Acute Management of Sepsis beyond 24 Hours

Abstract

Sepsis manifests as a dysregulated immune response to an infection, leading to tissue damage, organ failure, and potentially death or long-term health issues. Sepsis remains a major health challenge globally, causing approximately 50 million cases and 11 million deaths annually. Early management of sepsis focuses on source control, antimicrobial treatment, and supporting vital organ function. Subsequent care includes metabolic, nutritional, and immune therapies to address the complex needs of septic patients. Metabolic management is based on obtaining moderate glucose targets. Nutritional support aims to mitigate hypercatabolism and muscle wasting, but aggressive early nutrition does not improve outcomes and could even be harmful. Immune modulation is crucial due to the dual nature of sepsis-induced immune responses. Corticosteroids have shown benefits in shock and organ dysfunction reversal and in mortality reduction with current guidelines recommending them in vasopressor therapy-dependent patients. In conclusion, sepsis management beyond the initial hours requires a multifaceted approach, focusing on metabolic, nutritional, and immune system support tailored to individual patient needs to enhance survival and recovery.

Keywords

septic shock - metabolism - immunology - personalized medicine - intensive care unit

Authors' Contributions

Conception and design: all authors; administrative support: N.H.; provision of study materials or patients: all authors; collection and assembly of data: all authors; data analysis and interpretation: all authors; manuscript writing: all authors; final approval of manuscript: all authors.

