Sepsis outside intensive care unit: the other side of the coin

Abstract

Introduction

A growing body of evidence points out that a large amount of patients with sepsis are admitted and treated in medical ward (MW). With most of the sepsis studies conducted in intensive care unit (ICU), these patients, older and with more comorbidities have received poor attention. Provided the differences between the two groups of patients, results of diagnostic and therapeutic trials from ICU should not be routinely transferred to MW, where sepsis seems to be at least as common as in ICU.

Methods

We analyzed clinical trials on novel tools for an early diagnosis of sepsis published in the last two year adopting strict research criteria. Moreover we conducted a target review of the literature on non-invasive monitoring of severe sepsis and septic shock.

Results and Conclusions

The combination of innovative and non-invasive tools for sepsis rule in/out, as quick alternatives to blood cultures (gold standard) with bedside integrated ultrasonography could impact triage, diagnosis and prognosis of septic patients managed in MW, preventing ICU admissions, poor outcomes and costly complications, especially in elderly that are usually highly vulnerable to invasive procedures.

Full text

1 23
Infection
A Journal of Infectious Disease
ISSN 0300-8126
Infection
DOI 10.1007/s15010-014-0673-6
Sepsis outside intensive care unit: the other
side of the coin
F.Mearelli, D.Orso, N.Fiotti,
N.Altamura, A.Breglia, M.De Nardo,
I.Paoli, M.Zanetti, C.Casarsa &
G.Biolo

1 23
Your article is protected by copyright and
all rights are held exclusively by Springer-
Verlag Berlin Heidelberg. This e-offprint is
for personal use only and shall not be self-
archived in electronic repositories. If you wish
to self-archive your article, please use the
accepted manuscript version for posting on
your own website. You may further deposit
the accepted manuscript version in any
repository, provided it is only made publicly
available 12 months after official publication
or later and provided acknowledgement is
given to the original source of publication
and a link is inserted to the published article
on Springer's website. The link must be
accompanied by the following text: "The final
publication is available at link.springer.com”.

REVIEW
Sepsis outside intensive care unit: the other side of the coin
F. Mearelli •D. Orso •N. Fiotti •N. Altamura •
A. Breglia •M. De Nardo •I. Paoli •
M. Zanetti •C. Casarsa •G. Biolo
Received: 4 April 2014 / Accepted: 28 July 2014
Springer-Verlag Berlin Heidelberg 2014
Abstract
Introduction A growing body of evidence points out that
a large amount of patients with sepsis are admitted and
treated in medical ward (MW). With most of the sepsis
studies conducted in intensive care unit (ICU), these
patients, older and with more comorbidities have received
poor attention. Provided the differences between the two
groups of patients, results of diagnostic and therapeutic
trials from ICU should not be routinely transferred to MW,
where sepsis seems to be at least as common as in ICU.
Methods We analyzed clinical trials on novel tools for an
early diagnosis of sepsis published in the last two year
adopting strict research criteria. Moreover we conducted a
target review of the literature on non-invasive monitoring
of severe sepsis and septic shock.
Results and Conclusions The combination of innovative
and non-invasive tools for sepsis rule in/out, as quick
alternatives to blood cultures (gold standard) with bedside
integrated ultrasonography could impact triage, diagnosis
and prognosis of septic patients managed in MW, pre-
venting ICU admissions, poor outcomes and costly com-
plications, especially in elderly that are usually highly
vulnerable to invasive procedures.
Keywords Sepsis Non-invasive management 
Biomarkers
Epidemiology
Settings and mortality
The estimate of true incidence of sepsis is flawed by the
lack of clarity in definitions (Table 1) used in daily clinical
practice and in research studies, which are mainly based on
administrative data sets (ex ICD-9CM) [1,2]. In a large
retrospective study conducted in USA between 1979 and
2000, sepsis was identified in 10,319,418 patients; it is
often lethal and represents the tenth leading cause of death
[1]. This might explain why most of the studies about
sepsis had focused on patients admitted to intensive care
unit (ICU) [1–3]. The ICU septic patients usually suffer
from organ dysfunction and/or perfusion abnormalities and
so they would be more acutely ill than septic patients
treated in medical ward (MW). Recent evidence, mainly
from Europe, shows that a significant percentage of
patients with sepsis are admitted and treated in MW [4–8]:
about 50 % of all septic patients admitted to the Medical
University of Vienna do not receive intensive care, but
only general ward care [9]. In Spain, more than 80 % of the
patients with sepsis were managed outside ICU setting, and
at least 20 % of MW sepsis were ill enough to be cate-
gorized as severe sepsis [10,11]. Moreover, in Europe, a
large number of patients initially admitted to MW will
develop, over time, severe sepsis and septic shock and then
account for 50 % of all septic patients admitted to ICU. In
USA, the corresponding figure is 25 % (with 60 % origi-
nating from emergency department, ED) [4]. In spite of
these figures, epidemiologic studies in non-ICU setting
Electronic supplementary material The online version of this
article (doi:10.1007/s15010-014-0673-6) contains supplementary
material, which is available to authorized users.
F. Mearelli (&)D. Orso N. Fiotti N. Altamura A. Breglia 
M. De Nardo I. Paoli M. Zanetti C. Casarsa G. Biolo
Unit of Clinica Medica Generale e Terapia Medica, Surgical
Health Sciences, Department of Medical, University of Trieste,
Strada di Fiume Cattinara, Trieste 447 34149, Italy
e-mail: filippome@libero.it
123
Infection
DOI 10.1007/s15010-014-0673-6
Author's personal copy

