Sepsis in the critically ill patient: current and emerging management strategies

References

• Singer M, Deutschman CS, Seymour CW, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016;315:801.
   PubMed Web of Science ®Google Scholar
• Freund Y, Lemachatti N, Krastinova E, et al. Prognostic accuracy of sepsis-3 criteria for in-hospital mortality among patients with suspected infection presenting to the emergency department. JAMA. 2017;317:301.
   PubMed Web of Science ®Google Scholar
• Rudd KE, Johnson SC, Agesa KM, et al. Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the global burden of disease study. Lancet. 2020;395:200–211.
   PubMed Web of Science ®Google Scholar
• Iwashyna TJ, Ely EW, Smith DM, et al. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA. 2010;304:1787.
   PubMed Web of Science ®Google Scholar
• Annane D, Sharshar T. Cognitive decline after sepsis. Lancet Respir Med. 2015;3:61–69.
   PubMed Web of Science ®Google Scholar
• WHA. Improving the prevention, diagnosis and clinical management of sepsis [Internet]. [cited 2020 Jun 19]. https://apps.who.int/gb/ebwha/pdf_files/WHA70/A70_R7-en.pdf?ua=1.
   Google Scholar
• Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34:1589–1596.
   PubMed Web of Science ®Google Scholar
• Ferrer R, Martin-Loeches I, Phillips G, et al. Empiric antibiotic treatment reduces mortality in severe sepsis and septic shock from the first hour: results from a guideline-based performance improvement program. Crit Care Med. 2014;42:1749–1755.
   PubMed Web of Science ®Google Scholar
• Seymour CW, Gesten F, Prescott HC, et al. Time to treatment and mortality during mandated emergency care for sepsis. N Engl J Med. 2017;376:2235–2244.
   PubMed Web of Science ®Google Scholar
• Kahn JM, Davis BS, Yabes JG, et al. Association between state-mandated protocolized sepsis care and in-hospital mortality among adults with sepsis. JAMA. 2019;322:240.
   PubMed Web of Science ®Google Scholar
• Alam N, Oskam E, Stassen PM, et al. Prehospital antibiotics in the ambulance for sepsis: a multicentre, open label, randomised trial. Lancet Respir Med. 2018;6:40–50.
   PubMed Web of Science ®Google Scholar
• Rhodes A, Evans LE, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med. 2017;43:304–377.
   PubMed Web of Science ®Google Scholar
• Levy MM, Evans LE, Rhodes A. The surviving sepsis campaign bundle: 2018 update. Crit Care Med. 2018;46:997–1000.
   PubMed Web of Science ®Google Scholar
• Kumar A, Ellis P, Arabi Y, et al. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock. Chest. 2009;136:1237–1248.
   PubMed Web of Science ®Google Scholar
• Zilberberg MD, Shorr AF, Micek ST, et al. Antimicrobial therapy escalation and hospital mortality among patients with health-care-associated Pneumonia. Chest. 2008;134:963–968.
   PubMed Web of Science ®Google Scholar
• Hranjec T, Rosenberger LH, Swenson B, et al. Aggressive versus conservative initiation of antimicrobial treatment in critically ill surgical patients with suspected intensive-care-unit-acquired infection: a quasi-experimental, before and after observational cohort study. Lancet Infect Dis. 2012;12:774–780.
   PubMed Web of Science ®Google Scholar
• Kumar A, Safdar N, Kethireddy S, et al. A survival benefit of combination antibiotic therapy for serious infections associated with sepsis and septic shock is contingent only on the risk of death: A meta-analytic/meta-regression study. Crit Care Med. 2010;38:1651–1664.
   PubMed Web of Science ®Google Scholar
• Kumar A, Zarychanski R, Light B, et al. Early combination antibiotic therapy yields improved survival compared with monotherapy in septic shock: a propensity-matched analysis. Crit Care Med. 2010;38:1773–1785.
   PubMed Web of Science ®Google Scholar
• Clerc O, Prod’hom G, Senn L, et al. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry and PCR-based rapid diagnosis of Staphylococcus aureus bacteraemia. Clin Microbiol Infect. 2014;20:355–360.
   PubMed Web of Science ®Google Scholar
• DIANA study group. De Bus L, Depuydt P, Steen J, et al. Antimicrobial de-escalation in the critically ill patient and assessment of clinical cure: the DIANA study. Intensive Care Med. 2020;46:1404–1417.
