $??%2, comorbidities, clinical conte't -eg, community* or
hospital*acuired2, Hram stain data, and local resistance patterns $?,?A,?4%.
0oor outcomes are associated #ith inadeuate or inappropriate antimicrobial therapy -ie, treatment #ith
antibiotics to #hich the pathogen #as later sho#n to be resistant in vitro2 $A!*A6%. They are also
associated #ith delays in initiating antimicrobial therapy, even short delays -eg, an hour2.
38 prospective cohort study of )1)( patients demonstrated that inappropriate antibiotic selection#as surprisingly common -E) percent2 $AE%. 9ortality #as markedly increased in these patients
compared to those #ho had received appropriate antibiotics -E( versus 1A percent2.
38 retrospective analysis of )?E1 patients #ith septic shock demonstrated that the time to initiation
of appropriate antimicrobial therapy #as the strongest predictor of mortality $A(%.
Bhen the potential pathogen or infection source is not immediately obvious, #e favor broad*spectrum
antibiotic coverage directed against both gram*positive and gram*negative bacteria. Je# guidelines e'ist
for the initial selection of empiric antibiotics in severe sepsis or septic shock.
Staphylococcus aureus is associated #ith significant morbidity if not treated early in the course of
infection $A?%. There is gro#ing recognition that methicillin*resistant S. aureus -95S82 is a cause of
sepsis not only in hospitalized patients, but also in community d#elling individuals #ithout recenthospitalization $AA,A4%. Jor these reasons, #e recommend that severely ill patients presenting #ith sepsis
of unclear etiology be treated #ith intravenous vancomycin -adIusted for renal function2 until the possibility
of 95S8 sepsis has been e'cluded. 0otential alternative agents to vancomycin -eg, daptomycin for non*
pulmonary 95S8,linezolid, ceftaroline2 should be considered for patients #ith refractory or virulent
95S8, or a contraindication to vancomycin. These agents are discussed separately. -See Treatment of
invasive methicillin*resistant Staphylococcus aureus infections in adults, section on
:=acteremia: and Treatment of hospital*acuired, ventilator*associated, and healthcare*associated
pneumonia in adults, section on :9ethicillin*resistant Staphylococcus aureus:.2
+n our practice, if 0seudomonas is an unlikely pathogen, #e favor combining vancomycin #ith one of the
follo#ing/
3ephalosporin, Erd generation -eg, ceftria'one or cefota'ime2 or (th generation -cefepime2, or
3=eta*lactamCbeta*lactamase inhibitor -eg, piperacillin*tazobactam, ticarcillin*clavulanate2, or
3arbapenem -eg, imipenem or meropenem2
8lternatively, if 0seudomonas is a possible pathogen, #e favor combining vancomycin #ith t#o of the
follo#ing -see 0rinciples of antimicrobial therapy of 0seudomonas aeruginosa infections2/
http://www.uptodate.com/content-not-availablehttp://www.uptodate.com/contents/evaluation-and-management-of-severe-sepsis-and-septic-shock-in-adults/abstract/75http://www.uptodate.com/contents/evaluation-and-management-of-severe-sepsis-and-septic-shock-in-adults/abstract/7,76http://www.uptodate.com/contents/evaluation-and-management-of-severe-sepsis-and-septic-shock-in-adults/abstract/77http://www.uptodate.com/contents/evaluation-and-management-of-severe-sepsis-and-septic-shock-in-adults/abstract/77http://www.uptodate.com/contents/evaluation-and-management-of-severe-sepsis-and-septic-shock-in-adults/abstract/7,78,79http://www.uptodate.com/contents/evaluation-and-management-of-severe-sepsis-and-septic-shock-in-adults/abstract/80-86http://www.uptodate.com/contents/evaluation-and-management-of-severe-sepsis-and-septic-shock-in-adults/abstract/80-86http://www.uptodate.com/contents/evaluation-and-management-of-severe-sepsis-and-septic-shock-in-adults/abstract/83http://www.uptodate.com/contents/evaluation-and-management-of-severe-sepsis-and-septic-shock-in-adults/abstract/84http://www.uptodate.com/contents/evaluation-and-management-of-severe-sepsis-and-septic-shock-in-adults/abstract/87http://www.uptodate.com/contents/evaluation-and-management-of-severe-sepsis-and-septic-shock-in-adults/abstract/88,89http://www.uptodate.com/contents/vancomycin-drug-information?source=see_linkhttp://www.uptodate.com/contents/daptomycin-drug-information?