(like MW) have received little attention in research. This
might explain why even epidemiologic data on sepsis
patients (with all the spectrum of gravity) admitted and
discharged from the MW are still lacking. Research in
sepsis outside ICU is eagerly needed, since a reduction in
mortality for sepsis has been documented in ICU, but not
outside such a setting [12]. MW sepsis patients typically
suffer from comorbidities which hinder an aggressive
approach either because they are contraindicated or
because limited benefit could be obtained from them.
While detracted treatment of sepsis (treatment ceiling?
inadequate resuscitation?) [4] in patients outside ICU could
account for high mortality in apparently less severe
patients, in Esteban’s prospective trial, the rate of with-
drawal or withholding of treatment was not so dissimilar
between MW and ICU [10,13]. Levy et al. [4] detect a
significant increase in raw hospital mortality in Europe,
where the patient seemed to be sicker (and reached ICU
2 days later) than in USA, but this difference in outcome
disappeared with severity adjustment.
Age and pathophysiology of sepsis
Severe sepsis patients admitted in non-intensive care
units are usually older than those admitted to ICU [10].
A trend towards increasing age of septic patients was
also observed in ICU over the years, being more than
60 % of severe sepsis patients older than 65 years [14].
These patients are frequently ruled out from clinical
trials, and treated as usual care. Sepsis is becoming a
disease of the elderly in which age, load and virulence
of the microorganisms may specifically affect the path-
ophysiology of the disease [15]. The host response to
sepsis encompasses a pro-inflammatory (PI) phase,
directed to clear causative microorganism, and an anti-
inflammatory (AI) phase, necessary to turn off the
inflammation and limit tissue injury. In previously heal-
thy patients, an initial PI response prevails and its
uncontrolled form, called hyper-inflammation, represents
the cause for the early death in sepsis (70 % of all fatal
events) [15] (Fig. 1, red lines). When older individuals—
frequently affected by comorbidities impairing their host
immunity—develop sepsis, a dulled or absent PI phase is
more common: this may explain why these patients
hardly display the typical signs and symptoms of sepsis
(with the paucity of symptoms making them more suit-
able for admission outside ICUs) [15]. Moreover, elderly
promptly develop predominant and protracted AI phase.
Such ‘‘immune hibernation’’ is the explanation for the
late deaths in sepsis usually related to unresolved
infective foci, and reactivation of viral or nosocomial
infections [16,17] (Fig. 1, blue lines).
Etiology and site of infection
Gram-positive bacteria and fungi are common causes of
sepsis in ICU, probably due to more extensive use of
invasive procedures in this rather than other settings [3]
while, in MW, sepsis is still more frequently due to Gram-
negative pathogens [7,8]. In clinical practice, at least 50 %
of sepsis do not have a microbiologically confirm of
infection, irrespective of the department of admission of
the patients [18–21]. The lack of a definite microbiological
diagnosis raises uncertainty about the nature of the acute
process, thus hampering its prompt therapeutic approach.
Definitive confirmation is particularly challenging for the
lung, which is the most frequent site of infection [3]. Many
reasons may account for such a difficulty: the first is the
common observation that many patients with pneumonia
are unconscious or disoriented. In these patients, the col-
lection of the sputum is not easy, even after induction.
Broncho-alveolar lavage could be useful for this purpose,
but bronchoscopy is not readily available and it may be
unsuitable for patients suffering from some comorbidities
(e.g., thrombocytopenia), especially outside ICU (i.e., non-
intubated patients). Second if the sputum is available, the
distinction between pathogens of the respiratory tract and
colonizing bacteria or contaminant flora is challenging; this
awkward challenge contributes to heterogeneity in defini-
tive adjudication of the cases. Third, most of the septic
patients receive antibiotics ahead of collection of the
respiratory tract specimen, reducing the sensitivity of cul-
tures. These conspicuous percentage of culture-negative
infections and, in general, the absence of a solid gold
standard contribute to the need of surrogate of sepsis
diagnosis.
Table 1 Sepsis definitions
SIRS Two or more of the following:
Temperature
•[38 C, or \36 C
Respiratory rate
•[20 breaths/min, or pCO
2
\32 mmHg
WBC
•[12000/mm
3
,\4000 mm
3
,or[10 %
immature forms
Heart rate
•[90 beats/min
Sepsis SIRS plus presumed or proven infection
Severe sepsis Sepsis plus organ dysfunction
Septic shock Sepsis plus hypotension despite fluid
resuscitation
Bacteremia Presence of viable bacteria in the blood
Culture-negative
Sepsis
Sepsis without microbiological documentation
of infection
F. Mearelli et al.
123
Author's personal copy

Clinical presentation and diagnosis
Sepsis is a frequently missed diagnosis since it looks quite
similar to other causes of non-infective systemic inflam-
matory response syndrome (SIRS) [18]. In USA, ED per-
sonnel missed up to 69 % of patients with serious infection
and 52 % of those with severe sepsis. In UK, preliminary
work-up at the ED allowed the identification of only 17 %
of the severe sepsis patients [22], while the remaining
uncategorized patients reach other wards then ICU, espe-
cially MW, with harmful delay in the administration of
therapy. In a retrospective cohort study performed between
1989 and 2004 in USA and Canada on patients with severe
sepsis, each hour of delay in the administration of antibi-
otics was associated to an 8 % increased mortality [23]. A
later retrospective study conducted by Pallin et al. [24]
demonstrating that 30 % of septic patients did not receive
antimicrobial therapy during a period of 8 h of ED staying,
further corroborates the need of diagnostic tools for an
early diagnosis of sepsis. On the other hand, the liberal use
of antimicrobial therapy, frequently adopted to face mor-
tality in sepsis, has induced a quick rise in multi-drug
resistant strains and other serious adverse events, like
Clostridium difficile infections, which are becoming sur-
prisingly common and difficult to treat [25,26]. Stan-
dardized SIRS definition was first announced in 1991 to
assist clinicians in the early diagnosis of sepsis [27]. This
bedside approach does not require expensive assay or
specific expertise and can be rapidly performed in an
overcrowded ED to identify patients who require a prompt
medical evaluation. However, in a large prospective study,
the 1991 criteria failed to identify 34 % of patients with
severe sepsis and 24 % of those with septic shock [28].
Consequently, sepsis definition underwent some refine-
ments in 2001, implementing diagnostic criteria into a set
of items, five inflammatory, three hemodynamic, seven on
organ dysfunction, and two tissue perfusion [29]. A large
observational study conducted in septic patients admitted
to seven ICU in the USA evaluates the performance for
sepsis diagnosis of the two sets of clinical criteria. Com-
pared to the earlier, the 2001 sepsis definition had a slight
increase in sensitivity but a decreased specificity for sepsis
diagnosis [30]. Some Authors criticized such an approach,
in favor of a more complex scoring system in which each
clinical variable has different weights, as indicated by their
odds ratios for sepsis diagnosis (i.e., PIRO system) [31–
33]. These multidimensional models collide with the
‘‘paradox of respiratory rate’’: the respiratory rate, i.e., the
second most common physiological derangement in sepsis
[34], continues to be frequently skipped in the clinical
practice of many ED and MW physicians [35]. Therefore, a
change in sepsis definition is needed and recent evidence
provides impetus to re-evaluate clinical approach and
define sepsis as a condition of infection and occurrence of
an associated organ dysfunction [31]. Which of the clinical
variables can better describe these ‘‘looks bad’’ patients
continues to be a challenging issue. In a prospective trial,
fever, high white blood cell count, low Glasgow Coma
Scale score, oedema, a positive fluid balance, high cardiac
index, low PaO
2
/FIO
2
ratio, high levels of creatinine,
Fig. 1 The two phases of sepsis
according to absence (red lines)
or presence (blue lines) of host
co morbidities
Early diagnosis and monitoring of septic patients
123
Author's personal copy

lactate were the most powerful positive predictors of sepsis
using both 1991 and 2001 definitions [30].
Markers for early diagnosis
Single biomarker
Biomarkers offer a tool to increase diagnostic accuracy for
sepsis diagnosis among SIRS patients. The list of potential
biomarkers is rapidly expanding; their use in clinical
practice, identifying non-infective patients, could decrease
adverse events related to improper administration of anti-
biotics and reduce the widespread of bacterial resistance.
Most of the trials on biomarkers, though, have been eval-
uated in patients admitted in ICU, whilst those from EDs
and MWs have been historically disregarded [36–39]. The
most promising biomarkers for sepsis diagnosis, identified
by studies published in the last two years using strict
selection criteria (see Supplementary Appendix), are
reported in Fig. 2[40–61]. Procalcitonin (PCT) is the most
investigated marker. In a recent meta-analysis, PCT per-
formance in the ruling in/out of sepsis among patients
suffering from SIRS was found to be only moderate (AUC
0.85, sensitivity 0.77, specificity 0.79) [38]. An even worse
performance resulted in a second analysis on the same
trials, by Rucker and Schumacher, (sensitivity 0.72,
Fig. 2 Oversimplification of sepsis physiopathology. Promising
biomarkers for sepsis diagnosis fulfilling research criteria (see
Supplementary Appendix) were reported according to their different
role. DAMPs damage associated patter, PAMPs pathogen associated
pattern, PPRs pattern recognition receptors, PCR C-reactive protein,
PCT procalcitonin, PSP pancreatic stone protein, sCD14-st: Presep-
sin, nCD64: CD64 expression on neutrophils, sTREM-1: Soluble
triggering receptor expressed on myeloid cells-1, sCD25: Soluble IL2
receptor alpha, sCD163: Soluble hemoglobin scavenger receptor,
miRNA-15a: micro RNA-15a
F. Mearelli et al.
123
Author's personal copy

