Surviving sepsis campaign: research priorities for sepsis and septic shock

Intensive Care Medicine

Volumn 44, Issue 9, 2018, Pages 1400-1426

  Coopersmith, Craig M ^a   De Backer, Daniel ^b   Deutschman, Clifford S ^c,d   Ferrer, Ricard ^e,f   Lat, Ishaq ^g   Machado, Flavia R ^h   Martin, Greg S ^a   Martin Loeches, Ignacio ⁱ   Nunnally, Mark E ^j   Antonelli, Massimo ^k   Evans, Laura E ^j   Hellman, Judith ^l   Jog, Sameer ^m   Kesecioglu, Jozef ⁿ   Levy, Mitchell M ^o   Rhodes, Andrew ^p  

^a EMORY UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b UNIVERSITÉ LIBRE DE BRUXELLES   (Belgium)

^c Northwell Health   (United States)

^d FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH   (United States)

^e HOSPITAL UNIVERSITARI VALL D HEBRON   (Spain)

^f HOSPITAL UNIVERSITARI VALL D HEBRON   (Spain)

^g RUSH UNIVERSITY MEDICAL CENTER   (United States)

^h FEDERAL UNIVERSITY OF SÃO PAULO   (Brazil)

ⁱ ST JAMES S HOSPITAL   (Ireland)

^j NEW YORK UNIVERSITY SCHOOL OF MEDICINE   (United States)

^k CATHOLIC UNIVERSITY   (Italy)

^l UNIVERSITY OF CALIFORNIA   (United States)

^m DEENANATH MANGESHKAR HOSPITAL   (India)

ⁿ UNIVERSITY MEDICAL CENTER UTRECHT   (Netherlands)

^o BROWN UNIVERSITY   (United States)

^p ST GEORGE'S UNIVERSITY HOSPITALS NHS FOUNDATION TRUST   (United Kingdom)

more..

Author keywords

Priorities; Research; Sepsis; Septic shock; Surviving Sepsis Campaign

Indexed keywords

ANTIBIOTIC AGENT; ANTIVIRUS AGENT; HYPERTENSIVE FACTOR; ANTIINFECTIVE AGENT; VASOCONSTRICTOR AGENT;

ARTICLE; CLINICAL OUTCOME; CLINICAL PRACTICE; DIAGNOSTIC TEST; FLUID INTAKE; HEALTH CARE ORGANIZATION; HUMAN; MEDICAL RESEARCH; RESUSCITATION; SEPSIS; SEPTIC SHOCK; TELECONFERENCE; ARTIFICIAL VENTILATION; COMPLICATION; CONSENSUS DEVELOPMENT; DIAGNOSIS; DISEASE PREDISPOSITION; DRUG COMBINATION; EARLY DIAGNOSIS; ENERGY METABOLISM; FLUID THERAPY; HEALTH CARE DELIVERY; HEMOFILTRATION; IMMUNOLOGICAL TOLERANCE; MICROFLORA; MORTALITY; NUTRITIONAL SUPPORT; PERSONALIZED MEDICINE; PHYSIOLOGY; PLASMAPHERESIS; POINT OF CARE TESTING; PRACTICE GUIDELINE; PROCEDURES; RESEARCH; RISK ASSESSMENT; TREATMENT OUTCOME;

ANTI-BACTERIAL AGENTS; ANTIVIRAL AGENTS; DELIVERY OF HEALTH CARE; DISEASE SUSCEPTIBILITY; DRUG COMBINATIONS; EARLY DIAGNOSIS; ENERGY METABOLISM; FLUID THERAPY; HEMOFILTRATION; HUMANS; IMMUNE TOLERANCE; MICROBIOTA; NUTRITIONAL SUPPORT; PLASMAPHERESIS; POINT-OF-CARE TESTING; PRACTICE GUIDELINES AS TOPIC; PRECISION MEDICINE; RESEARCH; RESPIRATION, ARTIFICIAL; RESUSCITATION; RISK ASSESSMENT; SEPSIS; SHOCK, SEPTIC; TREATMENT OUTCOME; VASOCONSTRICTOR AGENTS;

EID: 85049573184     PISSN: 03424642     EISSN: 14321238     Source Type: Journal    
DOI: 10.1007/s00134-018-5175-z     Document Type: Article

References (237)

1. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC (2016) The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 315:801–810. 10.1001/jama.2016.0287
2. Fleischmann C, Scherag A, Adhikari NK, Hartog CS, Tsaganos T, Schlattmann P, Angus DC, Reinhart K (2016) Assessment of global incidence and mortality of hospital-treated sepsis. Current estimates and limitations. Am J Respir Crit Care Med 193:259–272. 10.1164/rccm.201504-0781OC
3. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, Rochwerg B, Rubenfeld GD, Angus DC, Annane D, Beale RJ, Bellinghan GJ, Bernard GR, Chiche JD, Coopersmith C, De Backer DP, French CJ, Fujishima S, Gerlach H, Hidalgo JL, Hollenberg SM, Jones AE, Karnad DR, Kleinpell RM, Koh Y, Lisboa TC, Machado FR, Marini JJ, Marshall JC, Mazuski JE, McIntyre LA, McLean AS, Mehta S, Moreno RP, Myburgh J, Navalesi P, Nishida O, Osborn TM, Perner A, Plunkett CM, Ranieri M, Schorr CA, Seckel MA, Seymour CW, Shieh L, Shukri KA, Simpson SQ, Singer M, Thompson BT, Townsend SR, van der Poll T, Vincent JL, Wiersinga WJ, Zimmerman JL, Dellinger RP (2017) Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Crit Care Med 45:486–552. 10.1097/CCM.0000000000002255
4. Levy MM, Rhodes A, Phillips GS, Townsend SR, Schorr CA, Beale R, Osborn T, Lemeshow S, Chiche JD, Artigas A, Dellinger RP (2015) Surviving sepsis campaign: association between performance metrics and outcomes in a 7.5-year study. Crit Care Med 43:3–12. 10.1097/CCM.0000000000000723
5. Levy MM, Dellinger RP, Townsend SR, Linde-Zwirble WT, Marshall JC, Bion J, Schorr C, Artigas A, Ramsay G, Beale R, Parker MM, Gerlach H, Reinhart K, Silva E, Harvey M, Regan S, Angus DC (2010) The surviving sepsis campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Crit Care Med 38:367–374. 10.1097/CCM.0b013e3181cb0cdc
6. Seymour CW, Gesten F, Prescott HC, Friedrich ME, Iwashyna TJ, Phillips GS, Lemeshow S, Osborn T, Terry KM, Levy MM (2017) Time to treatment and mortality during mandated emergency care for sepsis. N Engl J Med 376:2235–2244. 10.1056/NEJMoa1703058
7. 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 (2006) Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 34:1589–1596. 10.1097/01.CCM.0000217961.75225.E9
8. Kumar A, Safdar N, Kethireddy S, Chateau D (2010) 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 38:1651–1664. 10.1097/CCM.0b013e3181e96b91
9. Kumar A, Zarychanski R, Light B, Parrillo J, Maki D, Simon D, Laporta D, Lapinsky S, Ellis P, Mirzanejad Y, Martinka G, Keenan S, Wood G, Arabi Y, Feinstein D, Kumar A, Dodek P, Kravetsky L, Doucette S (2010) Early combination antibiotic therapy yields improved survival compared with monotherapy in septic shock: a propensity-matched analysis. Crit Care Med 38:1773–1785. 10.1097/CCM.0b013e3181eb3ccd
10. Brunkhorst FM, Oppert M, Marx G, Bloos F, Ludewig K, Putensen C, Nierhaus A, Jaschinski U, Meier-Hellmann A, Weyland A, Grundling M, Moerer O, Riessen R, Seibel A, Ragaller M, Buchler MW, John S, Bach F, Spies C, Reill L, Fritz H, Kiehntopf M, Kuhnt E, Bogatsch H, Engel C, Loeffler M, Kollef MH, Reinhart K, Welte T (2012) Effect of empirical treatment with moxifloxacin and meropenem vs meropenem on sepsis-related organ dysfunction in patients with severe sepsis: a randomized trial. JAMA 307:2390–2399. 10.1001/jama.2012.5833
11. Sjovall F, Perner A, Hylander MM (2017) Empirical mono- versus combination antibiotic therapy in adult intensive care patients with severe sepsis—a systematic review with meta-analysis and trial sequential analysis. J Infect 74:331–344. 10.1016/j.jinf.2016.11.013
12. Paul M, Lador A, Grozinsky-Glasberg S, Leibovici L (2014) Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis. Cochrane Database Syst Rev. 10.1002/14651858.cd003344.pub3
13. Ong DSY, Frencken JF, Klein Klouwenberg PMC, Juffermans N, van der Poll T, Bonten MJM, Cremer OL (2017) Short-course adjunctive gentamicin as empirical therapy in patients with severe sepsis and septic shock: a prospective observational cohort study. Clin Infect Dis 64:1731–1736. 10.1093/cid/cix186
14. Klompas M (2017) Monotherapy is adequate for septic shock due to gram-negative organisms. Crit Care Med 45:1930–1932. 10.1097/CCM.0000000000002678
15. Kalil AC (2017) Antibiotic combination therapy for patients with gram-negative septic shock. Crit Care Med 45:1933–1936. 10.1097/CCM.0000000000002677
16. Diaz-Martin A, Martinez-Gonzalez ML, Ferrer R, Ortiz-Leyba C, Piacentini E, Lopez-Pueyo MJ, Martin-Loeches I, Levy MM, Artigas A, Garnacho-Montero J (2012) Antibiotic prescription patterns in the empiric therapy of severe sepsis: combination of antimicrobials with different mechanisms of action reduces mortality. Crit Care 16:R223. 10.1186/cc11869
17. Al-Hasan MN, Wilson JW, Lahr BD, Thomsen KM, Eckel-Passow JE, Vetter EA, Tleyjeh IM, Baddour LM (2009) Beta-lactam and fluoroquinolone combination antibiotic therapy for bacteremia caused by gram-negative bacilli. Antimicrob Agents Chemother 53:1386–1394. 10.1128/AAC.01231-08
18. Delannoy PY, Boussekey N, Devos P, Alfandari S, Turbelin C, Chiche A, Meybeck A, Georges H, Leroy O (2012) Impact of combination therapy with aminoglycosides on the outcome of ICU-acquired bacteraemias. Eur J Clin Microbiol Infect Dis 31:2293–2299. 10.1007/s10096-012-1568-z
19. Martin-Loeches I, Lisboa T, Rodriguez A, Putensen C, Annane D, Garnacho-Montero J, Restrepo MI, Rello J (2010) Combination antibiotic therapy with macrolides improves survival in intubated patients with community-acquired pneumonia. Intensive Care Med 36:612–620. 10.1007/s00134-009-1730-y
20. Micek ST, Welch EC, Khan J, Pervez M, Doherty JA, Reichley RM, Kollef MH (2010) Empiric combination antibiotic therapy is associated with improved outcome against sepsis due to Gram-negative bacteria: a retrospective analysis. Antimicrob Agents Chemother 54:1742–1748. 10.1128/AAC.01365-09
21. Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB, Napolitano LM, O’Grady NP, Bartlett JG, Carratala J, El Solh AA, Ewig S, Fey PD, File TM Jr, Restrepo MI, Roberts JA, Waterer GW, Cruse P, Knight SL, Brozek JL (2016) Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the infectious diseases Society of America and the American Thoracic Society. Clin Infect Dis 63:e61–e111. 10.1093/cid/ciw353
22. Perner A, Rhodes A, Venkatesh B, Angus DC, Martin-Loeches I, Preiser JC, Vincent JL, Marshall J, Reinhart K, Joannidis M, Opal SM (2017) Sepsis: frontiers in supportive care, organisation and research. Intensive Care Med 43:496–508. 10.1007/s00134-017-4677-4
23. Martin-Loeches I, Perner A (2016) Focus on infection and sepsis in intensive care patients. Intensive Care Med 42:491–493. 10.1007/s00134-016-4234-6
24. Roberts JA, Abdul-Aziz MH, Davis JS, Dulhunty JM, Cotta MO, Myburgh J, Bellomo R, Lipman J (2016) Continuous versus Intermittent beta-lactam infusion in severe sepsis. A meta-analysis of individual patient data from randomized trials. Am J Respir Crit Care Med 194:681–691. 10.1164/rccm.201601-0024OC
25. Abdul-Aziz MH, Sulaiman H, Mat-Nor MB, Rai V, Wong KK, Hasan MS, Abd Rahman AN, Jamal JA, Wallis SC, Lipman J, Staatz CE, Roberts JA (2016) Beta-Lactam Infusion in Severe Sepsis (BLISS): a prospective, two-centre, open-labelled randomised controlled trial of continuous versus intermittent beta-lactam infusion in critically ill patients with severe sepsis. Intensive Care Med 42:1535–1545. 10.1007/s00134-015-4188-0
26. Ferrer R, Martin-Loeches I, Phillips G, Osborn TM, Townsend S, Dellinger RP, Artigas A, Schorr C, Levy MM (2014) 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 42:1749–1755. 10.1097/CCM.0000000000000330
27. Boomer JS, To K, Chang KC, Takasu O, Osborne DF, Walton AH, Bricker TL, Jarman SD, Kreisel D, Krupnick AS, Srivastava A, Swanson PE, Green JM, Hotchkiss RS (2011) Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA 306:2594–2605. 10.1001/jama.2011.1829
28. Hotchkiss RS, Coopersmith CM, McDunn JE, Ferguson TA (2009) The sepsis seesaw: tilting toward immunosuppression. Nat Med 15:496–497. 10.1038/nm0509-496
29. Griffiths P, Baraniak I, Reeves M (2015) The pathogenesis of human cytomegalovirus. J Pathol 235:288–297. 10.1002/path.4437
30. Caston JJ, Cantisan S, Gonzalez-Gasca F, Paez-Vega A, Abdel-Hadi H, Illescas S, Alonso G, Torre-Cisneros J (2016) Interferon-gamma production by CMV-specific CD8+ T lymphocytes provides protection against cytomegalovirus reactivation in critically ill patients. Intensive Care Med 42:46–53. 10.1007/s00134-015-4077-6
31. Papazian L, Hraiech S, Lehingue S, Roch A, Chiche L, Wiramus S, Forel JM (2016) Cytomegalovirus reactivation in ICU patients. Intensive Care Med 42:28–37. 10.1007/s00134-015-4066-9
