Critical Care Alert: Effectiveness of Fludrocortisone and Hydrocortisone vs. Hydrocortisone Alone Among Patients with Septic Shock

ARTICLE: Bosch NA, Teja B, Law AC, Pang B, Jafarzadeh SR, Walkey AJ. Comparative Effectiveness of Fludrocortisone and Hydrocortisone vs Hydrocortisone Alone Among Patients With Septic Shock. JAMA Intern Med. 2023;183(5):451-459.

OBJECTIVE

To compare the effectiveness of fludrocortisone added to hydrocortisone versus hydrocortisone alone among patients with septic shock

BACKGROUND

Septic shock, the most severe form of sepsis, is associated with fatality rates >30% and often necessitates the use of vasopressors to support blood pressure.¹ For these patients, the 2021 Surviving Sepsis campaign suggests adding intravenous corticosteroids (eg, hydrocortisone 200 mg/d) based on randomized clinical trials (RCTs) and meta-analyses that found that steroids shortened shock duration and reduced mortality (weak recommendation with moderate-quality evidence).² Hydrocortisone is a short-acting corticosteroid that decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversal of increased capillary permeability.³

Of the above clinical trials, the ones that showed reduced mortality (eg, The APROCCHSS trial)⁴ combined hydrocortisone with fludrocortisone, a potent mineralocorticoid with high glucocorticoid activity which promotes reabsorption of sodium and loss of potassium from renal distal tubules.⁵ Despite this, international guidelines still recommend hydrocortisone alone in patients with septic shock with persistent vasopressor requirements as it was felt that hydrocortisone had adequate mineralocorticoid effects on its own. The authors of this paper felt that fludrocortisone has additional pleiotropic benefits to hydrocortisone including activation of innate immunity and facilitation of clearance of increased alveolar fluid (a hallmark of acute respiratory distress syndrome, a common comorbidity in patients with septic shock).⁶

One RCT (Combination of Corticotherapy and Intensive Insulin Therapy for Septic Shock [COIITSS] trial)⁷ has looked into this and showed a statistically nonsignificant 2.9% lower absolute mortality among patients randomized to combination hydrocortisone-fludrocortisone versus hydrocortisone alone, but this trial was underpowered. Given the potential for a clinically significant benefit of hydrocortisone-fludrocortisone combination therapy compared with hydrocortisone alone, this study used target trial emulation to evaluate the effectiveness of the addition of fludrocortisone to hydrocortisone vs hydrocortisone alone in patients with septic shock admitted to U.S. hospitals.

DESIGN

Observational data was used to emulate a target trial that would randomize hospitalized adults with septic shock within 3 days of hospital admission who were started on hydrocortisone to receive fludrocortisone within the same calendar day in an unblinded fashion. The hypothetical trial would follow participants until hospital discharge for the primary composite outcome of hospital mortality or discharge to hospice care. Patients were selected from the Premier Healthcare Database 2016-2020, a claims database designed for measuring quality and health care utilization that contains data from ~25% of all U.S. inpatient hospitalizations.

Study day 0 was the day in which hydrocortisone treatment was first initiated (in the hydrocortisone monotherapy arm), or the day that hydrocortisone and fludrocortisone were co-initiated (in the combination therapy arm). Treatment assignment was based on whether enteral fludrocortisone treatment was initiated on the day that hydrocortisone treatment was initiated. Patients initially started on hydrocortisone who then received fludrocortisone on subsequent days were assigned to the hydrocortisone-only group consistent with intention-to-treat principles. Unlike prior clinical trials that randomized patients to 7 days of corticosteroids, the treatment assignment in this study emulated a hypothetical trial that randomized patients to an initial corticosteroid strategy without specification of subsequent doses or duration. Outcomes were ascertained from study day 0 (start of hydrocortisone or hydrocortisone-fludrocortisone) until hospital discharge.

This study identified covariates on or before study day 0 that were likely to confound the association between treatment assignment and outcomes. Included covariates were age; sex; health insurance type; hospital discharge quarter and year; validated measures of comorbidity burden and acute organ dysfunction; major surgery; history of congestive heart failure or connective tissue disease; pneumonia present on admission; resuscitative fluid volume; enteral administration of medications other than fludrocortisone (as the receipt of enteral medications may reflect lower severity of acute illness); time from hospital admission and norepinephrine initiation to treatment assignment; use of etomidate, kidney replacement therapy, vasopressors, and invasive mechanical ventilation; assessments of the hypothalamic-pituitary-adrenal axis; surgical care unit admission; admission hospital; and hospital teaching status, size, caseload, and U.S. census region.