specificity 0.73) [62]. Moreover, different assays (mainly
by Liaison and Kryptor BRAHMS Hennigsdorf, Germany)
and diverse cut-offs have been derived from different set-
tings and in patients with different severity and comor-
bidities [38]. It is not surprising, therefore, that several
clinical flow-charts, incorporating PCT, in the management
of sepsis have been recently put forward [63,64]. PCT
seems to be helpful in deciding the timing of start and end
of antimicrobial therapy for the treatment of acute respi-
ratory tract infections [65]; however, recent trials from ICU
have not been able to demonstrate that PCT guidance
decreases antibiotic consumption, costs, and mortality [66–
68]. More studies are needed on severe infections before a
PCT-based strategy could be routinely and safely imple-
mented in clinical practice.
Turn around time and timing of sampling
Latest evidence has highlighted CD64 expression on neu-
trophil (nCD64) as the most promising ‘‘silver bullet’’ for
an early diagnosis of sepsis [49,61]. Gibot enrolled 300
patients admitted to a French ICU with suspected infection:
increased nCD64, within 12 h from admission, showed a
95 % positive predictive value and an 85 % negative pre-
dictive value in sepsis diagnosis. Such a result was con-
firmed in a small external cohort [49]. The ideal biomarker
must have a rapid turn around time, and nCD64 (measured
using flow cytometry) seems still far away from such a
requirement. The cytofluorimeter is not available in vast
majority of the wards worldwide and, where accessible, the
type of expertise and turn around time strongly jeopardize
the clinical use in ‘‘prime time’’ [49,61]. Rivers et al. have
recently examined the kinetic of 13 circulatory biomarkers
in 100 patients with severe sepsis and septic shock [69].
Biomarker levels were measured at 0, 3, 6, 12, 24, 48, 60 h
after patient enrolment. The main result was that the bio-
markers cascade was activated at the most proximal point
from hospital presentation. In this study, the pattern of
biomarkers may overlap; some of them exhibits a bimodal
pattern reaching a climax between 3 and 36 h from
admission, and a nadir within the subsequent 72 h. Such a
pattern, examined in some biomarkers, could be exploited
to increase likelihood of correct diagnosis of sepsis; nev-
ertheless, in most of the trials in which serial measurements
of biomarkers were assessed, no improvement in predicting
sepsis was found over a single determination [42,61].
Multimarker models
A panel of biomarkers (‘‘homogeneous models’’) eventu-
ally combined with clinical signs (‘‘heterogeneous mod-
els’’) could increase accuracy in the diagnosis of sepsis,
compared to the ‘‘silver-bullet’’ approach. The choice of
the biomarkers and the way they should be combined to
achieve a good diagnostic accuracy is still challenging.
Clinical trials on biomarkers for an early diagnosis of
sepsis adopting strict research criteria and published in the
last 2 years (see Supplementary Appendix) [40–61] are
significantly heterogeneous in:
•Methodological quality: only one study has confirmed
the performance of the biomarkers in an external cohort
different from the inception cohort [49].
•Setting: ICU is more frequently studied than ED and
only few trials were conducted in MW setting [38,42,
53].
•Admission criteria: consecutive, SIRS (according to
both 1991 and 2001 criteria), febrile, suspected sepsis
(not otherwise specified) patients were all prospectively
enrolled in the trials [40–61].
•Documentation of sepsis: most of the studies did not
provide accurate information on how infection was
established. The inadequate standardization of clinical
and radiological findings could cause inter-observer
variability and hinder the comparability of the trials
[40–61].
•Biomarkers: at least 10 different biomarkers have been
tested in these 2 years [16,17,36,37]. The most
frequent categories studied, according to their different
pathophysiological role, were pro-inflammatory, solu-
ble and cell expressed receptors biomarkers [40–61].
•Statistical combinations: two main methods were
reported in the literature. The first is the method of
Xiong et al. [70], based on linear logistic regression
using dichotomized variables and expressed by the
‘‘logit’’ value. Some authors used this analytical
approach to combine biomarkers in a comprehensive
index [71], as Sepsis Score [72] or Bioscore [49]. The
other method is based on decision trees and, in
particular, on CART (Classification And Regression
Tree). This method was firstly applied by Wong in this
setting [58], and represents a feasible alternative to
Xiong’s approach.
So far, most of the homogeneous biomarker panels have
suggested a limited predictive benefit over single bio-
marker alone [73], although four recent trials highlight
some combinations particularly promising for sepsis
diagnosis:
•PCT ?soluble triggering receptor expressed on mye-
loid cells-1(sTREM1) ?expression of CD64 on neu-
trophils (nCD64): the performance of a ‘‘bioscore’’
including the three biomarkers was better (AUC 0.97)
than that of each individual biomarker (AUC 0.91,
0.73, and 0.95 for PCT, sTREM1, and nCD-64,
respectively) [49].
Early diagnosis and monitoring of septic patients
123
Author's personal copy

