Management of Sepsis and Septic Shock 2026

- REFERENCES

1. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic shock 2026. Critical Care Medicine April 2026; 54 (4): 715-812

2. Singer M, Deutschman CS, Seymour CW, et al: The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016; 315:801–810

3. Arabi YM, Alsaawi A, Alzahrani M, et al; SCREEN Trial Group and the Saudi Critical Care Trials Group: Electronic sepsis screening among patients admitted to hospital wards: A stepped-wedge cluster randomized trial. JAMA 2025; 333:763–773

4. Freund Y, Cancella de Abreu M, Lebal S, et al: Effect of the 1-h bundle on mortality in patients with suspected sepsis in the emergency department: A stepped wedge cluster randomized clinical trial. Intensive Care Med 2024; 50:1086–1095

5. Damiani E, Donati A, Serafini G, et al: Effect of performance improvement programs on compliance with sepsis bundles and mortality: A systematic review and meta-analysis of observational studies. PLoS One 2015; 10:e0125827

6. Tarabichi Y, Cheng A, Bar-Shain D, et al: Improving timeliness of antibiotic administration using a provider and pharmacist facing sepsis early warning system in the emergency department setting: A randomized controlled quality improvement initiative. Crit Care Med 2022; 50:418–427

7. CDC: Hospital Sepsis Program Core Elements. 2023. Available at: https://www.cdc.gov/sepsis/media/pdfs/sepsis- core-elements-H.pdf Accessed August 14, 2025

8. Guirgis FW, Jones L, Esma R, et al: Managing sepsis: Electronic recognition, rapid response teams, and standardized care save lives. J Crit Care 2017; 40:296–302

9. Patocka C, Turner J, Xue X, et al: Evaluation of an emergency department triage screening tool for suspected severe sepsis and septic shock. J Healthc Qual 2014; 36:52–61; quiz 59

10. Williams G, Alberto L, Taha M, et al: The challenges of compliance with sepsis management protocols in low and low-middle income countries - A cross-sectional study. Intensive Crit Care Nurs 2025; 90:104032

11. Piedmont S, Goldhahn L, Swart E, et al: Sepsis incidence, suspicion, prediction and mortality in emergency medical services: A cohort study related to the current international sepsis guideline. Infection 2024; 52:1325–1335

12. Troncoso R Jr, Garfinkel EM, Hinson JS, et al: Do prehospital sepsis alerts decrease time to complete CMS sepsis measures? Am J Emerg Med 2023; 71:81–85

13. Hunter CL, Silvestri S, Stone A, et al: Prehospital sepsis alert notification decreases time to initiation of CMS sepsis core measures. Am J Emerg Med 2019; 37:114–117

14. Guerra WF, Mayfield TR, Meyers MS, et al: Early detection and treatment of patients with severe sepsis by prehospital personnel. J Emerg Med 2013; 44:1116–1125

15. Mixon M, Dietrich S, Floren M, et al: Time to antibiotic administration: Sepsis alerts called in emergency department versus in the field via emergency medical services. Am J Emerg Med 2021; 44:291–295

16. Adegbite BR, Edoa JR, Ndzebe Ndoumba WF, et al: A comparison of different scores for diagnosis and mortality prediction of adults with sepsis in Low-and-Middle-Income Countries: A systematic review and meta-analysis. E Clinical Medicine 2021; 42:101184

17. Chua WL, Rusli KDB, Aitken LM: Early warning scores for sepsis identification and prediction of in-hospital mortality in adults with sepsis: A systematic review and meta-analysis. J Clin Nurs 2024; 33:2005–2018

18. Elperin J, Van Perre K, Bryant NH: 1193: Sepsis: Is it time to leave sirs behind? A systematic review and meta-analysis of sepsis definitions. Crit Care Med 2023; 51:59

19. Qiu X, Lei Y, Zhou RX: SIRS, SOFA, qSOFA, and NEWS in the diagnosis of sepsis and prediction of adverse outcomes: A systematic review and meta-analysis. Expert Rev Anti Infect Ther 2023; 21:891–900

20. Crouser ED, Parrillo JE, Seymour CW, et al: Monocyte distribution width: A novel indicator of sepsis-2 and sepsis-3 in high- risk emergency department patients. Crit Care Med 2019; 47:1018–1025

21. Vashti A, Mullan PJ, Nitzberg M: Single-site sampling strategy versus multi-site sampling strategy in blood culture collection within the hospital setting: A systematic review. Am J Infect Control 2025; 53:1113–1120

22. S3-Leitlinie: Sepsis – Prävention, Diagnose, Therapie und Nachsorge – Update 2025. Available at: https://reg- ister.awmf.org/assets/guidelines/079-001l_S3_Sepsis-Praevention-Diagnose-Therapie-Nachsorge_2025-07.pdf Accessed August 12, 2025

23. Cheng MP, Stenstrom R, Paquette K, et al; FABLED Investigators: Blood culture results before and after anti- microbial administration in patients with severe manifestations of sepsis: A diagnostic study. Ann Intern Med 2019; 171:547–554

24. Evans L, Rhodes A, Alhazzani W, et al: Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock 2021. Intensive Care Med 2021; 47:1181–1247

25. Evans L, Rhodes A, Alhazzani W, et al: Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock 2021. Crit Care Med 2021; 49:e1063–e1143

26. Borthwick HA, Brunt LK, Mitchem KL, et al: Does lactate measurement performed on admission predict clinical outcome on the intensive care unit? A concise systematic review. Ann Clin Biochem 2012; 49:391–394

27. Liu G, An Y, Yi X, et al: Early lactate levels for prediction of mortality in patients with sepsis or septic shock: A meta-analysis. Int J Exp Med 2017; 10:37–47

28. Levy MM, Evans LE, Rhodes A: The surviving sepsis campaign bundle: 2018 update. Crit Care Med 2018; 46:997–1000

29. Shankar-Hari M, Phillips GS, Levy ML, et al; Sepsis Definitions Task Force: 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 2016; 315:775–787

