ARTICLE
Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. N Engl J Med. 2018;378:809-818.
BACKGROUND
Septic shock is characterized by a dysregulated host response to an infection resulting in metabolic, cellular and cardiovascular dysfunction. Apart from early resuscitation and antibiotics there is no proven adjunct therapy in critically ill septic patients. Corticosteroids have been used in the treatment of septic shock. However, there is clinical equipoise regarding their use. This is a hotly debated subject, with two seemingly conflicting papers, ADRENAL and APROCCHSS, published this year. Prior studies such as the 2002 paper by Annane, the CORTICUS trial in 2008, and the recent ADRENAL trial show a faster resolution in shock duration, but no mortality benefit. The HYPRESS trial in 2016 showed no mortality or shock duration resolution but was underpowered. Thus, due to conflicting data available regarding the use of corticosteroids, many physicians have a wide range of practice for the use of steroids in sepsis and septic shock.
STUDY DESIGN
- Randomized placebo-controlled trial with 2-by-2 factorial design
- Groups
1) hydrocortisone + fludrocortisone+ drotrecogin alfa
2) hydrocortisone + fludrocortisone + drotrecogin alfa placebo
3) corticosteroid placebo + drotrecogin alfa
4) corticosteroid placebo + drotrecogin alfa placebo
**Drotrecogin alfa was withdrawn from the market. The trial proceeded with a two-group parallel design of corticosteroid vs placebo groups.
▪ Sites – Multi-Centered in 34 French ICUs
▪ Time – September 2008-June 2015
Sponsor
Publicly Funded
Intervention
Hydrocortisone 50mg IV bolus every six hours with fludrocortisone 50 mcg tablet once in the morning for seven days without tapering.
Randomization
Patients were randomized in permuted blocks of eight
Inclusion Criteria
- ICU patients who had probable or certain septic shock for less than 24 hours
- Hospitalized in the ICU for less than 7 days
- With at least two organ failures each defined by an organ specific SOFA score greater than 3 for at least 6 consecutive hours
- Treated with vasopressors for at least 6 hours and less than 24 hours
Exclusion Criteria
- Septic shock for 24 hours or longer
- High risk of bleeding
- Pregnancy or lactation
- Known hypersensitivity to drotrecogin alfa (removed after drotrecogin alfa was removed from the market)
- Previous treatment with corticosteroids
- Underlying pathology with life expectancy of less than 1 month
- Recent surgery less than 72 hours prior
- GI bleeding within the past 6 weeks
- Chronic liver disease with a Child score C
- Severe thrombocytopenia <30,000/mm^3
- Ongoing therapeutic anticoagulation that cannot be interrupted
Primary Outcome
- 90-day all-cause mortality
Secondary Outcomes
- All-cause mortality at ICU discharge, hospital discharge, day 28, and day 180
- Percentage of patients from whom care was withheld or withdrawn
- Percentage of patients who are able to be weaned from vasopressors at days 28 and 90
- Speed of weaning patients from vasopressors
- Vasopressor-free days up to days 28 and 90
- Percentage of patients weaned from ventilation by days 28 and 90
- Speed of weaning off the ventilator
- Time to reach a SOFA score below 6
- Organ failure free days up to day 28 and 90
- Percentage of patients discharged from the ICU and hospital at days 28 and 90
- Time to discharge from the ICU and hospital
- ICU and hospital free days at days 28 and 90
KEY RESULTS
Primary Outcomes
- Mortality of 43.0% of the hydrocortisone plus fludrocortisone group and 49.1% in the placebo group with a relative risk of death of .88 (95% CI .78-.99). P=.003
- Absolute Risk Reduction of 6.1% (95% CI .6% to 11.7%) P=0.03
- NNT 17
Secondary Outcomes
- Mortality was lower in the hydrocortisone plus fludrocortisone group than the placebo group at ICU discharge 35.4% vs 41%, at hospital discharge at 39% and 45.3% and at day 180 at 46.6% and 52.2%.
- The hydrocortisone plus fludrocortisone was weaned faster off both vasopressors and ventilation.
- The hydrocortisone plus fludrocortisone group was faster at reaching a SOFA score below 6.
- The hydrocortisone plus fludrocortisone group had more vasopressor and organ failure free days.
Strengths
- Randomized multi-center-controlled trial with intention to treat analysis.
- Patient centered outcome.
- Similar demographic data between the groups
Limitations
- Originally designed and powered to have drotrecogin alfa as part of the intervention arm
- Approximately a third the size of the ADRENAL trial
- The trial occurred over a long period during which the standard of care has changed (Process, Arise, and Promise trials were all published in this timeframe)
- Fragility index of 3
DISCUSSION
The ADRENAL and APROCCHSS trials were published this year in The New England Journal of Medicine, with both trials examining the effects of steroids on septic shock while using mortality as the primary endpoint. However, they reached different conclusions. A full post will be dedicated to the ADRENAL trial in the next edition of Critical Care Alert.
The patient cohort in APROCCHSS were sicker compared to the cohort in ADRENAL (higher pressor requirement), and had steroids initiated earlier (<24hrs vs 20+/-90hrs). One might conclude that maybe early administration of steroid to the sickest septic patients reduces mortality. Furthermore, the steroids were given as a bolus in the APROCCHSS trial as compared to a continuous infusion in the ADRENAL trial.
We also should keep in mind that the mortality benefit in APROCCHSS has a fragility index of 3 with p-value of <0.03. With fragility index of 3, this means that if 3 patients with mortality benefit had changed into no mortality benefit, the result would be statistically non-significant.
Both ADRENAL and APROCHSS had similar secondary outcomes which have also been demonstrated by prior studies examining steroids in septic shock. Both studies show earlier weaning from the mechanical ventilator and from vasopressor. Both have similar side effect profiles with hyperglycemia being the major adverse effect. Thus, given the safety of steroids, the trend towards faster time off vasopressors and the vent it is a reasonable strategy to give septic shock patients steroids even with the questionable mortality benefit.
ED Take-Away
Steroids are an option in critically ill septic shock patients who are not improving after initial resuscitation.
References
Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. N Engl J Med. 2018;378:809-818.
Venkatesh B, Finfer S, Cohen J, et al. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. N Engl J Med. 2018;378:797-808.