A randomized prospective clinical trial to assess the role of procalcitonin-guided antimicrobial therapy to reduce long-term infections sequelae: the PROGRESS trial

Rationale: Although early antimicrobial discontinuation guided by procalcitonin (PCT) has showed decreased antibiotic consumption in lower respiratory tract infections (LRTIs), the outcomes in long-term sepsis sequelae remain unclear. Objective To investigate if PCT-guidance may reduce the incidence of long-term infection-associated adverse events in sepsis. Methods: In this multicenter trial, 266 sepsis (by Sepsis-3 definitions) patients with LRTIs, acute pyelonephritis, or primary bloodstream infection were randomized (1:1) to receive either PCT-guided discontinuation of antimicrobials or standard-of-care (SOC). The discontinuation criterion was ≥80% reduction in PCT levels or any PCT ≤0.5 μg/l at day 5 or later. The primary outcome was the rate of infection-associated adverse events at day 180, a composite of the incidence of any new infection by Clostridioides difficile or multidrug-resistant organisms (MDRO), or any death attributed to baseline C. difficile or MDRO infection. Secondary outcomes included 28-day mortality, length of antibiotic therapy (LOT), and cost of hospitalization. Measurements and Main Results: The rate of infection-associated adverse events was 7.2% (95% CI, 3.8-13.1%; 9/125) versus 15.3% (95% CI, 10.1-22.4%; 20/131) (hazard ratio [HR], 0.45; 95% CI, 0.20-0.98; P=0.045); 28-day mortality 15.2% (95% CI,10-22.5%; 19/125) versus 28.2% (95% CI, 21.2-36.5%; 37/131) (HR, 0.51; 95% CI, 0.29-0.89; P =0.02); and median LOT 5 (range 5 to 7) versus 10 (range 7 to 15) days (P <0.001) in the PCT and SOC arms, respectively. The cost of hospitalization was also reduced in the PCT arm. Conclusions: In sepsis, PCT-guidance was effective in reducing infection-associated adverse events, 28-day mortality, and cost of hospitalization.Εισαγωγή: Παρά το γεγονός ότι η έγκαιρη διακοπή αντιμικροβιακών κατευθυνόμενη από την προκαλσιτονίνη (PCT) έχει συντελέσει στη μείωση της κατανάλωσης αντιμικροβιακών, τα αποτελέσματα της χρήσης της στις μακροχρόνιες επιπλοκές της σήψης δεν έχουν μελετηθεί επαρκώς. Η κλινική δοκιμή αυτή είχε ως σκοπό να διερευνήσει κατά πόσον μια πρώιμη διακοπή αντιμικροβιακών που κατευθύνεται από την PCT στη σήψη θα μπορούσε να μειώσει την επίπτωση ανεπιθύμητων συμβάντων που σχετίζονται με χρονίζουσες λοιμώδεις επιπλοκές. Μέθοδοι: Σε αυτή την ανοικτή, πολυκεντρική μελέτη, 266 ασθενείς με σήψη (οριζόμενη κατά Σήψη-3) και λοιμώξεις κατώτερου αναπνευστικού, οξεία πυελονεφρίτιδα ή πρωτοπαθή βακτηριαιμία τυχαιοποιήθηκαν (1:1) να λάβουν είτε αντιμικροβιακή αγωγή με διακοπή κατευθυνόμενη από την PCT είτε καθιερωμένη αγωγή. Το κριτήριο διακοπής ήταν η μείωση ≥80% των επιπέδων PCT ορού ή οποιαδήποτε τιμή PCT ορού χαμηλότερη από 0,5 μg/l την πέμπτη ημέρα αγωγής. Το πρωτογενές καταληκτικό σημείο ήταν η διαφορά στην επίπτωση των ανεπιθύμητων συμβάντων που σχετίζονται με λοιμώδεις επιπλοκές ως την ημέρα 180, πρόκειται για ένα σύνθετο καταληκτικό σημείο της επίπτωσης νέων λοιμώξεων από Clostridioides difficile ή πολυανθεκτικούς μικροοργανισμούς (MDRO) η οποιουδήποτε θανάτου που οφείλεται σε αρχική λοίμωξη από C. difficile ή MDRO. Δευτερογενή καταληκτικά σημεία ήταν η θνητότητα 28 ημερών, η διάρκεια αντιμικροβιακής αγωγής και το κόστος νοσηλείας. Αποτελέσματα: Η επίπτωση ανεπιθύμητων συμβάντων που σχετίζονται με λοιμώδεις επιπλοκές ήταν 7,2% (9/125) στην ομάδα της αγωγής που κατευθύνεται από την PCT έναντι 15,3% (20/131) στην ομάδα καθιερωμένης αγωγής (αναλογικός κίνδυνος 0,45, 95% ΔΕ 0,20 ως 0,98, p=0,045). Η θνητότητα 28 ημερών ήταν 15,2% (19/125) έναντι 28,2% (20/131) (αναλογικός κίνδυνος 0,51, 95% ΔΕ 0,29 ως 0,89, Ρ=0,02) και η διάμεση διάρκεια αντιμικροβιακής αγωγής 5 (εύρος, 5-7) έναντι 10 (εύρος 7-15) ημερών (p<0,0001). Το κόστος νοσηλείας στην ομάδα PCT μειώθηκε επίσης. Συμπεράσματα: Η αντιμικροβιακή αγωγή που κατευθύνεται από την PCT στη σήψη μείωσε αποτελεσματικά την επίπτωση ανεπιθύμητων συμβάντων σχετιζόμενων με χρονίζουσες λοιμώδεις επιπλοκές, τη θνητότητα 28 ημερών και το κόστος νοσηλείας