30. Ljungström L, Pernestig AK, Jacobsson G, et al: Diagnostic accuracy of procalcitonin, neutrophil-lymphocyte count ratio, C-reactive protein, and lactate in patients with suspected bacterial sepsis. PLoS One 2017; 12:e0181704

31. Morris E, McCartney D, Lasserson D, et al: Point-of-care lactate testing for sepsis at presentation to health care: A systematic review of patient outcomes. Br J Gen Pract 2017; 67:e859–e870

32. Rhodes A, Evans LE, Alhazzani W, et al: Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016. Crit Care Med 2017; 45:486–552

33. Shankar-Hari M, Phillips GS, Levy ML, et al; Sepsis Definitions Task Force: 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 2016; 315:775–787

34. Kuttab HI, Lykins JD, Hughes MD, et al: Evaluation and predictors of fluid resuscitation in patients with severe sepsis and septic shock. Crit Care Med 2019; 47:1582–1590

35. Corl KA, Levy MM, Holder AL, et al: Moderate IV fluid resuscitation is associated with decreased sepsis mortality. Crit Care Med 2024; 52:e557–e567

36. Peake SL, Delaney A, Bellomo R; ARISE Investigators: Goal- directed resuscitation in septic shock. N Engl J Med 2015; 372:190–191

37. Pro CI, et al.: A randomized trial of protocol-based care for early septic shock. N Engl J Med 2014; 370:1683–1693

38. Mouncey PR, Osborn TM, Power GS, et al; ProMISe Trial Investigators: Trial of early, goal-directed resuscitation for septic shock. N Engl J Med 2015; 372:1301–1311

39. Ward MA, Kuttab HI, Badgett RG: The effect of early fluid resuscitation on mortality in sepsis: A systematic review and meta-analysis. Crit Care Med 2025; 53:e1790–e1802

40. Taylor SP, Karvetski CH, Templin MA, et al: Initial fluid resus- citation following adjusted body weight dosing is associated with improved mortality in obese patients with suspected septic shock. J Crit Care 2018; 43:7–12

41. Mekontso Dessap A, AlShamsi F, Belletti A, et al; European Society of Intensive Care Medicine: European Society of Intensive Care Medicine (ESICM) 2025 clinical practice guideline on fluid therapy in adult critically ill patients: Part 2-the volume of resuscitation fluids. Intensive Care Med 2025; 51:461–477

42. Ahn C, Yu G, Shin TG, et al: Comparison of early and late norepinephrine administration in patients with septic shock: A systematic review and meta-analysis. Chest 2024; 166:1417–1430

43. 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 Med2019; 199:1097–1105

44. Shi R, Braïk R, Monnet X, et al: Early norepinephrine for patients with septic shock: An updated systematic review and meta-analysis with trial sequential analysis. Crit Care2025; 29:182

45. Li Y, Li H, Zhang D: Timing of norepinephrine initiation in patients with septic shock: A systematic review and meta-analysis. Crit Care2020; 24:488

46. Zhou HX, Yang C-F, Wang H-Y, et al: Should we initiate vasopressors earlier in patients with septic shock: A mini systemic review. World J Crit Care Med2023; 12:204–216

47. Elbouhy MA, Soliman M, Gaber A, et al: Early use of norepinephrine improves survival in septic shock: Earlier than early. Arch Med Res2019; 50:325–332

48. Bai X, Yu W, Ji W, et al: Early versus delayed administration of norepinephrine in patients with septic shock. Crit Care2014; 18:532

49. Colon Hidalgo D, Patel J, Masic D, et al: Delayed vasopressor initiation is associated with increased mortality in patients with septic shock. J Crit Care2020; 55:145–148

50. National Heart L, et al.: Early restrictive or liberal fluid management for sepsis-induced hypotension. The multicenter CLOVERS RCT. N Engl J Med2023; 388:499–510

51. Owen VS, Rosgen BK, Cherak SJ, et al: Adverse events associated with administration of vasopressor medications through a peripheral intravenous catheter: A systematic review and meta-analysis. Crit Care2021; 25:146

52. Tian DH, Smyth C, Keijzers G, et al: Safety of peripheral administration of vasopressor medications: A systematic review. Emerg Med Australas2020; 32:220–227

53. Ricard JD, Salomon L, Boyer A, et al: Central or peripheral catheters for initial venous access of ICU patients: A randomized controlled trial. Crit Care Med2013; 41:2108–2115

54. Stolz A, Efendy R, Apte Y, et al: Safety and efficacy of peripheral versus centrally administered vasopressor infusion: A single-center retrospective observational study. Aust Crit Care2022; 35:506–511

55. Delaney A, Finnis M, Bellomo R, et al: Initiation of vasopressor infusions via peripheral versus central access in patients with early septic shock: A retrospective cohort study. Emerg Med Australas2020; 32:210–219

56. Munroe ES, Heath ME, Eteer M, et al: Use and outcomes of peripheral vasopressors in early sepsis-induced hypotension across Michigan hospitals: A retrospective cohort study. Chest2024; 165:847–857

57. Munroe ES, Co IN, Douglas I, et al; NHLBI PETAL Network: Peripheral vasopressor use in early sepsis-induced hypotension. JAMA Netw Open2025; 8:e2529148

58. Asher E, Karameh H, Nassar H, et al; Jerusalem Platelets Thrombosis and Intervention in Cardiology (JUPITER-16) Study Group: Safety and outcomes of peripherally administered vasopressor infusion in patients admitted with shock to an intensive cardiac care unit-A single-center prospective study. J Clin Med2023; 12:5734

59. Groetzinger LM, Williams J, Svec S, et al: Peripherally infused norepinephrine to avoid central venous catheter placement in a medical intensive care unit: A pilot study. Ann Pharmacother2022; 56:773–781

60. Medlej K, Kazzi AA, El Hajj Chehade A, et al: Complications from administration of vasopressors through peripheral ve-nous catheters: An observational study. J Emerg Med2018; 54:47–53

