Oxidative Stress in Critical Illness

Reviewed and revised 28 August 2015


Definitions (Goodyear-Bruch and Pierce, 2002):

  • Oxidative stress is refers an imbalance between production of reactive oxygen species and the protection of antioxidants, due to the accumulation of free radicals and/or the inability of antioxidants to counter their accumulation or effects.
  • Free radicals are molecules containing one or more unpaired electrons in the outer orbit. They are highly reactive and are responsible for many chemical reactions that can lead to cellular damage.”
  • Reactive oxygen species (ROS) are molecules or atoms formed by reduction of oxygen. They can be either free radicals or non-radicals. They include superoxide (O2•), hydrogen peroxide (H2O2), and the hydroxyl radical (OH•).
  • Reduction-oxidation (“redox”) is a term used to represent the balance of reduction-oxidation reactions involving loss and gain of electrons during chemical reactions. Oxidation is the loss of electrons in a redox reaction, whereas reduction involves the gain of electrons.
  • Antioxidants are diet-derived substances that can decrease the accumulation of free radicals by removing them or countering their damaging effects on the cell


Formation of ROS

  • Normal physiological processes e.g. absorption of radiant energy, metabolic reactions, transitional metals
  • Drug metabolism
  • Infection and immune reactions (e.g. phagocytosis)
  • Ischaemia-reperfusion injury (e.g. endothelial production of xanthine oxidase)

Damage caused by ROS

  • DNA damage — includes case modification, strand breaks, and cross-linking; Hydroxyl radicals tend to target thymine
  • Lipid peroxidation — hydroxyl radical initiates removal of hydrogen from a lipid molecule in the cell membrane, making the lipid a free radical that can then react with an oxygen radical, creating a peroxy radical. The peroxy radical then obtains another hydrogen molecule from the next lipid molecule, creating lipid peroxide and another peroxy radical (Goodyear-Bruch and Pierce, 2002)
  • Protein damage — ROS oxidize amino acids (e.g lysine, serine, arginine, and proline) leading to loss of protein function and their associated cellular activities +/- autoantibody formation
  • Redox signalling — changes in ROS lead to changes in cell activities such as cell proliferation, apoptosis, gene regulation, and necrosis

Important conditions to which ROS are thought to contribute to the pathogenesis of:

  • Septic shock
  • Acute respiratory distress syndrome
  • Systemic inflammatory response syndrome
  • Disseminated intravascular coagulation
  • Multiple organ dysfunction
  • Burns
  • Cardiovascular disease
  • Diabetes mellitus
  • Trauma
  • Reperfusion Injury
  • Cancer


In normal homeostasis redox reactions are balanced by physiological counter-mechanisms involving:

  • enzymatic scavengers
  • antioxidants

Enzymatic mechanisms

  • Superoxide dismutases (O2• -> H2O2 + O2)
  • Catalase (2H2O2 -> 2H2O + O2)
  • Glutathione system, including glutathione peroxidase (converts H2O2 and glutathione to glutathione disulfide and water)
  • Peroxidases
  • Thioredoxin reductase system
  • Lipoamide system

Non-enzymatic mechanisms (antioxidants)

  • Thiols
  • Ascorbic acid
  • Urates
  • Vitamin E
  • Vitamin A and carotenes
  • Ubiquinones and ubiquinol


Numerous measures of oxidative stress have been suggested, including:

Serum levels

  • Selenium (a component of glutathione peroxidase)
  • Ascorbic acid
  • Carotene
  • Enzymatic scavengers (e.g. superoxide dismutase, lipid peroxidases, catalases)
  • Reduced and total glutathione

Urinary levels

  • metabolites (e.g. F2-isoprostanes)

Exhaled levels (breath)

  • H2O2
  • alkanes and metabolites (e.g. 8-isoprostane)


  • Evidence supporting clinical applications of interventions aimed at ameliorating oxidative stress is lacking.

References and Links

Journal articles

  • Bayir H, Kagan VE. Bench-to-bedside review: Mitochondrial injury, oxidative stress and apoptosis–there is nothing more practical than a good theory. Crit Care. 2008;12(1):206. PMC2374589.
  • Goodyear-Bruch C, Pierce JD. Oxidative stress in critically ill patients. Am J Crit Care. 2002 Nov;11(6):543-51; quiz 552-3. PMID: 12425405. [Free Full Text]
  • Hatwalne MS. Free radical scavengers in anaesthesiology and critical care. Indian J Anaesth. 2012 May;56(3):227-33. PMC3425280.
  • Helmerhorst HJ, Schultz MJ, van der Voort PH, de Jonge E, van Westerloo DJ. Bench-to-bedside review: the effects of hyperoxia during critical illness. Critical care (London, England). 19(1):284. 2015. [pubmed]

FOAM and web resources

CCC 700 6

Critical Care


Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also a Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE.  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of three amazing children.

On Twitter, he is @precordialthump.

| INTENSIVE | RAGE | Resuscitology | SMACC

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