Η βραδυκαρδία κατά τη στοχευμένη διαχείριση θερμοκρασίας: Συσχέτιση με την έκβαση

Εισαγωγή Η θετική επίδραση της φλεβοκομβικής βραδυκαρδίας κατά τη διάρκεια της Στοχευμένης Διαχείρισης Θερμοκρασίας (ΣΔΘ) παραμένει αμφισβητουμένη. Σκοπός της παρούσας μελέτης ήταν να διερευνηθεί η επίδραση της φλεβοκομβικής βραδυκαρδίας στην επιβίωση και νευρολογική έκβαση. Mέθοδοι Έγινε αναζήτηση στις βάσεις δεδομένων MEDLINE(PubMed), Cochrane, Google Scholar και http://www.clinicaltrials.gov προκειμένου να βρεθούν μελέτες που αναφέρονται σε κωματώδεις μετά από καρδιακή ανακοπή ασθενείς και εμφανίζουν φλεβοκομβική βραδυκαρδία κατά τη ΣΔΘ. Ως αποτέλεσμα ενδιέφερε η επιβίωση των 180 ημερών και η νευρολογική λειτουργικότητα, αξιολογούμενη κατά την Κλίμακα Cerebral Performance Category (CPC). Τα αποτελέσματα της μελέτης παρουσιάζονται ως σχετικός κίνδυνος (ΣΚ) με 95% όρια αξιοπιστίας (ΟΑ). Αποτελέσματα Στην παρούσα έρευνα περιλήφθηκαν δύο μελέτες με συνολικό αριθμό ασθενών 1184. Σε σύγκριση με την ομάδα της μη φλεβοκομβικής βραδυκαρδίας, οι ασθενείς με φλεβοκομβική βραδυκαρδία χαμηλότερη των 50 σφύξεων ανά λεπτό εμφάνισαν μειωμένη θνητότητα στις 180 ημέρες (ΣΚ 0,42, 95% ΟΑ: 0,29-0,59). Δεν ανιχνεύτηκε ετερογένεια. Συμπεράσματα Η φλεβοκομβική βραδυκαρδία χαμηλότερη των 50 σφύξεων ανά λεπτό κατά τη ΣΔΘ πιθανά είναι προστατευτική και καλό θα ήταν να τη σκέφτεται κανείς κατά την αντιμετώπιση ασθενών σε κωματώδη κατάσταση μετά από καρδιακή ανακοπή.Introduction The beneficial effect of sinus-bradycardia during targeted temperature management (TTM) in cardiac arrest patients remains doubtful. We aimed to investigate the impact of sinus-bradycardia on survival and neurological outcome. Methods MEDLINE(PubMed), Cochrane, Google Scholar and http://www.clinicaltrials.gov databases were searched for studies reporting on comatose post-cardiac arrest patients presenting sinus-bradycardia during TTM. Outcomes were the 180-day survival and final neurologic function assessed by the Cerebral Performance Category (CPC) scale. The effect size on study outcomes is presented as odds ratio (OR) with 95% confidence interval (CI). Results Two studies with 1184 patients were included. Compared to no-sinus-bradycardia group, in patients with sinus bradycardia below 50 bpm a significant effect of sinus-bradycardia on reduction of 180-day mortality was reported (OR 0.42; 95% CI: 0.29-0.59). No heterogeneity was detected. Conclusions Sinus-bradycardia below 50 bpm during TTM may be protective and should be considered in comatose post-cardiac arrest patients

