@article{376fc7e5e68f49288d5cb9f5c3da78cf,
title = "Redefining Critical Illness",
abstract = "Both research and practice in critical care medicine have long been defined by syndromes. Though clinically recognizable entities, these are in fact loose amalgams of heterogeneous states, within which responses to therapy may vary. Mounting translational evidence suggests the current syndrome-based framework of critical illness should be reconsidered. Moreover, research done during the COVID-19 pandemic illustrates how the study of a more biologically homogeneous condition – respiratory failure due to SARS-CoV-2 infection – can increase the efficiency with which actionable results are generated. We discuss recent findings from basic science and clinical research in critical care, and explore how these might inform a new conceptual model of critical illness. De-emphasizing syndromes, we focus instead on the underlying biological changes that underpin critical illness states, and that may be amenable to treatment. We hypothesize that such an approach will accelerate translational critical care research, leading to a richer understanding of the pathobiology of critical illness, and of the proximate determinants of ICU outcomes. The specificity and granularity gained will support the design of more effective clinical trials, and inform a more precise, effective practice at the bedside.",
author = "Maslove, {David M} and Benjamin Tang and Manu Shankar-Hari and Lawler, {Patrick R} and Angus, {Derek C} and Baillie, {J Kenneth} and Baron, {Rebecca M} and Michael Bauer and Buchman, {Timothy G} and Calfee, {Carolyn S} and {dos Santos}, {Claudia C} and Giamarellos-Bourboulis, {Evangelos J} and Anthony Gordon and Kellum, {John A} and Knight, {Julian C} and Aleksandra Leligdowicz and McAuley, {Daniel F} and McLean, {Anthony S} and Menon, {David K} and Meyer, {Nuala J} and Moldawer, {Lyle L} and Kiran Reddy and Reilly, {John P} and Russell, {James K.} and Sevransky, {Jonathan E} and Seymour, {Christopher W} and Shapiro, {Nathan I} and Mervyn Singer and Charlotte Summers and Sweeney, {Timothy E} and Taylor Thompson and Poll, {Tom van der} and Bala Venkatesh and Walley, {Keith R} and Walsh, {Timothy S.} and War, {Lorraine B} and Wong, {Hector R} and Zsolt, {Zador E} and Marshall, {John C}",
note = "Funding Information: R.M.B. reports having served on advisory boards for Merck and Genentech. M.B. is a stockholder of SmartDyeLivery, a company developing nanodrugs for sepsis. T.G.B. has no direct conflicts of interest. His employer, Emory University, collects a stipend for his service as Editor-in-Chief of Critical Care Medicine from the Society of Critical Care Medicine. Emory University also collects a stipend from the US Government for his service as senior advisor to the Biomedical Advanced Research and Development Authority. C.S.C. receives grant funding from the NIH, US Food and Drug Administration, US Department of Defense, Quantum Leap Healthcare Collaborative and Roche-Genentech and has provided consulting services for Quark, Vasomune, Gen1e Life Sciences, Cellenkos, and Janssen. A.C.G. is supported by an NIHR Research Professorship (RP-2015-06-018) and the NIHR Imperial Biomedical Research Centre. Outside of this work he has received personal fees from 30 Respiratory paid to his institution. Outside the submitted work, D.F.M. reports personal fees from consultancy for GlaxoSmithKline, Boehringer Ingelheim, Bayer, Novartis, Sobi and Eli Lilly and from sitting on a Data Monitoring and Ethics Committee for trials undertaken by Vir Biotechnology and Faron Pharmaceuticals. In addition, his institution has received funds from grants from the National Institute for Health and Care Research (NIHR), the Wellcome Trust, Innovate-UK, the Medical Research Council (MRC) and the Northern Ireland HSC R&D Division. D.F.M. also holds a patent for an anti-inflammatory treatment issued to Queen{\textquoteright}s University Belfast. D.F.M. was Director of Research for the UK Intensive Care Society (term ended in June 2021) and is NIHR/MRC Efficacy and Mechanism Evaluation Programme Director. D.K.M. reports grants from the European Union, the NIHR and the Canadian Institute for Advanced Research supporting the submitted work; grants from GlaxoSmithKline and Lantmannen; and consulting fees from Calico, GlaxoSmithKline, Lantmannen, NeuroTrauma Sciences and Integra Neurosciences outside the submitted work. L.L.M. reports grants and contracts from the NIGMS, NICHD, and NIAID (NIH), as well as subcontracts from Inflammatix and Beckman-Coulter through awards from BARDA (HHS). In addition, L.L.M. participates in clinical studies supported by RevImmune, Immunex, Faraday and Beckman-Coulter. J.A.R. reports patents owned by the University of British Columbia that are related to (1) the use of PCSK9 inhibitor(s) in sepsis and (2) the use of vasopressin in septic shock, as well as (3) a patent owned by Ferring Pharmaceuticals for the use of selepressin in septic shock. J.A.R. is an inventor on these patents. J.A.R. was a founder, director and shareholder in Cyon Therapeutics and is a shareholder in Molecular You Corp. J.A.R. is no longer actively consulting for any industry. J.A.R. reports receiving consulting fees in the last 3 years from SIB Therapeutics (developing a sepsis drug), Ferring Pharmaceuticals (manufactures vasopressin and is developing selepressin) and PAR Pharma (sells prepared bags of vasopressin). J.A.R. was a funded member of the Data and Safety Monitoring Board of a National Institutes of Health-sponsored trial of plasma in COVID-19 (PASS-IT-ON) (2020–2021). J.A.R. reports having received an investigator-initiated grant from Grifols (titled {\textquoteleft}Is HBP a mechanism of albuminʼs efficacy in human septic shock?{\textquoteright}) that was provided to and administered by the University of British Columbia. J.A.R. has received four grants for COVID-19 research from the Canadian Institutes of Health Research and two grants from the St. Paul{\textquoteright}s Foundation. J.A.R. was also a non-funded science advisor and member of the Government of Canada COVID-19 Therapeutics Task Force (2020–2021). N.I.S. reports research funding from the National Institutes of Health, Luminos, Inflammatix and Google and is a consultant for Diagnostic Robotics. M.S. has served on advisory boards for infection and sepsis-related projects from Abbott, AM Pharma, Aptarion, Biotest, Biomerieux, deePull, Pfizer, Roche, Safeguard Biosystems and Spiden, and from Deltex Medical, Fresenius and Nestle outside the submitted work. M.S. holds a patent owned by University College London related to a sulphide-releasing molecule for ischaemia-reperfusion injury and a pending patent for phytosterol use in sepsis. UCL also holds shares in Deltex Medical and receives research funding from the Medical Research Council, Wellcome Trust, NIHR, Innovate UK, the European Commission and the UCL Technology Fund. T.E.S. is stockholder in, and employee of, Inflammatix, which is developing a rapid test for sepsis endotypes. Outside the submitted work, B.T.T. reports personal fees from consultancy for Bayer and Genentech. B.V. reports being an NHMRC Investigator Fellow. Publisher Copyright: {\textcopyright} 2022, Springer Nature America, Inc.",
year = "2022",
month = jun,
day = "17",
doi = "10.1038/s41591-022-01843-x",
language = "English",
volume = "28",
pages = "1141–1148",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Research",
}