   PubMed Web of Science ®Google Scholar
• For the AZUREA Network Investigators. Leone M, Bechis C, Baumstarck K, et al. De-escalation versus continuation of empirical antimicrobial treatment in severe sepsis: a multicenter non-blinded randomized noninferiority trial. Intensive Care Med. 2014;40:1399.
   PubMedGoogle Scholar
• Vincent J-L, Sakr Y, Sprung CL, et al. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med. 2006;34:344–353.
   PubMed Web of Science ®Google Scholar
• Roberts JA, Lipman J. Antibacterial dosing in intensive care: pharmacokinetics, degree of disease and pharmacodynamics of sepsis. Clin Pharmacokinet. 2006;45:755–773.
   PubMed Web of Science ®Google Scholar
• Sawyer RG, Claridge JA, Nathens AB, et al. Trial of short-course antimicrobial therapy for intraabdominal infection. N Engl J Med. 2015;372:1996.
   PubMed Web of Science ®Google Scholar
• de Jong E, van Oers JA, Beishuizen A, et al. Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial. Lancet Infect Dis. 2016;16:819–827.
   PubMed Web of Science ®Google Scholar
• Wirz Y, Meier MA, Bouadma L, et al. Effect of procalcitonin-guided antibiotic treatment on clinical outcomes in intensive care unit patients with infection and sepsis patients: a patient-level meta-analysis of randomized trials. Crit Care. 2018;22:191.
   PubMed Web of Science ®Google Scholar
• Levy MM, Rhodes A, Phillips GS, et al. Surviving sepsis campaign: association between performance metrics and outcomes in a 7.5-year study. Crit Care Med. 2015;43:3–12.
   PubMed Web of Science ®Google Scholar
• Narayanan N, Gross AK, Pintens M, et al. Effect of an electronic medical record alert for severe sepsis among ED patients. Am J Emergency Med. 2016;34:185–188.
   PubMed Web of Science ®Google Scholar
• Guirgis FW, Jones L, Esma R, et al. Managing sepsis: electronic recognition, rapid response teams, and standardized care save lives. J Crit Care.. 2017;40:296.
   PubMed Web of Science ®Google Scholar
• Arabi YM, Al-Dorzi HM, Alamry A, et al. The impact of a multifaceted intervention including sepsis electronic alert system and sepsis response team on the outcomes of patients with sepsis and septic shock. Ann Intensive Care.. 2017;7:57.
   PubMed Web of Science ®Google Scholar
• Barbash IJ, Kahn JM. Sepsis quality in safety-net hospitals: an analysis of Medicare’s SEP-1 performance measure. J Crit Care. 2019;54:88–93.
   PubMed Web of Science ®Google Scholar
• Rhee C, Filbin MR, Massaro AF, et al. Compliance with the national SEP-1 quality measure and association with sepsis outcomes: a multicenter retrospective cohort study. Crit Care Med. 2018;46:1585–1591.
   PubMed Web of Science ®Google Scholar
• Wang J, Strich JR, Applefeld WN, et al. Driving blind: instituting SEP-1 without high quality outcomes data. J Thorac Dis. 2020;12:S22–S36.
   PubMed Web of Science ®Google Scholar
• Richard C. Early use of the pulmonary artery catheter and outcomes in patients with shock and acute respiratory distress syndromea randomized controlled trial. JAMA. 2003;290:2713.
   PubMed Web of Science ®Google Scholar
• Shah MR, Hasselblad V, Stevenson LW, et al. Impact of the pulmonary artery catheter in critically Ill patients: meta-analysis of randomized clinical trials. JAMA. 2005;294:1664.
   PubMed Web of Science ®Google Scholar
• Young P, Bailey M, Beasley R, et al. Effect of a buffered crystalloid solution vs saline on acute kidney injury among patients in the intensive care unit: the SPLIT randomized clinical trial. JAMA. 2015;314:1701.
   PubMed Web of Science ®Google Scholar
• Semler MW, Wanderer JP, Ehrenfeld JM, et al. Balanced crystalloids versus saline in the intensive care unit. The SALT randomized trial. Am J Respir Crit Care Med. 2017;195:1362–1372.
   PubMed Web of Science ®Google Scholar
• Malbrain MLNG, Langer T, Annane D, et al. Intravenous fluid therapy in the perioperative and critical care setting: executive summary of the international fluid academy (IFA). Ann Intensive Care. 2020;10:64.