Monitoring immunomodulation in patients with sepsis

Introduction: This review aims to summarize current progress of the last ten years in the development of biomarkers used for classifying the immune response of the septic host and for monitoring the efficacy of the applied adjunctive immunotherapy. Areas covered: An extensive search of the literature was performed. In this review the authors discuss available biomarkers of host immune response in sepsis toward two directions; immunosuppression and hyperinflammation. Ferritin, sCD163, sIL-2 ra, and IL-18 may help in the diagnosis of macrophage activation syndrome (MAS) complicating sepsis whereas lymphopenia, decreased HLA-DR expression on monocytes, overexpression of Programmed cell death protein-1 (PD-1)/Programmed death-ligand 1 (PD-L1) and IL-10 are indicators of sepsis-induced immunosuppression. Novel approaches in the classification of immune state in sepsis include Myeloid-Derived Suppressor Cells (MDSC) and specific endotypes, defined by gene expression and molecular techniques. Expert opinion: HLA-DR and ferritin are the most commonly used biomarkers to monitor immunomodulation in clinical practice whereas developing specific sepsis endotypes is the future target. New immunotherapy trials in sepsis need to incorporate biomarkers for a personalized treatment

Antimicrobial Stewardship Using Biomarkers: Accumulating Evidence for the Critically Ill

This review aims to summarize current progress in the management of critically ill, using biomarkers as guidance for antimicrobial treatment with a focus on antimicrobial stewardship. Accumulated evidence from randomized clinical trials (RCTs) and observational studies in adults for the biomarker-guided antimicrobial treatment of critically ill (mainly sepsis and COVID-19 patients) has been extensively searched and is provided. Procalcitonin (PCT) is the best studied biomarker; in the majority of randomized clinical trials an algorithm of discontinuation of antibiotics with decreasing PCT over serial measurements has been proven safe and effective to reduce length of antimicrobial treatment, antibiotic-associated adverse events and long-term infectious complications like infections by multidrug-resistant organisms and Clostridioides difficile. Other biomarkers, such as C-reactive protein and presepsin, are already being tested as guidance for shorter antimicrobial treatment, but more research is needed. Current evidence suggests that biomarkers, mainly procalcitonin, should be implemented in antimicrobial stewardship programs even in the COVID-19 era, when, although bacterial coinfection rate is low, antimicrobial overconsumption remains high

The early change of SOFA score as a prognostic marker of 28-day sepsis mortality: Analysis through a derivation and a validation cohort

Background: Since the Sepsis-3 criteria, change in Sequential Organ Failure Assessment (SOFA) score has become a key component of sepsis identification. Thus, it could be argued that reversal of this change (ΔSOFA) may reflect sepsis response and could be used as measure of efficacy in interventional trials. We aimed to assess the predictive performance of ΔSOFA for 28-day mortality. Methods: Data from two previously published randomized controlled trials were studied: the first reporting on patients with severe Gram-negative infections as a derivation cohort and the second reporting on patients with ventilator-associated pneumonia as a validation cohort. Only patients with sepsis according to the Sepsis-3 definition were included in this analysis. SOFA scores were calculated on days 1, 2, 3, 5, 7, 14, and 28. Results: We included 448 patients within the derivation cohort and 199 within the validation cohort. Mean SOFA scores on day 1 were 6.06 ± 4.07 and 7.84 ± 3.39, and 28 day mortality 22.8% and 29.6%, respectively. In the derivation cohort, the earliest time point where ΔSOFA score predicted mortality was day 7 (AUROC (95% CI) 0.84 (0.80-0.89); p < 0.001). The best tradeoff for prediction was found with 25% changes (78% sensitivity, 80% specificity); less than 25% decrease of admission SOFA was associated with increased mortality (odds ratio for death 14.87). This finding was confirmed in the validation cohort. Conclusions: ΔSOFA on day 7 is a useful early prognostic marker of 28-day mortality and could serve as an endpoint in future sepsis trials alongside mortality.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

BIOMARKERS: CAN THEY REALLY GUIDE OUR DAILY PRACTICE?