•PCT ?serum IL2 receptor alpha (sCD25) and pancre-
atic stone protein (PSP): on 219 ICU patients, the
combination of sCD25 and sCD25 plus PSP with PCT
increases AUC to 0.89 and 0.94, respectively [56].
•PCT ?interleukin 27 (IL-27): in a previous study [49],
the performance of a combination of IL-27 and PCT
was evaluated through CART. The AUC for this model
was 0.92, which significantly improved the value of
PCT alone [58].
•nCD64 ?C-reactive protein: double positivity (both
nCD64 and C-reactive protein above cut-off limits) was
associated with a 92 % and 93 % positive and negative
predictive value, respectively [61].
Polymerase chain reaction (PCR)
New technologies allow detection of microbial DNA
directly in different biological fluids, as blood culture flasks
(growth-required assays) or whole blood (no growth-
required assay). Three groups of techniques can be iden-
tified in growth-required methods: PCR-based (ex.
StaphSR BDGeneOhm, Xpert MRSA/SA Cepheid Diag-
nostic, LightCycler Staphilococcus RocheMolecular,
Prove-it Sepsis Mobidiag), non-amplified nucleic acid-
based (FHA and FISH), and non-nucleic acid-based tech-
nology methods assays (ex. MALDI–TOF MS) [74]. These
techniques may be useful to improve sensitivity of standard
blood cultures, especially in patients previously treated
with antibiotics [75]. Polymerase Chain Reaction methods
in whole blood (no growth-required assay) may be subdi-
vided in: pathogen specific (mainly to detect coagulase
positive and negative staphylococci), broad range assays
(e.g., SeptiTest Molzym, PLEX-ID BAC Spectrum Ibis/
Abott) and multiple assays (e.g., LightCycler SeptiFast,
VYOO SIRS-lab) [76]. These methods do not require the
6–12 h of incubation and the 24–48 h necessary for the
definitive identification of the causative agents of sepsis,
mandatory for blood cultures. LightCycler SeptiFast is the
only commercial PCR approved for clinical use in Europe.
This method can detect 25 common bacterial and fungal
pathogens involved in sepsis. In a recent meta-analysis,
detection of bacteremia is far from perfection (sensitivity
0.80, specificity 0.95, positive likelihood ratio 1.5, negative
likelihood ratio 0.21) and false negative results are the
major concerns [77]. Other barriers to the use of Light-
Cycler SeptiFast may be represented by the high cost of a
single test (300 dollars/patient) and the lack of suscepti-
bility profile for antimicrobial agents of the detected
pathogen. VYOO (multiplex PCR with gel electrophoresis)
and PLEX-ID BAC (broad range PCR combined with
electrospray ionization mass spectrometry) detecting some
gene/markers involved in resistance to antimicrobial agents
can face the last obstacle, increasing the potential impact of
the molecular approach to sepsis [74].
Monitoring septic patients outside icu
Early goal-directed therapy (EGDT) had been shown to
reduce mortality of severe sepsis and septic shock patients
[78]. However, a survey by Jones et al., in 2005, showed
that only 7 % of the ED physicians working in 30 USA
academic tertiary hospitals applied consistently EGDT.
The main obstacle to its implementation in clinical
practice is the need to measure central venous oxygen
saturation (ScVO
2
) through a central venous catheter
(CVC) using equipment (i.e., continuous central venous
oxygen spectrophotometer) that require a high level of
expertize [79]. In septic patients with comorbidities, as
the elderly, the risk of invasive procedures might out-
weigh the benefits, thus limiting the generalizability of
EGDT. In spite of this concern, in two recent retrospec-
tive studies conducted in ED setting do not resuscitated
(DNR) patients received a similar rate of CVC placement
and vasopressor administration if compared to non-DNR
status [13,80]. Moreover, 50 % of DNR cases were
dismissed at home suggesting, even in these cases, the
chance for an aggressive treatment [13]. On the other
hand, in an Austrian prospective trial, admission to ICU
was denied in more than two-thirds of the patients with
severe sepsis over 80 years [81]. In an era when health
requirements outweigh the available resources, health care
system might be prone to a smoldering reverse triage
based on ‘‘ageism’’. The controversial issues in the
management of complex/comorbid patients [82] might be
handled by some non-invasive diagnostic techniques, like
bedside ultrasonography (US). US could narrow the
spectrum of differential diagnosis of critical patients [82–
85] and provide accurate information about their hemo-
dynamic status [86–88]. At present, evidence that inferior
vena cava diameter–collapsibility [85,87–92], lung
echography [86,93,94], and ventricular contractility [84–
87,94] may identify responsiveness to fluid infusion or
the need for vasoconstrictor or inotropes [85,87,94–96]
comes just from small heterogeneous studies concerning
patients with severe sepsis/septic shock admitted in ICU.
Consequently, there is no consensus about the best US
signs to use: a pragmatic approach is reported in Table 2.
Among the advantages of US are that it does not require
prohibitive expertise, may be quickly performed (evalua-
tion of inferior vena cava and lungs takes less than
3 min), can be repeated [85,91,93–95], and can be used
