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==Major Points==
==Major Points==
<!-- This section should be able to stand on its own as a summary of the trial, i.e., if someone read just that section, they should be able to know why the trial was done, what was found, and the implications of the findings. This can be done by writing three paragraphs: 1. Background leading to the study, 2. an overview of the findings of the study, and 3. implications of the study/follow-up studies (if there are such studies).
A few paragraphs summarizing the clinical question, the study itself, and how to apply it to practice. A simple approach is to use the first paragraph to discuss the background, use the second paragraph to discuss the study design and outcomes, and the third paragraph for interpretation which should incorporate criticisms, meta-analyses, and review-type content.-->
Multiple RCTs have investigated the potential role for steroid therapy in patients with septic shock. The [[Annane Trial]] in 2002 with 299 patients demonstrated a short-term mortality benefit with IV hydrocortisone and fludrocortisone among patients with evidence of adrenal insufficiency on ACTH stimulation testing. [[CORTICUS]] with 499 patients in 2008 investigated hydrocortisone in patients with and without adrenal insufficiency and found a faster reversal of shock but no benefit in either subgroup with suggestion of increased infection rates in patients receiving hydrocortisone. [[HYPRESS]] in 2016 with 380 patients showed no difference in mortality but showed decrease time to reversal of shock. In the same edition of the journal but selected to be epublished ahead of print, the [[ADRENAL]] trial included 3800, demonstrated no difference in 90 day mortality.
Multiple RCTs have investigated the potential role for steroid therapy in patients with septic shock. The [[Annane Trial]] in 2002 with 299 patients demonstrated a short-term mortality benefit with IV hydrocortisone and fludrocortisone among patients with evidence of adrenal insufficiency on ACTH stimulation testing. [[CORTICUS]] with 499 patients in 2008 investigated hydrocortisone in patients with and without adrenal insufficiency and found a faster reversal of shock but no benefit in either subgroup with suggestion of increased infection rates in patients receiving hydrocortisone. [[HYPRESS]] in 2016 with 380 patients showed no difference in mortality but showed decrease time to reversal of shock. In the same edition of the journal but selected to be epublished ahead of print, the [[ADRENAL]] trial included 3800, demonstrated no difference in 90 day mortality.


Published in 2018, the Hydrocortisone plus Fludrocortisone for Adults with Septic Shock, was the reporting of the steroid vs. placebo parallel arm of the Activated Protein C and Corticosteroids for Human Septic Shock (APROCCHSS) trial <ref name=APC>{{#pmid:23525934}}</ref>. After withdrawal of activated protein C from the market, that arm was suspended and analyzed to show no statistical difference with activated protein C on mortality nor interaction with the low-dose steroids.
Published in 2018, the Hydrocortisone plus Fludrocortisone for Adults with Septic Shock, was the reporting of the steroid vs. placebo parallel arms of the Activated Protein C and Corticosteroids for Human Septic Shock (APROCCHSS) trial <ref name=APC>{{#pmid:23525934}}</ref>. After withdrawal of activated protein C from the market, that arm was suspended and analyzed to show no statistical difference with activated protein C on mortality nor interaction with the low-dose steroids. From the same lead author as the origianl [[Annane Trial]] in 2002, this trial closely replicated the first trial in intervention and outcomes. The authors opted to again use a combination of hydrocortisone 60mg IV bolus every 6 hours and fludrocortisone 50 mcg via nasogastric tube for 7 days, in contrast to [[CORTICUS]] and subsequent trials that did not show affect of the addition of fludrocortisone in the French ICU population.<ref>{{#pmid:20103758}}</ref> Randomizing 1241 patients over a seven year span (with two hiatus) this trial showed an absolute risk reduction of 6% in mortality at 90 days, NNT 16. This is in stark contrast to several other major trials. It also a demonstrated faster reversal of shock and organ failure which aligned with other trials.  
 
the Adjunctive Corticosteroid Treatment in Critically Ill Patients with Septic Shock (ADRENAL) trial randomized 3800 patients from 69 international sites with septic shock on vasopressors and mechanical ventilation to hydrocortisone 200 mg/day continuous infusion or placebo. There was no difference at the primary outcome of death from any cause at 90 days, nor were any difference found in any of the six prespecified subgroups. The hydrocortisone group had faster time to reversal of shock, shorter time to discharge from the ICU, time to extubation, and decreased number of blood transfusion. These additional outcomes may best be regarded as hypothesis-generating.  


The 2016 Surviving Sepsis Campaign severe sepsis and septic shock<ref>[http://journals.lww.com/ccmjournal/Abstract/publishahead/Surviving_Sepsis_Campaign___International.96723.aspx Rhodes A, et al. "Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock: 2016." ''Critical Care Medicine.'' 2017;45(3)1-67.]</ref> suggests using IV hydrocortisone if hemodynamics cannot be stabilized using fluids and vasopressors. This recommendation was made before the release of the large ADRENAL trial and may lead to re-evaluation of this recommendation. This trial likely puts to rest steroids for all-comers in sepsis, however, does not settle if steroids would be beneficial in patients that are non-responders to initial fluid resuscitation and vasopressor administration, as recommended in the guidelines.
The 2016 Surviving Sepsis Campaign severe sepsis and septic shock<ref>[http://journals.lww.com/ccmjournal/Abstract/publishahead/Surviving_Sepsis_Campaign___International.96723.aspx Rhodes A, et al. "Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock: 2016." ''Critical Care Medicine.'' 2017;45(3)1-67.]</ref> suggests using IV hydrocortisone if hemodynamics cannot be stabilized using fluids and vasopressors. This recommendation was made before the release of [[ADRENAL]] and this trial and may lead to re-evaluation of this recommendation. The seemingly contradictory findings of this trial may be attributed to the difference in severity of illness of the patients found in this trial with high mortality and severity scores as compared to other trials, as well as the use of a minerocorticoid. The findings of the trial may support the use of steroids in patients that are continuing to fail despite adequate fluid resuscitation and vasopressor support. Meta-analysis of these findings may better aid in interpretation and application at the bedside.


==Guidelines==
==Guidelines==
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