Urosepsis PDF
Urosepsis PDF
Urosepsis PDF
UrosepsisEtiology, Diagnosis,
and Treatment
Nici Markus Dreger*, Stephan Degener*, Parviz Ahmad-Nejad,
Gabriele Wbker, Stephan Roth
SUMMARY
Background: Sepsis is among the most common causes of
death in Germany. Urosepsis accounts for 931% of all
cases and has a mortality of 2040%, which is low compared with that of sepsis in general. As the population
ages, the incidence of urosepsis is likely to rise.
Methods: Review of pertinent articles and guidelines
retrieved by a selective search in PubMed.
Results: Enterobacteria and Gram-positive organisms are
the pathogens that most commonly cause urosepsis. The
diagnosis can and must be made early on the basis of the
typical clinical features, altered vital signs, and laboratory
abnormalities, so that timely treatment can be initiated.
80% of cases are due to obstructive uropathy. The diagnostic evaluation includes physical examination, blood
cultures, urinalysis, procalcitonin measurement, and ultrasonography. In one study, each additional hour of delay in
the treatment of urosepsis with antibiotics was found to
lower the survival rate by 7.6%. Antibiotics should be
chosen in consideration of local resistance patterns and
the expected pathogen spectrum.
Conclusion: Urologists, intensive care specialists, and
microbiologists should all be involved in the interdisciplinary treatment of urosepsis. Patients outcomes have improved recently, probably because of the frequent use of
minimally invasive treatments to neutralize foci of infection. New biomarkers and new treatments still need to be
validated in multicenter trials.
Cite this as:
Dreger NM, Degener S, Ahmad-Nejad P, Wbker G, Roth S:
Urosepsisetiology, diagnosis and treatment.
Dtsch Arztebl Int 2015; 112: 83748.
DOI: 10.3238/arztebl.2015.0837
Learning objectives
This article is intended to inform readers about:
The definition of urosepsis and the distinctions
between sepsis, severe sepsis, and septic shock.
Risk factors for sepsis and the most common
causes of urosepsis.
The crucial importance of time in the diagnosis
and treatment of urosepsis.
The pathophysiology of the sepsis syndrome.
The diagnostic evaluation and the cause-directed,
supportive, and adjunctive treatment of urosepsis.
Methods
This review is based on pertinent articles published up
to August 2015 that were retrieved by a selective search
in PubMed, as well as on the following guidelines:
The guideline of the Surviving Sepsis Campaign
(SSC) [January 2013] (4)
The guideline of the European Association of Urology [March 2015] (5)
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BOX
Diagnostic criteria for sepsis, severe sepsis, and septic schock, according to the
German Sepsis Society (Deutsche Sepsis-Gesellschaft) (2)
I. Demonstration of infection
Diagnosis of an infection by microbiological demonstration or clinical criteria
II. Systemic inflammatory response syndrome (SIRS) (at least 2 criteria) (6)
Body temperature: 38C or 36C
Tachycardia: 90/min
Tachypnea: 20/min
Respiratory alkalosis: paCO2 32 mm Hg (< 4.3 kPa)
Leukocyte count: leukocytosis 12/nL or leukopenia 4/nL or band
forms 10% (= left shift, i.e., increased percentage of immature neutrophilic granulocytes and granulocyte precursors)
III. Acute organ dysfunction (at least 1 criterion)
Acute encephalopathy: decreased wakefulness, disorientation, agitation, delirium
Relative or absolute thrombocytopenia: decline by >30% in 24 h or 100/nL
Arterial hypoxemia: paO2 75 mm Hg ( 10 kPa) on room air or paO2/FiO2 250 mm Hg ( 33 kPa)
Renal dysfunction: urine output 0.5 mL/kg/h for at least 2 hours despite fluid administration, and/or rise of the serum creatinine level
> 2 upper limit of normal
Metabolic acidosis: base excess 5 mmoL/L or lactate > 1.5 upper limit of normal*
Sepsis: criteria I and II
Severe sepsis: criteria I, II, and III
Septic shock: criteria I and II and SBP 90 mm Hg for at least 1 h or
MAP 65 mm Hg or need for vasopressors to keep SBP >90 mm Hg or
MAP >65 mm Hg. Hypotension is present despite fluid administration and is not explicable by other causes.