to monitor the acute changes induced by resuscitation
therapy. The combination of point-of-care multi-organ US
with serum prognostic markers has not been assessed
F. Mearelli et al.
123
Author's personal copy

through Bayesian analysis, but seems very attractive in
monitoring septic patients. Among the circulating bio-
markers, lactate is a hypoperfusion index in patients with
sepsis, even if normotensive [85]. Although contradictory
results have arisen about its role as a surrogate of ScVO
2
[97–101], the prognostic utility of single [99] and serial
[99–102] lactate determinations (i.e., lactate clearance)
has been largely documented in ED and it represents an
independent end point of early resuscitation. In 4329
severe sepsis and septic shock ICU patients, treatment
based on early non-invasive approach encompassing lac-
tate measurement (beyond blood cultures sampling ahead
of antibiotic therapy administration, and early adminis-
tration of antibiotics), within 3 h, strongly reduced the
need of a more invasive approach [103]. The ProCESS
multicenter trial confirmed the decisive role of a prompt,
rather than invasive, approach to septic shock. SIRS cri-
teria and lactate were used to diagnose 1431 sepsis, to
achieve an early treatment with antibiotics. Afterwards,
three different strategies of septic shock resuscitation
were compared to evaluate their impact in mortality;
results showed that EGDT arm did not improve outcome
if compared to the other two arms, which did not nec-
essarily required a CVC placement [104].
Conclusions
Sepsis management can be different in USA and Europe.
Many factors may have influenced this dissimilar approach,
as cultural perspectives in allocation of resources, number
of ICU beds available, and different end-life practice pat-
terns. Lack of clear diagnostic criteria for sepsis and
overlapping clinical and laboratory presentation with non-
infective SIRS induce diagnostic mistakes and to a life
threatening delay in antimicrobial therapy administration.
The use of a panel of biomarkers might enhance clinician’s
ability to recognize sepsis. At present, no single diagnostic
test has been proven sufficiently accurate for the rule in/out
of sepsis, but there are several candidates: pancreatic stone
protein, presepsin, expression of CD64 on neutrophils,
soluble triggering receptor expressed on myeloid cells-1,
soluble IL2 receptor alpha, soluble hemoglobin scavenger
receptor and micro RNA 15a, by themselves, are at least as
accurate as procalcitonin. Their use, combined with non-
invasive, quick and repeatable techniques as point-of-care
US, could improve decision making of septic patients
managed outside the ICU.
Conflict of interest There is no conflict of interest to declare.
References
1. Martin GS, Mannino DM, Eaton S, Moss M. The Epidemiology
of sepsis in the United States from 1979 through 2000. N Engl J
Med. 2003;348(16):1546–54.
2. Sepsis and multiorgan dysfunction. Abstracts of the 6th inter-
national congress, Weimer sepsis update 2013-consensus and
controversies. September 4–6, 2013. Weimer, Germany. Infec-
tion. 2013;41(Suppl 1):1–90.
3. Angus DC, van der Poll T. Severe sepsis and septic shock.
N Engl J Med. 2013;369(21):2063.
4. Levy MM, Artigas A, Philips GS, Rhodes A, Beale R, Osborn T,
Vincent JL, Townsend S, Lemeshow S, Dellinger RP. Outcomes
of the surviving sepsis campaign in intensive care units in the
USA and Europe: a prospective cohort study. Lancet Infect Dis.
2012;12:919–24.
5. Carmona-Torre F, Martinez-Urbistondo D, Landecho MF,
Lucena JF. Surviving sepsis in an intermediate care unit. Lancet
Infect Dis. 2013;13(4):294–5.
6. Bion J. Surviving sepsis: a systems issue. Lancet Infect Dis.
2012;12(12):898–9.
7. Mearelli F, Fiotti N, Altamura N, Zanetti M, Fernandes G,
Burekovic I, Occhipinti A, Orso D, Giansante C, Casarsa C,
Biolo G (2013) Heterogeneous models for an early discrimina-
tion between sepsis and non-infective SIRS in medical ward
patients: a pilot study. Intern Emerg Med Dec 22 [Epub ahead of
print].
8. Rohde JM, Odden AJ, Bonham C, Kuhn L, Malani PN, Chen
LM, Flanders SA, Iwashyna TJ. The epidemiology of acute
organ system dysfunction from severe sepsis outside of the
intensive care unit. J Hosp Med. 2013;8(5):243–7.
Table 2 Pragmatic approach to manage severe sepsis and septic
shock using non-invasive techniques in spontaneous breathing
patients
Parameters Possible clinical
implications
Blood pressure
MAP
a
C65 mmHg and urine output
C0.5 ml/kg/h
Titrate resuscitation
accordingly
Inferior cava and lung echography
Ø\1 cm, VCI
b
C40 % and absence of
B lines
c
Responsive to fluids
1\Ø\2.5 cm Indeterminate
Ø[2.5 cm and VCI \40 % (presence
of B lines)
Non-responsive to fluids
Ecocardiography
Left/right ventricular dysfunction Inotropes
Normal left/right ventricular function Vasocostrictors
Lactate
Clearence
d
Titrate resuscitation
accordingly
a
Mean arterial blood pressure
b
VCI =vena cava index is calculated by maximum inferior vena
cava Ø–minimum inferior vena cava Ø/maximum inferior vena cava
Ø9100) [85–89]
c
Ultrasonographic sign of increased extra vascular lung water [91]
d
10 % or more, measuring lactate in two determinations within first
6 h of resuscitation [98]
Early diagnosis and monitoring of septic patients
123
Author's personal copy