   PubMed Web of Science ®Google Scholar
• Finfer S, Bellomo R, Boyce N, et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004;350:2247–2256.
   PubMed Web of Science ®Google Scholar
• The SAFE Study Investigators. Impact of albumin compared to saline on organ function and mortality of patients with severe sepsis. Intensive Care Med. 2011;37:86–96.
   PubMed Web of Science ®Google Scholar
• Caironi P, Tognoni G, Masson S, et al. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med. 2014;370:1412–1421.
   PubMed Web of Science ®Google Scholar
• Perner A, Haase N, Guttormsen AB, et al. Hydroxyethyl starch 130/0.42 versus ringer’s acetate in severe sepsis. N Engl J Med. 2012;367:124–134.
   PubMed Web of Science ®Google Scholar
• European Medicines Agency. Hydroxyethyl starch solutions: cMDh introduces new measures to protect patients [Internet]. 2018 [cited 2020 Jul 6]. https://www.ema.europa.eu/en/documents/referral/hydroxyethyl-starch-article-107i-referral-hydroxyethyl-starch-solutions-cmdh-introduces-new-measures_en.pdf
   Google Scholar
• Acheampong A, Vincent J-L. A positive fluid balance is an independent prognostic factor in patients with sepsis. Crit Care. 2015;19:251.
   PubMed Web of Science ®Google Scholar
• Brotfain E, Koyfman L, Toledano R, et al. Positive fluid balance as a major predictor of clinical outcome of patients with sepsis/septic shock after ICU discharge. Am J Emergency Med. 2016;34:2122–2126.
   PubMed Web of Science ®Google Scholar
• The CLASSIC Trial Group, The Scandinavian Critical Care Trials Group. Hjortrup PB, Haase N, Bundgaard H, et al. Restricting volumes of resuscitation fluid in adults with septic shock after initial management: the CLASSIC randomised, parallel-group, multicentre feasibility trial. Intensive Care Med. 2016;42:1695.
   PubMed Web of Science ®Google Scholar
• Permpikul C, Tongyoo S, Viarasilpa T, et al. Early use of norepinephrine in septic shock resuscitation (CENSER). A randomized trial. Am J Respir Crit Care Med. 2019;199:1097.
   PubMed Web of Science ®Google Scholar
• Annane D, Vignon P, Renault A, et al. Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial. Lancet. 2007;370:676–684.
   PubMed Web of Science ®Google Scholar
• Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358:877–887.
   PubMed Web of Science ®Google Scholar
• Gordon AC, Mason AJ, Thirunavukkarasu N, et al. Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock: the VANISH randomized clinical trial. JAMA. 2016;316:509.
   PubMed Web of Science ®Google Scholar
• Hernández G, Ospina-Tascón GA, Damiani LP, et al. Effect of a resuscitation strategy targeting peripheral perfusion status vs serum lactate levels on 28-day mortality among patients with septic shock: the ANDROMEDA-SHOCK randomized clinical trial. JAMA. 2019;321:654.
   PubMed Web of Science ®Google Scholar
• Asfar P, Meziani F, Hamel J-F, et al. High versus Low blood-pressure target in patients with septic shock. N Engl J Med. 2014;370:1583–1593.
   PubMed Web of Science ®Google Scholar
• Lamontagne F, Richards-Belle A, Thomas K, et al. Effect of reduced exposure to vasopressors on 90-day mortality in older critically Ill patients with vasodilatory hypotension: a randomized clinical trial. JAMA. 2020;323(10):938–949.
   PubMed Web of Science ®Google Scholar
• Heming N, Sivanandamoorthy S, Meng P, et al. Immune effects of corticosteroids in sepsis. Front Immunol. 2018;9:1736.
   PubMed Web of Science ®Google Scholar
• Annane D, Bellissant E, Bollaert PE, et al. Corticosteroids for treating sepsis in children and adults. Cochrane Database Syst Re. 2019;12:CD002243.
   PubMedGoogle Scholar
• Venkatesh B, Finfer S, Cohen J, et al. Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med. 2018;378:797–798.
   PubMed Web of Science ®Google Scholar
• Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone plus fludrocortisone for adults with septic shock. N Engl J Med. 2018;378:809–818.