source=see_linkhttp://www.uptodate.com/contents/daptomycin-drug-information?source=see_linkhttp://www.uptodate.com/contents/linezolid-drug-information?source=see_linkhttp://www.uptodate.com/contents/linezolid-drug-information?source=see_linkhttp://www.uptodate.com/contents/ceftaroline-drug-information?source=see_linkhttp://www.uptodate.com/contents/treatment-of-invasive-methicillin-resistant-staphylococcus-aureus-infections-in-adults?source=see_link§ionName=Bacteremia&anchor=H14#H14http://www.uptodate.com/contents/treatment-of-invasive-methicillin-resistant-staphylococcus-aureus-infections-in-adults?source=see_link§ionName=Bacteremia&anchor=H14#H14http://www.uptodate.com/contents/treatment-of-invasive-methicillin-resistant-staphylococcus-aureus-infections-in-adults?source=see_link§ionName=Bacteremia&anchor=H14#H14http://www.uptodate.com/contents/treatment-of-invasive-methicillin-resistant-staphylococcus-aureus-infections-in-adults?source=see_link§ionName=Bacteremia&anchor=H14#H14http://www.uptodate.com/contents/treatment-of-invasive-methicillin-resistant-staphylococcus-aureus-infections-in-adults?source=see_link§ionName=Bacteremia&anchor=H14#H14http://www.uptodate.com/contents/treatment-of-hospital-acquired-ventilator-associated-and-healthcare-associated-pneumonia-in-adults?source=see_link§ionName=Methicillin-resistant+Staphylococcus+aureus&anchor=H7#H7http://www.uptodate.com/contents/treatment-of-hospital-acquired-ventilator-associated-and-healthcare-associated-pneumonia-in-adults?source=see_link§ionName=Methicillin-resistant+Staphylococcus+aureus&anchor=H7#H7http://www.uptodate.com/contents/vancomycin-drug-information?source=see_linkhttp://www.uptodate.com/contents/ceftriaxone-drug-information?source=see_linkhttp://www.uptodate.com/contents/ceftriaxone-drug-information?source=see_linkhttp://www.uptodate.com/contents/ceftriaxone-drug-information?source=see_linkhttp://www.uptodate.com/contents/cefotaxime-drug-information?source=see_linkhttp://www.uptodate.com/contents/cefepime-drug-information?source=see_linkhttp://www.uptodate.com/contents/piperacillin-and-tazobactam-sodium-drug-information?source=see_linkhttp://www.uptodate.com/contents/piperacillin-and-tazobactam-sodium-drug-information?source=see_linkhttp://www.uptodate.com/contents/ticarcillin-and-clavulanate-potassium-drug-information?source=see_linkhttp://www.uptodate.com/contents/imipenem-and-cilastatin-drug-information?source=see_linkhttp://www.uptodate.com/contents/meropenem-drug-information?source=see_linkhttp://www.uptodate.com/contents/meropenem-drug-information?source=see_linkhttp://www.uptodate.com/contents/vancomycin-drug-information?source=see_linkhttp://www.uptodate.com/contents/vancomycin-drug-information?source=see_linkhttp://www.uptodate.com/contents/vancomycin-drug-information?source=see_linkhttp://www.uptodate.com/contents/principles-of-antimicrobial-therapy-of-pseudomonas-aeruginosa-infections?source=see_linkhttp://www.uptodate.com/content-not-availablehttp://www.uptodate.com/contents/evaluation-and-management-of-severe-sepsis-and-septic-shock-in-adults/abstract/75http://www.uptodate.com/contents/evaluation-and-management-of-severe-sepsis-and-septic-shock-in-adults/abstract/7,76http://www.uptodate.com/contents/evaluation-and-management-of-severe-sepsis-and-septic-shock-in-adults/abstract/77http://www.uptodate.com/contents/evaluation-and-management-of-severe-sepsis-and-septic-shock-in-adults/abstract/7,78,79http://www.uptodate.com/contents/evaluation-and-management-of-severe-sepsis-and-septic-shock-in-adults/abstract/80-86http://www.uptodate.com/contents/evaluation-and-management-of-severe-sepsis-and-septic-shock-in-adults/abstract/83http://www.uptodate.com/contents/evaluation-and-management-of-severe-sepsis-and-septic-shock-in-adults/abstract/84http://www.uptodate.com/contents/evaluation-and-management-of-severe-sepsis-and-septic-shock-in-adults/abstract/87http://www.uptodate.com/contents/evaluation-and-management-of-severe-sepsis-and-septic-shock-in-adults/abstract/88,89http://www.uptodate.com/contents/vancomycin-drug-information?source=see_linkhttp://www.uptodate.com/contents/daptomycin-drug-information?source=see_linkhttp://www.uptodate.com/contents/linezolid-drug-information?source=see_linkhttp://