*Elevated lactate levels due to inadequate perfusion can arise even if the blood pressure is within normal limits (cryptic shock); falling lactate levels seem to be at least as good an indicator for successful treatment as the central venous oxygen saturation (Scv02) (e39).
DSG, German Sepsis Society (Deutsche Sepsis-Gesellschaft); MAP, mean arterial blood pressure
The
Definition
Sepsis is defined as a complex inflammatory host
response to infection.
838
Definition
The DSG and the DIVI define sepsis as a complex
inflammatory host response to infection (the host
response itself is called the systemic inflammatory
response syndrome [SIRS]; see Box). This definition
is in accordance with those of analogous societies in
other countries (eBox 1) (2, 6) (recommendation grade
E, evidence level V).
If an infection has been demonstrated or is clinically
suspected, and the SIRS criteria (Box) are met, then
Severe sepsis
If, in the setting of sepsis, at least one organ fails
(multi-organ dysfunction syndrome [MODS]), then
severe sepsis is present (severe sepsis = infection + SIRS + organ dysfunction).
MEDICINE
FIGURE 1
Insult
Trigger
Sensors &
effector cells
Complex
protein systems
Complement
system
Clotting
system
Mediators &
biomarkers
Brain
Lung
Cardiovascular
system
Kidney
Liver
Bowel
Microcirculation
Oliguria/anuria
Failure of bile
secretion
Effects on organ
function
Confusion
Result
Dyspnea
Shock
Normalization of biomarkers
Reversal of organ dysfunction
Recovery
Pathophysiology
Infection or trauma leads to the release of pathogens and pathogen products that serve as PAMPs
(pathogen-associated molecular patterns), and/or
intrinsic signaling molecules of the body, called
DAMPs (danger-asociated molecular patterns).
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a)
b)
Epidemiology
In 2003, a prospective cross-sectional study entitled
PRVALENZ carried out by the Sepsis Competence
Network (SepNet) yielded the first set of specific epidemiologic data on sepsis in Germany (8). The one-day
prevalence of sepsis in 310 hospitals and 454 intensive
care units was assessed. 1348 of 3877 patients (34.8%)
had an infection, and 30.8% of these had severe sepsis
or septic shock. The related prevalence figures were, for
sepsis, 85116/100 000 persons, and, for severe sepsis
or septic shock, 76110/100 000 persons; the mean age
of the affected persons was 67 years. The mortality of
severe sepsis varied depending on the origin of the infection (9); it was 55.2% overall (8).
The prognosis of urosepsis is more favorable, with
reported mortality rates of 2040% for severe urosepsis
(5, 10). In general, sepsis is more common in men than
in women (9).
Even though the incidence of sepsis is increasing
(for example, from 82.7 to 240.4 cases per 100 000 persons per year in the USA over the period 19792000,
corresponding to an average annual increase of 8.7%),
the mortality due to sepsis has markedly declined (9),
partly because of the introduction of guidelines (4, 11).
According to Martin et al., the mortality of sepsis
dropped from 27.6% in 1994 to 17.9% in 2000 (9).
Economic aspects
sepsis is present (sepsis = infection + SIRS) (2, e1).
If, in the setting of sepsis, at least one organ fails
(multi-organ dysfunction syndrome, [MODS]), then
severe sepsis is present (severe sepsis = infection +
SIRS + organ dysfunction) (Box) (2, e1). In particular,
acute renal failure is defined by international consensus
as acute oliguria (<0.5 mL/kg/h or 45 mmol/L for
2 h) and a rise of the serum creatinine level by at least
0.5 mg/dL (e2).
Septic shock is defined as sepsis with treatmentresistant hypotension or hypoperfusion despite adequate fluid administration, resulting in the need for
vasopressor drugs (Box) (2, e1).
The SIRS criteria were newly defined in an international consensus conference in 2003. The general, inflammatory, and hemodynamic variables incorporated
in these criteria indicate early organ dysfunction and
are interpreted as warning signs (eBox 1) (7). There is
no minimum requirement for the number of criteria that
must be met for SIRS to be diagnosed.