Publikationsverlauf

Artikel online veröffentlicht:
05. Juli 2024

• References

• 1 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 (11) 1181-1247
• 2 Singer M, Deutschman CS, Seymour CW. et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016; 315 (08) 801-810
• 3 Rudd KE, Johnson SC, Agesa KM. et al. Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study. Lancet 2020; 395 (10219): 200-211
• 4 van den Berghe G, Wouters P, Weekers F. et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001; 345 (19) 1359-1367
• 5 Finfer S, Chittock DR, Su SYS. et al; NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009; 360 (13) 1283-1297
• 6 Finfer S, Liu B, Chittock DR. et al; NICE-SUGAR Study Investigators. Hypoglycemia and risk of death in critically ill patients. N Engl J Med 2012; 367 (12) 1108-1118
• 7 Gunst J, Debaveye Y, Güiza F. et al; TGC-Fast Collaborators. Tight blood-glucose control without early parenteral nutrition in the ICU. N Engl J Med 2023; 389 (13) 1180-1190
• 8 Adigbli D, Yang L, Hammond N. et al. Intensive glucose control in critically ill adults: a protocol for a systematic review and individual patient data meta-analysis. Crit Care Sci 2023; 35 (04) 345-354
• 9 Honarmand K, Sirimaturos M, Hirshberg EL. et al. Society of Critical Care Medicine Guidelines on glycemic control for critically ill children and adults 2024. Crit Care Med 2024; 52 (04) e161-e181
• 10 Benichou N, Gaudry S, Dreyfuss D. The artificial kidney induces acute kidney injury: yes. Intensive Care Med 2020; 46 (03) 513-515
• 11 Barbar SD, Clere-Jehl R, Bourredjem A. et al; IDEAL-ICU Trial Investigators and the CRICS TRIGGERSEP Network. Timing of renal-replacement therapy in patients with acute kidney injury and sepsis. N Engl J Med 2018; 379 (15) 1431-1442
• 12 Gaudry S, Hajage D, Schortgen F. et al. Timing of renal support and outcome of septic shock and acute respiratory distress syndrome. a post hoc analysis of the AKIKI randomized clinical trial. Am J Respir Crit Care Med 2018; 198 (01) 58-66
• 13 Bagshaw SM, Wald R, Adhikari NKJ. et al; 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. Timing of initiation of renal-replacement therapy in acute kidney injury. N Engl J Med 2020; 383 (03) 240-251
• 14 Gaudry S, Hajage D, Benichou N. et al. Delayed versus early initiation of renal replacement therapy for severe acute kidney injury: a systematic review and individual patient data meta-analysis of randomised clinical trials. Lancet 2020; 395 (10235): 1506-1515
• 15 Jaber S, Paugam C, Futier E. et al; BICAR-ICU Study Group. Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): a multicentre, open-label, randomised controlled, phase 3 trial. Lancet 2018; 392 (10141): 31-40
• 16 Jung B, Huguet H, Molinari N, Jaber S. Sodium bicarbonate for the treatment of severe metabolic acidosis with moderate or severe acute kidney injury in the critically ill: protocol for a randomised clinical trial (BICARICU-2). BMJ Open 2023; 13 (08) e073487
• 17 Gaudry S, Hajage D, Martin-Lefevre L. et al. Comparison of two delayed strategies for renal replacement therapy initiation for severe acute kidney injury (AKIKI 2): a multicentre, open-label, randomised, controlled trial. Lancet 2021; 397 (10281): 1293-1300
• 18 Wald R, Gaudry S, da Costa BR. et al; STARRT-AKI Investigators. Initiation of continuous renal replacement therapy versus intermittent hemodialysis in critically ill patients with severe acute kidney injury: a secondary analysis of STARRT-AKI trial. Intensive Care Med 2023; 49 (11) 1305-1316
• 19 Gaudry S, Grolleau F, Barbar S. et al. Continuous renal replacement therapy versus intermittent hemodialysis as first modality for renal replacement therapy in severe acute kidney injury: a secondary analysis of AKIKI and IDEAL-ICU studies. Crit Care 2022; 26 (01) 93
• 20 Piton G, Le Gouge A, Boisramé-Helms J. et al; Clinical Research in Intensive Care and Sepsis (CRICS) group. Factors associated with acute mesenteric ischemia among critically ill ventilated patients with shock: a post hoc analysis of the NUTRIREA2 trial. Intensive Care Med 2022; 48 (04) 458-466
• 21 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 randomised, controlled, multicentre, open-label, parallel-group study (NUTRIREA-2). Lancet 2018; 391 (10116): 133-143
• 22 Doig GS, Simpson F, Sweetman EA. et al; Early PN Investigators of the ANZICS Clinical Trials Group. Early parenteral nutrition in critically ill patients with short-term relative contraindications to early enteral nutrition: a randomized controlled trial. JAMA 2013; 309 (20) 2130-2138
• 23 Casaer MP, Mesotten D, Hermans G. et al. Early versus late parenteral nutrition in critically ill adults. N Engl J Med 2011; 365 (06) 506-517