www.uptodate.com/contents/ceftaroline-drug-information?source=see_linkhttp://www.uptodate.com/contents/treatment-of-invasive-methicillin-resistant-staphylococcus-aureus-infections-in-adults?source=see_link§ionName=Bacteremia&anchor=H14#H14http://www.uptodate.com/contents/treatment-of-invasive-methicillin-resistant-staphylococcus-aureus-infections-in-adults?source=see_link§ionName=Bacteremia&anchor=H14#H14http://www.uptodate.com/contents/treatment-of-invasive-methicillin-resistant-staphylococcus-aureus-infections-in-adults?source=see_link§ionName=Bacteremia&anchor=H14#H14http://www.uptodate.com/contents/treatment-of-hospital-acquired-ventilator-associated-and-healthcare-associated-pneumonia-in-adults?source=see_link§ionName=Methicillin-resistant+Staphylococcus+aureus&anchor=H7#H7http://www.uptodate.com/contents/treatment-of-hospital-acquired-ventilator-associated-and-healthcare-associated-pneumonia-in-adults?source=see_link§ionName=Methicillin-resistant+Staphylococcus+aureus&anchor=H7#H7http://www.uptodate.com/contents/vancomycin-drug-information?source=see_linkhttp://www.uptodate.com/contents/ceftriaxone-drug-information?source=see_linkhttp://www.uptodate.com/contents/cefotaxime-drug-information?source=see_linkhttp://www.uptodate.com/contents/cefepime-drug-information?source=see_linkhttp://www.uptodate.com/contents/piperacillin-and-tazobactam-sodium-drug-information?source=see_linkhttp://www.uptodate.com/contents/ticarcillin-and-clavulanate-potassium-drug-information?source=see_linkhttp://www.uptodate.com/contents/imipenem-and-cilastatin-drug-information?source=see_linkhttp://www.uptodate.com/contents/meropenem-drug-information?source=see_linkhttp://www.uptodate.com/contents/vancomycin-drug-information?source=see_linkhttp://www.uptodate.com/contents/principles-of-antimicrobial-therapy-of-pseudomonas-aeruginosa-infections?source=see_link
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38ntipseudomonal cephalosporin -eg, ceftazidime, cefepime2, or
38ntipseudomonal carbapenem -eg, imipenem, meropenem2, or
38ntipseudomonal beta*lactamCbeta*lactamase inhibitor -eg, piperacillin*tazobactam, ticarcillin*
clavulanate2, or
3Jluorouinolone #ith good anti*pseudomonal activity -eg, ciproflo'acin2, or
38minoglycoside -eg, gentamicin, amikacin2, or
39onobactam -eg, aztreonam2
Selection of t#o agents from the same class, for e'ample, t#o beta*lactams, should be avoided. Be
emphasize the importance of considering local susceptibility patterns #hen choosing an empiric antibiotic
regimen.
8fter culture results and antimicrobial susceptibility data return, #e recommend that therapy be pathogen*
and susceptibility*directed, even if there has been clinical improvement #hile on the initial antimicrobial
regimen. Hram*negative pathogens have historically been covered #ith t#o agents from different
antibiotic classes. ;o#ever, several clinical trials and t#o meta*analyses have failed to demonstrate
superior overall efficacy of combination therapy compared to monotherapy #ith a third generationcephalosporin or a carbapenem $AE,4!*4(%. Jurthermore, one meta*analysis found double coverage that
included an aminoglycoside #as associated #ith an increased incidence of adverse events
-nephroto'icity2 $4E,4(%. Jor this reason, in patients #ith gram negative pathogens, #e recommend use of
a single agent #ith proven efficacy and the least possible to'icity, e'cept in patients #ho are either
neutropenic or #hose severe sepsis is due to a kno#n or suspected 0seudomonas infection $?,4)%.
-See 0seudomonas aeruginosa bacteremia and endocarditis and 0rinciples of antimicrobial therapy of
0seudomonas aeruginosa infections.2
5egardless of the antibiotic regimen selected, patients should be observed closely for to'icity, evidence of
response, and the development of nosocomial superinfection $4%. There are no published randomized
controlled trials testing safety of de*escalation of antibiotic therapy in adult patients #ith sepsis or septic
shock $46%. The duration of therapy is typically ? to 1! days, although longer courses may be appropriate
in patients #ho have a slo# clinical response, an undrainable focus of infection, or immunologic
deficiencies $?%. +n patients #ho are neutropenic, antibiotic treatment s