Review of a randomised controlled trial
Despite the development of new effective antimicrobial therapies, source control techniques and aggressive cardiovascular support, septic shock remains one of the most common causes of death in the Intensive Care Unit (ICU). Its incidence, depending on the definition, is up to 25% of all new ICU admissions whereas the reported mortality ranges from 27 to 54%.  The complex pathophysiologic changes that take place in severe sepsis have an important impact on endocrine organs and impairment of thyroid, pancreatic and hypophysis-pituitary-adrenal (HPA) functions is well documented. [2,3] The HPA dysfunction, seen as either inappropriately low production of or reduced response to glucocorticosteroids may result in an exaggerated and protracted proinflammatory response, termed critical-illness-related corticosteroid insufficiency (CIRCI).  Even though CIRCI should be suspected in hypotensive patients who do not respond to fluid and vasopressor agents, especially in the context of sepsis, its diagnosis and management remain a topic of intense controversy. [2,5,6]
Glucocorticosteroids have been extensively studied as an adjunctive therapy in septic patients for the past 50 years, initially as high dose (30mg/kg methylprednisolone)  and later as low dose (50mg hydrocortisone every 6 hours) treatment. [8,9] Despite a significant number of observational and randomised controlled studies, as well as several meta-analyses and systematic reviews addressing the issue of steroid administration in sepsis and septic shock, results concerning the mortality benefit have been discordant and the uncertainty remains. [8-11]
Keh and colleagues take a step back and focus on the effect of early steroid administration (hydrocortisone) in the prevention of septic shock. In HYPRESS, Hydrocortisone for Prevention of Septic Shock, they test the hypothesis that steroids will inhibit the progression of sever sepsis to shock by attenuating the exaggerated inflammatory response.  In their multi-centre, placebo-controlled, double-blind RCT, patients with evidence of at least two systemic inflammatory response syndrome (SIRS) criteria and evidence of organ dysfunction for less than 48 hours were randomised to receive either a continuous effusion of 200mg of hydrocortisone or placebo for 5 days.
The primary outcome was occurrence of septic shock within 14 days or discharge from ICU and the secondary end points were: 28-, 90- and 180-day mortality, length of ICU and hospital stay, time until septic shock develops, organ dysfunctions (as indicated by SOFA scores), frequency and duration of mechanical ventilation and renal replacement therapy, incidence of delirium, and frequency of adverse events (muscle weakness, GI bleed, secondary infections, weaning failure).
HYPRESS didn’t show any statistically significant difference in the proportion of septic shock after 14 days in the hydrocortisone and placebo groups (18.7% vs. 21.2% respectively, p=0.59), a result that didn’t change with the intention-to-treat analysis (21.2% vs. 22.9% respectively, p=0.70). There were also no significant differences in most of the secondary endpoints in the 2 groups: 28- (8.2% vs. 8.8%, p=0.86), 90- (16.7% vs. 19.9%, p=0.44) and 180-day mortality (22.2% vs. 26.8%, p=0.32), length of ICU (9 vs. 8 days, p=0.23)) and hospital (25 vs. 26 days, p=0.26) stay, ventilation- (5 vs. 4 days, p=0.34) and renal replacement free-days (7 vs. 6 days, p=0.35), as well as organ dysfunction (SOFA score 5 vs. 4.7, p=0.69) and time to septic shock (p=0.69). Secondary infections, GI bleeds, weaning failure and other adverse events were not significant between the 2 groups, apart from significantly more episodes of hyperglycaemia in the hydrocortisone group (90.9% vs. 81.5%, p=0.009).
This trial attempts to address a long-standing question which many intensivists continue to struggle with. It is a well-designed, randomised, multi-centred, prospective trial with a protocol that, even though was not pre-published, is available as a supplement. This study is the first published RCT to investigate the effect of hydrocortisone to patients that present with sepsis but without septic shock. It is methodologically robust with specific and relevant primary and secondary outcomes, and a focus on side effects and thus safety. The lack of statistically significant difference in adverse events (apart from hyperglycaemia) and in development of septic shock with or without CIRCI, confirms data from previous results [9,11] and will hopefully resolve once and for all the uncertainty around the safety profile of low dose steroids and the usefulness of a corticotrophin-stimulation test to determine CIRCI.
There are a few considerations when interpreting the trial’s results with the first being the power of the study. The authors have estimated that 169 patients per arm were required to demonstrate a difference of 15% in septic shock, assuming that its’ frequency was 40%. However, the observed rate of septic shock was 22.9% and 21.2% in the placebo and hydrocortisone groups respectively, rendering the trial under-powered and decreasing its’ ability to detect a statistically significant difference. Another limitation is the choice of ‘septic shock development’ as a primary outcome and the assumption that severe sepsis and septic shock reflect a disease continuum. The recent Third International Consensus on the definitions of Sepsis and Septic Shock based the need for re-examination of these definitions partly on the ‘misleading model that sepsis follows a continuum through severe sepsis to shock’.  The task force defined septic shock not as a progression but as a subset of sepsis, in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality.  In this light, the hypothesis that early administration of hydrocortisone might prevent the development of shock is flawed. Emerging evidence  suggest that the immunological response in sepsis is too complex to simply be described as ‘hyper-inflammation’; more accurately, sepsis should be considered as a dysregulated response to infection in which some patients might benefit from inhibition of the immune response, whereas others (with predominant immunosuppression) might die. It is possible the molecular and genomic assays that were mentioned in the trial’s protocol as secondary end points but were not addressed in the JAMA publication, could have provided more data towards a more personalised, ‘precision medicine’ approach in this patient cohort.  Lastly, the generalisability of the trial’s results is somewhat limited, as a large number of assessed patients (6073 of the 9953, 61%) were excluded as having pre-existing septic shock. Thus no recommendations can be made for the effectiveness of hydrocortisone in patients who present with septic shock by the HYPRESS trial.
In conclusion, despite being well designed, the HYPRESS trial still leaves the ‘steroid question’ unanswered. Future studies need to focus on determining the immune status of the septic patients, before assessing the immunomodulatory effect of corticosteroids. Once the subgroup that will benefit from steroids is clearly identified, other important questions like what dose to use, which mode of administration and for how long will need to be addressed. Until then trials that treat septic patients as ‘one size fits all’ are unlikely to provide meaningful results.
Article review was submitted by EJRC member Victoria Metaxa.
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