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The Septic Shock 3.0 Definition and Trials: A Vasopressin and Septic Shock Trial Experience*

Russell, James A. MD1,2; Lee, Terry PhD3; Singer, Joel PhD3; Boyd, John H. MD1,2; Walley, Keith R. MD1,2; on behalf of the Vasopressin and Septic Shock Trial (VASST) Group

doi: 10.1097/CCM.0000000000002323
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Objectives: The Septic Shock 3.0 definition could alter treatment comparisons in randomized controlled trials in septic shock. Our first hypothesis was that the vasopressin versus norepinephrine comparison and 28-day mortality of patients with Septic Shock 3.0 definition (lactate > 2 mmol/L) differ from vasopressin versus norepinephrine and mortality in Vasopressin and Septic Shock Trial. Our second hypothesis was that there are differences in plasma cytokine levels in Vasopressin and Septic Shock Trial for lactate less than or equal to 2 versus greater than 2 mmol/L.

Design: Retrospective analysis of randomized controlled trial.

Setting: Multicenter ICUs.

Methods: We compared vasopressin-to-norepinephrine group 28- and 90-day mortality in Vasopressin and Septic Shock Trial in lactate subgroups. We measured 39 cytokines to compare patients with lactate less than or equal to 2 versus greater than 2 mmol/L.

Patients: Patients with septic shock with lactate greater than 2 mmol/L or less than or equal to 2 mmol/L, randomized to vasopressin or norepinephrine.

Interventions: Concealed vasopressin (0.03 U/min.) or norepinephrine infusions.

Measurements and Main Results: The Septic Shock 3.0 definition would have decreased sample size by about half. The 28- and 90-day mortality rates were 10–12 % higher than the original Vasopressin and Septic Shock Trial mortality. There was a significantly (p = 0.028) lower mortality with vasopressin versus norepinephrine in lactate less than or equal to 2 mmol/L but no difference between treatment groups in lactate greater than 2 mmol/L. Nearly all cytokine levels were significantly higher in patients with lactate greater than 2 versus less than or equal to 2 mmol/L.

Conclusions: The Septic Shock 3.0 definition decreased sample size by half and increased 28-day mortality rates by about 10%. Vasopressin lowered mortality versus norepinephrine if lactate was less than or equal to 2 mmol/L. Patients had higher plasma cytokines in lactate greater than 2 versus less than or equal to 2 mmol/L, a brisker cytokine response to infection. The Septic Shock 3.0 definition and our findings have important implications for trial design in septic shock.

1Centre for Heart Lung Innovation, St. Paul’s Hospital, Vancouver, BC, Canada.

2Division of Critical Care Medicine, Department of Medicine, St. Paul’s Hospital, University of British Columbia, Vancouver, BC, Canada.

3Centre for Health Evaluation and Outcome Science (CHEOS), St. Paul’s Hospital, University of British Columbia, Vancouver, BC, Canada.

*See also p. 1094.

Drs. Russell, Lee, Singer, Boyd, and Walley contributed in conception and design; analysis and interpretation; and drafting the article for important intellectual content.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Additional members of the Vasopressin and Septic Shock Trial (VASST) Group are listed in Appendix 1.

Supported, in part, by Canadian Institutes of Health Research, grant number: MCT 44152 (to Vasopressin and Septic Shock Trial; Registration: ISRCTN94845869).

Dr. Russell received funding from Cubist Pharmaceuticals, Leading Biosciences, Ferring Pharmaceuticals (manufactures vasopressin and is developing selepressin), Grifols (sells albumin), La Jolla Pharmaceuticals (developing angiotensin II; Dr. Russell chairs the data safety monitoring board [DSMB] of a trial of angiotensin II), CytoVale (developing a sepsis diagnostic), and from Asahi Kesai Pharmaceuticals of America (developing recombinant thrombomodulin). He reports patents owned by the University of British Columbia (UBC) that are related to proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor(s) and sepsis and related to the use of vasopressin in septic shock. He is an inventor on these patents. He is a founder, Director, and shareholder in Cyon Therapeutics (developing a sepsis therapy). He has share options in Leading Biosciences, and he is a shareholder in Molecular You Corp. He reports having received an investigator-initiated grant from Grifols that is provided to and administered by UBC. He disclosed off-label product use: Vasopressin for septic shock. Dr. Singer received funding from Astellas Pharma (DSMB member), La Jolla Pharma (DSMB member), and Ontario Clinical Oncology Group (DSMB chair). Dr. Walley disclosed: I am an inventor on a patent owned by the University of British Columbia and licensed to Cyon Therapeutics regarding the use of PCSK9 inhibitors in sepsis. I am a founder and shareholder of Cyon Therapeutics. Dr. Walley disclosed off-label product use: vasopressin in septic shock. The remaining authors have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: Jim.Russell@hli.ubc.ca

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