9. Stiermaier T, Herkner H, Tobudic S, Burgmann K, Staudinger
T, Schellongowski P, Burgmann H. Incidence and long-term
outcome of sepsis on general wards and in an ICU at the general
hospital of Vienna: an observational cohort study. Wien Klin
Wochenschr. 2013;125(11–12):302–8.
10. Esteban A, Frutos-Vivar F, Ferguson ND, Pen
˜uelas O, Lorente
JA, Gordo F, Honrubia T, Algora A, Bustos A, Garcı
´a G, Diaz-
Regan
˜o
´n IR, de Luna RR. Sepsis incidence and outcome: con-
trasting the intensive care unit with the hospital ward. Crit Care
Med. 2007;35(5):1284–9.
11. Howell MD, Shapiro NI. Surviving sepsis outside the intensive
care unit. Crit Care Med. 2007;35(5):1422–3.
12. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich
B, Peterson E, Tomlanovich M. Early Goal-Directed Therapy
Collaborative Group. Early goal-directed therapy in the treat-
ment of severe sepsis and septic shock. N Engl J Med.
2001;345(19):1368–77.
13. Powell ES, Sauser K, Cheema N, Pirotte MJ, Quattromani E,
Avula U, Khare RK, Courtney DM. Severe sepsis in do-not-
resuscitate patients: intervention and mortality rates. J Emerg
Med. 2013;44(4):742–9.
14. Gaieski DF, Edwards JM, Kallan MJ, Carr BG. Benchmarking
the incidence and mortality of severe sepsis in the United States.
Crit Care Med. 2013;41(5):1167–74.
15. Hotchkiss RS, Monneret G, Payen D. Immunosuppression in
sepsis: a novel understanding of the disorder and a new thera-
peutic approach. Lancet Infect Dis. 2013;13(3):260–8.
16. Wiersinga WJ, Leopold SJ, Cranendonk DR, van der Poll T. Host
innate immune responses to sepsis. Virulence 2013;4(8):17.
17. Faix JD. Biomarkers of sepsis. Crit Rev Clin Lab Sci.
2013;50(1):23–36.
18. Heffner AC, Horton JM, Marchick MR, Jones AE. Etiology of
illness in patients with severe sepsis admitted to the hospital
from the emergency department. Clin Infect Dis.
2010;50(6):814–20.
19. Phua J, Ngerng WJ, See KC, Tay CK, Kiong T, Lim HF, Chew
MY, Yip HS, Tan A, Khalizah HJ, Capistrano R, Lee KH,
Mukhopadhyay A. Characteristics and outcomes of culture-
negative versus culture-positive severe sepsis. Crit Care.
2013;17(5):R202.
20. Pavon A, Binquet C, Kara F, Martinet O, Ganster F, Navellou
JC, Castelain V, Barraud D, Cousson J, Louis G, Perez P,
Kuteifan K, Noirot A, Badie J, Mezher C, Lessire H, Quantin C,
Abrahamowicz M, Quenot JP, EPI demiology of Septic Shock
(EPISS) Study Group. Profile of the risk of death after septic
shock in the present era: an epidemiologic study. Crit Care Med.
2013;41(11):2600–9.
21. Otto GP, Kropf M, Sossdorf M, Recknagel P, Lo
¨sche W, Ro
¨del
J, Claus RA, Busch M. Screening for bacteremia in sepsis and
renal failure using hemofilters for renal replacement therapy.
Infection. 2013;41(2):387–90.
22. Groenewoudt M, Roest AA, Leijten FM, Stassen PM. Septic
patients arriving with emergency medical services: a seriously ill
population. Eur J Emerg Med 2013 Nov 6. [Epub ahead of print].
23. Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S,
Suppes R, Feinstein D, Zanotti S, Taiberg L, Gurka D, Kumar A,
Cheang M. Duration of hypotension before initiation of effective
antimicrobial therapy is the critical determinant of survival in
human septic shock. Crit Care Med. 2006;34(6):1589–96.
24. Filbin MR, Arias SA, Camargo CA Jr, Barche A, Pallin DJ.
Sepsis visits and antibiotic utilization in U.S. Emergency
departments. Crit Care Med 2013 Nov 6. [Epub ahead of print].
25. Laxminarayan R, Duse A, Wattal C, Zaidi AK, Wertheim HF,
Sumpradit N, Vlieghe E, Hara GL, Gould IM, Goossens H,
Greko C, So AD, Bigdeli M, Tomson G, Woodhouse W, Om-
baka E, Peralta AQ, Qamar FN, Mir F, Kariuki S, Bhutta ZA,
Coates A, Bergstrom R, Wright GD, Brown ED, Cars O. Anti-
biotic resistance-the need for global solutions. Lancet Infect Dis.
2013;13(12):1057–98.
26. Bouza E. Consequences of Clostridium difficile infection:
understanding the healthcare burden. Clin Microbiol Infect.
2012;18(Suppl 6):5–12.
27. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus
WA, Schein RM, Sibbald WJ. ACCP/SCCM Consensus Con-
ference Committee. Definitions for sepsis and organ failure and
guidelines for the use of innovative therapies in sepsis. The
ACCP/SCCM Consensus Conference Committee. American
College of Chest Physicians/Society of Critical Care Medicine.
1992. Chest. 2009;136(5 Suppl):e28.
28. Shapiro N, Howell MD, Bates DW, Angus DC, Ngo L, Talmor
D. The association of sepsis syndrome and organ dysfunction
with mortality in emergency department patients with suspected
infection. Ann Emerg Med. 2006;48(5):583–90.
29. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook
D, Cohen J, Opal SM, Vincent JL, Ramsay G. SCCM/ESICM/
ACCP/ATS/SIS. 2001 SCCM/ESICM/ACCP/ATS/SIS Interna-
tional Sepsis Definitions Conference. Crit Care Med.
2003;31(4):1250–6.
30. Zhao H, Heard SO, Mullen MT, Crawford S, Goldberg RJ,
Frendl G, Lilly CM. An evaluation of the diagnostic accuracy of
the 1991 American College of Chest Physicians/Society of
Critical Care Medicine and the 2001 Society of Critical Care
Medicine/European Society of Intensive Care Medicine/Amer-
ican College of Chest Physicians/American Thoracic Society/
Surgical Infection Society sepsis definition. Crit Care Med.
2012;40(6):1700–6.
31. Vincent JL, Opal SM, Marshall JC, Tracey KJ. Sepsis defini-
tions: time for change. Lancet. 2013;381(9868):774–5.
32. Howell MD, Talmor D, Schuetz P, Hunziker S, Jones AE,
Shapiro NI. Proof of principle: the predisposition, infection,
response, organ failure sepsis staging system. Crit Care Med.
2011;39(2):322–7.
33. Granja C, Po
´voa P, Lobo C, Teixeira-Pinto A, Carneiro A,
Costa-Pereira A. The predisposition, infection, response and
organ failure (Piro) sepsis classification system: results of hos-
pital mortality using a novel concept and methodological
approach. PLoS One 2013;8(1).
34. Gray A, Ward K, Lees F, Dewar C, Dickie S, McGuffie C.
STAG steering committee. The epidemiology of adults with
severe sepsis and septic shock in Scottish emergency depart-
ments. Emerg Med J. 2013;30(5):397–401.
35. Kenzaka T, Okayama M, Kuroki S, Fukui M, Yahata S, Hayashi
H, Kitao A, Sugiyama D, Kajii E, Hashimoto M. Importance of
vital signs to the early diagnosis and severity of sepsis: associ-
ation between vital signs and sequential organ failure assess-
ment score in patients with sepsis. Intern Med.
2012;51(8):871–6.
36. Pierrakos and Vincent. Sepsis biomarkers: a review. Crit Care.
2010;14:1–18.
37. Samraj RS, Zingarelli B, Wong HR. Role of biomarkers in
sepsis care. Shock. 2013;40(5):358–65.
38. Wacker C, Prkno A, Brunkhorst FM, Schlattmann P. Procalci-
tonin as a diagnostic marker for sepsis: a systematic review and
meta-analysis. Lancet Infect Dis. 2013;13(5):426–35.
39. Lipinska-Gediga M, Mierzchala M, Durek G. Pro-atrial natri-
uretic peptide (pro-ANP) level in patients with severe sepsis and
septic shock: prognostic and diagnostic significance. Infection.
2012;40(3):303–9.
40. Gros A, Roussel M, Sauvadet E, Gacouin A, Marque S, Chimot
L, et al. The sensitivity of neutrophil CD64 expression as a
biomarker of bacterial infection is low in critically ill patients.
Intensive Care Med. 2012;38(3):445–52.
F. Mearelli et al.
123
Author's personal copy