32. Walton AH, Muenzer JT, Rasche D, Boomer JS, Sato B, Brownstein BH, Pachot A, Brooks TL, Deych E, Shannon WD, Green JM, Storch GA, Hotchkiss RS (2014) Reactivation of multiple viruses in patients with sepsis. PLoS ONE 9:e98819. 10.1371/journal.pone.0098819
33. Osawa R, Singh N (2009) Cytomegalovirus infection in critically ill patients: a systematic review. Crit Care 13:R68. 10.1186/cc7875
34. Kalil AC, Florescu DF (2009) Prevalence and mortality associated with cytomegalovirus infection in nonimmunosuppressed patients in the intensive care unit. Crit Care Med 37:2350–2358. 10.1097/CCM.0b013e3181a3aa43
35. Limaye AP, Stapleton RD, Peng L, Gunn SR, Kimball LE, Hyzy R, Exline MC, Files DC, Morris PE, Frankel SK, Mikkelsen ME, Hite D, Enfield KB, Steingrub J, O’Brien J, Parsons PE, Cuschieri J, Wunderink RG, Hotchkin DL, Chen YQ, Rubenfeld GD, Boeckh M (2017) Effect of ganciclovir on IL-6 levels among cytomegalovirus-seropositive adults with critical illness: a randomized clinical trial. JAMA 318:731–740. 10.1001/jama.2017.10569
36. Cowley NJ, Owen A, Shiels SC, Millar J, Woolley R, Ives N, Osman H, Moss P, Bion JF (2017) Safety and efficacy of antiviral therapy for prevention of cytomegalovirus reactivation in immunocompetent critically ill patients: a randomized clinical trial. JAMA Intern Med 177:774–783. 10.1001/jamainternmed.2017.0895
37. Martin-Loeches I, Forster R, Prina-Mello A (2017) Intensive care medicine in 2050: nanotechnology. Emerging technologies and approaches and their impact on critical care. Intensive Care Med. 10.1007/s00134-017-5002-y
38. Huang AM, Newton D, Kunapuli A, Gandhi TN, Washer LL, Isip J, Collins CD, Nagel JL (2013) Impact of rapid organism identification via matrix-assisted laser desorption/ionization time-of-flight combined with antimicrobial stewardship team intervention in adult patients with bacteremia and candidemia. Clin Infect Dis 57:1237–1245. 10.1093/cid/cit498
39. Zilahi G, Artigas A, Martin-Loeches I (2016) What’s new in multidrug-resistant pathogens in the ICU? Ann Intensive Care 6:96. 10.1186/s13613-016-0199-4
40. Timbrook TT, Morton JB, McConeghy KW, Caffrey AR, Mylonakis E, LaPlante KL (2017) The effect of molecular rapid diagnostic testing on clinical outcomes in bloodstream infections: a systematic review and meta-analysis. Clin Infect Dis 64:15–23. 10.1093/cid/ciw649
41. Stevenson M, Pandor A, Martyn-St JM, Rafia R, Uttley L, Stevens J, Sanderson J, Wong R, Perkins GD, McMullan R, Dark P (2016) Sepsis: the LightCycler SeptiFast Test MGRADE(R), SepsiTest and IRIDICA BAC BSI assay for rapidly identifying bloodstream bacteria and fungi—a systematic review and economic evaluation. Health Technol Assess 20:1–246. 10.3310/hta20460
42. Vincent JL, Brealey D, Libert N, Abidi NE, O’Dwyer M, Zacharowski K, Mikaszewska-Sokolewicz M, Schrenzel J, Simon F, Wilks M, Picard-Maureau M, Chalfin DB, Ecker DJ, Sampath R, Singer M (2015) Rapid diagnosis of infection in the critically ill, a multicenter study of molecular detection in bloodstream infections, pneumonia, and sterile site infections. Crit Care Med 43:2283–2291. 10.1097/CCM.0000000000001249
43. Makristathis A, Riss S, Hirschl AM (2014) A novel fluorescence in situ hybridization test for rapid pathogen identification in positive blood cultures. Clin Microbiol Infect 20:O760–O763. 10.1111/1469-0691.12561
44. Tissari P, Zumla A, Tarkka E, Mero S, Savolainen L, Vaara M, Aittakorpi A, Laakso S, Lindfors M, Piiparinen H, Maki M, Carder C, Huggett J, Gant V (2010) Accurate and rapid identification of bacterial species from positive blood cultures with a DNA-based microarray platform: an observational study. Lancet 375:224–230. 10.1016/S0140-6736(09)61569-5
45. Delport JA, Strikwerda A, Armstrong A, Schaus D, John M (2016) Quality of care is improved by rapid short incubation MALDI-ToF identification from blood cultures as measured by reduced length of stay and patient outcomes as part of a multi-disciplinary approach to bacteremia in pediatric patients. PLoS ONE 11:e0160618. 10.1371/journal.pone.0160618
46. Cecconi M, De BD, Antonelli M, Beale R, Bakker J, Hofer C, Jaeschke R, Mebazaa A, Pinsky MR, Teboul JL, Vincent JL, Rhodes A (2014) Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine. Intensive Care Med 40:1795–1815. 10.1007/s00134-014-3525-z
47. Leisman DE, Doerfler ME, Ward MF, Masick KD, Wie BJ, Gribben JL, Hamilton E, Klein Z, Bianculli AR, Akerman MB, D’Angelo JK, D’Amore JA (2017) Survival benefit and cost savings from compliance with a simplified 3-hour sepsis bundle in a series of prospective, multisite, observational cohorts. Crit Care Med 45:395–406. 10.1097/CCM.0000000000002184
48. Kalil AC, Johnson DW, Lisco SJ, Sun J (2017) Early goal-directed therapy for sepsis: a novel solution for discordant survival outcomes in clinical trials. Crit Care Med 45:607–614. 10.1097/CCM.0000000000002235
49. Andrews B, Semler MW, Muchemwa L, Kelly P, Lakhi S, Heimburger DC, Mabula C, Bwalya M, Bernard GR (2017) Effect of an early resuscitation protocol on in-hospital mortality among adults with sepsis and hypotension: a randomized clinical trial. JAMA 318:1233–1240. 10.1001/jama.2017.10913
50. Gattinoni L, Brazzi L, Pelosi P, Latini R, Tognoni G, Pesenti A, Fumagalli R (1995) A trial of goal-oriented hemodynamic therapy in critically ill patients. SvO2 Collaborative Group. N Engl J Med 333:1025–1032
51. Walley KR (2011) Use of central venous oxygen saturation to guide therapy. Am J Respir Crit Care Med 184:514–520. 10.1164/rccm.201010-1584CI
52. Cecconi M, Hofer C, Teboul JL, Pettila V, Wilkman E, Molnar Z, Della RG, Aldecoa C, Artigas A, Jog S, Sander M, Spies C, Lefrant JY, De BD (2015) Fluid challenges in intensive care: the FENICE study: a global inception cohort study. Intensive Care Med 41:1529–1537. 10.1007/s00134-015-3850-x
53. Osman D, Ridel C, Ray P, Monnet X, Anguel N, Richard C, Teboul JL (2007) Cardiac filling pressures are not appropriate to predict hemodynamic response to volume challenge. Crit Care Med 35:64–68. 10.1097/01.CCM.0000249851.94101.4F
54. Marik PE, Cavallazzi R, Vasu T, Hirani A (2009) Dynamic changes in arterial waveform derived variables and fluid responsiveness in mechanically ventilated patients: a systematic review of the literature. Crit Care Med 37:2642–2647. 10.1097/CCM.0b013e3181a590da
55. Monnet X, Teboul JL (2015) Passive leg raising: five rules, not a drop of fluid! Crit Care 19:18. 10.1186/s13054-014-0708-5
56. Chen C, Kollef MH (2015) Targeted fluid minimization following initial resuscitation in septic shock: a pilot study. Chest 148:1462–1469. 10.1378/chest.15-1525
57. Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R (2004) A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 350:2247–2256
58. Caironi P, Tognoni G, Masson S, Fumagalli R, Pesenti A, Romero M, Fanizza C, Caspani L, Faenza S, Grasselli G, Iapichino G, Antonelli M, Parrini V, Fiore G, Latini R, Gattinoni L (2014) Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med 370:1412–1421. 10.1056/NEJMoa1305727
59. Vincent JL, De BD, Wiedermann CJ (2016) Fluid management in sepsis: the potential beneficial effects of albumin. J Crit Care 35:161–167. 10.1016/j.jcrc.2016.04.019
60. Reinhart K, Perner A, Sprung CL, Jaeschke R, Schortgen F, Johan Groeneveld AB, Beale R, Hartog CS (2012) Consensus statement of the ESICM task force on colloid volume therapy in critically ill patients. Intensive Care Med 38:368–383. 10.1007/s00134-012-2472-9
61. Annane D, Siami S, Jaber S, Martin C, Elatrous S, Declere AD, Preiser JC, Outin H, Troche G, Charpentier C, Trouillet JL, Kimmoun A, Forceville X, Darmon M, Lesur O, Reignier J, Abroug F, Berger P, Clec’h C, Cousson J, Thibault L, Chevret S (2013) Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock: the CRISTAL randomized trial. JAMA 310:1809–1817. 10.1001/jama.2013.280502
62. Perner A, Haase N, Guttormsen AB, Tenhunen J, Klemenzson G, Aneman A, Madsen KR, Moller MH, Elkjaer JM, Poulsen LM, Bendtsen A, Winding R, Steensen M, Berezowicz P, Soe-Jensen P, Bestle M, Strand K, Wiis J, White JO, Thornberg KJ, Quist L, Nielsen J, Andersen LH, Holst LB, Thormar K, Kjaeldgaard AL, Fabritius ML, Mondrup F, Pott FC, Moller TP, Winkel P, Wetterslev J (2012) Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med 367:124–134. 10.1056/NEJMoa1204242
63. Schortgen F, Lacherade JC, Bruneel F, Cattaneo I, Hemery F, Lemaire F, Brochard L (2001) Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study. Lancet 357:911–916. 10.1016/S0140-6736(00)04211-2
64. Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, Moerer O, Gruendling M, Oppert M, Grond S, Olthoff D, Jaschinski U, John S, Rossaint R, Welte T, Schaefer M, Kern P, Kuhnt E, Kiehntopf M, Hartog C, Natanson C, Loeffler M, Reinhart K (2008) Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 358:125–139
65. Myburgh JA, Finfer S, Bellomo R, Billot L, Cass A, Gattas D, Glass P, Lipman J, Liu B, McArthur C, McGuinness S, Rajbhandari D, Taylor CB, Webb SA (2012) Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med 367:1901–1911. 10.1056/NEJMoa1209759
66. Yunos NM, Bellomo R, Hegarty C, Story D, Ho L, Bailey M (2012) Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA 308:1566–1572. 10.1001/jama.2012.13356
67. Raghunathan K, Bonavia A, Nathanson BH, Beadles CA, Shaw AD, Brookhart MA, Miller TE, Lindenauer PK (2015) Association between initial fluid choice and subsequent in-hospital mortality during the resuscitation of adults with septic shock. Anesthesiology 123:1385–1393. 10.1097/ALN.0000000000000861
68. Duburcq T, Favory R, Mathieu D, Hubert T, Mangalaboyi J, Gmyr V, Quintane L, Maboudou P, Pattou F, Jourdain M (2014) Hypertonic sodium lactate improves fluid balance and hemodynamics in porcine endotoxic shock. Crit Care 18:467. 10.1186/s13054-014-0467-3
69. Young P, Bailey M, Beasley R, Henderson S, Mackle D, McArthur C, McGuinness S, Mehrtens J, Myburgh J, Psirides A, Reddy S, Bellomo R (2015) 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 314:1701–1710. 10.1001/jama.2015.12334
70. Semler MW, Self WH, Wanderer JP, Ehrenfeld JM, Wang L, Byrne DW, Stollings JL, Kumar AB, Hughes CG, Hernandez A, Guillamondegui OD, May AK, Weavind L, Casey JD, Siew ED, Shaw AD, Bernard GR, Rice TW (2018) Balanced crystalloids versus saline in critically ill adults. N Engl J Med 378:829–839. 10.1056/NEJMoa1711584
71. Self WH, Semler MW, Wanderer JP, Wang L, Byrne DW, Collins SP, Slovis CM, Lindsell CJ, Ehrenfeld JM, Siew ED, Shaw AD, Bernard GR, Rice TW (2018) Balanced crystalloids versus saline in noncritically ill adults. N Engl J Med 378:819–828. 10.1056/NEJMoa1711586
72. De BD, Biston P, Devriendt J, Madl C, Chochrad D, Aldecoa C, Brasseur A, Defrance P, Gottignies P, Vincent JL (2010) Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med 362:779–789. 10.1056/NEJMoa0907118
73. Russell JA, Walley KR, Singer J, Gordon AC, Hebert PC, Cooper DJ, Holmes CL, Mehta S, Granton JT, Storms MM, Cook DJ, Presneill JJ, Ayers D (2008) Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 358:877–887. 10.1056/NEJMoa067373
74. Gordon AC, Mason AJ, Thirunavukkarasu N, Perkins GD, Cecconi M, Cepkova M, Pogson DG, Aya HD, Anjum A, Frazier GJ, Santhakumaran S, Ashby D, Brett SJ (2016) Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock: the VANISH randomized clinical trial. JAMA 316:509–518. 10.1001/jama.2016.10485
75. Khanna A, English SW, Wang XS, Ham K, Tumlin J, Szerlip H, Busse LW, Altaweel L, Albertson TE, Mackey C, McCurdy MT, Boldt DW, Chock S, Young PJ, Krell K, Wunderink RG, Ostermann M, Murugan R, Gong MN, Panwar R, Hastbacka J, Favory R, Venkatesh B, Thompson BT, Bellomo R, Jensen J, Kroll S, Chawla LS, Tidmarsh GF, Deane AM (2017) Angiotensin II for the treatment of vasodilatory shock. N Engl J Med 377:419–430. 10.1056/NEJMoa1704154
76. Lopez A, Lorente JA, Steingrub J, Bakker J, McLuckie A, Willatts S, Brockway M, Anzueto A, Holzapfel L, Breen D, Silverman MS, Takala J, Donaldson J, Arneson C, Grove G, Grossman S, Grover R (2004) Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock. Crit Care Med 32:21–30. 10.1097/01.CCM.0000105581.01815.C6
77. Asfar P, Meziani F, Hamel JF, Grelon F, Megarbane B, Anguel N, Mira JP, Dequin PF, Gergaud S, Weiss N, Legay F, Le TY, Conrad M, Robert R, Gonzalez F, Guitton C, Tamion F, Tonnelier JM, Guezennec P, Van Der Linden T, Vieillard-Baron A, Mariotte E, Pradel G, Lesieur O, Ricard JD, Herve F, du Cheyron D, Guerin C, Mercat A, Teboul JL, Radermacher P (2014) High versus low blood-pressure target in patients with septic shock. N Engl J Med 370:1583–1593. 10.1056/NEJMoa1312173
78. Davenport EE, Burnham KL, Radhakrishnan J, Humburg P, Hutton P, Mills TC, Rautanen A, Gordon AC, Garrard C, Hill AV, Hinds CJ, Knight JC (2016) Genomic landscape of the individual host response and outcomes in sepsis: a prospective cohort study. Lancet Respir Med 4:259–271. 10.1016/S2213-2600(16)00046-1
79. Rautanen A, Mills TC, Gordon AC, Hutton P, Steffens M, Nuamah R, Chiche JD, Parks T, Chapman SJ, Davenport EE, Elliott KS, Bion J, Lichtner P, Meitinger T, Wienker TF, Caulfield MJ, Mein C, Bloos F, Bobek I, Cotogni P, Sramek V, Sarapuu S, Kobilay M, Ranieri VM, Rello J, Sirgo G, Weiss YG, Russwurm S, Schneider EM, Reinhart K, Holloway PA, Knight JC, Garrard CS, Russell JA, Walley KR, Stuber F, Hill AV, Hinds CJ (2015) Genome-wide association study of survival from sepsis due to pneumonia: an observational cohort study. Lancet Respir Med 3:53–60. 10.1016/S2213-2600(14)70290-5
80. Henry KE, Hager DN, Pronovost PJ, Saria S (2015) A targeted real-time early warning score (TREWScore) for septic shock. Sci Transl Med 7:299ra122. 10.1126/scitranslmed.aab3719
81. Christaki E, Giamarellos-Bourboulis EJ (2014) The beginning of personalized medicine in sepsis: small steps to a bright future. Clin Genet 86:56–61. 10.1111/cge.12368
82. da Pinheiro SF, Cesar Machado MC (2015) Personalized medicine for sepsis. Am J Med Sci 350:409–413. 10.1097/MAJ.0000000000000558
83. Wong HR, Cvijanovich NZ, Anas N, Allen GL, Thomas NJ, Bigham MT, Weiss SL, Fitzgerald J, Checchia PA, Meyer K, Shanley TP, Quasney M, Hall M, Gedeit R, Freishtat RJ, Nowak J, Shekhar RS, Gertz S, Dawson E, Howard K, Harmon K, Beckman E, Frank E, Lindsell CJ (2015) Developing a clinically feasible personalized medicine approach to pediatric septic shock. Am J Respir Crit Care Med 191:309–315. 10.1164/rccm.201410-1864OC
84. Panacek EA, Marshall JC, Albertson TE, Johnson DH, Johnson S, MacArthur RD, Miller M, Barchuk WT, Fischkoff S, Kaul M, Teoh L, Van Meter L, Daum L, Lemeshow S, Hicklin G, Doig C (2004) Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab’)2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels. Crit Care Med 32:2173–2182
85. Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, Capellier G, Cohen Y, Azoulay E, Troche G, Chaumet-Riffaut P, Bellissant E (2002) Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 288:862–871
86. Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, Weiss YG, Benbenishty J, Kalenka A, Forst H, Laterre PF, Reinhart K, Cuthbertson BH, Payen D, Briegel J (2008) Hydrocortisone therapy for patients with septic shock. N Engl J Med 358:111–124
87. Gordon AC, Perkins GD, Singer M, McAuley DF, Orme RM, Santhakumaran S, Mason AJ, Cross M, Al-Beidh F, Best-Lane J, Brealey D, Nutt CL, McNamee JJ, Reschreiter H, Breen A, Liu KD, Ashby D (2016) Levosimendan for the prevention of acute organ dysfunction in sepsis. N Engl J Med 375:1638–1648. 10.1056/NEJMoa1609409
88. Zhou F, Peng Z, Murugan R, Kellum JA (2013) Blood purification and mortality in sepsis: a meta-analysis of randomized trials. Crit Care Med 41:2209–2220. 10.1097/CCM.0b013e31828cf412
89. Safety and efficacy of polymyxin B hemoperfusion (PMX) for septic shock (EUPHRATES). PrFont34Bin0BinSub0Frac0Def1Margin0Margin0Jc1Indent1440Lim0Lim1. https://clinicaltrials.gov/ct2/show/NCT01046669
90. Gomes F, Schuetz P, Bounoure L, Austin P, Ballesteros-Pomar M, Cederholm T, Fletcher J, Laviano A, Norman K, Poulia KA, Ravasco P, Schneider SM, Stanga Z, Weekes CE, Bischoff SC (2017) ESPEN guidelines on nutritional support for polymorbid internal medicine patients. Clin Nutr. 10.1016/j.clnu.2017.06.025
91. Casaer MP, Van den Berghe G (2014) Nutrition in the acute phase of critical illness. N Engl J Med 370:1227–1236. 10.1056/NEJMra1304623
92. Arabi YM, Aldawood AS, Haddad SH, Al-Dorzi HM, Tamim HM, Jones G, Mehta S, McIntyre L, Solaiman O, Sakkijha MH, Sadat M, Afesh L (2015) Permissive underfeeding or standard enteral feeding in critically ill adults. N Engl J Med 372:2398–2408. 10.1056/NEJMoa1502826
93. Rice TW, Wheeler AP, Thompson BT, Steingrub J, Hite RD, Moss M, Morris A, Dong N, Rock P (2012) Initial trophic vs full enteral feeding in patients with acute lung injury: the EDEN randomized trial. JAMA 307:795–803. 10.1001/jama.2012.137
94. Taylor BE, McClave SA, Martindale RG, Warren MM, Johnson DR, Braunschweig C, McCarthy MS, Davanos E, Rice TW, Cresci GA, Gervasio JM, Sacks GS, Roberts PR, Compher C (2016) 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.). Crit Care Med 44:390–438. 10.1097/CCM.0000000000001525