   PubMed Web of Science ®Google Scholar
• Annane D. Why my steroid trials in septic shock were “positive”. Crit Care Med. 2019;47:1789–1793.
   PubMed Web of Science ®Google Scholar
• Venkatesh B, Cohen J. Why the adjunctive corticosteroid treatment in critically Ill patients with septic shock (ADRENAL) trial did not show a difference in mortality. Crit Care Med. 2019;47:1785–1788.
   PubMed Web of Science ®Google Scholar
• Jabre P, Combes X, Lapostolle F, et al. Etomidate versus ketamine for rapid sequence intubation in acutely ill patients: a multicentre randomised controlled trial. Lancet. 2009;374:293–300.
   PubMed Web of Science ®Google Scholar
• Gu W-J, Wang F, Tang L, et al. Single-dose etomidate does not increase mortality in patients with sepsis. Chest. 2015;147:335–346.
   PubMed Web of Science ®Google Scholar
• Lamontagne F, Rochwerg B, Lytvyn L, et al. Corticosteroid therapy for sepsis: a clinical practice guideline. BMJ. 2018;362:k3284.
   PubMedGoogle Scholar
• Bagshaw SM, Uchino S, Bellomo R, et al. Septic acute kidney injury in critically Ill patients: clinical characteristics and outcomes. Clin J Am Soc Nephrol. 2007;2:431–439.
   PubMed Web of Science ®Google Scholar
• Gaudry S, Hajage D, Schortgen F, et al. Initiation strategies for renal-replacement therapy in the intensive care unit. N Engl J Med. 2016;375:122–133.
   PubMed Web of Science ®Google Scholar
• The STARRT-AKI Investigators. Timing of initiation of renal-replacement therapy in acute kidney injury. N Engl J Med. 2020;383:240–251.
   PubMed Web of Science ®Google Scholar
• Barbar SD, Clere-Jehl R, Bourredjem A, et al. Timing of renal-replacement therapy in patients with acute kidney injury and sepsis. N Engl J Med. 2018;379:1431–1442.
   PubMed Web of Science ®Google Scholar
• Gaudry S, Hajage D, Benichou N, et al. Delayed versus early initiation of renal replacement therapy for severe acute kidney injury: a systematic review and individual patient data meta-analysis of randomised clinical trials. Lancet. 2018;395:1506–1515.
   Web of Science ®Google Scholar
• Jaber S, Paugam C, Futier E, et al. Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): a multicentre, open-label, randomised controlled, phase 3 trial. Lancet. 2018;392:31–40.
   PubMedGoogle Scholar
• Vinsonneau C, Camus C, Combes A, et al. Continuous venovenous haemodiafiltration versus intermittent haemodialysis for acute renal failure in patients with multiple-organ dysfunction syndrome: a multicentre randomised trial. Lancet. 2006;368:379–385.
   PubMed Web of Science ®Google Scholar
• Augustine JJ, Sandy D, Seifert TH, et al. A randomized controlled trial comparing intermittent with continuous dialysis in patients with ARF. Am J Kidney Dis.. 2004;44:1000–1007.
   PubMed Web of Science ®Google Scholar
• Mehta RL, Mcdonald B, Gabbai FB, et al. A randomized clinical trial of continuous versus intermittent dialysis for acute renal failure. Kidney Int. 2001;60:1154–1163.
   PubMed Web of Science ®Google Scholar
• Wernerman J, Christopher KB, Annane D, et al. Metabolic support in the critically ill: a consensus of 19. Crit Care. 2019;23:318.
   PubMed Web of Science ®Google Scholar
• McClave SA, Taylor BE, Martindale RG, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically Ill patient: society of critical care medicine (SCCM) and American society for parenteral and enteral nutrition (A. S.P.E.N.). J Parenter Enter Nutr. 2016;40:159.
   PubMed Web of Science ®Google Scholar
• Singer P, Blaser AR, Berger MM, et al. ESPEN guideline on clinical nutrition in the intensive care unit. Clin Nutr. 2019;38:48–79.
   PubMed Web of Science ®Google Scholar
• Harvey SE, Parrott F, Harrison DA, et al. Trial of the route of early nutritional support in critically Ill adults. N Engl J Med. 2014;371:1673–1684.
   PubMed Web of Science ®Google Scholar
• Reignier J, Boisramé-Helms J, Brisard L, et al. Enteral versus parenteral early nutrition in ventilated adults with shock: a randomised, controlled, multicentre, open-label, parallel-group study (NUTRIREA-2. Lancet. 2018;391:133–143.