61. Meng L, Wang Y, Zhang L, et al: Heterogeneity and variability in pressure autoregulation of organ blood flow: lessons learned over 100+ years. Crit Care Med2019; 47:436–448

62. Asfar P, Meziani F, Hamel J-F, et al; SEPSISPAM Investigators: High versus low blood-pressure target in patients with septic shock. N Engl J Med2014; 370:1583–1593

63. Hylands M, Moller MH, Asfar P, et al: A systematic review of vasopressor blood pressure targets in critically ill adults with hypotension. Can J Anaesth2017; 64:703–715

64. Lamontagne F, Richards-Belle A, Thomas K, et al; 65 trial investigators: Effect of reduced exposure to vasopressors on 90-day mortality in older critically ill patients with vasodilatory hypotension: A randomized clinical trial. JAMA2020; 323:938–949

65. Angriman F, Momenzade N, Adhikari NKJ, et al: Blood pressure targets for adults with vasodilatory shock - An individual patient data meta-analysis. NEJM Evid2025;4:EVIDoa 2400359

66. Endo A, Yamakawa K, Tagami T, et al; OPTPRESS trial investigators: Efficacy of targeting high mean arterial pressure for older patients with septic shock (OPTPRESS): A multicenter , pragmatic, open-label, randomized controlled trial. Intensive Care Med2025; 51:883–892

67. Cardoso LT, Grion CM, Matsuo T, et al: Impact of delayed admission to intensive care units on mortality of critically ill patients: A cohort study. Crit Care 2011; 15:R28

68. Groenland CNL, Termorshuizen F, Rietdijk WJR, et al: Emergency department to ICU time is associated with hospital mortality: A registry analysis of 14,788 patients from Six University Hospitals in The Netherlands. Crit Care Med 2019; 47:1564–1571

69. Chalfin DB, Trzeciak S, Likourezos A, et al; DELAY-ED study group: Impact of delayed transfer of critically ill patients from the emergency department to the intensive care unit. Crit Care Med 2007; 35:1477–1483

70. Harris S, Singer M, Sanderson C, et al: Impact on mortality of prompt admission to critical care for deteriorating ward patients: An instrumental variable analysis using critical care bed strain. Intensive Care Med 2018; 44:606–615

71. Kalil AC, Johnson DW, Lisco SJ, et al: Early goal-directed therapy for sepsis: A novel solution for discordant survival outcomes in clinical trials. Crit Care Med 2017; 45:607–614

72. Klompas M, Calandra T, Singer M: Antibiotics for sepsis-finding the equilibrium. JAMA2018; 320:1433–1434

73. Leung LY, Huang H-L, Hung KK, et al: Door-to-antibiotic time and mortality in patients with sepsis: Systematic review and meta-analysis. Eur J Intern Med2024; 129:48–61

74. Pak TR, Young J, McKenna CS, et al: Risk of misleading conclusions in observational studies of time-to-antibiotics and mortality in suspected sepsis. Clin Infect Dis2023; 77:1534–1543

75. Hechtman RK, Kipnis P, Cano J, et al: Heterogeneity of benefit from earlier time-to-antibiotics for sepsis. Am J Respir Crit Care Med2024; 209:852–860

76. Alam N, Oskam E, Stassen PM, et al; PHANTASi Trial Investigators and the ORCA (Onderzoeks Consortium Acute Geneeskunde) Research Consortium the Netherlands: Prehospital antibiotics in the ambulance for sepsis: A multicenter, open label, randomized trial. Lancet Respir Med2018; 6:40–50

77. Thwaites L, Nasa P, Abbenbroek B, et al: Management of adult sepsis in resource-limited settings: Global expert consensus statements using a Delphi method. Intensive Care Med 2025; 51:21–38

78. Lane D, Ichelson RI, Drennan IR, et al: Prehospital management and identification of sepsis by emergency medical serv- ices: A systematic review. Emerg Med J 2016; 33:408–413

79. Varney J, Motawea KR, Kandil OA, et al: Prehospital administration of broad-spectrum antibiotics for sepsis patients: A systematic review and meta-analysis. Health Sci Rep 2022; 5:e582

80. Poynter MJ, Farrugia A, Kelly E, et al: Prehospital administration of antibiotics in addition to usual care versus usual care alone for patients with suspected sepsis – a systematic review. Paramedicine 2023; 21:52–65

81. Peng F, Chang W, Xie JF, et al: Ineffectiveness of procalcitonin-guided antibiotic therapy in severely critically ill patients: A meta-analysis. Int J Infect Dis 2019; 85:158–166

82. Wacker C, Prkno A, Brunkhorst FM, et al: Procalcitonin as a diagnostic marker for sepsis: A systematic review and meta-analysis. Lancet Infect Dis 2013; 13:426–435

83. Jensen JU, Hein L, Lundgren B, et al; Procalcitonin And Survival Study (PASS) Group: Procalcitonin-guided interventions against infections to increase early appropriate antibiotics and improve survival in the intensive care unit: A randomized trial. Crit Care Med 2011; 39:2048–2058

84. Layios N, Lambermont B, Canivet JL, et al: Procalcitonin usefulness for the initiation of antibiotic treatment in intensive care unit patients. Crit Care Med 2012; 40:2304–2309

85. Najafi A, Khodadadian A, Sanatkar M, et al: The comparison of procalcitonin guidance administer antibiotics with empiric antibiotic therapy in critically ill patients admitted in intensive care unit. Acta Med Iran 2015; 53:562–567

86. Metlay JP, Waterer GW, Long AC, et al: Diagnosis and treatment of adults with community-acquired pneumonia. An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med 2019; 200:e45–e67

87. Huston JM, Barie PS, Dellinger EP, et al: Surgical infection society guidelines on management of intra-abdominal infection: 2024 update. Surg Infect (Larchmt) 2024; 25:419–435

88. Coccolini F, Sartelli M, Sawyer R, et al: Source control in emergency general surgery: WSES, GAIS, SIS-E, SIS-A guidelines. World J Emerg Surg 2023; 18:41