INCLUSION CRITERIA

• Patients ≥ 18 years of age admitted to intensive or intermediate care units with an explicit septic shock diagnosis who received norepinephrine and began hydrocortisone treatment within 3 days of hospital admission

EXCLUSION CRITERIA

• <18 years
• Patients with alternative indications for fludrocortisone
  • primary adrenal insufficiency
  • orthostatic hypotension
  • congenital adrenal hyperplasia

PRIMARY OUTCOME

Composite of hospital death or discharge to hospice

SECONDARY OUTCOMES

• Hospital death
• Vasopressor-free days
• Hospital-free days by day 28
• Proportion of patients who developed hypernatremia and health care–associated infection in each treatment arm to assess for potential complications of corticosteroid treatment

KEY RESULTS

Among 384,394 patients with septic shock who received norepinephrine, 88,275 received hydrocortisone within 3 days of hospitalization, met eligibility criteria, and were included in analyses. Among those, 85,995 (97.4%) were treated with hydrocortisone alone (median age, 67; female≈male), and 2280 (2.6%) were treated with combination hydrocortisone-fludrocortisone (median age, 64 years; female≈male). The median time from norepinephrine to hydrocortisone initiation was 0 (0-1) days in both treatment groups. Patients who received hydrocortisone-fludrocortisone were more likely to receive medications other than fludrocortisone via the enteral route (83.1%) compared with patients who received hydrocortisone alone (60.4%; SMD, 0.52). Baseline characteristics related to admission to hospital also differed between treatment assignments.

Primary outcome

• Median days of follow-up:
  • Hydrocortisone-fludrocortisone: 6 (2-13)
  • Hydrocortisone alone: 5 (1-12)
• Median duration of treatment:
  • Hydrocortisone-fludrocortisone: 3 (1-4) days
  • Hydrocortisone alone: 3 (2-6) days
• The median total dose of hydrocortisone on study day 0:
  • Hydrocortisone-fludrocortisone: 225 (200-300) mg
  • Hydrocortisone alone: 200 (100-300) mg
• The median total dose of fludrocortisone was 0.1 mg.
• Died or were discharged to hospice:
  • Hydrocortisone-fludrocortisone: 47.2% (1,076)
  • Hydrocortisone alone: 50.8% (43,669)
• Receipt of hydrocortisone-fludrocortisone was associated with an adjusted absolute risk difference of −3.7% (95% CI, −4.2% to −3.1%; P < .001) in hospital mortality or discharge to hospice compared with hydrocortisone alone

Secondary outcomes

• The rate of hospital death (adjusted risk difference, −3.7%; 95% CI, −4.2% to −3.3%):
  • Hydrocortisone-fludrocortisone: 39.3%
  • Hydrocortisone alone: 42.7%
• Vasopressor-free days and hospital-free days were higher among patients who received hydrocortisone-fludrocortisone.
  • Adjusted mean difference in vasopressor-free days and hospital-free days comparing hydrocortisone-fludrocortisone vs hydrocortisone alone was 0.9 (95% CI, 0.8-1.1) days and 0.7 (95% CI, 0.6-0.8) days, respectively
• Incidence of hypernatremia:
  • Hydrocortisone-fludrocortisone: 11.4% (236 of 2,066)
  • Hydrocortisone alone: 11.3% (8,872 of 78,484)
• Incidence of health care-associated infection:
  • Hydrocortisone-fludrocortisone: 1.4% (31 of 2,175)
  • Hydrocortisone alone: 1% (811 of 82,783)

LIMITATIONS

• Nonrandom sample of U.S. hospitals
• The time from hydrocortisone to fludrocortisone initiation unknown so it’s possible that:
  • Fludrocortisone preceded hydrocortisone (increasing the risk of misclassification)
  • Fludrocortisone was given up to 24 hours after hydrocortisone (increasing the risk of immortal time bias)
• Opportunities for confounding variables:
  • Observational study
  • Use of Premier Healthcare Database
    • Did not contain comprehensive electronic medical record physiological/vital sign data or vasopressor doses
    • Possibility of post exposure confounders

EM TAKE-AWAYS

Fludrocortisone added to hydrocortisone was associated with increased hospital survival, shorter hospital lengths of stay, and decreased vasopressor duration when compared to hydrocortisone alone. ER doctors should consider adding fludrocortisone when using hydrocortisone in patients with septic shock who require vasopressors.

REFERENCES

1. Bauer M, Gerlach H, Vogelmann T, et al. Mortality in sepsis and septic shock in Europe, North America and Australia between 2009 and 2019- results from a systematic review and meta-analysis. Critical Care (London, England). 2020;24(1):239.
2. Evans L, Rhodes A, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021;47(11):1181–1247.
3. Puckett Y, Gabbar A, Bokhari AA. Prednisone. [Updated 2023 Mar 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK534809/.
4. Annane D, Renault A, Brun-Buisson C, et al. for the CRICS-TRIGGERSEP Network. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. N Engl J Med. 2018;378(9):809–818.
5. Rahman M, Anjum F. Fludrocortisone. [Updated 2023 Apr 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK564331/.
6. Heming N, Sivanandamoorthy S, Meng P, Bounab R, Annane D. Immune Effects of Corticosteroids in Sepsis. Front Immunol. 2018;9:1736.
7. COIITSS Study Investigators, Annane D, Cariou A, et al. Corticosteroid treatment and intensive insulin therapy for septic shock in adults: a randomized controlled trial. JAMA. 2010;303(4):341-348.
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