Prevalence
Despite increasing incidence, the mortality due to
sepsis has markedly declined, partly because of
the introduction of guidelines.
840
Common pathogens
E. coli, Proteus spp., Enterobacter spp., Klebsiella
spp., P. aeruginosa, and Gram-positive bacteria
such as enterococci.
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FIGURE 3
6hrs
1hr
Clinical suspicion of sepsis
Observation
no
General ward
yes
SIRS criteria positive
Observation
no
yes
Initial O2 administration
and fluid replacement
Microbiology (urine/blood)
no
Transfer
to alternative
department
yes
1. Early goal-directed therapy (EGDT) &
empirical antibiotic therapy
2. Imaging
no
yes
Source control (focus, entry portal)
components of the bacterial cell wall act as pathogenassociated molecular patterns (PAMP) that bind to
pattern-recognition receptors (PRR) on the surface of
macrophages, neutrophils, and endothelial or urothelial
cells (Figure 1) (10, e10). The transcription factor
NF-B mediates the production of pro-inflammatory
cytokines such as IL-6, IL-12, and TNF (e11e14).
The production of further mediators (chemokines, prostaglandins, thromboxans, and leukotrienes) adds to the
mediator storm (e6). High-mobility group protein B1
(HMGB-1), which is released during cell death as a
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a)
b)
Predisposition to thrombosis
Surface receptors on endothelial cells and neutrophils are up-regulated, causing increased mutual
adhesiveness. Moreover, the clotting system is activated by endothelially synthesized plasminogenactivator inhibitor.
842
Effects on hemostasis
The over-activated complement system is closely linked
to the clotting system. Surface receptors on endothelial
cells and neutrophils are up-regulated, causing increased
mutual adhesiveness. Moreover, the clotting system is
activated by endothelially synthesized plasminogenactivator inhibitor; this predisposes to thrombosis and to
disseminated intravascular coagulation (DIC). A low
antithrombin III level, Quick value, and platelet count
may be the first signs of DIC. At the same time, anticoagulant substances such as protein C are inhibited,
promoting systemic coagulation and leading to microcirculatory insufficiency and tissue hypoxia (4, 10, 14).
These recently elaborated scientific facts are
inadequately reflected in the sepsis criteria. Thus, the
PIRO (predisposition, infection, response, and organ
dysfunction) staging system has been developed.
Although the PIRO system has not yet entered into
wide clinical use, a study in more than 680 patients
has demonstrated its superiority to both the wellestablished MEDS score and the APACHE-II score
with respect to both stratification and prognosis (area
under the curve [AUC] = 0.889 for need of treatment in
an intensive care unit, 0.817 for organ failure, and
0.744 for 28-day mortality; p<0.05) (e16).
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Urinalysis
Urinalysis and urine culture must be performed in
all patients with urosepsis before antibiotic treatment is begun. The findings of midstream urine
culture are of limited utility in obstructive pyelonephritis.
TABLE 1
Early-goal-directed therapy (EGDT) (1)
Variable
Target
812 mm Hg *
6590 mm Hg
70%
65%
Hematocrit (Hct)
>30%
Urine output
>40 mL/h
Biomarkers
Urosepsis cannot be diagnosed from biomarkers
alone. Among all available inflammatory markers, procalcitonin (PCT) is the best studied.
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TABLE 2
Cause-directed treatment
Empirical initial parenteral therapy as recommended by the Paul Ehrlich
Society for Chemotherapy (Paul-Ehrlich-Gesellschaft fr Chemotherapie e. V.)
Common pathogens
1
E. coli *
Proteus mirabilis
Pseudomonas spp.
Enterobacteriaceae
Nosocomially acquired
Community-acquired
Aminopenicillin/(BLI)
Fluoroquinolone group 2/3
Cephalosporin group 3a
Carbapenem group 2
Monotherapy
E. coli
Klebsiella pneumoniae
Proteus mirabilis
Aminopenicillin/BLI
Acylaminopenicillin/BLI
Cephalosporin group
3a/3b/4
Fluoroquinolone group 2/3
Carbapenem
ESBL-forming E. coli
Klebsiella pneumoniae
Proteus mirabilis
Carbapenem
P. aeruginosa
Combination therapy
Carbapenem + fosfomycin
Carbapenem + tigecycline
Colistin + fosfomycin
Cephalosporin group 3b/4 +
fluoroquinolone group 2/3 or
fosfomycin or
aminoglycoside
Acylaminopenicillin/BLI +
fluoroquinolone group 2/3 or
fosfomycin or
aminoglycoside
Carbapenem group 1 +
fluoroquinolone group 2/3 or
fosfomycin + aminoglycoside
Citrobacter freundii
Enterobacter spp.