89. Paul M, Carrara E, Retamar P, et al: European society of clinical microbiology and infectious diseases (ESCMID) guidelines for the treatment of infections caused by multidrug-resistant Gram-negative bacilli (endorsed by European society of intensive care medicine). Clin Microbiol Infect 2022; 28:521–547

90. Carey GB, Holleck JL, Ein Alshaeba S, et al: Estimated mortality with early empirical MRSA coverage in hospitalized patients: Systematic review and meta-analysis. J Antimicrob Chemother 2023; 78:1150–1159

91. Cortegiani A, Russotto V, Maggiore A, et al: Antifungal agents for preventing fungal infections in non-neutropenic critically ill patients. Cochrane Database Syst Rev 2016; 2016:CD004920

92. Timsit JF, Azoulay E, Schwebel C, et al; EMPIRICUS Trial Group: Empirical micafungin treatment and survival without invasive fungal infection in adults with ICU-acquired sepsis (EMPIRICUS). JAMA 2016; 316:1555–1564

93. Petersen MW, Perner A, Jonsson AB, et al: Empirical metronidazole for patients with severe bacterial infection: Systematic review with meta-analysis and trial sequential analysis. Acta Anaesthesiol Scand 2019; 63:802–813

94. Chanderraj R, Baker JM, Kay SG, et al: In critically ill patients, anti-anaerobic antibiotics increase risk of adverse clinical outcomes. Eur Respir J 2023; 61:2200910

95. Metlay JP, Waterer GW, Long AC, et al: Diagnosis and treatment of adults with community-acquired pneumonia. ATS/IDSA guideline. Am J Respir Crit Care Med 2019; 200:e45–e67

96. Mazuski JE, Tessier JM, May AK, et al: Surgical Infection Society revised guidelines on management of intra-abdominal infection. Surg Infect (Larchmt) 2017; 18:1–76

97. Kullberg RFJ, Haak BW, Chanderraj R, et al: Empirical antibiotic therapy for sepsis: Save the anaerobic microbiota. Lancet Respir Med 2025; 13:92–100

98. Anton-Vazquez V, Hine P, Krishna S, et al: Rapid versus standard antimicrobial susceptibility testing to guide treatment of bloodstream infection. Cochrane Database Syst Rev 2021; 5:CD013235

99. Caspar Y, Deves A, Richarme C, et al: Clinical impact and cost-consequence analysis of ePlex® blood culture identification panels for rapid diagnosis of bloodstream infections. Eur J Clin Microbiol Infect Dis 2024; 43:1193–1203

100. Timbrook TT, Morton JB, McConeghy KW, et al: The effect of molecular rapid diagnostic testing on clinical outcomes in bloodstream infections: Systematic review and meta-analysis. Clin Infect Dis 2017; 64:15–23

101. Mohd Hafiz AA, Staatz CE, Kirkpatrick CMJ, et al: Continuous infusion vs. bolus dosing: Implications for beta-lactam antibiotics. Minerva Anesthesiol 2012; 78:94–104

102. Abdul-Aziz MH, Lipman J, Akova M, et al; DALI Study Group: Is prolonged infusion of piperacillin/tazobactam and meropenem associated with improved pharmacokinetic/pharmacodynamic and patient outcomes? (DALI cohort). J Antimicrob Chemother 2016; 71:196–207

103. Abdul-Aziz MH, Hammond NE, Brett SJ, et al: Prolonged vs intermittent infusions of beta-lactam antibiotics in adults with sepsis or septic shock: A systematic review and meta-analysis. JAMA 2024; 332:638–648

104. Dulhunty JM, Brett SJ, De Waele JJ, et al; BLING III Study Investigators: Continuous vs intermittent beta-lactam antibiotic infusions in critically ill patients with sepsis: The BLING III randomized clinical trial. JAMA 2024; 332:629–637

105. Roberts JA, Abdul-Aziz MH, Lipman J, et al: Individualized antibiotic dosing for patients who are critically ill: Challenges and potential solutions. Lancet Infect Dis 2014; 14:498–509

106. Veiga R, Paiva JA: Pharmacokinetics-pharmacodynamics issues relevant for the clinical use of beta-lactam antibiotics in critically ill patients. Crit Care 2018; 22:233

107. Sanz-Codina M, Bozkir HO, Jorda A, et al: Individualized antimicrobial dose optimization: A systematic review and meta-analysis of randomized controlled trials. Clin Microbiol Infect 2023; 29:845–857

108. Abdul-Aziz MH, Alffenaar JC, Bassetti M, et al; ESICM Infection Section: Antimicrobial therapeutic drug monitoring in critically ill adult patients: A Position Paper. Intensive Care Med 2020; 46:1127–1153

109. Leone M, Bechis C, Baumstarck K, et al; AZUREA Network Investigators: De-escalation versus continuation of empirical antimicrobial treatment in severe sepsis: A multicenter non-blinded randomized noninferiority trial. Intensive Care Med 2014; 40:1399–1408

110. Lopez-Cortes LE, Delgado-Valverde M, Moreno-Mellado E, et al; SIMPLIFY study group: Efficacy and safety of a structured de-escalation from antipseudomonal beta-lactams in bloodstream infections due to Enterobacterales. Lancet Infect Dis 2024; 24:375–385

111. Tabah A, Bassetti M, Kollef MH, et al: Antimicrobial de- escalation in critically ill patients: A position statement from a task force of the European society of intensive care medicine (ESICM) and European society of clinical microbiology and infectious diseases (ESCMID) critically ill patients study group (ESGCIP). Intensive Care Med 2020; 46:245–265

112. NICE organization. Surveillance report 2018 – Antimicrobial stewardship: systems and processes for effective antimicrobial medicine use (2015) NICE guideline NG15. Available at: https://www.nice.org.uk/guidance/ng15/resources/ surveillance-report-2018-antimicrobial-stewardship-systems-and-processes-for-effective-antimicrobial-medicine- use-2015-nice-guideline-ng15-pdf-6119358364357 Accessed July 18, 2025.

