Hector R Wong1,2, Kimberly W Hart3, Christopher J Lindsell3, Timothy E Sweeney4. 1. Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH. 2. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH. 3. Vanderbilt University Medical Center, Nashville, TN. 4. Inflammatix, Burlingame, CA.
Abstract
OBJECTIVES: We previously reported gene expression-based endotypes of pediatric septic shock, endotypes A and B, and that corticosteroid exposure was independently associated with increased mortality among pediatric endotype A patients. The Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock trial tested the efficacy of vasopressin as initial vasopressor therapy for septic shock among adult patients, when compared with norepinephrine. Patients who reached a prespecified dose of either vasopressor were further randomized to receive hydrocortisone or placebo. A proportion of patients in the Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock trial had transcriptomic data generated at baseline using whole blood-derived messenger RNA. We used the publicly available transcriptomic data from the Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock trial to assign the study subjects to pediatric septic shock endotype A or B, and tested the hypothesis that hydrocortisone treatment is associated with increased mortality among patients in endotype A. DESIGN: Secondary analysis of publicly available transcriptomic data. SETTING: Multiple adult ICUs. PATIENTS: Adults with septic shock randomized to hydrocortisone (n = 47) or placebo (n = 50). INTERVENTIONS: Randomization to the Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock trial experimental arms. MEASUREMENTS AND MAIN RESULTS: Endotype A patients receiving hydrocortisone had a mortality rate of 46%, whereas endotype A patients receiving placebo had a mortality rate of 22% (p = 0.105). In contrast, the mortality rates for endotype B patients receiving hydrocortisone or placebo were 19% and 22%, respectively. The odds of death were more than three times greater in endotype A patients receiving hydrocortisone than endotype A patients receiving placebo (p = 0.05). CONCLUSIONS: This exploratory analysis provides further evidence that corticosteroid exposure may be associated with increased mortality among septic shock endotype A patients.
OBJECTIVES: We previously reported gene expression-based endotypes of pediatric septic shock, endotypes A and B, and that corticosteroid exposure was independently associated with increased mortality among pediatric endotype A patients. The Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock trial tested the efficacy of vasopressin as initial vasopressor therapy for septic shock among adult patients, when compared with norepinephrine. Patients who reached a prespecified dose of either vasopressor were further randomized to receive hydrocortisone or placebo. A proportion of patients in the Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock trial had transcriptomic data generated at baseline using whole blood-derived messenger RNA. We used the publicly available transcriptomic data from the Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock trial to assign the study subjects to pediatric septic shock endotype A or B, and tested the hypothesis that hydrocortisone treatment is associated with increased mortality among patients in endotype A. DESIGN: Secondary analysis of publicly available transcriptomic data. SETTING: Multiple adult ICUs. PATIENTS: Adults with septic shock randomized to hydrocortisone (n = 47) or placebo (n = 50). INTERVENTIONS: Randomization to the Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock trial experimental arms. MEASUREMENTS AND MAIN RESULTS: Endotype A patients receiving hydrocortisone had a mortality rate of 46%, whereas endotype A patients receiving placebo had a mortality rate of 22% (p = 0.105). In contrast, the mortality rates for endotype B patients receiving hydrocortisone or placebo were 19% and 22%, respectively. The odds of death were more than three times greater in endotype A patients receiving hydrocortisone than endotype A patients receiving placebo (p = 0.05). CONCLUSIONS: This exploratory analysis provides further evidence that corticosteroid exposure may be associated with increased mortality among septic shock endotype A patients.