Serratia marcescens
Carbapenem
Cephalosporin group 4
Fluoroquinolone group 2/3
Acinetobacter baumanii
Carbapenem group 1
Carbapenem group 1 +
fluoroquinolone group 2/3 or
tigecycline
Colistin + tigecycline
Enterococcus faecalis
Aminopenicillin
(high-dosed)
Acylaminopenicillin
(high-dosed)
Aminopenicillin +
aminoglycoside
Acylaminopenicillin +
aminoglycoside
In penicillin allergy: glycopeptide + aminoglycoside
Enterococcus faecium
Glycopeptide
Daptomycin
Linezolid
Linezolid
Daptomycin
Tigecycline
Imaging studies
Ultrasonography is the imaging method of first
choice because of its rapidity and wide availability
(recommendation grade B, evidence level Ic). It
enables the rapid detection of, for example,
hydronephrosis (Figure 4a), renal abscesses (Figure
4b), and prostatic abscesses. Abscesses should be
punctured under ultrasonographic (or other radiological)
guidance, and the removed fluid should be studied
microbiologically (recommendation grade D,
evidence level V) (e23). If it is unclear whether
obstructive pyelonephritis or merely a fixed, ectatic
calyx system of the renal pelvis is present, a diagnostic
puncture of the renal pelvis can be considered: low
pressure and a negative urine dipstick test rule out
infection, so that a nephrostomy can be avoided (e24).
If the ultrasonographic findings are equivocal, abdominal computed tomography (CT) is recommended,
so that any anatomical abnormalities that have caused
or exacerbated urosepsis can be identified with high
sensitivity (e25, e26).
Treatment
In an oft-cited trial involving 260 patients, Rivers et al.
(2001) showed that EGDT (mentioned above) lowers
the mortality of severe sepsis and septic shock. In combination with the rapid correction of target variables
(Table 1), EGDT lowered mortality from 46.5% to
30.5%, with a number needed to treat (NNT) of 68 (1).
Kumar et al. confirmed the importance of timing as a
prognostic factor (24, 25): the initiation of empirical
antibiotic treatment within one hour of the diagnosis of
hypotension was associated with an 80% survival rate.
Delays in starting antibiotics were associated with an
average 7.6% decline in survival rate for each hour of
delay (79.9% versus 70.5% at 12 hours, 42.0% at 56
hours, and 25.4% at 912 hours) (25).
Early goal-directed therapy (EGDT) is now controversial, as the ProMISe, ARISE, and ProCESS trials
showed no significant survival benefit from strict adherence to the EGDT protocol. It should be pointed out,
however, that the septic patients central venous oxygen
saturation levels (ScvO2) on first contact were not below
70% in any of these three trials (2628), whereas
Rivers et al. identified ScvO2 < 70% as an indicator of
the need for hemodynamic treatment (Table 1) (1).
Therefore, in the absence of subgroup analyses of such
high-risk patients, and in the absence of further trials,
these findings cannot be considered conclusive (e27).
Glycopeptide + aminoglycoside
*1Adjust depending on local E. coli resistance pattern. + As a result of increasing fluoroquinolone resistance,
fluoroquinolones are now inferior to a combination of cephalosporin + BLI (40). In areas with a high rate of
ESBL-forming enterobacteria (>10%), carbapenem is recommended for initial treatment (e42).
Imaging studies
Ultrasonography is the imaging method of first
choice. It enables the rapid detection of, for
example, hydronephrosis, renal abscesses, and
prostatic abscesses.