   PubMed Web of Science ®Google Scholar
• Reignier J, Mercier E, Le Gouge A, et al. Effect of Not Monitoring Residual Gastric Volume on Risk of Ventilator-Associated Pneumonia in Adults Receiving Mechanical Ventilation and Early Enteral Feeding: A Randomized Controlled Trial. JAMA. 2013;309:249.
   PubMed Web of Science ®Google Scholar
• Lewis K, Alqahtani Z, Mcintyre L, et al. The efficacy and safety of prokinetic agents in critically ill patients receiving enteral nutrition: a systematic review and meta-analysis of randomized trials. Crit Care. 2016;20:259.
   PubMed Web of Science ®Google Scholar
• on behalf of the CGAO-REA Study Group. Kalfon P, Le Manach Y, Ichai C, et al. Severe and multiple hypoglycemic episodes are associated with increased risk of death in ICU patients. Crit Care. 2015;19:153.
   PubMed Web of Science ®Google Scholar
• Krinsley JS. Glycemic variability: A strong independent predictor of mortality in critically ill patients. Crit Care Med. 2008;36:3008–3013.
   PubMed Web of Science ®Google Scholar
• The NICE-SUGAR Study Investigators. Hypoglycemia and risk of death in critically Ill patients. N Engl J Med. 2012;367:1108–1118.
   PubMed Web of Science ®Google Scholar
• The ARDS Definition Task Force. Acute respiratory distress syndrome: the berlin definition. JAMA. 2012;307(23):2526–2533.
   PubMed Web of Science ®Google Scholar
• The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342:1301–1308.
   PubMed Web of Science ®Google Scholar
• Amato MBP, Meade MO, Slutsky AS, et al. Driving pressure and survival in the acute respiratory distress syndrome. N Engl J Med. 2015;372:747.
   PubMed Web of Science ®Google Scholar
• Papazian L, Forel J-M, Gacouin A, et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010;363:1107–1116.
   PubMed Web of Science ®Google Scholar
• The National Heart, Lung, and Blood Institute PETAL Clinical Trials Network. Early neuromuscular blockade in the acute respiratory distress syndrome. N Engl J Med. 1997–08;380:2019.
   Google Scholar
• Guérin C, Reignier J, Richard J-C, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013;368:2159–2168.
   PubMed Web of Science ®Google Scholar
• The National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006;354:2564–2575.
   PubMed Web of Science ®Google Scholar
• Jacob ST, Crozier I, Fischer WA, et al. Ebola virus disease. Nat Rev Dis Primer. 2020;6:13.
   PubMed Web of Science ®Google Scholar
• Guan W, Ni Z, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382:1708–1720.
   PubMed Web of Science ®Google Scholar
• Johns Hopkins University. OVID-19 dashboard by the center for systems science and engineering (CSSE) at Johns Hopkins university (JHU) [Internet]. 2020. [cited 2020 Sep 30]. Available from: https://coronavirus.jhu.edu/map.html
   Google Scholar
• Chen G, Wu D, Guo W, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020;130:2620–2629.
   PubMed Web of Science ®Google Scholar
• Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497.
   PubMed Web of Science ®Google Scholar
• Dequin P-F, Heming N, Meziani F, et al. Effect of hydrocortisone on 21-day mortality or respiratory support among critically Ill patients with COVID-19: a randomized clinical trial. JAMA. 2020;324(13):1298.
   PubMed Web of Science ®Google Scholar
• The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Sterne JAC, Murthy S, Diaz JV, et al. Association between administration of systemic corticosteroids and mortality among critically Ill patients with COVID-19: a meta-analysis. JAMA. 2020;324(13):1330–1341.
   PubMed Web of Science ®Google Scholar
• The RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with Covid-19 — preliminary report. N Engl J Med. 2020;NEJMoa2021436. DOI:10.1056/NEJMoa2021436
   Web of Science ®Google Scholar
• Siemieniuk RA, Bartoszko JJ, Ge L, et al. Drug treatments for covid-19: living systematic review and network meta-analysis. BMJ. 2020;m2980. DOI:10.1136/bmj.m2980
   PubMedGoogle Scholar
• Lamontagne F, Agoritsas T, Macdonald H, et al. A living WHO guideline on drugs for covid-19. BMJ. 2020;m3379.