95. Reignier J, Boisrame-Helms J, Brisard L, Lascarrou JB, Ait HA, Anguel N, Argaud L, Asehnoune K, Asfar P, Bellec F, Botoc V, Bretagnol A, Bui HN, Canet E, Da SD, Darmon M, Das V, Devaquet J, Djibre M, Ganster F, Garrouste-Org Gaudry S, Gontier O, Guerin C, Guidet B, Guitton C, Herbrecht JE, Lacherade JC, Letocart P, Martino F, Maxime V, Mercier E, Mira JP, Nseir S, Piton G, Quenot JP, Richecoeur J, Rigaud JP, Robert R, Rolin N, Schwebel C, Sirodot M, Tinturier F, Thevenin D, Giraudeau B, Le GA (2017) Enteral versus parenteral early nutrition in ventilated adults with shock: a randomised, controlled, multicentre, open-label, parallel-group study (NUTRIREA-2). Lancet. 10.1016/S0140-6736(17)32146-3
96. Patel JJ, Kozeniecki M, Biesboer A, Peppard W, Ray AS, Thomas S, Jacobs ER, Nanchal R, Kumar G (2016) Early trophic enteral nutrition is associated with improved outcomes in mechanically ventilated patients with septic shock: a retrospective review. J Intensive Care Med 31:471–477. 10.1177/0885066614554887
97. Rice TW, Wheeler AP, Thompson BT, deBoisblanc BP, Steingrub J, Rock P (2011) Enteral omega-3 fatty acid, gamma-linolenic acid, and antioxidant supplementation in acute lung injury. JAMA 306:1574–1581. 10.1001/jama.2011.1435
98. Pontes-Arruda A, Martins LF, de Lima SM, Isola AM, Toledo D, Rezende E, Maia M, Magnan GB (2011) Enteral nutrition with eicosapentaenoic acid, gamma-linolenic acid and antioxidants in the early treatment of sepsis: results from a multicenter, prospective, randomized, double-blinded, controlled study: the INTERSEPT study. Crit Care 15:R144. 10.1186/cc10267
99. The Acute Respiratory Distress Syndrome Network (2000) 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 342:1301–1308
100. Cavalcanti AB, Suzumura EA, Laranjeira LN, Paisani DM, Damiani LP, Guimaraes HP, Romano ER, Regenga MM, Taniguchi LNT, Teixeira C, de Pinheiro OR, Machado FR, Diaz-Quijano FA, Filho MSA, Maia IS, Caser EB, Filho WO, Borges MC, Martins PA, Matsui M, Ospina-Tascon GA, Giancursi TS, Giraldo-Ramirez ND, Vieira SRR, Assef MDGP, Hasan MS, Szczeklik W, Rios F, Amato MBP, Berwanger O, Ribeiro de Carvalho CR (2017) Effect of lung recruitment and titrated positive end-expiratory pressure (PEEP) vs low PEEP on mortality in patients with acute respiratory distress syndrome: a randomized clinical trial. JAMA 318:1335–1345. 10.1001/jama.2017.14171
101. Gajic O, Dara SI, Mendez JL, Adesanya AO, Festic E, Caples SM, Rana R, St Sauver JL, Lymp JF, Afessa B, Hubmayr RD (2004) Ventilator-associated lung injury in patients without acute lung injury at the onset of mechanical ventilation. Crit Care Med 32:1817–1824 (pii:00003246-200409000-00001)
102. Serpa NA, Simonis FD, Barbas CS, Biehl M, Determann RM, Elmer J, Friedman G, Gajic O, Goldstein JN, Horn J, Juffermans NP, Linko R, de Oliveira RP, Sundar S, Talmor D, Wolthuis EK, de Abreu MG, Pelosi P, Schultz MJ (2014) Association between tidal volume size, duration of ventilation, and sedation needs in patients without acute respiratory distress syndrome: an individual patient data meta-analysis. Intensive Care Med 40:950–957. 10.1007/s00134-014-3318-4
103. Serpa NA, Cardoso SO, Manetta JA, Pereira VG, Esposito DC, Pasqualucci MO, Damasceno MC, Schultz MJ (2012) Association between use of lung-protective ventilation with lower tidal volumes and clinical outcomes among patients without acute respiratory distress syndrome: a meta-analysis. JAMA 308:1651–1659. 10.1001/jama.2012.13730
104. Futier E, Constantin JM, Paugam-Burtz C, Pascal J, Eurin M, Neuschwander A, Marret E, Beaussier M, Gutton C, Lefrant JY, Allaouchiche B, Verzilli D, Leone M, De JA, Bazin JE, Pereira B, Jaber S (2013) A trial of intraoperative low-tidal-volume ventilation in abdominal surgery. N Engl J Med 369:428–437. 10.1056/NEJMoa1301082
105. Simonis FD, Binnekade JM, Braber A, Gelissen HP, Heidt J, Horn J, Innemee G, de Jonge E, Juffermans NP, Spronk PE, Steuten LM, Tuinman PR, Vriends M, de Vreede G, de Wilde RB, Serpa NA, Gama de Abreu M, Pelosi P, Schultz MJ (2015) PReVENT—protective ventilation in patients without ARDS at start of ventilation: study protocol for a randomized controlled trial. Trials 16:226. 10.1186/s13063-015-0759-1
106. Seymour CW, Liu VX, Iwashyna TJ, Brunkhorst FM, Rea TD, Scherag A, Rubenfeld G, Kahn JM, Shankar-Hari M, Singer M, Deutschman CS, Escobar GJ, Angus DC (2016) Assessment of clinical criteria for sepsis: for the third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 315:762–774. 10.1001/jama.2016.0288
107. Shankar-Hari M, Phillips GS, Levy ML, Seymour CW, Liu VX, Deutschman CS, Angus DC, Rubenfeld GD, Singer M (2016) Developing a new definition and assessing new clinical criteria for septic shock: for the third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 315:775–787. 10.1001/jama.2016.0289
108. Ferreira FL, Bota DP, Bross A, Melot C, Vincent JL (2001) Serial evaluation of the SOFA score to predict outcome in critically ill patients. JAMA 286:1754–1758 (pii:jce00056)
109. Besen BAMP, Romano TG, Nassar AP Jr, Taniguchi LU, Azevedo LCP, Mendes PV, Zampieri FG, Park M (2016) Sepsis-3 definitions predict ICU mortality in a low-middle-income country. Ann Intensive Care 6:107. 10.1186/s13613-016-0204-y
110. Huson MAM, Katete C, Chunda L, Ngoma J, Wallrauch C, Heller T, van der Poll T, Grobusch MP (2017) Application of the qSOFA score to predict mortality in patients with suspected infection in a resource-limited setting in Malawi. Infection 45:893–896. 10.1007/s15010-017-1057-5
111. Huson MA, Kalkman R, Grobusch MP, van der Poll T (2017) Predictive value of the qSOFA score in patients with suspected infection in a resource limited setting in Gabon. Travel Med Infect Dis 15:76–77. 10.1016/j.tmaid.2016.10.014
112. Freund Y, Lemachatti N, Krastinova E, Van LM, Claessens YE, Avondo A, Occelli C, Feral-Pierssens AL, Truchot J, Ortega M, Carneiro B, Pernet J, Claret PG, Dami F, Bloom B, Riou B, Beaune S (2017) Prognostic accuracy of Sepsis-3 criteria for in-hospital mortality among patients with suspected infection presenting to the emergency department. JAMA 317:301–308. 10.1001/jama.2016.20329
113. Williams JM, Greenslade JH, McKenzie JV, Chu K, Brown AFT, Lipman J (2017) Systemic inflammatory response syndrome, quick sequential organ function assessment, and organ dysfunction: insights from a prospective database of ED patients with infection. Chest 151:586–596. 10.1016/j.chest.2016.10.057
114. Angus DC, Seymour CW, Coopersmith CM, Deutschman CS, Klompas M, Levy MM, Martin GS, Osborn TM, Rhee C, Watson RS (2016) A framework for the development and interpretation of different sepsis definitions and clinical criteria. Crit Care Med 44:e113–e121. 10.1097/CCM.0000000000001730
115. Raith EP, Udy AA, Bailey M, McGloughlin S, MacIsaac C, Bellomo R, Pilcher DV (2017) Prognostic accuracy of the SOFA score, SIRS criteria, and qSOFA score for in-hospital mortality among adults with suspected infection admitted to the intensive care unit. JAMA 317:290–300. 10.1001/jama.2016.20328
116. Forward E, Konecny P, Burston J, Adhikari S, Doolan H, Jensen T (2017) Predictive validity of the qSOFA criteria for sepsis in non-ICU inpatients. Intensive Care Med 43:945–946. 10.1007/s00134-017-4776-2
117. Finkelsztein EJ, Jones DS, Ma KC, Pabon MA, Delgado T, Nakahira K, Arbo JE, Berlin DA, Schenck EJ, Choi AM, Siempos II (2017) Comparison of qSOFA and SIRS for predicting adverse outcomes of patients with suspicion of sepsis outside the intensive care unit. Crit Care 21:73. 10.1186/s13054-017-1658-5
118. Levy MM, Artigas A, Phillips GS, Rhodes A, Beale R, Osborn T, Vincent JL, Townsend S, Lemeshow S, Dellinger RP (2012) Outcomes of the Surviving Sepsis Campaign in intensive care units in the USA and Europe: a prospective cohort study. Lancet Infect Dis 12:919–924. 10.1016/S1473-3099(12)70239-6
119. Miller RR III, Dong L, Nelson NC, Brown SM, Kuttler KG, Probst DR, Allen TL, Clemmer TP (2013) Multicenter implementation of a severe sepsis and septic shock treatment bundle. Am J Respir Crit Care Med 188:77–82. 10.1164/rccm.201212-2199OC
120. Rhodes A, Phillips G, Beale R, Cecconi M, Chiche JD, De BD, Divatia J, Du B, Evans L, Ferrer R, Girardis M, Koulenti D, Machado F, Simpson SQ, Tan CC, Wittebole X, Levy M (2015) The Surviving Sepsis Campaign bundles and outcome: results from the International Multicentre Prevalence Study on Sepsis (the IMPreSS study). Intensive Care Med 41:1620–1628. 10.1007/s00134-015-3906-y