*2 Recommended for catheter-associated infections, which are usually mixed infections with enterococci
(because of the enterococcal gap of cephalosporins, fluoroquinolones, and aminoglycosides)
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Cause-directed treatment
Antibiotic treatment should be begun as soon as possible
(within an hour) after diagnosis, but only after blood and
urine cultures have been obtained (recommendation grade
B, evidence level Ic). The antibiotic(s) should be chosen in
the light of local resistance rates and the expected pathogen
spectrum. The recommendations of the Paul Ehrlich Society
are reproduced in Table 2.
In view of the presence of capillary leakage leading to
edema formation and lower volumes of distribution, as well
as increased clearance because of the hyperdynamic circulatory situation or low clearance rates because of multiple
organ dysfunction, antibiotics should generally be given
initially at high doses, which are reduced later on in the
course of treatment. This consideration applies above all
to hydrophilic, renally eliminated antibiotics (-lactam
antibiotics and aminoglycosides) (e26, e28). In contrast,
fluoroquinolones are concentration-dependent and are
barely influenced by altered volumes of distribution; their
doses should only be adjusted in the setting of elevated renal
retention values (e26, e28). The MAXSEP trial revealed no
additional benefit from dual empirical antibiotic treatment
(meropenem in 298 patients vs. meropenem/moxifloxacin
in 302 patients) (e29). The antibiotic regimen should be
re-evaluated daily with a view toward potential de-escalation,
to avoid both drug resistance and unnecessary costs (recommendation grade E, evidence level V).
The elimination of foci of infection and the early control
of complicating factors are important components of
causally directed treatment (recommendation grade A,
evidence level Ic). In the case of an infected kidney above
an obstruction, this is accomplished by internal ureteral
stenting (Figure 2a) or percutaneous nephrostomy (Figure
2b). A meta-analysis did not show either of these methods to
be superior to the other (29); the choice between them can
be made individually.
Urosepsis due to a high residual urine volume or acute
urinary retention (even without pyuria) is best treated with
a transurethral bladder catheter; in the setting of acute
prostatitis or epididymitis, a suprapubic catheter should be
Supportive treatment
According to the concept of early goal-directed therapy
(EGDT), hemodynamic stabilization promotes the
delivery of an adequate oxygen supply to the tissues.
As soon as the diagnosis of urosepsis is suspected, the
intravenous administration of isotonic crystalloid solution
should be begun within 15 minutes, with the goal of
adminstering at least 30 mL/kg of body weight in the first
hour (proceed with caution in case of congestive heart
failure) (recommendation grade A, evidence level Ic).
On the basis of the findings of the VISEP,
CRYSTMAS, 6S, and CHEST trials (recommendation
grade A, evidence level Ia), colloid HAES solutions are
no longer recommended in the treatment of severe sepsis
and septic shock (3033). The results of the CRYSTAL
trial (NCT00318942) are now pending. The findings of
the SAFE trial imply that the additional administration of
human albumin can be considered (recommendation
grade E, evidence level V) (18).
Low mean arterial pressure (MAP < 65 mm Hg)
despite volume substitution is an indication for
vasopressor administration (recommendation grade B,
evidence level Ic); norepinephrine is the vasopressor
drug of first choice (recommendation grade E, evidence
level IIb) (34). If the cardiac output is low despite
volume therapy, the positive inotrope dobutamine
(20 g/kg/min) is the catecholamine of first choice
(recommendation grade E, evidence level V) (2). Once
tissue perfusion is normal, and in the absence of
coronary heart disease, anemia with hemoglobin values
under 7 g/dL should be treated with erythrocyte
concentrate transfusion (e30). Low-dose dopamine
(5 g/kg/min) for nephroprotection is not recommended
(recommendation grade A, evidence level Ia) (33).
Pulmonary stabilization to achieve an arterial oxygen
saturation above 93% and a central venous oxygen
saturation of at least 70% should be an early goal, with
controlled, lung-sparing ventilation at low tidal volumes
(6 mL/kg of body weight) and peak pressures no higher
than 30 mbar, whenever adequate oxygenation (>90% by
Supportive treatment
According to the concept of early goal-directed
therapy (EGDT), hemodynamic stabilization promotes the delivery of an adequate oxygen supply
to the tissues.