113. Dark P, Hossain A, McAuley DF, et al; ADAPT-Sepsis Collaborators: Biomarker-guided antibiotic duration for hospitalized patients with suspected sepsis: The ADAPT-sepsis randomized clinical trial. JAMA 2025; 333:682–693

114. Gershengorn HB, Garland A, Kramer A, et al: Variation of arterial and central venous catheter use in United States in- tensive care units. Anesthesiology 2014; 120:650–664

115. Muller G, Contou D, Ehrmann S, et al: Deferring arterial catheterization in critically ill patients with shock. N Engl J Med 2025; 393:1875–1888

116. Hammond NE, Zampieri FG, Di Tanna GL, et al: Balanced crystalloids versus saline in critically ill adults - A systematic review with meta-analysis. NEJM Evid 2022; 1:EVIDoa2100010

117. Zampieri FG, Cavalcanti AB, Di Tanna GL, et al: Balanced crystalloids versus saline for critically ill patients (BEST-Living): A systematic review and individual patient data meta- analysis. Lancet Respir Med 2024; 12:237–246

118. Diz JC, Luna-Rojas P, Díaz-Vidal P, et al: Effect of treatment with balanced crystalloids versus normal saline on the mortality of critically ill patients with and without traumatic brain injury: A systematic review and meta-analysis. Anesth Analg 2025; 141:152–161

119. Investigators SS, et al: Saline or albumin for fluid resuscitation in patients with traumatic brain injury. N Engl J Med 2007; 357:874–884

120. Philips CA, Maiwall R, Sharma MK, et al: Comparison of 5% human albumin and normal saline for fluid resuscitation in sepsis induced hypotension among patients with cirrhosis (FRISC study): A randomized controlled trial. Hepatol Int 2021; 15:983–994

121. Caironi P, Tognoni G, Masson S, et al; ALBIOS Study Investigators: Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med 2014; 370:1412–1421

122. Arabi YM, Belley-Cote E, Carsetti A, et al; European Society of Intensive Care Medicine: European society of intensive care medicine clinical practice guideline on fluid therapy in adult critically ill patients. Part 1: The choice of resuscitation fluids. Intensive Care Med 2024; 50:813–831

123. Rochwerg B, Alhazzani W, Sindi A, et al; Fluids in Sepsis and Septic Shock Group: Fluid resuscitation in sepsis: A systematic review and network meta-analysis. Ann Intern Med 2014; 161:347–355

124. Moeller C, Fleischmann C, Thomas-Rueddel D, et al: How safe is gelatin? A systematic review and meta-analysis of gelatin-containing plasma expanders vs crystalloids and albumin. J Crit Care 2016; 35:75–83

125. Haase N, Perner A, Hennings LI, et al: Hydroxyethyl starch 130/0.38-0.45 versus crystalloid or albumin in patients with sepsis: Systematic review with meta-analysis and trial sequential analysis. BMJ 2013; 346:f839

126. Macdonald SPJ, Keijzers G, Taylor DM, et al; REFRESH trial investigators: Restricted fluid resuscitation in suspected sepsis associated hypotension (REFRESH): A pilot randomized controlled trial. Intensive Care Med 2018; 44:2070–2078

127. Jessen MK, Andersen LW, Thomsen MH, et al: Restrictive fluids versus standard care in adults with sepsis in the emergency department (REFACED): A multicenter, randomized feasibility trial. Acad Emerg Med 2022; 29:1172–1184

128. Meyhoff TS, Hjortrup PB, Wetterslev J, et al; CLASSIC Trial Group: Restriction of intravenous fluid in ICU patients with septic shock. N Engl J Med 2022; 386:2459–2470

129. Bednarczyk JM, Fridfinnson JA, Kumar A, et al: Incorporating dynamic assessment of fluid responsiveness into goal- directed therapy: A systematic review and meta-analysis. Crit Care Med 2017; 45:1538–1545

130. Ehrman RR, Gallien JZ, Smith RK, et al: Resuscitation guided by volume responsiveness does not reduce mortality in sepsis: A meta-analysis. Crit Care Explor 2019; 1:e0015

131. Azadian M, Win S, Abdipour A, et al: Mortality benefit from the passive leg raise maneuver in guiding resuscitation of septic shock patients: A systematic review and meta-analysis of randomized trials. J Intensive Care Med 2022; 37:611–617

132. Basmaji J, Arntfield R, Desai K, et al: The impact of point-of- care ultrasound-guided resuscitation on clinical outcomes in patients with shock: A systematic review and meta-analysis. Crit Care Med 2024; 52:1661–1673

133. Putowski Z, Gołdyn M, Pluta MP, et al: Correlation between mean arterial pressure and capillary refill time in patients with septic shock: A systematic review and meta-analysis. J Intensive Care Med 2023; 38:838–846

134. Hernandez G, Ospina-Tascón GA, Damiani LP, et al; The ANDROMEDA SHOCK Investigators and the Latin America Intensive Care Network (LIVEN): 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; 321:654–664

135. Castro R, Kattan E, Ferri G, et al: Effects of capillary refill time-vs. lactate-targeted fluid resuscitation on regional, microcirculatory and hypoxia-related perfusion parameters in septic shock: A randomized controlled trial. Ann Intensive Care 2020; 10:150

136. Kattan E, Bakker J, Estenssoro E, et al: Hemodynamic phenotype-based, capillary refill time-targeted resuscitation in early septic shock: The ANDROMEDA-SHOCK-2 randomized clinical trial study protocol. Rev Bras Ter Intensiva 2022; 34:96–106

137. Levy B: Lactate and shock state: The metabolic view. Curr Opin Crit Care 2006; 12:315–321

138. Pan J, Peng M, Liao C, et al: Relative efficacy and safety of early lactate clearance-guided therapy resuscitation in patients with sepsis: A meta-analysis. Medicine (Baltim) 2019; 98:e14453

139. Gordon AC, Mason AJ, Thirunavukkarasu N, et al; VANISH Investigators: Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock: The VANISH randomized clinical trial. JAMA 2016; 316:509–518