121. Noritomi DT, Ranzani OT, Monteiro MB, Ferreira EM, Santos SR, Leibel F, Machado FR (2014) Implementation of a multifaceted sepsis education program in an emerging country setting: clinical outcomes and cost-effectiveness in a long-term follow-up study. Intensive Care Med 40:182–191. 10.1007/s00134-013-3131-5
122. Polito CC, Isakov A, Yancey AH, Wilson DK, Anderson BA, Bloom I, Martin GS, Sevransky JE (2015) Prehospital recognition of severe sepsis: development and validation of a novel EMS screening tool. Am J Emerg Med 33:1119–1125. 10.1016/j.ajem.2015.04.024
123. Seymour CW, Rea TD, Kahn JM, Walkey AJ, Yealy DM, Angus DC (2012) Severe sepsis in pre-hospital emergency care: analysis of incidence, care, and outcome. Am J Respir Crit Care Med 186:1264–1271. 10.1164/rccm.201204-0713OC
124. Esper AM, Martin GS (2011) The impact of comorbid conditions on critical illness. Crit Care Med 39:2728–2735. 10.1097/CCM.0b013e318236f27e
125. Esper AM, Moss M, Martin GS (2009) The effect of diabetes mellitus on organ dysfunction with sepsis: an epidemiological study. Crit Care 13:R18. 10.1186/cc7717
126. Danai PA, Moss M, Mannino DM, Martin GS (2006) The epidemiology of sepsis in patients with malignancy. Chest 129:1432–1440
127. Soto GJ, Martin GS, Gong MN (2013) Healthcare disparities in critical illness. Crit Care Med 41:2784–2793. 10.1097/CCM.0b013e3182a84a43
128. Beck MK, Jensen AB, Nielsen AB, Perner A, Moseley PL, Brunak S (2016) Diagnosis trajectories of prior multi-morbidity predict sepsis mortality. Sci Rep 6:36624. 10.1038/srep36624
129. Soares M, Caruso P, Silva E, Teles JM, Lobo SM, Friedman G, Dal PF, Mello PV, Bozza FA, Silva UV, Torelly AP, Knibel MF, Rezende E, Netto JJ, Piras C, Castro A, Ferreira BS, Rea-Neto A, Olmedo PB, Salluh JI (2010) Characteristics and outcomes of patients with cancer requiring admission to intensive care units: a prospective multicenter study. Crit Care Med 38:9–15. 10.1097/CCM.0b013e3181c0349e
130. Torres VB, Azevedo LC, Silva UV, Caruso P, Torelly AP, Silva E, Carvalho FB, Vianna A, Souza PC, Godoy MM, Azevedo JR, Spector N, Bozza FA, Salluh JI, Soares M (2015) Sepsis-associated outcomes in critically ill patients with malignancies. Ann Am Thorac Soc. 10.1513/AnnalsATS.201501-046OC
131. Rhee C, Dantes R, Epstein L, Murphy DJ, Seymour CW, Iwashyna TJ, Kadri SS, Angus DC, Danner RL, Fiore AE, Jernigan JA, Martin GS, Septimus E, Warren DK, Karcz A, Chan C, Menchaca JT, Wang R, Gruber S, Klompas M (2017) Incidence and trends of sepsis in US hospitals using clinical vs claims data, 2009–2014. JAMA 318:1241–1249. 10.1001/jama.2017.13836
132. Martin GS, Mannino DM, Eaton S, Moss M (2003) The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 348:1546–1554
133. Gaieski DF, Edwards JM, Kallan MJ, Carr BG (2013) Benchmarking the incidence and mortality of severe sepsis in the United States. Crit Care Med 41:1167–1174. 10.1097/CCM.0b013e31827c09f8
134. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR (2001) Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 29:1303–1310
135. Sweeney TE, Wong HR (2016) Risk stratification and prognosis in sepsis: what have we learned from microarrays? Clin Chest Med 37:209–218. 10.1016/j.ccm.2016.01.003
136. Ventetuolo CE, Levy MM (2008) Biomarkers: diagnosis and risk assessment in sepsis. Clin Chest Med 29:591–603, vii. 10.1016/j.ccm.2008.07.001
137. Vincent JL, Beumier M (2013) Diagnostic and prognostic markers in sepsis. Expert Rev Anti Infect Ther 11:265–275. 10.1586/eri.13.9
138. Quartin AA, Schein RM, Kett DH, Peduzzi PN (1997) Magnitude and duration of the effect of sepsis on survival. Department of Veterans Affairs Systemic Sepsis Cooperative Studies Group. JAMA 277:1058–1063
139. Linder A, Guh D, Boyd JH, Walley KR, Anis AH, Russell JA (2014) Long-term (10-year) mortality of younger previously healthy patients with severe sepsis/septic shock is worse than that of patients with nonseptic critical illness and of the general population. Crit Care Med 42:2211–2218. 10.1097/CCM.0000000000000503
140. Shankar-Hari M, Ambler M, Mahalingasivam V, Jones A, Rowan K, Rubenfeld GD (2016) Evidence for a causal link between sepsis and long-term mortality: a systematic review of epidemiologic studies. Crit Care 20:101. 10.1186/s13054-016-1276-7
141. Prescott HC, Osterholzer JJ, Langa KM, Angus DC, Iwashyna TJ (2016) Late mortality after sepsis: propensity matched cohort study. BMJ 353:i2375
142. Ou SM, Chu H, Chao PW, Lee YJ, Kuo SC, Chen TJ, Tseng CM, Shih CJ, Chen YT (2016) Long-term mortality and major adverse cardiovascular events in sepsis survivors. a nationwide population-based study. Am J Respir Crit Care Med 194:209–217. 10.1164/rccm.201510-2023OC
143. Prescott HC, Langa KM, Iwashyna TJ (2015) Readmission diagnoses after hospitalization for severe sepsis and other acute medical conditions. JAMA 313:1055–1057. 10.1001/jama.2015.1410
144. Norman BC, Cooke CR, Ely EW, Graves JA (2017) Sepsis-associated 30-day risk-standardized readmissions: analysis of a nationwide medicare sample. Crit Care Med 45:1130–1137. 10.1097/CCM.0000000000002476
145. Goodwin AJ, Rice DA, Simpson KN, Ford DW (2015) Frequency, cost, and risk factors of readmissions among severe sepsis survivors. Crit Care Med 43:738–746. 10.1097/CCM.0000000000000859
146. Needham DM, Davidson J, Cohen H, Hopkins RO, Weinert C, Wunsch H, Zawistowski C, Bemis-Dougherty A, Berney SC, Bienvenu OJ, Brady SL, Brodsky MB, Denehy L, Elliott D, Flatley C, Harabin AL, Jones C, Louis D, Meltzer W, Muldoon SR, Palmer JB, Perme C, Robinson M, Schmidt DM, Scruth E, Spill GR, Storey CP, Render M, Votto J, Harvey MA (2012) Improving long-term outcomes after discharge from intensive care unit: report from a stakeholders’ conference. Crit Care Med 40:502–509. 10.1097/CCM.0b013e318232da75
147. Shah FA, Pike F, Alvarez K, Angus D, Newman AB, Lopez O, Tate J, Kapur V, Wilsdon A, Krishnan JA, Hansel N, Au D, Avdalovic M, Fan VS, Barr RG, Yende S (2013) Bidirectional relationship between cognitive function and pneumonia. Am J Respir Crit Care Med 188:586–592. 10.1164/rccm.201212-2154OC
148. Iwashyna TJ, Ely EW, Smith DM, Langa KM (2010) Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA 304:1787–1794. 10.1001/jama.2010.1553
149. Wunsch H, Christiansen CF, Johansen MB, Olsen M, Ali N, Angus DC, Sorensen HT (2014) Psychiatric diagnoses and psychoactive medication use among nonsurgical critically ill patients receiving mechanical ventilation. JAMA 311:1133–1142. 10.1001/jama.2014.2137
150. Davydow DS, Hough CL, Langa KM, Iwashyna TJ (2013) Symptoms of depression in survivors of severe sepsis: a prospective cohort study of older Americans. Am J Geriatr Psychiatry 21:887–897. 10.1097/JGP.0b013e31825c0aed
151. Wintermann GB, Brunkhorst FM, Petrowski K, Strauss B, Oehmichen F, Pohl M, Rosendahl J (2015) Stress disorders following prolonged critical illness in survivors of severe sepsis. Crit Care Med 43:1213–1222. 10.1097/CCM.0000000000000936
152. Rosendahl J, Brunkhorst FM, Jaenichen D, Strauss B (2013) Physical and mental health in patients and spouses after intensive care of severe sepsis: a dyadic perspective on long-term sequelae testing the Actor–Partner Interdependence Model. Crit Care Med 41:69–75. 10.1097/CCM.0b013e31826766b0
153. Jaenichen D, Brunkhorst FM, Strauss B, Rosendahl J (2012) Physical and mental long-term sequelae following intensive care of severe sepsis in patients and relatives. Psychother Psychosom Med Psychol 62:335–343. 10.1055/s-0032-1306354
154. Boer KR, van Ruler O, van Emmerik AA, Sprangers MA, de Rooij SE, Vroom MB, de Borgie CA, Boermeester MA, Reitsma JB (2008) Factors associated with posttraumatic stress symptoms in a prospective cohort of patients after abdominal sepsis: a nomogram. Intensive Care Med 34:664–674. 10.1007/s00134-007-0941-3
155. Winters BD, Eberlein M, Leung J, Needham DM, Pronovost PJ, Sevransky JE (2010) Long-term mortality and quality of life in sepsis: a systematic review. Crit Care Med 38:1276–1283. 10.1097/CCM.0b013e3181d8cc1d
156. Nesseler N, Defontaine A, Launey Y, Morcet J, Malledant Y, Seguin P (2013) Long-term mortality and quality of life after septic shock: a follow-up observational study. Intensive Care Med 39:881–888. 10.1007/s00134-013-2815-1
157. Cuthbertson BH, Elders A, Hall S, Taylor J, Maclennan G, Mackirdy F, Mackenzie SJ (2013) Mortality and quality of life in the five years after severe sepsis. Crit Care 17:R70. 10.1186/cc12616
158. Yende S, Austin S, Rhodes A, Finfer S, Opal S, Thompson T, Bozza FA, LaRosa SP, Ranieri VM, Angus DC (2016) Long-term quality of life among survivors of severe sepsis: analyses of two international trials. Crit Care Med 44:1461–1467. 10.1097/CCM.0000000000001658