Authors: Hector R Wong; Natalie Z Cvijanovich; Geoffrey L Allen; Neal J Thomas; Robert J Freishtat; Nick Anas; Keith Meyer; Paul A Checchia; Scott L Weiss; Thomas P Shanley; Michael T Bigham; Sharon Banschbach; Eileen Beckman; Kelli Harmon; Jerry J Zimmerman Journal: Am J Respir Crit Care Med Date: 2014-04-15 Impact factor: 21.405
Authors: Hector R Wong; Sarah J Atkinson; Natalie Z Cvijanovich; Nick Anas; Geoffrey L Allen; Neal J Thomas; Michael T Bigham; Scott L Weiss; Julie C Fitzgerald; Paul A Checchia; Keith Meyer; Michael Quasney; Mark Hall; Rainer Gedeit; Robert J Freishtat; Jeffrey Nowak; Shekhar S Raj; Shira Gertz; Christopher J Lindsell Journal: Crit Care Med Date: 2016-10 Impact factor: 7.598
Authors: Timothy E Sweeney; Tej D Azad; Michele Donato; Winston A Haynes; Thanneer M Perumal; Ricardo Henao; Jesús F Bermejo-Martin; Raquel Almansa; Eduardo Tamayo; Judith A Howrylak; Augustine Choi; Grant P Parnell; Benjamin Tang; Marshall Nichols; Christopher W Woods; Geoffrey S Ginsburg; Stephen F Kingsmore; Larsson Omberg; Lara M Mangravite; Hector R Wong; Ephraim L Tsalik; Raymond J Langley; Purvesh Khatri Journal: Crit Care Med Date: 2018-06 Impact factor: 7.598
Authors: Brendon P Scicluna; Lonneke A van Vught; Aeilko H Zwinderman; Maryse A Wiewel; Emma E Davenport; Katie L Burnham; Peter Nürnberg; Marcus J Schultz; Janneke Horn; Olaf L Cremer; Marc J Bonten; Charles J Hinds; Hector R Wong; Julian C Knight; Tom van der Poll Journal: Lancet Respir Med Date: 2017-08-29 Impact factor: 30.700
Authors: Hector R Wong; Natalie Z Cvijanovich; Nick Anas; Geoffrey L Allen; Neal J Thomas; Michael T Bigham; Scott L Weiss; Julie Fitzgerald; Paul A Checchia; Keith Meyer; Thomas P Shanley; Michael Quasney; Mark Hall; Rainer Gedeit; Robert J Freishtat; Jeffrey Nowak; Raj S Shekhar; Shira Gertz; Emily Dawson; Kelli Howard; Kelli Harmon; Eileen Beckman; Erin Frank; Christopher J Lindsell Journal: Am J Respir Crit Care Med Date: 2015-02-01 Impact factor: 21.405
Authors: Hector R Wong; Timothy E Sweeney; Kimberly W Hart; Purvesh Khatri; Christopher J Lindsell Journal: Crit Care Med Date: 2017-12 Impact factor: 7.598
Authors: Emma E Davenport; Katie L Burnham; Jayachandran Radhakrishnan; Peter Humburg; Paula Hutton; Tara C Mills; Anna Rautanen; Anthony C Gordon; Christopher Garrard; Adrian V S Hill; Charles J Hinds; Julian C Knight Journal: Lancet Respir Med Date: 2016-02-23 Impact factor: 102.642
Authors: David B Antcliffe; Katie L Burnham; Farah Al-Beidh; Shalini Santhakumaran; Stephen J Brett; Charles J Hinds; Deborah Ashby; Julian C Knight; Anthony C Gordon Journal: Am J Respir Crit Care Med Date: 2019-04-15 Impact factor: 21.405
Authors: David M Maslove; Benjamin Tang; Manu Shankar-Hari; Patrick R Lawler; Derek C Angus; J Kenneth Baillie; Rebecca M Baron; Michael Bauer; Timothy G Buchman; Carolyn S Calfee; Claudia C Dos Santos; Evangelos J Giamarellos-Bourboulis; Anthony C Gordon; John A Kellum; Julian C Knight; Aleksandra Leligdowicz; Daniel F McAuley; Anthony S McLean; David K Menon; Nuala J Meyer; Lyle L Moldawer; Kiran Reddy; John P Reilly; James A Russell; Jonathan E Sevransky; Christopher W Seymour; Nathan I Shapiro; Mervyn Singer; Charlotte Summers; Timothy E Sweeney; B Taylor Thompson; Tom van der Poll; Balasubramanian Venkatesh; Keith R Walley; Timothy S Walsh; Lorraine B Ware; Hector R Wong; Zsolt E Zador; John C Marshall Journal: Nat Med Date: 2022-06-17 Impact factor: 87.241