Annane Trial

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Annane D, et al. "Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock". Journal of the American Medical Association. 2002. 288(7):862-871.
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Clinical Question

Among patients with septic shock and relative adrenal insufficiency, do corticosteroids reduce 28-day mortality?

Bottom Line

Among patients with septic shock and relative adrenal insufficiency, administration of corticosteroids reduces 28-day mortality, although this finding was not confirmed in the follow-up CORTICUS trial.

Major Points

Sepsis is associated with relative adrenal insufficiency and according to classical teaching, this results in greater rates of shock and hypotension refractory to standard resuscitation measures including IV fluids and vasopressors. Thus, a common practice has been to treat refractory shock with corticosteroids, the so-called "stress-dose steroids" approach. Because of the immunosuppression that corticosteroids induce, some have argued that corticosteroid administration should be limited to patients with documented adrenal insufficiency, where the benefit of corticosteroids would theoretically be greatest. Regardless of rationale, for decades corticosteroids have been in wide use among ICU physicians despite a paucity of strong supporting clinical trial data. The Annane Trial aimed to reverse this trend by investigating the role of corticosteroids in patients with septic shock and documented adrenal insufficiency.

The Annane Trial (occasionally referred to as the "French Trial") randomized 300 adults with septic shock to receive seven days of corticosteroids or placebo. Patients in the corticosteroid group received hydrocortisone 50mg IV q6h and fludrocortisone 50µg enterally per day. All patients underwent short ACTH stimulation testing at the time of enrollment and were classified as responders (change in cortisol >9 µg/dL) or nonresponders (change ≤9 µg/dL), and the study's primary outcome was 28-day survival among nonresponders. Among nonresponders, corticosteroid use was associated with a 10% absolute reduction in 28-day mortality (53% vs. 63%), although there was no difference at one year (68% vs. 77%). Corticosteroids were also associated with a more rapid reversal of shock.

The editorial that accompanied the Annane Trial[1] used the trial's results to argue against the blanket administration of corticosteroids in patients with septic shock, and instead to tailor their administration to those with relative adrenal insufficiency. Since then, several other trials have been published that bring even this recommendation into question. Among them, the largest and most well designed is the CORTICUS trial (2008), which also evaluated corticosteroids in septic shock. However, CORTICUS did not demonstrate the same mortality benefit at 28 days, even among patients with relative adrenal insufficiency. Some of the differences in outcomes may have resulted from the baseline characteristics of the populations studied. For example, patients in the Annane Trial were more critically ill both by SAPS II scores and by mortality in the placebo group (61% in the Annane Trial and 32% in CORTICUS), limiting the study's generalizability.

Guidelines

Surviving Sepsis Campaign severe sepsis and septic shock (2016, adapted)[2]

  • If adequate fluid resuscitation and vasopressor therapy can restore hemodynamics, suggest against using IV hydrocortisone (weak recommendation, low quality of evidence)
    • If above isn't achievable, suggest hydrocortisone 200 mg IV qday (weak recommendation, low quality of evidence)

Design

  • Randomized, prospective, double-blind, parallel-group, placebo-controlled trial
  • Sites: 19 French ICUs
  • Timeline: 1995-1999
  • N=300 patients with septic shock
    • Corticosteroids (n=151)
    • Placebo (n=149)
  • Analysis: Intention-to-treat
  • Primary outcome: 28-day survival

Population

Inclusion Criteria

  • Age ≥18 years
  • Hospitalized in ICU
  • Documented site or strong suspicion of infection
  • Temperature ≥38.3°C or ≤35.6°C
  • Heart rate ≥90 BPM
  • SBP <90 mmHg for ≥1 hour despite IVF, dopamine >5µg/kg/min, any epinephrine, or any norepinephrine
  • Urine output ≤0.5 mL/kg for ≥1 hour or the PaO2/FiO2 ≤280 mmHg
  • Lactate levels ≥2 mmol/L
  • Mechanical ventilation

Exclusion Criteria

  • Pregnancy
  • MI
  • PE
  • Advanced cancer
  • AIDS
  • Contraindication for corticosteroids
  • Etomidate in the previous 6 hours (late amendment to protocol)

Baseline Characteristics

From the corticosteroid group.