159. Cavassani KA, Carson WF, Moreira AP, Wen H, Schaller MA, Ishii M, Lindell DM, Dou Y, Lukacs NW, Keshamouni VG, Hogaboam CM, Kunkel SL (2010) The post sepsis-induced expansion and enhanced function of regulatory T cells create an environment to potentiate tumor growth. Blood 115:4403–4411. 10.1182/blood-2009-09-241083
160. Yende S, Linde-Zwirble W, Mayr F, Weissfeld LA, Reis S, Angus DC (2014) Risk of cardiovascular events in survivors of severe sepsis. Am J Respir Crit Care Med 189:1065–1074. 10.1164/rccm.201307-1321OC
161. Shih CJ, Chao PW, Ou SM, Chen YT (2017) Long-term risk of cardiovascular events in patients with chronic kidney disease who have survived sepsis: a nationwide cohort study. J Am Heart Assoc. 10.1161/JAHA.116.004613
162. Delano MJ, Ward PA (2016) The immune system’s role in sepsis progression, resolution, and long-term outcome. Immunol Rev 274:330–353. 10.1111/imr.12499
163. Yende S, D’Angelo G, Kellum JA, Weissfeld L, Fine J, Welch RD, Kong L, Carter M, Angus DC (2008) Inflammatory markers at hospital discharge predict subsequent mortality after pneumonia and sepsis. Am J Respir Crit Care Med 177:1242–1247. 10.1164/rccm.200712-1777OC
164. Bagshaw SM, Uchino S, Bellomo R, Morimatsu H, Morgera S, Schetz M, Tan I, Bouman C, Macedo E, Gibney N, Tolwani A, Oudemans-van Straaten HM, Ronco C, Kellum JA (2007) Septic acute kidney injury in critically ill patients: clinical characteristics and outcomes. Clin J Am Soc Nephrol 2:431–439. 10.2215/CJN.03681106
165. Kitsios GD, Morowitz MJ, Dickson RP, Huffnagle GB, McVerry BJ, Morris A (2017) Dysbiosis in the intensive care unit: microbiome science coming to the bedside. J Crit Care 38:84–91. 10.1016/j.jcrc.2016.09.029
166. Prescott HC, Dickson RP, Rogers MA, Langa KM, Iwashyna TJ (2015) Hospitalization type and subsequent severe sepsis. Am J Respir Crit Care Med 192:581–588. 10.1164/rccm.201503-0483OC
167. Iwashyna TJ, Netzer G, Langa KM, Cigolle C (2012) Spurious inferences about long-term outcomes: the case of severe sepsis and geriatric conditions. Am J Respir Crit Care Med 185:835–841. 10.1164/rccm.201109-1660OC
168. Sjoding MW, Cooke CR, Iwashyna TJ, Hofer TP (2016) Acute respiratory distress syndrome measurement error. Potential effect on clinical study results. Ann Am Thorac Soc 13:1123–1128. 10.1513/AnnalsATS.201601-072OC
169. Prescott HC, Sjoding MW, Langa KM, Iwashyna TJ, McAuley DF (2017) Late mortality after acute hypoxic respiratory failure. Thorax. 10.1136/thoraxjnl-2017-210109
170. DeMerle KM, Vincent BM, Iwashyna TJ, Prescott HC (2017) Increased healthcare facility use in veterans surviving sepsis hospitalization. J Crit Care 42:59–64. 10.1016/j.jcrc.2017.06.026
171. Gluck S, Summers MJ, Goddard TP, Andrawos A, Smith NC, Lange K, Iwashyna TJ, Deane AM (2017) Wide disagreement between alternative assessments of premorbid physical activity: subjective patient and surrogate reports and objective smartphone data. Crit Care Med 45:e1036–e1042. 10.1097/CCM.0000000000002599
172. Ahasic AM, Van Ness PH, Murphy TE, Araujo KL, Pisani MA (2015) Functional status after critical illness: agreement between patient and proxy assessments. Age Ageing 44:506–510. 10.1093/ageing/afu163
173. Valley TS, Sjoding MW, Ryan AM, Iwashyna TJ, Cooke CR (2015) Association of intensive care unit admission with mortality among older patients with pneumonia. JAMA 314:1272–1279. 10.1001/jama.2015.11068
174. Guidet B, Leblanc G, Simon T, Woimant M, Quenot JP, Ganansia O, Maignan M, Yordanov Y, Delerme S, Doumenc B, Fartoukh M, Charestan P, Trognon P, Galichon B, Javaud N, Patzak A, Garrouste-Org Thomas C, Azerad S, Pateron D, Boumendil A (2017) Effect of systematic intensive care unit triage on long-term mortality among critically ill elderly patients in France: a randomized clinical trial. JAMA 318:1450–1459. 10.1001/jama.2017.13889
175. Marra A, Ely EW, Pandharipande PP, Patel MB (2017) The ABCDEF bundle in critical care. Crit Care Clin 33:225–243. 10.1016/j.ccc.2016.12.005
176. Cuthbertson BH, Rattray J, Campbell MK, Gager M, Roughton S, Smith A, Hull A, Breeman S, Norrie J, Jenkinson D, Hernandez R, Johnston M, Wilson E, Waldmann C (2009) The PRaCTICaL study of nurse led, intensive care follow-up programmes for improving long term outcomes from critical illness: a pragmatic randomised controlled trial. BMJ 339:b3723
177. Walsh TS, Salisbury LG, Merriweather JL, Boyd JA, Griffith DM, Huby G, Kean S, Mackenzie SJ, Krishan A, Lewis SC, Murray GD, Forbes JF, Smith J, Rattray JE, Hull AM, Ramsay P (2015) Increased hospital-based physical rehabilitation and information provision after intensive care unit discharge: the RECOVER randomized clinical trial. JAMA Intern Med 175:901–910. 10.1001/jamainternmed.2015.0822
178. Rehabilitation after critical illness in adults. https://www.nice.org.uk/guidance/qs158. Accessed 11 May 2018
179. McPeake J, Iwashyna TJ, Devine H, MacTavish P, Quasim T (2017) Peer support to improve recovery following critical care discharge: a case-based discussion. Thorax 72:856–858. 10.1136/thoraxjnl-2016-209661
180. Mikkelsen ME, Jackson JC, Hopkins RO, Thompson C, Andrews A, Netzer G, Bates DM, Bunnell AE, Christie LM, Greenberg SB, Lamas DJ, Sevin CM, Weinhouse G, Iwashyna TJ (2016) Peer support as a novel strategy to mitigate post-intensive care syndrome. AACN Adv Crit Care 27:221–229. 10.4037/aacnacc2016667
181. Welcome to the partnership for patients. https://partnershipforpatients.cms.gov/. Accessed 11 May 2018
182. Ruggieri AJ, Levy RJ, Deutschman CS (2010) Mitochondrial dysfunction and resuscitation in sepsis. Crit Care Clin 26:567–575. 10.1016/j.ccc.2010.04.007
183. Brealey D, Brand M, Hargreaves I, Heales S, Land J, Smolenski R, Davies NA, Cooper CE, Singer M (2002) Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 360:219–223
184. Levy RJ, Deutschman CS (2007) Cytochrome c oxidase dysfunction in sepsis. Crit Care Med 35:S468–S475. 10.1097/01.CCM.0000278604.93569.27
185. Munoz C, Carlet J, Fitting C, Misset B, Bleriot JP, Cavaillon JM (1991) Dysregulation of in vitro cytokine production by monocytes during sepsis. J Clin Invest 88:1747–1754. 10.1172/JCI115493
186. Baker CS, Evans TW, Randle BJ, Haslam PL (1999) Damage to surfactant-specific protein in acute respiratory distress syndrome. Lancet 353:1232–1237. 10.1016/S0140-6736(98)09449-5
187. Greene KE, Wright JR, Steinberg KP, Ruzinski JT, Caldwell E, Wong WB, Hull W, Whitsett JA, Akino T, Kuroki Y, Nagae H, Hudson LD, Martin TR (1999) Serial changes in surfactant-associated proteins in lung and serum before and after onset of ARDS. Am J Respir Crit Care Med 160:1843–1850. 10.1164/ajrccm.160.6.9901117
188. Endo S, Sato N, Nakae H, Yamada Y, Makabe H, Abe H, Imai S, Wakabayashi G, Inada K, Sato S (2002) Surfactant protein A and D (SP-A, AP-D) levels in patients with septic ARDS. Res Commun Mol Pathol Pharmacol 111:245–251
189. Langouche L, Van den Berghe G (2006) The dynamic neuroendocrine response to critical illness. Endocrinol Metab Clin North Am 35:777–791, ix. 10.1016/j.ecl.2006.09.007
190. Deutschman CS, Raj NR, McGuire EO, Kelz MB (2013) Orexinergic activity modulates altered vital signs and pituitary hormone secretion in experimental sepsis. Crit Care Med 41:e368–e375. 10.1097/CCM.0b013e31828e9843
191. Van den Berghe G (2002) Dynamic neuroendocrine responses to critical illness. Front Neuroendocrinol 23:370–391 (pii:S0091302202000067)
192. Ingels C, Gunst J, Van den Berghe G (2018) Endocrine and metabolic alterations in sepsis and implications for treatment. Crit Care Clin 34:81–96. 10.1016/j.ccc.2017.08.006
193. Hotchkiss RS, Swanson PE, Freeman BD, Tinsley KW, Cobb JP, Matuschak GM, Buchman TG, Karl IE (1999) Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med 27:1230–1251
194. Hotchkiss RS, Tinsley KW, Swanson PE, Grayson MH, Osborne DF, Wagner TH, Cobb JP, Coopersmith C, Karl IE (2002) Depletion of dendritic cells, but not macrophages, in patients with sepsis. J Immunol 168:2493–2500
195. Imai Y, Parodo J, Kajikawa O, de Perrot M, Fischer S, Edwards V, Cutz E, Liu M, Keshavjee S, Martin TR, Marshall JC, Ranieri VM, Slutsky AS (2003) Injurious mechanical ventilation and end-organ epithelial cell apoptosis and organ dysfunction in an experimental model of acute respiratory distress syndrome. JAMA 289:2104–2112
196. Coopersmith CM, Chang KC, Swanson PE, Tinsley KW, Stromberg PE, Buchman TG, Karl IE, Hotchkiss RS (2002) Overexpression of Bcl-2 in the intestinal epithelium improves survival in septic mice. Crit Care Med 30:195–201