International audienceABSTRACT Optimal management of septic patients requires accurate assessment of both current severity status and prognosis. Since the 1990s, substantial advances have been made in the use of circulating biomarkers for such assessments. This summary of the session on “Biomarkers: can they really use guide our daily practice?” presented at the 2021 WEB-CONFERENCE OF THE EUROPEAN SHOCK SOCIETY, 6 November 2021. These biomarkers include ultrasensitive detection of bacteremia, circulating soluble urokina-type plasminogen activator receptor (suPAR), C-reactive protein (CRP) and ferritin and procalcitonin. In addition, the potential application of novel multiwavelength optical biosensor technology allows noninvasive monitoring of multiple metabolites that can be used to assess severity and prognosis in septic patients. The application these biomarkers and improved technologies provide the potential for improved personalized management of septic patients

Impact of comorbidities on the performance of interferon-gamma release assay in an elderly Greek population without overt immunodeficiency

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Soluble fms-like tyrosine kinase 1, placental growth factor and procalcitonin as biomarkers of gram-negative sepsis Analysis through a derivation and a validation cohort

Further improvement of the diagnostic and prognostic performance of biomarkers for the critically ill is needed. Procalcitonin (PCT), placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 raise interest for sepsis diagnosis and prognosis. Serum samples from 2 cohorts of 172 patients (derivation cohort) and of 164 patients (validation cohort) comprising only patients with microbiologically confirmed gram-negative infections were analyzed. PlGF, s-Flt-1 and procalcitonin (PCT) were measured in serum within 24 hours from sepsis onset and repeated on days 3 and 7. PCT and s-Flt-1 baseline levels were higher in sepsis and septic shock compared to non-sepsis; this was not the case for PlGF. s-Flt-1 at concentrations greater than 60 pg/ml diagnosed sepsis with sensitivity 72.3% and specificity 54.9% whereas at concentrations greater than 70 pg/ml predicted unfavorable outcome with specificity 73.0% and sensitivity 63.7%. At least 80% decrease of PCT and/or PCT less than 0.5 ng/ml on day 7 was protective from sepsis-associated death. Both s-Flt-1 and PCT should be measured in the critically ill since they provide additive information for sepsis diagnosis and prognosis. ClinicalTrials.gov numbers NCT01223690 and NCT00297674

Coronavirus Disease 2019 as Cause of Viral Sepsis: A Systematic Review and Meta-Analysis*

Objective: Coronavirus disease 2019 is a heterogeneous disease most frequently causing respiratory tract infection, which can induce respiratory failure and multiple organ dysfunction syndrome in its severe forms. The prevalence of coronavirus disease 2019-related sepsis is still unclear; we aimed to describe this in a systematic review. Data Sources: MEDLINE (PubMed), Cochrane, and Google Scholar databases were searched based on a prespecified protocol (International Prospective Register for Systematic Reviews: CRD42020202018). Study Selection: Studies reporting on patients with confirmed coronavirus disease 2019 diagnosed with sepsis according to sepsis-3 or according to the presence of infection-related organ dysfunctions necessitating organ support/replacement were included in the analysis. The primary end point was prevalence of coronavirus disease 2019-related sepsis among adults hospitalized in the ICU and the general ward. Among secondary end points were the need for ICU admission among patients initially hospitalized in the general ward and the prevalence of new onset of organ dysfunction in the ICU. Outcomes were expressed as proportions with respective 95% CI. Data Extraction: Two reviewers independently screened and reviewed existing literature and assessed study quality with the Newcastle-Ottawa Scale and the Methodological index for nonrandomized studies. Data Synthesis: Of 3,825 articles, 151 were analyzed, only five of which directly reported sepsis prevalence. Noting the high heterogeneity observed, coronavirus disease 2019-related sepsis prevalence was 77.9% (95% CI, 75.9-79.8; I-2 = 91%; 57 studies) in the ICU, and 33.3% (95% CI, 30.3-36.4; I-2 = 99%; 86 studies) in the general ward. ICU admission was required for 17.7% (95% CI, 12.9-23.6; I-2 = 100%) of ward patients. Acute respiratory distress syndrome was the most common organ dysfunction in the ICU (87.5%; 95% CI, 83.3-90.7; I-2 = 98%). CONCLUSIONS: The majority of coronavirus disease 2019 patients hospitalized in the ICU meet Sepsis-3 criteria and present infection-associated organ dysfunction. The medical and scientific community should be aware and systematically report viral sepsis for prognostic and treatment implications