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  • Perspective
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Redefining critical illness

Nature Medicine volume 28, pages 1141–1148 (2022)Cite this article

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Abstract

Research and practice in critical care medicine have long been defined by syndromes, which, despite being clinically recognizable entities, are, in fact, loose amalgams of heterogeneous states that may respond differently to therapy. Mounting translational evidence—supported by research on respiratory failure due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection—suggests that the current syndrome-based framework of critical illness should be reconsidered. Here 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 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 critical care research, leading to a richer understanding of the pathobiology of critical illness and of the key determinants of patient outcomes. This, in turn, will support the design of more effective clinical trials and inform a more precise and more effective practice at the bedside.

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Fig. 1: Three eras of critical care medicine.
Fig. 2: Schematic of a proposed conceptual model for critical illness based on biological features learned from translational research.
Fig. 3: Operationalizing a new conceptual model of critical illness.

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Acknowledgements

The authors would like to acknowledge the pioneering work of Hector Wong, whose leadership was instrumental in establishing the use of genome-wide analysis to more richly describe the heterogeneity of host responses to infection. His mentorship, generosity, collegiality, vision and tireless dedication will be deeply missed. Development of the concepts shaping this Perspective was facilitated through meetings of the Staging and Stratification Working Group of the International Forum for Acute Care Trialists.

Author information

Author notes

  1. These authors contributed equally: David M. Maslove, Benjamin Tang.

  2. Deceased: Hector R. Wong.

Authors and Affiliations

  1. Department of Critical Care Medicine, Queen’s University, Kingston, Ontario, Canada

    David M. Maslove

  2. Kingston Health Sciences Center, Kingston, Ontario, Canada

    David M. Maslove

  3. Department of Intensive Care Medicine, Nepean Hospital, Sydney, New South Wales, Australia

    Benjamin Tang & Anthony S. McLean

  4. The Queen’s Medical Research Institute, Centre for Inflammation Research, Institute for Regeneration and Repair, Edinburgh, UK

    Manu Shankar-Hari

  5. Intensive Care Medicine, Royal Infirmary of Edinburgh, NHS Lothian, Edinburgh, UK

    Manu Shankar-Hari & J. Kenneth Baillie

  6. Cardiac Intensive Care Unit, Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada

    Patrick R. Lawler

  7. Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada

    Patrick R. Lawler, Claudia C. dos Santos & John C. Marshall

  8. Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Derek C. Angus, John A. Kellum & Christopher W. Seymour

  9. University of Pittsburgh Medical Center, Pittsburgh, PA, USA

    Derek C. Angus

  10. Roslin Institute, University of Edinburgh, Edinburgh, UK

    J. Kenneth Baillie

  11. Pandemic Science Hub, Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK

    J. Kenneth Baillie

  12. Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    Rebecca M. Baron

  13. Harvard Medical School, Boston, MA, USA

    Rebecca M. Baron, Nathan I. Shapiro & B. Taylor Thompson

  14. Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany

    Michael Bauer

  15. Center for Sepsis Care & Control, Jena University Hospital, Jena, Germany

    Michael Bauer

  16. Emory Critical Care Center, Emory University, Atlanta, GA, USA

    Timothy G. Buchman & Jonathan E. Sevransky

  17. Santa Fe Institute, Santa Fe, NM, USA

    Timothy G. Buchman

  18. Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA

    Carolyn S. Calfee

  19. Keenan Centre for Biomedical Research of Saint Michael’s Hospital, Unity Health Toronto, Toronto, Ontario, Canada

    Claudia C. dos Santos

  20. 4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece

    Evangelos J. Giamarellos-Bourboulis

  21. Division of Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, London, UK

    Anthony C. Gordon

  22. Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK

    Julian C. Knight

  23. Department of Medicine, Division of Critical Care, University of Western Ontario, London, Ontario, Canada

    Aleksandra Leligdowicz

  24. Department of Microbiology and Immunology, University of Western Ontario, London, ON, Canada

    Aleksandra Leligdowicz

  25. Regional Intensive Care Unit, Royal Victoria Hospital, Belfast, UK

    Daniel F. McAuley & Kiran Reddy

  26. Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast, UK

    Daniel F. McAuley & Kiran Reddy

  27. Division of Anaesthesia, Department of Medicine, University of Cambridge, Cambridge, UK

    David K. Menon

  28. Department of Medicine, Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania, Philadelphia, PA, USA

    Nuala J. Meyer & John P. Reilly

  29. Sepsis and Critical Illness Research Center, Department of Surgery, University of Florida College of Medicine, Gainesville, FL, USA