140. Hajjar LA, Zambolim C, Belletti A, et al: Vasopressin versus norepinephrine for the management of septic shock in cancer patients: The VANCS II randomized clinical trial. Crit Care Med 2019; 47:1743–1750

141. Khanna A, English SW, Wang XS, et al; ATHOS-3 Investigators: Angiotensin II for the treatment of vasodilatory shock. N Engl J Med 2017; 377:419–430

142. Chawla LS, Busse L, Brasha-Mitchell E, et al: Intravenous angiotensin II for the treatment of high-output shock (ATHOS trial): a pilot study. Crit Care 2014; 18:534

143. Drugs.com. Comparing Levophed vs Vasopressin. Available at: https://www.drugs.com/compare/levophed-vs-vasopres- sin Accessed July 22, 2025

144. Russell JA, Walley KR, Singer J, et al; VASST Investigators: Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008; 358:877–887

145. Chen C, Pang L, Wang Y, et al: Combination era, using combined vasopressors showed benefits in treating septic shock patients: A network meta-analysis of randomized controlled trials. Ann Transl Med 2019; 7:535

146. Myburgh JA, Higgins A, Jovanovska A, et al; CAT Study investigators: A comparison of epinephrine and norepinephrine in critically ill patients. Intensive Care Med 2008; 34:2226–2234

147. Belletti A, Benedetto U, Biondi-Zoccai G, et al: The effect of vasoactive drugs on mortality in patients with severe sepsis and septic shock. A network meta-analysis of randomized trials. J Crit Care 2017; 37:91–98

148. McChesney C, Orozco N, Fiorini K, et al: Impact of short-acting beta-blockers on the outcomes of patients with septic shock: A systematic review and meta-analysis. Crit Care Med 2025; 53:e1125–e1139

149. Kilcommons SJ, Hammal F, Kamaleldin M, et al: Adjunctive midodrine therapy for vasopressor-dependent shock in the ICU: A systematic review and meta-analysis. Crit Care Med 2025; 53:e384–e399

150. Fernando SM, Tran A, Soliman K, et al: Methylene blue in septic shock: A systematic review and meta-analysis. Crit Care Explor 2024; 6:e1110

151. Chaudhuri D, Lazarte J, Shah K, et al. Approaches to converting Spo2/FIO2 ratio to PaO2/FIO2 ratio for assessment of respiratory failure in critically ill patients: A systematic review. Crit Care Med 2026 Jan 6. [online first]

152. Sjoding MW, Dickson RP, Iwashyna TJ, et al: Racial bias in pulse oximetry measurement. N Engl J Med 2020; 383:2477–2478

153. Martin D, Johns C, Sorrell L, et al: Effect of skin tone on the accuracy of the estimation of arterial oxygen saturation by pulse oximetry: A systematic review. Br J Anaesth 2024; 132:945–956

154. Alipanah-Lechner N, Cavalcanti AB, Diaz J, et al: From Berlin to global: The need for syndromic definitions of acute respiratory distress syndrome. Am J Respir Crit Care Med 2024; 209:21–23

155. Klitgaard TL, Schjørring OL, Nielsen FM, et al: Higher versus lower fractions of inspired oxygen or targets of arterial oxygenation for adults admitted to the intensive care unit. Cochrane Database Syst Rev 2023; 9:CD012631

156. Buell KG, Spicer AB, Casey JD, et al: Individualized treatment effects of oxygen targets in mechanically ventilated critically ill adults. JAMA 2024; 331:1195–1204

157. Frat JP, Quenot J-P, Badie J, et al; SOHO-COVID Study Group and the REVA Network: Effect of high-flow nasal cannula oxygen vs standard oxygen therapy on mortality in patients with respiratory failure due to COVID-19: The SOHO-COVID randomized clinical trial. JAMA 2022; 328:1212–1222

158. Perkins GD, Ji C, Connolly BA, et al; RECOVERY-RS Collaborators: Effect of noninvasive respiratory strategies on intubation or mortality among patients with acute hypoxemic respiratory failure and COVID-19: The RECOVERY-RS randomized clinical trial. JAMA 2022; 327:546–558

159. Crimi C, Noto A, Madotto F, et al; COVID-HIGH Investigators: High-flow nasal oxygen versus conventional oxygen therapy in patients with COVID-19 pneumonia and mild hypoxemia: A randomized controlled trial. Thorax 2023; 78:354–361

160. Nagata K, Yokoyama T, Tsugitomi R, et al; JaNP-Hi Study Investigators: Continuous positive airway pressure versus high-flow nasal cannula oxygen therapy for acute hypoxemic respiratory failure: A randomized controlled trial. Respirology 2024; 29:36–45

161. Investigators R, et al.: High-flow nasal oxygen vs noninvasive ventilation in patients with acute respiratory failure: The RENOVATE randomized clinical trial. JAMA 2025; 333:875–890

162. Coudroy R, Frat J-P, Ehrmann S, et al; FLORALI-IM study group and the REVA Research Network: High-flow nasal oxygen alone or alternating with non-invasive ventilation in critically ill immunocompromised patients with acute respiratory failure: A randomized controlled trial. Lancet Respir Med 2022; 10:641–649

163. Frat JP, Thille AW, Mercat A, et al; FLORALI Study Group: High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure. N Engl J Med 2015; 372:2185–2196

164. Luo J, Pavlov I, Tavernier E, et al; Awake Prone Positioning Meta-Analysis Group: Awake prone positioning in adults with COVID-19: An individual participant data meta-analysis. JAMA Intern Med 2025; 185:572–581

165. Alhazzani W, Parhar KKS, Weatherald J, et al; COVI- PRONE Trial Investigators and the Saudi Critical Care Trials Group: Effect of awake prone positioning on endo- tracheal intubation in patients with COVID-19 and acute respiratory failure: A randomized clinical trial. JAMA 2022; 327:2104–2113

166. Landry DW, Levin HR, Gallant EM, et al: Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation 1997; 95:1122–1125 354.

