Hydrocortisone plus Fludrocortisone in Septic Shock

D. Annane, A. Renault, C. Brun‑Buisson et el published results of APROCCHSS trial by CRICS-TRIGGERSEP Network  which was originally designed to test drotrecogin alfa (activated) in septic shock.   A human recombinant activated protein C, drotrecogin alpha (activated), initially showed a survival benefit in sepsis; this benefit was not confirmed in subsequent trials, resulting in the withdrawal of its commercial form (Xigris) from the market. However, the Hydrocortisone/Fludrocortisone arm of the trial continued.  It was public funded.

WHAT

Adult patients with indisputable or probable septic shock for less than 24 hours were randomized to receive 50-mg intravenous bolus every 6 hours, and fludrocortisone (50-μg tablet through a nasogastric tube once daily in the morning).  Administered for 7 days without tapering.

PATIENTS

A Sequential Organ Failure Assessment (SOFA) score of 3 or 4 who were receiving vasopressor therapy (norepinephrine, epinephrine, or any other vasopressor at the dose of  ≥0.25 μg per kilogram of body weight per
minute or ≥1 mg per hour) for at least 6 hours.

Total 1241 patients were enrolled in 34 participating centers.

 

EXCLUSION CRITERIA

More than 24 hours duration of septic shock, high risk of bleeding, pregnancy or lactation, underlying conditions
that could affect short-term survival, previous treatment with corticosteroids.

RESULTS

90-day all-cause mortality(Primary outcome) was lower among those who received hydrocortisone plus fludrocortisone. 43% vs 49.1%, P= 0.03. The relative risk of death was 0.88 (95% CI, 0.78 to 0.99).

Other significant results

  1. Lower mortality in treatment group at ICU discharge.
  2. Lower mortality in treatment group at Hospital discharge.
  3. Significantly shorter time to weaning from mechanical ventilation (P = 0.006),
  4. Significantly shorter time to weaning from vasopressor therapy (P<0.001)
  5. Significantly shorter time to reaching a SOFA score below 6 (P<0.001)

ADVERSE EFFECTS

Risk of hyperglycemia was significantly higher with hydrocortisone plus fludrocortisone (relative risk, 1.07; 95% CI, 1.03 to 1.12; P = 0.002) but no difference in rates of GI bleeding or superinfection.

DIFFERENCES with RECENTLY PUBLISHED ADRENAL TRIAL

Mortality in APROCCHSS trial(Both treatment and placebo group, around 43% ) was very high in comparison to ADRENAL trial ( Around 27%).  Patients in adrenal trial had higher surgical patients, lower rate of renal replacement therapy, blood infection, lung infection or urinary infection.

BOTTOMLINE

This trial and previous ADRENAL trial reinforces the utility of hydrocortisone in septic shock, specially in a
patient with a deteriorating condition who is receiving escalating doses of vasopressors, in whom other core interventions have been instituted (i.e., appropriate antibiotics and adequate volume resuscitation and source control).