Newly Published
Clinical Focus Review  |   January 2019
Adjunctive Corticosteroid Treatment in Septic Shock
Author Notes
  • From the University of Queensland, St. Lucia, Queensland, Australia (J.C., B.V.); the George Institute for Global Health, Sydney, New South Wales, Australia (J.C., B.V.); the Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia (J.C.); the Wesley Hospital, Brisbane, Queensland, Australia (J.C., B.V.); the Princess Alexandra Hospital, Brisbane, Queensland, Australia (B.V.); and the University of New South Wales, Sydney, New South Wales, Australia (B.V.).
  • Submitted for publication September 19, 2018. Accepted for publication November 30, 2018.
    Submitted for publication September 19, 2018. Accepted for publication November 30, 2018.×
  • Dr. Cohen and Dr. Venkatesh are authors on the Adjunctive Corticosteroid Treatment in Critically Ill Patients with Septic Shock (ADRENAL) Trial.
    Dr. Cohen and Dr. Venkatesh are authors on the Adjunctive Corticosteroid Treatment in Critically Ill Patients with Septic Shock (ADRENAL) Trial.×
  • Correspondence: Address correspondence to Dr. Cohen: ICU Offices, Level 3, Ned Hanlon Boulevard, Royal Brisbane and Women’s Hospital, Butterfield Street, Herston, Brisbane 4029 Queensland, Australia. cohenjeremy@me.com. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Clinical Focus Review
Clinical Focus Review   |   January 2019
Adjunctive Corticosteroid Treatment in Septic Shock
Anesthesiology Newly Published on January 28, 2019. doi:10.1097/ALN.0000000000002604
Anesthesiology Newly Published on January 28, 2019. doi:10.1097/ALN.0000000000002604
Interest in the role of the adrenal cortex in the recovery from an infection dates back nearly 100 yr. More than six decades of research on the role of corticosteroid supplementation as an adjunctive treatment for sepsis and septic shock failed to reveal conclusive results. Recently two large-scale randomized controlled trials have added substantial new data to inform opinion regarding the role of corticosteroids in the treatment of septic shock.1,2  In this article, we review the background, the current state of the evidence, and ongoing areas of uncertainty in this field and provide suggestions for clinical practice.
There is an established biologic rationale for the administration of adjunctive corticosteroids in the management of patients with septic shock. Septic shock arises as a result of inflammation and vasoplegia from a complex, biologic cascade that is dependent on inter- and intracellular signaling. Corticosteroids are steroid hormones synthesized in the adrenal gland from cholesterol precursors. They are divided into glucocorticoids and mineralocorticoids, which are distinguished by different target cells and effects. Mineralocorticoids have greater effects upon salt and water balance and appear to have a narrower focus of action than glucocorticoids. The biologic rationale for their use includes immune modulation, effects upon cardiovascular tone, and the treatment of relative corticosteroid deficiency. The anti-inflammatory effects of corticosteroids are well established. Corticosteroids modulate the transcription of an array of mainly nuclear factor κB–regulated genes that contribute to inflammation. The synthesis of interleukin-1, interleukin-6, and tumor necrosis factor-α is inhibited, as is inducible cyclooxygenase 2 and inducible nitric-oxide synthase.3  Corticosteroids also enhance the vasoconstrictor response to vasopressor drugs, in particular exogenous catecholamines. Although the precise mechanism by which this occurs is not known, inhibition of cyclooxygenase 2 and inducible nitric-oxide synthase are likely to play a role.4  Corticosteroids also mediate catecholamine release from neural cells, and this may partly explain the effect of corticosteroids on the vasculature.5  Suppression of proinflammatory cytokines and improved circulatory dynamics provide biologic plausibility that corticosteroids may reduce mortality through improved tissue perfusion and metabolic function. A more detailed description of the transcriptomic effect of corticosteroids is beyond the scope of this article, and the interested reader is directed to relevant reviews on the subject.6  The subject is further complicated by pathophysiological alterations in corticosteroid function that occur in the setting of sepsis. These include changes in concentrations of bound and free cortisol, differential expressions of subtypes of glucocorticoid receptors, and alterations in tissue sensitivity to corticosteroid action.7,8  These alterations are likely to impact upon our ability to adequately measure adrenocortical function in septic shock and hence add to the difficulty of conducting clinical trials.