41. Uusitalo-Seppala R, Peuravuori H, Koskinen P, Vahlberg T,
Rintala EM. Role of plasma bactericidal/permeability-increasing
protein, group IIA phospholipase A2, C-reactive protein, and
white blood cell count in the early detection of severe sepsis in
the emergency department. Scand J Infect Dis.
2012;44(9):697–704.
42. Tromp M, Lansdorp B, Bleeker-Rovers CP, Gunnewiek JM,
Kullberg BJ, Pickkers P. Serial and panel analyses of biomarkers
do not improve the prediction of bacteremia compared to one
procalcitonin measurement. J Infect. 2012;65(4):292–301.
43. Su L, Han B, Liu C, Liang L, Jiang Z, Deng J, et al. Value of
soluble Trem-1, procalcitonin, and C-reactive protein serum
levels as biomarkers for detecting bacteremia among sepsis
patients with new fever in intensive care units: a prospective
cohort study. BMC Infect Dis. 2012;18(12):157.
44. Wu Y, Wang F, Fan X, Bao R, Bo L, Li J, Deng X. Accuracy of
plasma sTREM-1 for sepsis diagnosis in systemic inflammatory
patients: a systematic review and meta-analysis. Crit Care
2012;16(6):R229.
45. Feng L, Zhou X, Su LX, Feng D, Jia YH, Xie LX. Clinical
significance of soluble hemoglobin scavenger receptor CD163
(sCD163) in Sepsis, a prospective study. PLoS One.
2012;7(7):e38400.
46. Hoenigl M, Raggam RB, Wagner J, Valentin T, Leitner E,
Seeber K, et al. Diagnostic accuracy of soluble urokinase plas-
minogen activator receptor (suPAR) for prediction of bacteremia
in patients with systemic inflammatory response syndrome. Clin
Biochem. 2013;46(3):225–9.
47. Endo S, Suzuki Y, Takahashi G, Shozushiuma T, Ishikura H,
Murai A, et al. Usefulness of presepsin in the diagnosis of sepsis
in a multicenter prospective study. J Infect Chemother.
2012;18(6):891–7.
48. Tsalik EL, Jaggers LB, Glickman SW, Langley RJ, van Velk-
inburgh JC, Park LP, et al. Dicrimative value of inflammatory
biomarkers for suspected sepsis. J Emerg Med.
2012;43(1):97–106.
49. Gibot S, Be
´ne
´MC, Noel R, Massin F, Guy J, Cravoisy A, et al.
Combination biomarkers to diagnose sepsis in the critically ill
patient. Am J Respir Crit Care Med. 2012;186(1):65–71.
50. Gille-Johnson P, Hansson KE, Gardlund B. Clinical and labo-
ratory variables identifying bacterial infection and bacteremia in
the emergency department. Scand J Infect Dis.
2012;44(10):745–52.
51. Wang H, Zhang P, Chen W, Feng D, Jia Y, Xie LX. Evidence
for serum miR-15a, and miR-16 levels as biomarkers that dis-
tinguish sepsis from systemic inflammatory response syndrome
in human subjects. Clin Chem Lab Med. 2012;50(8):1423–8.
52. Jaimes FA, De La Rosa GD, Valencia ML, Arango CM, Gomez
CI, Garcia A, et al. A latent class approach for sepsis diagnosis
supports use of procalcitonin in the emergency room for diag-
nosis of severe sepsis. BMC Anesthesiol. 2013;13(1):23.
53. Al Shuaibi M, Bahu RR, Chaftari AM, Al Wohoush I, Shomali
W, Jiang Y, et al. Pro-adrenomedullin as a novel biomarker for
predicting infections and response to antimicrobials in febrile
patients with hematologic malignancies. Clin Infect Disease.
2013;58(7):943–50.
54. Jekarl DW, Lee SY, Lee J, Park YJ, Kim Y, Wee JH, et al.
Procalcitonin as a diagnostic marker and IL-6 as a prognostic
marker for sepsis. Diagn Microbiol Infect Dis.
2013;75(4):342–7.
55. Ulla M, Pizzolato E, Lucchiari M, Loiacono M, Soardo F, Forno
D, et al. Diagnostic and prognostic value of presepsin in the
management of sepsis in the emergency department: a multi-
center prospective study. Crit Care. 2013;17(4):R168.
56. Llewelyn MJ, Berger M, Gregory M, Ramaiah R, Taylor AR,
Curdt L, et al. Sepsis biomarkers in unselected patients on
admission to intensive or high-dependency care. Crit Care.
2013;17(2):R60.
57. Su L, Feng L, Song Q, Kang H, Zhang X, Liang Z, et al.
Diagnostic value of dynamics serum sCD163, sTREM-1, PCT,
and CRP in differentiating sepsis, severity assesment, and
prognostic prediction. Mediators Inflamm. 2013;2013:969875.
58. Wong HR, Lindsell CJ, Lahni P, Hart KW, Gibot S. Interleukin
27 as a sepsis diagnostic biomarker in critically ill adults. Shock.
2013;40(5):382–6.
59. Ratzinger F, Schuardt M, Eichbichler K, Tsirkinidou I, Bauer M,
Haslacher H, et al. Utility of sepsis biomarkers and the infection
probability score to discriminate sepsis and systemic inflam-
matory response syndrome in standard care patients. PLoS One.
2013;8(12):e82946.
60. Liu B, Chen YX, Yin Q, Zhao YZ, Li CS. Diagnostic value and
prognostic evaluation of presepsin for sepsis in an emergency
department. Crit Care. 2013;17(5):R244.
61. Dimoula A, Pradier O, Kassengera Z, Dalcomune D, Turkan H,
Vincent JL. Serial determinations of neutrophil CD64 expres-
sion for the diagnosis and monitoring of sepsis in critically ill
patients. Clin Infect Dis 2014 Jan 28.
62. Pons-Salort M, Thie
´baut AC, Guillemot D, Favre M, Delaroc-
que-Astagneau E. HPV genotype replacement: too early to tell.
Lancet Infect Dis. 2013;13(12):1012.
63. Kopterides P, Siempos II, Tsangaris I, Tsantes A, Armaganidis
A. Procalcitonin-guided algorithms of antibiotic therapy in the
intensive care unit: a systematic review and meta-analysis of
randomized controlled trials. Crit Care Med.
2010;38(11):2229–41.
64. Bafadhel M, Clark TW, Reid C, Medina MJ, Batham S, Barer
MR, Nicholson KG, Brightling CE. Procalcitonin and C-reactive
protein in hospitalized adult patients with community-acquired
pneumonia or exacerbation of asthma or COPD. Chest.
2011;139(6):1410–8.
65. Schuetz P, Mu
¨ller B, Christ-Crain M, Stolz D, Tamm M, Bou-
adma L, Luyt CE, Wolff M, Chastre J, Tubach F, Kristoffersen
KB, Burkhardt O, Welte T, Schroeder S, Nobre V, Wei L,
Bhatnagar N, Bucher HC, Briel M. Procalcitonin to initiate or
discontinue antibiotics in acute respiratory tract infections. Evid
Based Child Health. 2013;8(4):1297–371.
66. Heyland DK, Johnson AP, Reynolds SC, Muscedere J. Pro-
calcitonin for reduced antibiotic exposure in the critical care
setting: a systematic review and an economic evaluation. Crit
Care Med. 2011;39(7):1792–9.
67. Jensen JU, Hein L, Lundgren B, Bestle MH, Mohr TT, Andersen
MH, Thornberg KJ, Løken J, Steensen M, Fox Z, Tousi H, Søe-
Jensen P, Lauritsen AØ, Strange D, Petersen PL, Reiter N,
Hestad S, Thormar K, Fjeldborg P, Larsen KM, Drenck NE,
Ostergaard C, Kjær J, Grarup J, Lundgren JD. Procalcitonin And
Survival Study (PASS) Group.: procalcitonin-guided interven-
tions against infections to increase early appropriate antibiotics
and improve survival in the intensive care unit: a randomized
trial. Crit Care Med. 2011;39(9):2048–58.
68. Layios N, Lambermont B, Canivet JL, Morimont P, Preiser JC,
Garweg C, Ledoux D, Frippiat F, Piret S, Giot JB, Wiesen P,
Meuris C, Massion P, Leonard P, Nys M, Lancellotti P, Chapelle
JP, Damas P. Procalcitonin usefulness for the initiation of
antibiotic treatment in intensive care unit patients. Crit Care
Med. 2012;40(8):2304–9.
69. Rivers EP, Jaehne AK, Nguyen HB, Papamatheakis DG, Singer
D, Yang JJ, Brown S, Klausner H. Early biomarker activity in
severe sepsis and septic shock and a contemporary review of
immunotherapy trials: not a time to give up, but to give it earlier.
Shock. 2013;39(2):127–37.
70. Xiong C, McKeel DW Jr, Miller JP, Morris JC. Combining
correlated diagnostic tests: application to neuropathologic
Early diagnosis and monitoring of septic patients
123
Author's personal copy