• 24 Fivez T, Kerklaan D, Mesotten D. et al. Early versus late parenteral nutrition in critically ill children. N Engl J Med 2016; 374 (12) 1111-1122
• 25 Arabi YM, Aldawood AS, Haddad SH. et al; PermiT Trial Group. Permissive underfeeding or standard enteral feeding in critically ill adults. N Engl J Med 2015; 372 (25) 2398-2408
• 26 Reignier J, Plantefeve G, Mira J-P. et al; NUTRIREA-3 Trial Investigators, Clinical Research in Intensive Care, Sepsis (CRICS-TRIGGERSEP)Group. Low versus standard calorie and protein feeding in ventilated adults with shock: a randomised, controlled, multicentre, open-label, parallel-group trial (NUTRIREA-3). Lancet Respir Med 2023; 11 (07) 602-612
• 27 Heyland DK, Patel J, Compher C. et al; EFFORT Protein Trial team. The effect of higher protein dosing in critically ill patients with high nutritional risk (EFFORT Protein): an international, multicentre, pragmatic, registry-based randomised trial. Lancet 2023; 401 (10376): 568-576
• 28 Lee Z-Y, Dresen E, Lew CCH. et al. The effects of higher versus lower protein delivery in critically ill patients: an updated systematic review and meta-analysis of randomized controlled trials with trial sequential analysis. Crit Care 2024; 28 (01) 15
• 29 Hermans G, Casaer MP, Clerckx B. et al. Effect of tolerating macronutrient deficit on the development of intensive-care unit acquired weakness: a subanalysis of the EPaNIC trial. Lancet Respir Med 2013; 1 (08) 621-629
• 30 Singer P, Blaser AR, Berger MM. et al. ESPEN practical and partially revised guideline: clinical nutrition in the intensive care unit. Clin Nutr 2023; 42 (09) 1671-1689
• 31 Fajgenbaum DC, June CH. Cytokine storm. N Engl J Med 2020; 383 (23) 2255-2273
• 32 Sprung CL, Annane D, Keh D. et al; CORTICUS Study Group. Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008; 358 (02) 111-124
• 33 Venkatesh B, Finfer S, Cohen J. et al; ADRENAL Trial Investigators and the Australian–New Zealand Intensive Care Society Clinical Trials Group. Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med 2018; 378 (09) 797-808
• 34 Pirracchio R, Annane D, Waschka AK. et al. Patient-level meta-analysis of low-dose hydrocortisone in adults with septic shock. NEJM Evid 2023; 2 (06) a2300034
• 35 Annane D, Pirracchio R, Billot L. et al; ULYSSES IPDMA Collaborators. Effects of low-dose hydrocortisone and hydrocortisone plus fludrocortisone in adults with septic shock: a protocol for a systematic review and meta-analysis of individual participant data. BMJ Open 2020; 10 (12) e040931
• 36 Annane D, Sébille V, Bellissant E. Ger-Inf-05 Study Group. Effect of low doses of corticosteroids in septic shock patients with or without early acute respiratory distress syndrome. Crit Care Med 2006; 34 (01) 22-30
• 37 Antcliffe DB, Burnham KL, Al-Beidh F. et al. Transcriptomic signatures in sepsis and a differential response to steroids. from the VANISH randomized trial. Am J Respir Crit Care Med 2019; 199 (08) 980-986
• 38 Pirracchio R, Hubbard A, Sprung CL, Chevret S, Annane D. Rapid Recognition of Corticosteroid Resistant or Sensitive Sepsis (RECORDS) Collaborators. Assessment of machine learning to estimate the individual treatment effect of corticosteroids in septic shock. JAMA Netw Open 2020; 3 (12) e2029050
• 39 Annane D, Renault A, Brun-Buisson C. et al; CRICS-TRIGGERSEP Network. Hydrocortisone plus fludrocortisone for adults with septic shock. N Engl J Med 2018; 378 (09) 809-818
• 40 Gordon AC, Mouncey PR, Al-Beidh F. et al; REMAP-CAP Investigators. Interleukin-6 receptor antagonists in critically ill patients with Covid-19. N Engl J Med 2021; 384 (16) 1491-1502
• 41 Salama C, Han J, Yau L. et al. Tocilizumab in patients hospitalized with Covid-19 pneumonia. N Engl J Med 2021; 384 (01) 20-30
• 42 Rosas IO, Bräu N, Waters M. et al. Tocilizumab in hospitalized patients with severe Covid-19 pneumonia. N Engl J Med 2021; 384 (16) 1503-1516
• 43 Stone JH, Frigault MJ, Serling-Boyd NJ. et al; BACC Bay Tocilizumab Trial Investigators. Efficacy of tocilizumab in patients hospitalized with Covid-19. N Engl J Med 2020; 383 (24) 2333-2344
• 44 Hermine O, Mariette X, Tharaux P-L, Resche-Rigon M, Porcher R, Ravaud P. CORIMUNO-19 Collaborative Group. Effect of tocilizumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia: a randomized clinical trial. JAMA Intern Med 2021; 181 (01) 32-40
• 45 Kalil AC, Patterson TF, Mehta AK. et al; ACTT-2 Study Group Members. Baricitinib plus remdesivir for hospitalized adults with Covid-19. N Engl J Med 2021; 384 (09) 795-807
• 46 Guimarães PO, Quirk D, Furtado RH. et al; STOP-COVID Trial Investigators. Tofacitinib in patients hospitalized with Covid-19 pneumonia. N Engl J Med 2021; 385 (05) 406-415
• 47 Rein L, Calero K, Shah R. et al. Randomized phase 3 trial of ruxolitinib for COVID-19-associated acute respiratory distress syndrome. Crit Care Med 2022; 50 (12) 1701-1713
