Infection (2015) 43:1–11 DOI 10.1007/s15010-014-0673-6

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 / Published online: 11 August 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, preventing ICU admissions, poor outcomes and costly complications, especially in elderly that are usually highly vulnerable to invasive procedures.

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: [email protected]

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 categorized 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 % originating from emergency department, ED) [4]. In spite of these figures, epidemiologic studies in non-ICU setting

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Table 1 Sepsis definitions SIRS

Two or more of the following: Temperature • [38 C, or \ 36 C Respiratory rate • [20 breaths/min, or pCO2 \32 mmHg WBC • [12000/mm3, \4000 mm3, or [10 % immature forms Heart rate • [90 beats/min

Sepsis

SIRS plus presumed or proven infection

Severe sepsis Septic shock

Sepsis plus organ dysfunction Sepsis plus hypotension despite fluid resuscitation

Bacteremia

Presence of viable bacteria in the blood

Culture-negative Sepsis

Sepsis without microbiological documentation of infection

(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 withdrawal 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 pathophysiology of the disease [15]. The host response to

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sepsis encompasses a pro-inflammatory (PI) phase, directed to clear causative microorganism, and an antiinflammatory (AI) phase, necessary to turn off the inflammation and limit tissue injury. In previously healthy 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 suitable 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 Gramnegative 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 collection 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., nonintubated 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 definitive adjudication of the cases. Third, most of the septic patients receive antibiotics ahead of collection of the respiratory tract specimen, reducing the sensitivity of cultures. 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.

Early diagnosis and monitoring of septic patients

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Fig. 1 The two phases of sepsis according to absence (red lines) or presence (blue lines) of host co morbidities

Clinical presentation and diagnosis Sepsis is a frequently missed diagnosis since it looks quite similar to other causes of non-infective systemic inflammatory response syndrome (SIRS) [18]. In USA, ED personnel 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, especially 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 antibiotics 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 mortality in sepsis, has induced a quick rise in multi-drug resistant strains and other serious adverse events, like Clostridium difficile infections, which are becoming surprisingly common and difficult to treat [25, 26]. Standardized 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 refinements 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. Compared 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 PaO2/FIO2 ratio, high levels of creatinine,

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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 antibiotics and reduce the widespread of bacterial resistance.

Most of the trials on biomarkers, though, have been evaluated 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 performance 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: Presepsin, 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

lactate were the most powerful positive predictors of sepsis using both 1991 and 2001 definitions [30]. Markers for early diagnosis Single biomarker

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Early diagnosis and monitoring of septic patients

specificity 0.73) [62]. Moreover, different assays (mainly by Liaison and Kryptor BRAHMS Hennigsdorf, Germany) and diverse cut-offs have been derived from different settings and in patients with different severity and comorbidities [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 respiratory 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 implemented in clinical practice. Turn around time and timing of sampling Latest evidence has highlighted CD64 expression on neutrophil (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 predictive value in sepsis diagnosis. Such a result was confirmed 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 biomarkers 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; nevertheless, 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’’) eventually combined with clinical signs (‘‘heterogeneous models’’) could increase accuracy in the diagnosis of sepsis, compared to the ‘‘silver-bullet’’ approach. The choice of

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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, soluble 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 biomarker alone [73], although four recent trials highlight some combinations particularly promising for sepsis diagnosis: •

PCT ? soluble triggering receptor expressed on myeloid cells-1(sTREM1) ? expression of CD64 on neutrophils (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].

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PCT ? serum IL2 receptor alpha (sCD25) and pancreatic 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 growthrequired assay). Three groups of techniques can be identified in growth-required methods: PCR-based (ex. StaphSR BDGeneOhm, Xpert MRSA/SA Cepheid Diagnostic, LightCycler Staphilococcus RocheMolecular, Prove-it Sepsis Mobidiag), non-amplified nucleic acidbased (FHA and FISH), and non-nucleic acid-based technology 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 subdivided 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 LightCycler SeptiFast may be represented by the high cost of a single test (300 dollars/patient) and the lack of susceptibility 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

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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 (ScVO2) 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 outweigh the benefits, thus limiting the generalizability of EGDT. In spite of this concern, in two recent retrospective 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 hemodynamic 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 (evaluation 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

Early diagnosis and monitoring of septic patients 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 MAPa C65 mmHg and urine output C0.5 ml/kg/h

Titrate resuscitation accordingly

Inferior cava and lung echography Ø \ 1 cm, VCIb C40 % and absence of B linesc

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 Clearenced a

Titrate resuscitation accordingly

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 Ø 9 100) [85–89] c

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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 patterns. Lack of clear diagnostic criteria for sepsis and overlapping clinical and laboratory presentation with noninfective 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 noninvasive, 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.

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]

References through Bayesian analysis, but seems very attractive in monitoring septic patients. Among the circulating biomarkers, 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 ScVO2 [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 lactate measurement (beyond blood cultures sampling ahead of antibiotic therapy administration, and early administration 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 criteria 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 necessarily required a CVC placement [104].

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