167. Gordon AC, Mason AJ, Thirunavukkarasu N, et al; VANISH Investigators: Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock: The VANISH randomized clinical trial. JAMA 2016; 316:509–518

168. Brower RG, Matthay MA, Morris A, et al; 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

169. Hager DN, Krishnan JA, Hayden DL, et al; ARDS Clinical Trials Network: Tidal volume reduction in patients with acute lung injury when plateau pressures are not high. Am J Respir Crit Care Med 2005; 172:1241–1245

170. Checkley W, Brower R, Korpak A, et al; Acute Respiratory Distress Syndrome Network Investigators: Effects of a clinical trial on mechanical ventilation practices in patients with acute lung injury. Am J Respir Crit Care Med 2008; 177:1215–1222

171. Amato MB, Meade MO, Slutsky AS, et al: Driving pressure and survival in the acute respiratory distress syndrome. N Engl J Med 2015; 372:747–755

172. de Haro C, Neto AS, Gomà G, et al: Effect of a low versus intermediate tidal volume strategy on pulmonary complications in patients at risk of acute respiratory distress syndrome- a randomized clinical trial. Front Med (Lausanne) 2023; 10:1172434

173. Writing Group for the PI, et al.: Effect of a low vs intermediate tidal volume strategy on ventilator-free days in intensive care unit patients without ARDS: A randomized clinical trial. JAMA 2018; 320:1872–1880

174. Brochard L, Roudot-Thoraval F, Roupie E, et al: Tidal volume reduction for prevention of ventilator-induced lung injury in acute respiratory distress syndrome. The Multicenter Trail Group on Tidal Volume reduction in ARDS. Am J Respir Crit Care Med 1998; 158:1831–1838

175. Brower RG, Shanholtz CB, Fessler HE, et al: Prospective, ran- domized, controlled clinical trial comparing traditional versus reduced tidal volume ventilation in acute respiratory distress syndrome patients. Crit Care Med 1999; 27:1492–1498

176. Papazian L, Aubron C, Brochard L, et al: Formal guidelines: Management of acute respiratory distress syndrome. Ann Intensive Care 2019; 9:69

177. Laffey JG, Bellani G, Pham T, et al; LUNG SAFE Investigators and the ESICM Trials Group: Potentially modifiable factors contributing to outcome from acute respiratory distress syn- drome: The LUNG SAFE study. Intensive Care Med 2016; 42:1865–1876

178. Villar J, Martín-Rodríguez C, Domínguez-Berrot AM, et al; Spanish Initiative for Epidemiology, Stratification and Therapies for ARDS (SIESTA) Investigators Network: A quantile analysis of plateau and driving pressures: Effects on mortality in patients with acute respiratory distress syn- drome receiving lung-protective ventilation. Crit Care Med 2017; 45:843–850

179. Brower RG, Lanken PN, MacIntyre N, et al; National Heart, Lung, and Blood Institute ARDS Clinical Trials Network: Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 2004; 351:327–336

180. Meade MO, Cook DJ, Guyatt GH, et al; Lung Open Ventilation Study Investigators: Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: A randomized controlled trial. JAMA 2008; 299:637–645

181. Mercat A, Richard JC, Vielle B, et al: Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: A randomized controlled trial. JAMA 2008; 299:646–655

182. Briel M, Meade M, Mercat A, et al: Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: Systematic review and meta-analysis. JAMA 2010; 303:865–873

183. Cavalcanti AB, Suzumura ÉA, Laranjeira LN, et al: 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 2017; 318:1335–1345

184. Munshi L, Del Sorbo L, Adhikari NKJ, et al: Prone position for acute respiratory distress syndrome. A systematic review and meta-analysis. Ann Am Thorac Soc 2017; 14(Suppl 4):S280–S288

185. Guérin C, Reignier J, Richard JC, et al; PROSEVA Study Group: Prone positioning in severe acute respiratory distress syndrome. N Engl J Med 2013; 368:2159–2168

186. National Heart, Lung, and Blood Institute PETAL Clinical Trials Network; Moss M, Huang DT, Brower RG, et al: Early neuromuscular blockade in the acute respiratory distress syndrome. N Engl J Med 2019; 380:1997–2008

187. Combes A, Hajage D, Capellier G, et al; EOLIA Trial Group, REVA, and ECMONet: Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome. N Engl J Med 2018; 378:1965–1975

188. Peek GJ, Mugford M, Tiruvoipati R, et al; CESAR trial collaboration: Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): A multicenter randomized controlled trial. Lancet 2009; 374:1351–1363

189. Munshi L, Walkey A, Goligher E, et al: Venovenous extracorporeal membrane oxygenation for acute respiratory distress syndrome: A systematic review and meta-analysis. Lancet Respir Med 2019; 7:163–172

190. Pitre T, Drover K, Chaudhuri D, et al: Corticosteroids in sepsis and septic shock: A systematic review, pairwise, and dose-response meta-analysis. Crit Care Explor 2024; 6:e1000

191. Diaz-Gomez JL, Sharif S, Ablordeppey E, et al: Society of critical care medicine guidelines on adult critical care ultrasonography: Focused update 2024. Crit Care Med 2025; 53:e447–e458

192. Sakkat A, Alquraini M, Aljazeeri J, et al: Temperature control in critically ill patients with fever: A meta-analysis of randomized controlled trials. J Crit Care 2021; 61:89–95

193. Reintam Blaser A, Alhazzani W, Belley-Cote E, et al: Intravenous vitamin C therapy in adult patients with sepsis: A rapid practice guideline. Acta Anaesthesiol Scand 2023; 67:1423–1431

194. Agarwal A, Basmaji J, Fernando SM, et al: Parenteral Vitamin C in patients with severe infection: A systematic review. NEJM Evid 2022; 1:EVIDoa2200105

195. Lamontagne F, Masse M-H, Menard J, et al; LOVIT Investigators and the Canadian Critical Care Trials Group: Intravenous Vitamin C in adults with sepsis in the intensive care unit. N Engl J Med 2022; 386:2387–2398