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Future prospects
New treatments are directed against the massive secretion of
inflammatory cytokines (the mediator storm). In initial
case reports, extracorporeal cytokine adsorption with
concentration-dependent but size-specific filtering of intermediate-sized molecules (1050 kDa) during continuous
veno-venous hemodialysis dramatically lowered the
Adjunctive treatment
Adjunctive treatment is given simultaneously
with, and in addition to, supportive treatment.
846
Conclusion
Urosepsis can usually be identified early in its course,
and distinguished from sepsis of other causes, by a basic
diagnostic evaluation consisting of physical examination,
urinalysis, laboratory blood tests, and ultrasonography.
Once urosepsis has been diagnosed, the treatment should be
begun at once. Rapid diagnosis and the (usually) minimally
invasive elimination of infectious foci have led to improved
outcomes in patients with urosepsis. Nonetheless, competence networks, standardized treatment recommendations,
and interdisciplinary collaboration during the acute illness
and beyond will be indispensable prerequisites for further
improvement.
Conflict of interest statement
The authors state that they have no conflict of interest.
Manuscript submitted on 19 June 2015, revised version accepted on
2 November 2015.
Translated from the original German by Ethan Taub, M.D.
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Supplementary material
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32. Myburgh JA, Finfer S, Bellomo R, et al.: Hydroxyethyl starch or saline for fluid
resuscitation in intensive care. N Engl J Med 2012; 367: 190111.
33. Perner A, Haase N, Guttormsen AB, et al.: Hydroxyethyl starch 130/0.42 versus
Ringer's acetate in severe sepsis. N Engl J Med 2012; 367: 12434.
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eREFERENCES
e1. Moerer O, Quintel M: [Sepsis in adult patients definitions, epidemiology and economic aspects]. Der Internist 2009; 50: 788,
904, 968.
e2. Mehta RL, Kellum JA, Shah SV, et al.: Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney
injury. Crit Care 2007; 11: R31.
e25. Hoddick W, Jeffrey RB, Goldberg HI, Federle MP, Laing FC: CT and
sonography of severe renal and perirenal infections. AJR Am J
Roentgenol 1983; 140: 51720.
e15. Wagenlehner FM, Lichtenstern C, Weigand MA, Weidner W: [Urosepsis and treatment]. Urologe A 2010; 49: 61822.
e36. Ranieri VM, Thompson BT, Barie PS, et al.: Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med 2012; 366:
205564.
e18. Cockerill FR, 3rd, Wilson JW, Vetter EA, et al.: Optimal testing
parameters for blood cultures. Clin Infect Dis 2004; 38: 172430.
e19. Bele N, Darmon M, Coquet I, et al.: Diagnostic accuracy of procalcitonin in critically ill immunocompromised patients. BMC Infect
Dis 2011; 11: 224.
e38. Wiegele M, Krenn CG: Cytosorb in a patient with legionella pneumonia-associated rhabdomyolysis: a case report. ASAIO J 2015;
61: e146.
e40. Johansen TE, Cek M, Naber KG, et al.: Hospital acquired urinary
tract infections in urology departments: pathogens, susceptibility
and use of antibiotics. Data from the PEP and PEAP-studies. Int J
Antimicrob Agents 2006; 28 (Suppl 1): S91107.
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eBOX 1
eBOX 2
ward*2 (39)
Prior urological interventions
*1 Candida spp., Pseudomonas spp., and coagulase-negative staphylococci are more common pathogens than in non-immunosuppressed
patients (e6, e40).
*2 Among patients with nosocomial urinary tract infections (UTIs)
acquired on urology wards, the prevalence of urosepsis is 12% (39).
In contrast, patients with nosocomial UTIs acquired on non-urological
wards have a 2% prevalence of severe sepsis and a 0.3% prevalence
of septic shock (e41).
* Elevated lactate levels due to inadequate perfusion can arise even when the blood pressure is
normal (cryptic shock); a falling lactate level seems to be at least as good an indicator of successful
treatment as the central venous oxygen saturation (Scv02) (e39).
ATS, American Thoracic Society; aPTT, activated partial thromboplastin time; CCP, American
College of Chest Physicians; ESICM, European Society of Intensive Care Medicine; INR, international normalized ratio; MAP, mean arterial blood pressure; SCCM, Society of Critical Care Medicine; SD, standard deviation; SIS, Surgical Infection Society
II
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