197. De BD, Orbegozo CD, Donadello K, Vincent JL (2013) Pathophysiology of microcirculatory dysfunction and the pathogenesis of septic shock. Virulence 5:73–79
198. Khakpour S, Wilhelmsen K, Hellman J (2015) Vascular endothelial cell Toll-like receptor pathways in sepsis. Innate Immun 21:827–846. 10.1177/1753425915606525
199. Arulkumaran N, Deutschman CS, Pinsky MR, Zuckerbraun B, Schumacker PT, Gomez H, Gomez A, Murray P, Kellum JA (2016) Mitochondrial function in sepsis. Shock 45:271–281. 10.1097/SHK.0000000000000463
200. Lewis AJ, Billiar TR, Rosengart MR (2016) Biology and metabolism of sepsis: innate immunity, bioenergetics, and autophagy. Surg Infect (Larchmt) 17:286–293. 10.1089/sur.2015.262
201. Giovannini I, Boldrini G, Castagneto M, Sganga G, Nanni G, Pittiruti M, Castiglioni G (1983) Respiratory quotient and patterns of substrate utilization in human sepsis and trauma. JPEN J Parenter Enter Nutr 7:226–230. 10.1177/0148607183007003226
202. Jacobs DO, Maris J, Fried R, Settle RG, Rolandelli RR, Koruda MJ, Chance B, Rombeau JL (1988) In vivo phosphorus 31 magnetic resonance spectroscopy of rat hind limb skeletal muscle during sepsis. Arch Surg 123:1425–1428
203. Brealey D, Karyampudi S, Jacques TS, Novelli M, Stidwill R, Taylor V, Smolenski RT, Singer M (2004) Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure. Am J Physiol Regul Integr Comp Physiol 286:R491–R497. 10.1152/ajpregu.00432.2003
204. Stoner HB, Little RA, Frayn KN, Elebute AE, Tresadern J, Gross E (1983) The effect of sepsis on the oxidation of carbohydrate and fat. Br J Surg 70:32–35
205. White RH, Frayn KN, Little RA, Threlfall CJ, Stoner HB, Irving MH (1987) Hormonal and metabolic responses to glucose infusion in sepsis studied by the hyperglycemic glucose clamp technique. JPEN J Parenter Enteral Nutr 11:345–353. 10.1177/0148607187011004345
206. Schmoch T, Uhle F, Siegler BH, Fleming T, Morgenstern J, Nawroth PP, Weigand MA, Brenner T (2017) The glyoxalase system and methylglyoxal-derived carbonyl stress in sepsis: glycotoxic aspects of sepsis pathophysiology. Int J Mol Sci. 10.3390/ijms18030657
207. Srivastava A, Mannam P (2015) Warburg revisited: lessons for innate immunity and sepsis. Front Physiol 6:70. 10.3389/fphys.2015.00070
208. Yang L, Xie M, Yang M, Yu Y, Zhu S, Hou W, Kang R, Lotze MT, Billiar TR, Wang H, Cao L, Tang D (2014) PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis. Nat Commun 5:4436. 10.1038/ncomms5436
209. Hobler SC, Tiao G, Fischer JE, Monaco J, Hasselgren PO (1998) Sepsis-induced increase in muscle proteolysis is blocked by specific proteasome inhibitors. Am J Physiol 274:R30–R37
210. Berger MM, Shenkin A (2006) Update on clinical micronutrient supplementation studies in the critically ill. Curr Opin Clin Nutr Metab Care 9:711–716. 10.1097/01.mco.0000247466.41661.ba
211. Carr AC, Rosengrave PC, Bayer S, Chambers S, Mehrtens J, Shaw GM (2017) Hypovitaminosis C and vitamin C deficiency in critically ill patients despite recommended enteral and parenteral intakes. Crit Care 21:300. 10.1186/s13054-017-1891-y
212. Sender R, Fuchs S, Milo R (2016) Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans. Cell 164:337–340. 10.1016/j.cell.2016.01.013
213. Ackerman J (2012) The ultimate social network. Sci Am 306:36–43
214. Hayakawa M, Asahara T, Henzan N, Murakami H, Yamamoto H, Mukai N, Minami Y, Sugano M, Kubota N, Uegaki S, Kamoshida H, Sawamura A, Nomoto K, Gando S (2011) Dramatic changes of the gut flora immediately after severe and sudden insults. Dig Dis Sci 56:2361–2365. 10.1007/s10620-011-1649-3
215. McDonald D, Ackermann G, Khailova L, Baird C, Heyland D, Kozar R, Lemieux M, Derenski K, King J, Vis-Kampen C, Knight R, Wischmeyer PE (2016) Extreme dysbiosis of the microbiome in critical illness. mSphere. 10.1128/msphere.00199-16
216. Alverdy JC, Krezalek MA (2017) Collapse of the microbiome, emergence of the pathobiome, and the immunopathology of sepsis. Crit Care Med 45:337–347. 10.1097/CCM.0000000000002172
217. Krezalek MA, Defazio J, Zaborina O, Zaborin A, Alverdy JC (2016) The shift of an intestinal “Microbiome” to a “Pathobiome” governs the course and outcome of sepsis following surgical injury. Shock 45:475–482. 10.1097/SHK.0000000000000534
218. Fay KT, Ford ML, Coopersmith CM (2017) The intestinal microenvironment in sepsis. Biochim Biophys Acta 1863:2574–2583. 10.1016/j.bbadis.2017.03.005
219. Klingensmith NJ, Coopersmith CM (2016) The gut as the motor of multiple organ dysfunction in critical illness. Crit Care Clin 32:203–212. 10.1016/j.ccc.2015.11.004
220. Lyons JD, Coopersmith CM (2017) Pathophysiology of the gut and the microbiome in the host response. Pediatr Crit Care Med 18:S46–S49. 10.1097/PCC.0000000000001046
221. Meng M, Klingensmith NJ, Coopersmith CM (2017) New insights into the gut as the driver of critical illness and organ failure. Curr Opin Crit Care 23:143–148. 10.1097/MCC.0000000000000386
222. Mittal R, Coopersmith CM (2014) Redefining the gut as the motor of critical illness. Trends Mol Med 20:214–223. 10.1016/j.molmed.2013.08.004
223. Romanowski K, Zaborin A, Valuckaite V, Rolfes RJ, Babrowski T, Bethel C, Olivas A, Zaborina O, Alverdy JC (2012) Candida albicans isolates from the gut of critically ill patients respond to phosphate limitation by expressing filaments and a lethal phenotype. PLoS ONE 7:e30119. 10.1371/journal.pone.0030119
224. Zaborin A, Gerdes S, Holbrook C, Liu DC, Zaborina OY, Alverdy JC (2012) Pseudomonas aeruginosa overrides the virulence inducing effect of opioids when it senses an abundance of phosphate. PLoS ONE 7:e34883. 10.1371/journal.pone.0034883
225. Zaborina O, Lepine F, Xiao G, Valuckaite V, Chen Y, Li T, Ciancio M, Zaborin A, Petroff E, Turner JR, Rahme LG, Chang E, Alverdy JC (2007) Dynorphin activates quorum sensing quinolone signaling in Pseudomonas aeruginosa. PLoS Pathog 3:e35
226. Zaborin A, Defazio JR, Kade M, Kaiser BL, Belogortseva N, Camp DG, Smith RD, Adkins JN, Kim SM, Alverdy A, Goldfeld D, Firestone MA, Collier JH, Jabri B, Tirrell M, Zaborina O, Alverdy JC (2014) Phosphate-containing polyethylene glycol polymers prevent lethal sepsis by multidrug-resistant pathogens. Antimicrob Agents Chemother 58:966–977. 10.1128/AAC.02183-13
227. Zaborin A, Smith D, Garfield K, Quensen J, Shakhsheer B, Kade M, Tirrell M, Tiedje J, Gilbert JA, Zaborina O, Alverdy JC (2014) Membership and behavior of ultra-low-diversity pathogen communities present in the gut of humans during prolonged critical illness. MBio 5:e01361-14. 10.1128/mBio.01361-14
228. Wu L, Estrada O, Zaborina O, Bains M, Shen L, Kohler JE, Patel N, Musch MW, Chang EB, Fu YX, Jacobs MA, Nishimura MI, Hancock RE, Turner JR, Alverdy JC (2005) Recognition of host immune activation by Pseudomonas aeruginosa. Science 309:774–777. 10.1126/science.1112422
229. Buckley CD, Gilroy DW, Serhan CN (2014) Proresolving lipid mediators and mechanisms in the resolution of acute inflammation. Immunity 40:315–327. 10.1016/j.immuni.2014.02.009
230. Spite M, Serhan CN (2010) Novel lipid mediators promote resolution of acute inflammation: impact of aspirin and statins. Circ Res 107:1170–1184. 10.1161/CIRCRESAHA.110.223883
231. Walker J, Dichter E, Lacorte G, Kerner D, Spur B, Rodriguez A, Yin K (2011) Lipoxin a4 increases survival by decreasing systemic inflammation and bacterial load in sepsis. Shock 36:410–416. 10.1097/SHK.0b013e31822798c1
232. Li Y, Dalli J, Chiang N, Baron RM, Quintana C, Serhan CN (2013) Plasticity of leukocytic exudates in resolving acute inflammation is regulated by MicroRNA and proresolving mediators. Immunity 39:885–898. 10.1016/j.immuni.2013.10.011
233. Nakahira K, Haspel JA, Rathinam VA, Lee SJ, Dolinay T, Lam HC, Englert JA, Rabinovitch M, Cernadas M, Kim HP, Fitzgerald KA, Ryter SW, Choi AM (2011) Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol 12:222–230. 10.1038/ni.1980
234. Terrasini N, Lionetti V (2017) Exosomes in critical illness. Crit Care Med 45:1054–1060. 10.1097/CCM.0000000000002328
235. Andersson U, Tracey KJ (2012) Reflex principles of immunological homeostasis. Annu Rev Immunol 30:313–335. 10.1146/annurev-immunol-020711-075015
236. Perner A, Gordon AC, Angus DC, Lamontagne F, Machado F, Russell JA, Timsit JF, Marshall JC, Myburgh J, Shankar-Hari M, Singer M (2017) The intensive care medicine research agenda on septic shock. Intensive Care Med. 10.1007/s00134-017-4821-1
237. Cohen J, Vincent JL, Adhikari NK, Machado FR, Angus DC, Calandra T, Jaton K, Giulieri S, Delaloye J, Opal S, Tracey K, van der Poll T, Pelfrene E (2015) Sepsis: a roadmap for future research. Lancet Infect Dis 15:581–614. 10.1016/S1473-3099(15)70112-X