Demographics:

  • Age: 63 years
  • Women: 37%
  • White: 93%

Comorbidities:

  • Hypertension: 31%
  • CAD: 13%
  • CHF: 9%
  • Neurological disease: 14%
  • Chronic pulmonary disease: 12%
  • Cancer: 13%
  • Diabetes: 16%
  • Liver disease: 7%

Type of admission:

  • Medical: 57%
  • Emergency surgery: 38%
  • Elective surgery: 5%

Vital signs:

  • Temperature:
    • Mean: 38.0°C
    • ≤35.6°C: 25%
  • Heart rate: 119/min
  • MAP: 54 mmHg
  • Health measurements:
    • SAPS II[3]: 60
    • LOD score[4]: 9

Laboratory:

  • Hemoglobin: 10.0 g/dL
  • Leukocytes: 12.7 x103/µL
  • Platelets: 153 x103/µL
  • Lactate: 4.8 mmol/L
  • PaO2:FiO2 ratio: 181
  • ACTH-stimulation test results:
    • Baseline cortisol: 18 µg/dL
    • 30 minutes after ACTH: 19 µg/dL
    • 60 minutes after ACTH: 20 µg/dL
    • Response to ACTH: 2 µg/dL

Treatment:

  • Fluid loading: 32 mL/kg
  • Vasopressors (if used):
    • Dopamine: 11.5 µg/kg/min
    • Dobutamine: 10.2 µg/kg/min
    • Epinephrine: 0.8 µg/kg/min
    • Norepinephrine: 1.1 µg/kg/min
  • Time from shock onset to vasopressor initiation: 4.3 hours
  • Time on vasopressor before study drugs: 3.6 hours
  • Ventilatory support:
    • Tidal volume: 2.3 mL/kg
    • FiO2: 80%
    • PEEP: 6.3 cm H2O

Infection and antibiotic information:

  • Type of infection:
    • Community-acquired: 61%
    • Post-surgical: 20%
    • Hospital acquired and other: 18%
  • Site of infection:
    • Only lung: 37%
    • Abdominoperitoneal: 19%
    • Only urinary tract: 5%
    • Only cellulitis: 6%
    • Other, one site: 5%
    • >1 site: 25%
    • Unknown: 2%
  • Appropriate antibiotics: 91%
  • Time to appropriate antibiotics: 9.4 hours

Interventions

  • Patients meeting the inclusion criteria were randomized to either corticosteroids or placebo for a total of 7 days
    • Hydrocortisone 50mg IV q6h and fludrocortisone 50µg daily
    • Placebo
  • After randomization (but prior to treatment), all patients underwent an ACTH-stimulation test with the synthetic corticotropin tetracosactrin (similar to cosyntropin, which is more commonly used in the US)
  • All patients had plasma cortisol levels measured immediately prior to ACTH bolus, and then at 30 and 60 minutes thereafter
  • Patients were classified according to response:
    • Responders (cortisol increase >9µg/dL)
    • Nonresponders (cortisol increase ≤9µg/dL)

Outcomes

Only outcomes in the nonresponders are presented. Comparisons are corticosteroids vs. placebo.

Primary Outcomes

Mortality at 28 days
53% vs. 63% (OR 0.54; 95% CI 0.31-0.97; P=0.04)

Secondary Outcomes

ICU mortality
58% vs. 70% (OR 0.50; 95% CI 0.28-0.89; P=0.02)
Hospital mortality
61% vs. 72% (OR 0.53; 95% CI 0.29-0.96; P=0.04)
Mortality at one year
68% vs. 77% (OR 0.57; 95% 0.31-1.04; P=0.07)
Median time to withdrawal of vasopressors
7 vs. 10 days

Adverse Events

There was no difference in the rate of adverse events between the placebo and steroid groups except for a higher rate of surgical wound infection in the placebo group.

Criticisms

  • Some of the "nonresponders" had a pre-ACTH cortisol level of <34µg/dL and therefore may have been classified as having absolute adrenal insufficiency.[5]
  • The study's generalizability is limited because patients receiving etomidate were excluded, patients were generally more ill, and all patients received mechanical ventilation.[5]

Funding

  • Grant GER-inf-05R2 from GERMED

Further Reading

  1. Abraham E, Evans T. "Corticosteroids and Septic Shock." JAMA. 2002. 288(7):886-887.
  2. 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.
  3. SAPS II score
  4. LOD score
  5. 5.0 5.1 "Letters: Corticosteroids for Patients With Septic Shock." JAMA. 2003;289(1):41-44.