journal club

1. Comparative Effectiveness of
Fludrocortisone and Hydrocortisone
vs Hydrocortisone Alone Among Patients
With Septic Shock
Nicholas A. Bosch, MD, MSc; Bijan Teja, MD; Anica C. Law, MD, MS; Brandon Pang, MD;
S. Reza Jafarzadeh, DVM, MPVM, PhD; Allan J.Walkey,MD, MSc
JAMA Intern Med. doi:10.1001/jamainternmed.2023.0258
Published online March 27, 2023.
Moderator- Dr Shreyas Gutte
Presenter- Dr Ashish Sharma
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2. Introduction
• Sepsis occurs in approximately 1.7 million US hospitalizations
• Fatality rate - >30%
• Adding corticosteroid therapy - weak recommendation
• Clinical trials that demonstrated improved mortality were limited to
interventions that paired hydrocortisone with fludrocortisone, not
trials comparing hydrocortisone alone with placebo.
• (Combination of Cortico therapy and Intensive Insulin Therapy for
Septic Shock [COIITSS]) - statistically non significant
• Lower absolute mortality among patients randomized to combination
hydrocortisone fludrocortisone as compared with hydrocortisone
alone
• Underpowered due to underestimated control group mortality and a
sample size 2

3. Method
• Used observational data to emulate a target trial that would
randomize hospitalized adults with septic shock who were
within 3 days of hospital admission, and who had initiated
hydrocortisone treatment, to receive fludrocortisone within the
same calendar day, or usual care, in an unblinded fashion.
• Approximately 25% of all US inpatient hospitalizations are
included in the database.
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4. Study population
• Data collected from- Premier Healthcare Database 2016-2020
• Data Extracted- demographics, ICD-10 diagnosis and procedures
code, and hospital day
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5. Inclusion criteria
• Patients admitted to intensive care or intermediate care units
with septic shock who received norepinephrine and began
hydrocortisone treatment within 3 days of hospital admission
Exclusion criteria
• Age < 18 years
• Patients with alternative indications for fludrocortisone
1. Primary adrenal insufficiency
2. Orthostatic hypotension
3. Congenital adrenal hyperplasia
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6. Treatment Assignment
• Treatment assignment was based on whether enteral
fludrocortisone treatment was initiated on the same calendar day
that hydrocortisone treatment was initiated (hereafter referred to
as combination “hydrocortisone-fludrocortisone” for those
receiving fludrocortisone
• “Hydrocortisone-alone” for those not receiving fludrocortisone.
• Patients initially started on hydrocortisone treatment who then
received fludrocortisone on subsequent days were assigned to
the “hydrocortisone-only” group.
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7. Outcomes
• Outcomes were ascertained from study day 0 (start of
hydrocortisone or hydrocortisone-fludrocortisone) until
hospital discharge
Primary outcome
• Composite of hospital death or discharge to hospice
Secondary outcomes
• Hospital death
• Vasopressor-free days
• Hospital-free days by day 28
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8. • “Free day” outcomes were calculated as 28 minus the number
of days of therapy (vasopressor use or hospitalization during
the index hospitalization)
• Patient who died in the hospital assigned “ zero free days”
Continuation….
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9. Study flow diagram
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10. Statistical Analysis
• SMD (standardized mean differences) - Used for Covariate
balance between treatment assignments
• Unadjusted survival curves - Kaplan-Meier estimator
• Unadjusted proportions and risk differences were calculated by
treatment assignment
• Calculated adjusted absolute risk differences (adjusted mean
differences for continuous outcomes) and 95% CIs using
doubly robust targeted maximum likelihood estimation
(TMLE) and an ensemble machine learner (Super Learner)
• Conducted subgroup analyses stratified by age, sex, history of
congestive heart failure, and days from hospital admission to
initiation of corticosteroid treatment
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11. Table- Baseline covariates of treatment assignment
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POA- present at admission, HCUP –health care cost and utilization project

12. 12

13. Results
Hydrocortisone Hydrocortisone+
fludrocortisone
Median (IQR) number
of days of follow-up
days
5 (1-12) 6 (2-13)
Median (IQR) duration
of treatment days
3 (2-6) 3 (1-4)
Median (IQR) total
dose
of hydrocortisone on
study day 0
200mg 225mg
Median (IQR) total
dose
of fludrocortisone
0.1 mg
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14. Primary outcome
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15. • Among patients who received hydrocortisone-fludrocortisone,
1076 (47.2%) died or were discharged to hospice vs 43669
(50.8%) for those who received hydrocortisone alone (adjusted
absolute risk difference of −3.7% (95% CI, −4.2% to −3.1%;
P < .001;E-value, 1.37)
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16. 28 days survival among treatment assignments
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17. 17
Secondary outcome

18. • The rate of hospital death was 39.3% among patients who received
hydrocortisone-fludrocortisone and 42.7% among patients who
received hydrocortisone (adjusted risk difference, −3.7%; 95% CI,
−4.2% to −3.3%).
• Vasopressor-free days and hospital-free days were higher among
patients who received hydrocortisone-fludrocortisone.
• The adjusted mean difference in vasopressor-free days and hospital-
free days comparing patients treated with 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.
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19. • There was no difference by treatment assignment for the negative
control outcome of blood transfusion after study day 0
(hydrocortisone- fludrocortisone: 28.3%; hydrocortisone alone:
29.9%; adjusted risk difference, −0.3%; 95% CI, −0.8% to
0.1%).
• The proportions of patients with incident hypernatremia (8872 of
78 484 [11.3%] for hydrocortisone alone; 236 of 2066 [11.4%]
for hydrocortisone fludrocortisone) and health care-associated
infection (811 of 82 783 [1.0%] for hydrocortisone alone; 31 of
2175 [1.4%] for hydrocortisone-fludrocortisone) were similar
between treatment arms.
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20. Limitations
• Observational study- increased risk of residual unmeasured confounding
• Premier Healthcare Database does not contain comprehensive electronic
medical record physiological/vital sign data or vasopressor doses that,
because not included in models, may increase the risk of unmeasured
confounding
• It is possible that initiation of fludrocortisone treatment did not occur
concurrently with hydrocortisone administration but instead occurred after
hydrocortisone initiation but still on the same calendar day, potentially
increasing the risk of immortal time bias within the same day
• The average dose of hydrocortisone used in hydrocortisone-fludrocortisone
(225mg) was higher than hydrocortisone alone (200mg) group
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21. Clinical appraisal
• Title- Title is clear, accurate and concise
• Abstracts- Abstract contain what was done, how it was done, the results and
their implications
• Definition of The Study Theme- All definitions are well covered
• Research Design- Observational Retrospective
• Sample – Adequate, No randomization was done
• Gauging of Information- Unblinded study
• Statistical Analysis – SMD analysis to overcome sample size variation in
treatment assignment
• Internal Consistency of Results- Appropriate
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22. • Interpretation of Results- Results not compared with previous studies
• Conclusions- Few study limitations are addressed
• Style- Clear and direct
• Bibliographic References - Sufficient
• Conflicts of Interest- None
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24. Indian studies SGPGIMS- LUCKNOW
2018
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25. 2011
JIPMER
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26. Hyderabad
2009
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27. SKIMS Kashmir
2020
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28. Thank You
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