    Lyle L. Moldawer

  30. Centre for Heart Lung Innovation and Critical Care Medicine, University of British Columbia, Vancouver, British Columbia, Canada

    James A. Russell & Keith R. Walley

  31. Division of Pulmonary, Allergy, Critical Care and Sleep, School of Medicine, Emory University, Atlanta, GA, USA

    Jonathan E. Sevransky

  32. Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA

    Nathan I. Shapiro

  33. Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, UK

    Mervyn Singer

  34. Department of Medicine, University of Cambridge School of Medicine, Cambridge, UK

    Charlotte Summers

  35. Inflammatix, Inc, Burlingame, CA, USA

    Timothy E. Sweeney

  36. Divisions of Biostatistics and Pulmonary/Critical Care Medicine, Massachusetts General Hospital, Boston, MA, USA

    B. Taylor Thompson

  37. Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands

    Tom van der Poll

  38. Department of Intensive Care, Wesley and Princess Alexandra Hospitals, Brisbane, Queensland, Australia

    Balasubramanian Venkatesh

  39. The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia

    Balasubramanian Venkatesh

  40. Usher Institute for Population Health Sciences, Deanery of Molecular, Genetics, and Population Health Sciences, University of Edinburgh, Edinburgh, UK

    Timothy S. Walsh

  41. Departments of Medicine and Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA

    Lorraine B. Ware

  42. Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Hector R. Wong

  43. Department of Surgery, University of Toronto, Toronto, Ontario, Canada

    Zsolt E. Zador & John C. Marshall

  44. Departments of Surgery and Critical Care Medicine, Unity Health Toronto, Toronto, Ontario, Canada

    John C. Marshall

Authors
  1. David M. Maslove
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  2. Benjamin Tang
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  3. Manu Shankar-Hari
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  4. Patrick R. Lawler
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  5. Derek C. Angus
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  7. Rebecca M. Baron
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  8. Michael Bauer
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  10. Carolyn S. Calfee
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  13. Anthony C. Gordon
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  14. John A. Kellum
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  15. Julian C. Knight
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  16. Aleksandra Leligdowicz
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  17. Daniel F. McAuley
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  18. Anthony S. McLean
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  19. David K. Menon
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  20. Nuala J. Meyer
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  21. Lyle L. Moldawer
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  22. Kiran Reddy
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  23. John P. Reilly
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  24. James A. Russell
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  25. Jonathan E. Sevransky
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  26. Christopher W. Seymour
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  28. Mervyn Singer
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  29. Charlotte Summers
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  30. Timothy E. Sweeney
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  31. B. Taylor Thompson
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  33. Balasubramanian Venkatesh
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  34. Keith R. Walley
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  35. Timothy S. Walsh
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  36. Lorraine B. Ware
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  37. Hector R. Wong
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  38. Zsolt E. Zador
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  39. John C. Marshall
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Contributions

B.T. and J.C.M. conceived of the idea, with all authors making important conceptual contributions and refining the writing of the manuscript. D.M.M., B.T., M.S.-H., P.R.L. and J.C.M. formed the primary writing group.

Corresponding author

Correspondence to David M. Maslove.

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Competing interests

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’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 ‘Is HBP a mechanism of albuminʼs efficacy in human septic shock?’) 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’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.

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Maslove, D.M., Tang, B., Shankar-Hari, M. et al. Redefining critical illness. Nat Med 28, 1141–1148 (2022). https://doi.org/10.1038/s41591-022-01843-x

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