196. Pan B, Sun P, Pei R, et al: Efficacy of IVIG therapy for patients with sepsis: A systematic review and meta-analysis. J Transl Med 2023; 21:765

197. Kaur M, Soni KD, Trikha A: Does vitamin D improve all-cause mortality in critically ill adults? An updated systematic review and meta-analysis of randomized controlled trials. Indian J Crit Care Med 2022; 26:853–862

198. National Heart L, et al.: Early high-dose Vitamin D(3) for critically ill, Vitamin D-deficient patients. N Engl J Med 2019; 381:2529–2540

199. Liu S, Yao C, Xie J, et al; EXIT-SEP Investigators: Effect of an herbal-based injection on 28-Day mortality in patients with sepsis: The EXIT-SEP randomized clinical trial. JAMA Intern Med 2023; 183:647–655

200. Li C, Wang P, Zhang Li, et al: Efficacy and safety of Xuebijing injection (a Chinese patent) for sepsis: A meta-analysis of randomized controlled trials. J Ethnopharmacol 2018; 224:512–521

201. Wang J, Zhu J, Guo J, et al: Could xuebijing injection reduce the mortality of severe pneumonia patients? A systematic review and meta-analysis. Evid Based Complement Alternat Med 2020; 2020:9605793

202. Chen JJ, Lai P-C, Lee T-H, et al: Blood purification for adult patients with severe infection or sepsis/septic shock: A net- work meta-analysis of randomized controlled trials. Crit Care Med 2023; 51:1777–1789

203. Rimmer E, Houston BL, Kumar A, et al: The efficacy and safety of plasma exchange in patients with sepsis and septic shock: A systematic review and meta-analysis. Crit Care 2014; 18:699

204. American Diabetes Association: 14. Diabetes care in the hospital: Standards of medical care in diabetes—2018. Diabetes Care 2018; 41(Suppl 1):S144–S151

205. Yatabe T, Inoue S, Sakaguchi M, et al: The optimal target for acute glycemic control in critically ill patients: A network meta-analysis. Intensive Care Med 2017; 43:16–28

206. Hirano Y, Miyoshi Y, Kondo Y, et al: Liberal versus restrictive red blood cell transfusion strategy in sepsis or septic shock: A systematic review and meta-analysis of randomized trials. Crit Care 2019; 23:262

207. Bergamin FS, Almeida JP, Landoni G, et al: Liberal versus restrictive transfusion strategy in critically ill oncologic patients: The transfusion requirements in critically ill oncologic patients randomized controlled trial. Crit Care Med 2017; 45:766–773

208. Wang Y, Parpia S, Ge L, et al: Proton-pump inhibitors to pre- vent gastrointestinal bleeding - an updated meta-analysis. NEJM Evid 2024; 3:EVIDoa2400134

209. Cook D, Deane A, Lauzier F, et al; REVISE Investigators: Stress ulcer prophylaxis during Invasive mechanical ventilation. N Engl J Med 2024; 391:9–20

210. Granholm A, Zeng L, Dionne JC, et al; GUIDE Group: Predictors of gastrointestinal bleeding in adult ICU patients: a systematic review and meta-analysis. Intensive Care Med 2019; 45:1347–1359

211. MacLaren R, Dionne JC, Granholm A, et al: Society of Critical Care Medicine and American Society of Health-System Pharmacists Guideline for the Prevention of Stress-Related Gastrointestinal Bleeding in Critically Ill Adults. Crit Care Med 2024; 52:e421–e430

212. STARRT-AKI Investigators; Canadian Critical Care Trials Group; Australian and New Zealand Intensive Care Society Clinical Trials Group; United Kingdom Critical Care Research Group; Canadian Nephrology Trials Network; Irish Critical Care Trials Group; Bagshaw SM, Wald R, Adhikari NKJ; et al: Timing of initiation of renal-replacement therapy in acute kidney injury. N Engl J Med 2020; 383:240–251

213. Zha J, Li C, Cheng G, et al: The efficacy of renal replacement therapy strategies for septic-acute kidney injury: A PRISMAcompliant network meta-analysis. Medicine (Baltimore) 2019; 98:e15257

214. Zhao Y, Chen Y: Effect of renal replacement therapy modalities on renal recovery and mortality for acute kidney injury: A PRISMA-compliant systematic review and meta-analysis. Semin Dial 2020; 33:127–132

215. Reignier J, Boisramé-Helms J, Brisard L, et al; NUTRIREA-2 Trial Investigators; Clinical Research in Intensive Care and Sepsis (CRICS) group: Enteral versus parenteral early nutrition in ventilated adults with shock: A randomized, controlled, multicenter, open-label, parallel-group study (NUTRIREA-2). Lancet 2018; 391:133–143

216. Jaber S, Paugam C, Futier E, et al; BICAR-ICU Study Group: Sodium bicarbonate therapy for patients with severe metabolic acidemia in the intensive care unit (BICAR-ICU): A multicenter, open-label, randomized controlled, phase 3 trial. Lancet 2018; 392:31–40

217. Ostermann M, Alshamsi F, Artigas Raventos A, et al: European society of intensive care medicine clinical practice guideline on fluid therapy in adult critically ill patients: Part 3-fluid removal at de-escalation phase. Intensive Care Med 2025; 51:1749–1763

218. Sharif S, Greer A, Skorupski C, et al: Probiotics in critical ill- ness: A systematic review and meta-analysis of randomized controlled trials. Crit Care Med 2022; 50:1175–1186

219. Johnstone J, Meade M, Lauzier F, et al; Prevention of Severe Pneumonia and Endotracheal Colonization Trial (PROSPECT) Investigators and the Canadian Critical Care Trials Group: Effect of probiotics on incident ventilator- associated pneumonia in critically ill patients: A randomized clinical trial. JAMA 2021; 326:1024–1033

220. Arabi YM, Al-Hameed F, Burns KEA, et al; Saudi Critical Care Trials Group: Adjunctive intermittent pneumatic compression for venous thromboprophylaxis. N Engl J Med 2019; 380:1305–1315