   PubMedGoogle Scholar
• Marshall JC. Why have clinical trials in sepsis failed? Trends Mol Med. 2014;20(4):195–203.
   PubMed Web of Science ®Google Scholar
• Sweeney TE, Khatri P. Generalizable biomarkers in critical care: toward precision medicine. Crit Care Med. 2017;45:934–939.
   PubMed Web of Science ®Google Scholar
• Fohner AE, Greene JD, Lawson BL, et al. Assessing clinical heterogeneity in sepsis through treatment patterns and machine learning. J Am Med Inform Assoc. 2019;26:1466–1477.
   PubMed Web of Science ®Google Scholar
• Seymour CW, Kennedy JN, Wang S, et al. Derivation, validation, and potential treatment implications of novel clinical phenotypes for sepsis. JAMA. 2019;321:2003.
   PubMed Web of Science ®Google Scholar
• Badawi O, Liu X, Hassan E, et al. Evaluation of ICU risk models adapted for use as continuous markers of severity of illness throughout the ICU stay. Crit Care Med. 2018;46:361–367.
   PubMed Web of Science ®Google Scholar
• Antcliffe DB, Burnham KL, Al-Beidh F, et al. Transcriptomic signatures in sepsis and a differential response to steroids. from the VANISH randomized trial. Am J Respir Crit Care Med. 2019;199:980–986.
   PubMed Web of Science ®Google Scholar
• Scicluna BP, van Vught LA, Zwinderman AH, et al. Classification of patients with sepsis according to blood genomic endotype: a prospective cohort study. Lancet Respir Med. 2017;5:816–826.
   PubMed Web of Science ®Google Scholar
• Wong HR, Lindsell CJ, Pettilä V, et al. A multibiomarker-based outcome risk stratification model for adult septic shock. Crit Care Med. 2014;42:781–789.
   PubMed Web of Science ®Google Scholar
• Eisfeld AJ, Halfmann PJ, Wendler JP, et al. Multi-platform ’omics analysis of human ebola virus disease pathogenesis. Cell Host Microbe. 2017;22:817–829.e8.
   PubMed Web of Science ®Google Scholar
• Reddy K, Sinha P, O’Kane CM, et al. Subphenotypes in critical care: translation into clinical practice. Lancet Respir Med. 2020;8:631–643.
   PubMed Web of Science ®Google Scholar
• Dybowski R, Gant V, Weller P, et al. Prediction of outcome in critically ill patients using artificial neural network synthesised by genetic algorithm. Lancet. 1996;347:1146–1150.
   PubMed Web of Science ®Google Scholar
• Henry KE, Hager DN, Pronovost PJ, et al. A targeted real-time early warning score (TREWScore) for septic shock. Sci Transl Med. 2015;7:299ra122–299ra122.
   PubMed Web of Science ®Google Scholar
• Komorowski M, Celi LA, Badawi O, et al. The artificial intelligence clinician learns optimal treatment strategies for sepsis in intensive care. Nat Med. 2018;24:1716–1720.
   PubMed Web of Science ®Google Scholar
• Rossignol DP, Lynn M. Antagonism of in vivo and ex vivo response to endotoxin by E5564, a synthetic lipid A analogue. J Endotoxin Res. 2002;8:483–488.
   PubMedGoogle Scholar
• Beutler B, Milsark IW, Cerami AC. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science. 1985;229:869–871.
   PubMed Web of Science ®Google Scholar
• Abraham E, Wunderink R, Silverman H, et al. Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter clinical trial. TNF-alpha MAb Sepsis Study Group. JAMA. 1995;273:934–941.
   PubMed Web of Science ®Google Scholar
• Fisher CJ, Agosti JM, Opal SM, et al. Treatment of septic shock with the tumor necrosis factor receptor:fc fusion protein. N Engl J Med. 1996;334:1697.
   PubMed Web of Science ®Google Scholar
• Qiu P, Cui X, Sun J, et al. Antitumor necrosis factor therapy is associated with improved survival in clinical sepsis trials: a meta-analysis. Crit Care Med. 2013;41:2419–2429.
   PubMed Web of Science ®Google Scholar
• Arend WP, Malyak M, Guthridge CJ, et al. Interleukin-1 receptor antagonist: role in biology. Annu Rev Immunol. 1998;16:27–55.
