The Timing of Initiating Hydrocortisone and Long-term Mortality in Septic Shock

BACKGROUND: Previous studies on the association between the timing of corticosteroid administration and mortality in septic shock focused only on short-term mortality and produced conflicting results. We performed a retrospective review of a large administrative database of intensive care unit (ICU) patients to evaluate the association between the timing of hydrocortisone initiation and short- and long-term mortality in septic shock. We hypothesized that a longer duration between the first vasopressor use for sepsis and steroid initiation was associated with increased mortality. METHODS: Data were extracted from the Medical Information Mart in the Intensive Care-IV database. We included adults who met Sepsis-3 definition for septic shock and received hydrocortisone. The exposure of interest was the time in hours from vasopressor use to hydrocortisone initiation (>12 as late and ≤12 as early). The primary outcome was 1-year mortality. Secondary outcomes included 28-day mortality, 90-day mortality, in-hospital mortality, and length of hospital stay. Cox proportional hazard models were used to estimate the association between exposure and mortality. Competing risk regression models were used to evaluate the association between exposure and length of hospital stay. RESULTS: A total of 844 patients were included in this cohort: 553 in the early group and 291 in the late group. The median time to hydrocortisone initiation was 7 hours (interquartile range, 2.0–19.0 hours). After multivariable Cox proportional hazard analysis, we found that hydrocortisone initiation >12 hours after vasopressor use was associated with increased 1-year mortality when compared with initiation <12 hours (adjusted hazard ratio, 1.39; 95% confidence interval, 1.13–1.71; P = .002, E-value = 2.13). Hydrocortisone initiation >12 hours was also associated with increased 28-day, 90-day, and in-hospital mortality and prolonged length of hospital stay. CONCLUSIONS: In patients with septic shock, initiating hydrocortisone >12 hours after vasopressor use was associated with an increased risk of both short-term and long-term mortality, and a prolonged length of hospital stay.

[1]  C. Libert,et al.  Sepsis: a failing starvation response , 2022, Trends in Endocrinology & Metabolism.

[2]  C. Sprung,et al.  Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021 , 2021, Intensive Care Medicine.

[3]  C. Cannon,et al.  Comparison of Early Versus Late Initiation of Hydrocortisone in Patients With Septic Shock in the ICU Setting , 2021, The Annals of pharmacotherapy.

[4]  A. Duggal,et al.  Evaluation of the Initiation Timing of Hydrocortisone in Adult Patients With Septic Shock. , 2020, Shock.

[5]  H. Gershengorn,et al.  Association of Pre-Morbid Blood Pressure with Vasopressor Infusion Duration in Patients with Shock. , 2020, American journal of respiratory and critical care medicine.

[6]  Richard D Riley,et al.  Calculating the sample size required for developing a clinical prediction model , 2020, BMJ.

[7]  Niranjan Kissoon,et al.  Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study , 2020, The Lancet.

[8]  J. Sevransky,et al.  Toward Increased Understanding of the Steroid Controversy in Septic Shock. , 2019, Critical care medicine.

[9]  Matthew H Samore,et al.  ED Door‐to‐Antibiotic Time and Long‐term Mortality in Sepsis , 2019, Chest.

[10]  P. Marik.  The role of glucocorticoids as adjunctive treatment for sepsis in the modern era. , 2018, The Lancet. Respiratory medicine.

[11]  G. Guyatt,et al.  Corticosteroid therapy for sepsis: a clinical practice guideline , 2018, British Medical Journal.

[12]  E. Lindsay.  Hydrocortisone plus Fludrocortisone for Adults with Septic Shock , 2018, The Journal of Emergency Medicine.

[13]  Jaakko Reinikainen,et al.  Time-varying covariates and coefficients in Cox regression models. , 2018, Annals of translational medicine.

[14]  B. Souweine,et al.  Hydrocortisone plus Fludrocortisone for Adults with Septic Shock , 2018, The New England journal of medicine.

[15]  R. Bellomo,et al.  Adjunctive Glucocorticoid Therapy in Patients with Septic Shock , 2018, The New England journal of medicine.

[16]  Tyler J. VanderWeele,et al.  Sensitivity Analysis in Observational Research: Introducing the E-Value , 2017, Annals of Internal Medicine.

[17]  Niranjan Kissoon,et al.  Recognizing Sepsis as a Global Health Priority - A WHO Resolution. , 2017, The New England journal of medicine.

[18]  Christopher W Seymour,et al.  Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). , 2016, JAMA.

[19]  Wu Ji,et al.  Early versus delayed administration of norepinephrine in patients with septic shock , 2014, Critical Care.

[20]  G. Hedenstierna,et al.  Glucocorticoid receptor function is decreased in neutrophils during endotoxic shock. , 2014, The Journal of infection.

[21]  I. Dimopoulou,et al.  Early Administration of Hydrocortisone Replacement After the Advent of Septic Shock: Impact on Survival and Immune Response* , 2014, Critical care medicine.

[22]  E. Kristiansson,et al.  Expression of the glucocorticoid receptor is decreased in experimental Staphylococcus aureus sepsis. , 2013, The Journal of infection.

[23]  I. Jo,et al.  Early initiation of low-dose corticosteroid therapy in the management of septic shock: a retrospective observational study , 2012, Critical Care.

[24]  Brian H Cuthbertson,et al.  Hydrocortisone therapy for patients with septic shock. , 2008, The New England journal of medicine.

[25]  S. Pocock,et al.  Strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies , 2007, BMJ : British Medical Journal.

[26]  Matthias Egger,et al.  The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: Guidelines for Reporting Observational Studies , 2007, PLoS medicine.

[27]  Fernando A Bozza,et al.  Cytokine profiles as markers of disease severity in sepsis: a multiplex analysis , 2007, Critical care.

[28]  K. Eckardt,et al.  Low-dose hydrocortisone improves shock reversal and reduces cytokine levels in early hyperdynamic septic shock* , 2005, Critical care medicine.

[29]  N. H. Steigbigel.  Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock , 2003, Current infectious disease reports.

[30]  H. Volk,et al.  Immunologic and hemodynamic effects of "low-dose" hydrocortisone in septic shock: a double-blind, randomized, placebo-controlled, crossover study. , 2003, American journal of respiratory and critical care medicine.

[31]  W. Schumer.  Steroids in the Treatment of Clinical Septic Shock , 1976, Annals of surgery.

[32]  Jeffrey M. Hausdorff,et al.  Physionet: Components of a New Research Resource for Complex Physiologic Signals". Circu-lation Vol , 2000 .