diagnosis of Alzheimer’s disease. Med Decis Making.
2004;24(6):659–69.
71. Kofoed K, Andersen O, Kronborg G, Tvede M, Petersen J,
Eugen-Olsen J, Larsen K. Use of plasma C-reactive protein,
procalcitonin, neutrophils, macrophage migration inhibitory
factor, soluble urokinase-type plasminogen activator receptor,
and soluble triggering receptor expressed on myeloid cells-1 in
combination to diagnose infections: a prospective study. Crit
Care. 2007;11(2):R38.
72. Selberg O, Hecker H, Martin M, Klos A, Bautsch W, Ko
¨hl J.
Discrimination of sepsis and systemic inflammatory response
syndrome by determination of circulating plasma concentrations
of procalcitonin, protein complement 3a, and interleukin-6. Crit
Care Med. 2000;28(8):2793–8.
73. Sankar V, Webster NR. Clinical application of sepsis bio-
markers. J Anesth. 2013;27(2):269–83.
74. Kotsaki A, Giamarellos-Bourboulis EJ. Molecular diagnosis of
sepsis. Expert Opin Med Diagn. 2012;6(3):209–19.
75. Lyle N, Boyd J. The potential for PCR based testing to improve
diagnosis and treatment of sepsis. Curr Infect Dis Rep.
2013;15(5):372–9.
76. Riedel S, Carroll KC. Laboratory detection of sepsis: biomarkers
and molecular approaches. Clin Lab Med. 2013;33(3):413–37.
77. Chang SS, Hsieh WH, Liu TS, Lee SH, Wang CH, Chou HC, Yeo
YH, Tseng CP, Lee CC. Multiplex PCR system for rapid detec-
tion of pathogens in patients with presumed sepsis—a systemic
review and meta-analysis. PLoS One. 2013;8(5):e62323.
78. Jones AE, Brown MD, Trzeciak S, Shapiro NI, Garrett JS,
Heffner AC, Kline JA. Emergency Medicine Shock Research
Network investigators. The effect of a quantitative resuscitation
strategy on mortality in patients with sepsis: a meta-analysis.
Crit Care Med. 2008;36(10):2734–9.
79. Jones AE, Kline JA. Use of goal-directed therapy for severe
sepsis and septic shock in academic emergency departments.
Crit Care Med 2005;33(8):1888–1889; author reply 1889–90.
80. Biston P, Aldecoa C, Devriendt J, Madl C, Chochrad D, Vincent
JL, De Backer D. Outcome of elderly patients with circulatory
failure. Intensive Care Med;40(1):50–56.
81. Ihra GC, Lehberger J, Hochrieser H, Bauer P, Schmutz R,
Metnitz B, Metnitz PG. Development of demographics and
outcome of very old critically ill patients admitted to intensive
care units. Intensive Care Med. 2012;38(4):620–6.
82. Bourcier JE, Paquet J, Seinger M, Gallard E, Redonnet JP,
Cheddadi F, Garnier D, Bourgeois JM, Geeraerts T. Perfor-
mance comparison of lung ultrasound and chest X-ray for the
diagnosis of pneumonia in the ED. Am J Emerg Med.
2014;32(2):115–8.
83. Cibinel GA, Casoli G, Elia F, Padoan M, Lupia E, Goffi A.
Diagnostic accuracy and reproducibility of pleural and lung
ultrasound in discriminating cardiogenic causes of acute dysp-
nea in the emergency department. Intern Emerg Med.
2012;7(1):65–70.
84. Jones AE, Tayal VS, Sullivan DM, Kline JA. Randomized,
controlled trial of immediate versus delayed goal-directed
ultrasound to identify the cause of nontraumatic hypotension in
emergency department patients. Crit Care Med.
2004;32(8):1703–8.
85. Volpicelli G, Lamorte A, Tullio M, Cardinale L, Giraudo M,
Stefanone V, Boero E, Nazerian P, Pozzi R, Frascisco MF.
Point-of-care multiorgan ultrasonography for the evaluation of
undifferentiated hypotension in the emergency department.
Intensive Care Med. 2013;39(7):1290–8.
86. Bouferrache K, Amiel JB, Chimot L, Caille V, Charron C, Vi-
gnon P, Vieillard-Baron A. Initial resuscitation guided by the
Surviving Sepsis Campaign recommendations and early echo-
cardiographic assessment of hemodynamics in intensive care
unit septic patients: a pilot study. Crit Care Med.
2012;40(10):2821–7.
87. Haydar SA, Moore ET, Higgins GL 3rd, Irish CB, Owens WB,
Strout TD. Effect of bedside ultrasonography on the certainty of
physician clinical decision making for septic patients in the
emergency department. Ann Emerg Med. 2012;60(3):346–58.
88. Nagdev AD, Merchant RC, Tirado-Gonzalez A, Sisson CA,
Murphy MC. Emergency department bedside ultrasonographic
measurement of the caval index for noninvasive determination
of low central venous pressure. Ann Emerg Med.
2010;55(3):290–5.
89. Schmidt GA, Koenig S, Mayo PH. Shock: ultrasound to guide
diagnosis and therapy. Chest. 2012;142(4):1042–8.
90. Muller Laurent, Xavier Bobbia, Toumi Mehdi, Louart Guillame,
Molinari Nicolas, Ragonnet Benoit, Quintard Herve, Leone
Marc, Zoreic Lana, Lefrant Jean Yves and the AzuRea group.
Respiratory variations of inferior cava diameter to predict fluid
responsiveness in spontaneously breathing patients with acute
circulatory failure: need for a cautions use. Critical Care
2012;(16):R188.
91. Feissel M, Michard F, Faller JP, Teboul JL. The respiratory
variation in inferior vena cava diameter as a guide to fluid
therapy. Intensive Care Med. 2004;30(9):1834–7.
92. Zhang Z, Xu X, Ye S, Xu L. Ultrasonographic measurement of
respiratory variation in the inferior vena cava diameter is pre-
dictive of fluid responsiveness in critically ill patients: system-
atic review and meta-analysis. Ultrasound in Med Biol
2014:1–9.
93. Coen D, Vaccaro A, Cazzaniga M, Cortellaro F, Monti G,
Tombini V. Toward a noninvasive approach to early goal-
directed therapy. Chest 2011;139(3):726–727; author reply 727.
94. Copetti R, Copetti P, Reissig A. Clinical integrated ultrasound of
the thorax including causes of shock in nontraumatic critically
ill patients. A practical approach. Ultrasound Med Biol.
2012;38(3):349–59.
95. Weekes AJ, Tassone HM, Babcock A, Quirke DP, Norton HJ,
Jayarama K, Tayal VS. Comparison of serial qualitative and
quantitative assessments of caval index and left ventricular
systolic function during early fluid resuscitation of hypotensive
emergency department patients. Acad Emerg Med.
2011;18(9):912–21.
96. Machare-Delgado E, Decaro M, Marik PE. Inferior vena cava
variation compared to pulse contour analysis as predictors of
fluid responsiveness: a prospective cohort study. J Intensive
Care Med. 2011;26(2):116–24.
97. Howell MD, Donnino M, Clardy P, Talmor D, Shapiro NI.
Occult hypoperfusion and mortality in patients with suspected
infection. Intensive Care Med. 2007;33(11):1892–9.
98. Jones AE. Point: should lactate clearance be substituted for
central venous oxygen saturation as goals of early severe sepsis
and septic shock therapy? Yes. Chest. 2011;140(6):1406–8.
99. Rivers EP, Elkin R, Cannon CM. Counterpoint: should lactate
clearance be substituted for central venous oxygen saturation as
goals of early severe sepsis and septic shock therapy? No. Chest
2011;140(6):1408–141. (Discussion 1413–1419).
100. Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA,
Kline JA. Emergency medicine shock research network (EM-
ShockNet) investigators. Lactate clearance vs central venous
oxygen saturation as goals of early sepsis therapy: a randomized
clinical trial. JAMA. 2010;303(8):739–46.
101. Puskarich MA, Trzeciak S, Shapiro NI, Albers AB, Heffner AC,
Kline JA, Jones AE. Whole blood lactate kinetics in patients
undergoing quantitative resuscitation for severe sepsis and septic
shock. Chest. 2013;143(6):1548–53.
102. Arnold RC, Shapiro NI, Jones AE, Schorr C, Pope J, Casner E,
Parrillo JE, Dellinger RP, Trzeciak S. Emergency Medicine
F. Mearelli et al.
123
Author's personal copy

Shock Research Network (EMShockNet) Investigators. Multi-
center study of early lactate clearance as a determinant of sur-
vival in patients with presumed sepsis. Shock. 2009;32(1):35–9.
103. Miller RR, Dong L, Nelson NC, Brown SM, Kuttler KG, Probst
DR, Allen TL, Clemmer TP. Intermountain Healthcare Intensive
Medicine Clinical Program. Multicenter implementation of a
severe sepsis and septic shock treatment bundle. Am J Respir
Crit Care Med. 2013;188(1):77–82.
104. The ProCESS Investigators. A randomized Trial of Protocol-
Based Care for Early Septic Shock. N Engl J Med.
2014;18:1–11.
Early diagnosis and monitoring of septic patients
123
Author's personal copy