   PubMed Web of Science ®Google Scholar
• Hotchkiss RS, Moldawer LL, Opal SM, et al. Sepsis and septic shock. Nat Rev Dis Primer. 2016;2:16045.
   PubMed Web of Science ®Google Scholar
• Fisher CJ, Dhainaut JF, Opal SM, et al. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group. JAMA. 1994;271:1836–1843.
   PubMed Web of Science ®Google Scholar
• Opal SM, Fisher CJ, Dhainaut J-FA, et al. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, doubleblind, placebo-controlled, multicenter trial. Crit Care Med. 1997;25:1115–1124.
   PubMed Web of Science ®Google Scholar
• Shakoory B, Carcillo JA, Chatham WW, et al. Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior phase III trial. Crit Care Med. 2016;44:275–281.
   PubMed Web of Science ®Google Scholar
• Hotchkiss RS, Monneret G, Payen D. Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis. 2013;13:260–268.
   PubMed Web of Science ®Google Scholar
• Unsinger J, McGlynn M, Kasten KR, et al. IL-7 promotes T cell viability, trafficking, and functionality and improves survival in sepsis. J Immunol. 2010;184:3768–3779.
   PubMed Web of Science ®Google Scholar
• Shindo Y, Fuchs AG, Davis CG, et al. Interleukin 7 immunotherapy improves host immunity and survival in a two-hit model of Pseudomonas aeruginosa pneumonia. J Leukoc Biol. 2017;101:543–554.
   PubMed Web of Science ®Google Scholar
• Francois B, Jeannet R, Daix T, et al. Interleukin-7 restores lymphocytes in septic shock: the IRIS-7 randomized clinical trial. JCI Insight. 2018;3:e98960.
   PubMed Web of Science ®Google Scholar
• Hotchkiss RS, Colston E, Yende S, et al. Immune checkpoint inhibition in sepsis: a phase 1b randomized, placebo-controlled, single ascending dose study of antiprogrammed cell death-ligand 1 antibody (BMS-936559). Crit Care Med. 2019;47:632–642.
   PubMed Web of Science ®Google Scholar
• Stolk RF, van der Poll T, Angus DC, et al. Potentially Inadvertent Immunomodulation: norepinephrine use in sepsis. Am J Respir Crit Care Med. 2016;194:550–558.
   PubMed Web of Science ®Google Scholar
• Stolk R, van der Pasch E, Naumann F, et al. Norepinephrine dysregulates the immune response and compromises host defense during sepsis. Am J Respir Crit Care Med. 2020;202(6):830–842.
   PubMed Web of Science ®Google Scholar
• Kakihana Y, Nishida O, Taniguchi T, et al. Efficacy and safety of landiolol, an ultra-short-acting β1-selective antagonist, for treatment of sepsis-related tachyarrhythmia (J-Land 3S): a multicentre, open-label, randomised controlled trial. Lancet Respir Med. 2020;8(9):863–872.
   PubMed Web of Science ®Google Scholar
• de Montmollin E, Aboab J, Mansart A, et al. Bench-to-bedside review: β-Adrenergic modulation in sepsis. Crit Care. 2009;13:230.
   PubMed Web of Science ®Google Scholar
• Borovikova LV, Ivanova S, Zhang M, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405:458–462.
   PubMed Web of Science ®Google Scholar
• Tracey KJ. Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest. 2007;117:289–296.
   PubMed Web of Science ®Google Scholar
• Deutschman CS, Tracey KJ. Sepsis: current dogma and new perspectives. Immunity. 2014;40:463–475.
   PubMed Web of Science ®Google Scholar
• Poulakou G, Lagou S, Karageorgopoulos DE, et al. New treatments of multidrug-resistant Gram-negative ventilator-associated pneumonia. Ann Transl Med. 2018;6:423.
   PubMed Web of Science ®Google Scholar
• Theuretzbacher U, Bush K, Harbarth S, et al. Critical analysis of antibacterial agents in clinical development. Nat Rev Microbiol. 2020;18:286–298.
   PubMed Web of Science ®Google Scholar
• Nair GB, Niederman MS. Updates on community acquired pneumonia management in the ICU. Pharmacol Ther. 2020;107663.
   Google Scholar
• Bassetti M, Righi E, Russo A, et al. New antibiotics for Pneumonia. Clin Chest Med. 2018;39:853–869.
   PubMed Web of Science ®Google Scholar