• 48 Cafardi J, Miller C, Terebelo H. et al. Efficacy and safety of pacritinib vs placebo for patients with severe COVID-19: a phase 2 randomized clinical trial. JAMA Netw Open 2022; 5 (12) e2242918
• 49 Aman J, Duijvelaar E, Botros L. et al. Imatinib in patients with severe COVID-19: a randomised, double-blind, placebo-controlled, clinical trial. Lancet Respir Med 2021; 9 (09) 957-968
• 50 Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol 2013; 13 (12) 862-874
• 51 Venet F, Foray A-P, Villars-Méchin A. et al. IL-7 restores lymphocyte functions in septic patients. J Immunol 2012; 189 (10) 5073-5081
• 52 Francois B, Jeannet R, Daix T. et al. Interleukin-7 restores lymphocytes in septic shock: the IRIS-7 randomized clinical trial. JCI Insight 2018; 3 (05) e98960
• 53 Daix T, Mathonnet A, Brakenridge S. et al. Intravenously administered interleukin-7 to reverse lymphopenia in patients with septic shock: a double-blind, randomized, placebo-controlled trial. Ann Intensive Care 2023; 13 (01) 17
• 54 Hotchkiss RS, Colston E, Yende S. et al. Immune checkpoint inhibition in sepsis: a phase 1b randomized, placebo-controlled, single ascending dose study of antiprogrammed cell death-ligand 1 antibody (BMS-936559). Crit Care Med 2019; 47 (05) 632-642
• 55 Hotchkiss RS, Colston E, Yende S. et al. Immune checkpoint inhibition in sepsis: a phase 1b randomized study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of nivolumab. Intensive Care Med 2019; 45 (10) 1360-1371
• 56 Pinder EM, Rostron AJ, Hellyer TP. et al. Randomised controlled trial of GM-CSF in critically ill patients with impaired neutrophil phagocytosis. Thorax 2018; 73 (10) 918-925
• 57 Leentjens J, Kox M, Koch RM. et al. Reversal of immunoparalysis in humans in vivo: a double-blind, placebo-controlled, randomized pilot study. Am J Respir Crit Care Med 2012; 186 (09) 838-845
• 58 Bouchon A, Facchetti F, Weigand MA, Colonna M. TREM-1 amplifies inflammation and is a crucial mediator of septic shock. Nature 2001; 410 (6832): 1103-1107
• 59 François B, Lambden S, Fivez T. et al; ASTONISH investigators. Prospective evaluation of the efficacy, safety, and optimal biomarker enrichment strategy for nangibotide, a TREM-1 inhibitor, in patients with septic shock (ASTONISH): a double-blind, randomised, controlled, phase 2b trial. Lancet Respir Med 2023; 11 (10) 894-904
• 60 Leventogiannis K, Kyriazopoulou E, Antonakos N. et al. Toward personalized immunotherapy in sepsis: the PROVIDE randomized clinical trial. Cell Rep Med 2022; 3 (11) 100817
• 61 Valenta J, Brodska H, Drabek T, Hendl J, Kazda A. High-dose selenium substitution in sepsis: a prospective randomized clinical trial. Intensive Care Med 2011; 37 (05) 808-815
• 62 Angstwurm MWA, Engelmann L, Zimmermann T. et al. Selenium in intensive care (SIC): results of a prospective randomized, placebo-controlled, multiple-center study in patients with severe systemic inflammatory response syndrome, sepsis, and septic shock. Crit Care Med 2007; 35 (01) 118-126
• 63 Heyland D, Muscedere J, Wischmeyer PE. et al; Canadian Critical Care Trials Group. A randomized trial of glutamine and antioxidants in critically ill patients. N Engl J Med 2013; 368 (16) 1489-1497
• 64 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 (25) 2387-2398
• 65 Agarwal A, Basmaji J, Fernando SM. et al. Parenteral vitamin C in patients with severe infection: a systematic review. NEJM Evid 2022; 1 (09) a2200105
• 66 Yanase F, Spano S, Maeda A. et al. Mega-dose sodium ascorbate: a pilot, single-dose, physiological effect, double-blind, randomized, controlled trial. Crit Care 2023; 27 (01) 371
• 67 Seymour CW, Kennedy JN, Wang S. et al. Derivation, validation, and potential treatment implications of novel clinical phenotypes for sepsis. JAMA 2019; 321 (20) 2003-2017
• 68 Scicluna BP, van Vught LA, Zwinderman AH. et al; MARS consortium. Classification of patients with sepsis according to blood genomic endotype: a prospective cohort study. Lancet Respir Med 2017; 5 (10) 816-826
• 69 Davenport EE, Burnham KL, Radhakrishnan J. et al. Genomic landscape of the individual host response and outcomes in sepsis: a prospective cohort study. Lancet Respir Med 2016; 4 (04) 259-271
• 70 Fleuriet J, Heming N, Meziani F. et al; RECORDS consortium, CRICS TRIGGERSEP network. Rapid rEcognition of COrticosteRoiD resistant or sensitive Sepsis (RECORDS): study protocol for a multicentre, placebo-controlled, biomarker-guided, adaptive Bayesian design basket trial. BMJ Open 2023; 13 (03) e066496
• 71 Kotsaki A, Pickkers P, Bauer M. et al. ImmunoSep (Personalised Immunotherapy in Sepsis) international double-blind, double-dummy, placebo-controlled randomised clinical trial: study protocol. BMJ Open 2022; 12 (12) e067251