Research

JAMA Internal Medicine | Original Investigation

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

Invited Commentary
IMPORTANCE Patients with septic shock may benefit from the initiation of corticosteroids. Multimedia
However, the comparative effectiveness of the 2 most studied corticosteroid regimens
Supplemental content
(hydrocortisone with fludrocortisone vs hydrocortisone alone) is unclear.
OBJECTIVE To compare the effectiveness of adding fludrocortisone to hydrocortisone
vs hydrocortisone alone among patients with septic shock using target trial emulation.

DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study from 2016 to 2020
used the enhanced claims-based Premier Healthcare Database, which included
approximately 25% of US hospitalizations. Participants were adult patients hospitalized
with septic shock and receiving norepinephrine who began hydrocortisone treatment.
Data analysis was performed from May 2022 to December 2022.

EXPOSURE Addition of fludrocortisone on the same calendar day that hydrocortisone

treatment was initiated vs use of hydrocortisone alone.

MAIN OUTCOME AND MEASURES Composite of hospital death or discharge to hospice.

Adjusted risk differences were calculated using doubly robust targeted maximum
Author Affiliations: The Pulmonary
likelihood estimation.
Center, Boston University Chobanian
& Avedisian School of Medicine,
RESULTS Analyses included 88 275 patients, 2280 who began treatment with
Department of Medicine, Boston,
hydrocortisone-fludrocortisone (median [IQR] age, 64 [54-73] years; 1041 female; Massachusetts (Bosch, Law, Pang,
1239 male) and 85 995 (median [IQR] age, 67 [57-76] years; 42 136 female; 43 859 male) Walkey); Department of
who began treatment with hydrocortisone alone. The primary composite outcome of death Anesthesiology and Pain Medicine,
University of Toronto, Toronto,
in hospital or discharge to hospice occurred among 1076 (47.2%) patients treated with
Ontario (Teja); Interdepartmental
hydrocortisone-fludrocortisone vs 43 669 (50.8%) treated with hydrocortisone alone Division of Critical Care Medicine,
(adjusted absolute risk difference, −3.7%; 95% CI, −4.2% to −3.1%; P < .001). University of Toronto, Toronto,
Ontario (Teja); Section of
CONCLUSIONS AND RELEVANCE In this comparative effectiveness cohort study Rheumatology, Boston University
among adult patients with septic shock who began hydrocortisone treatment, Chobanian & Avedisian School of
Medicine, Department of Medicine,
the addition of fludrocortisone was superior to hydrocortisone alone.
Boston, Massachusetts (Jafarzadeh).
Corresponding Author: Nicholas A.
JAMA Intern Med. doi:10.1001/jamainternmed.2023.0258 Bosch, MD, The Pulmonary Center,
Published online March 27, 2023. 72 E Concord St, R-304, Boston, MA
02118 (nabosch@bu.edu).

S
e p s i s o c c u r s i n a p p rox i m ate l y 1 .7 m i l l i o n US
hospitalizations1 and in more than a third of hospital-
izations that result in death.2 Septic shock—the most se-
vere form of sepsis in which vasoplegia and cardiovascular or-
gan dysfunction necessitate the use of vasopressor medications
to support blood pressure—is associated with fatality rates
greater than 30%.3 In patients with septic shock who require
ongoing support with vasopressors, guidelines4 suggest add-
ing corticosteroid therapy (weak recommendation, moderate-
quality evidence), with a recommendation for use of intrave-
nous hydrocortisone at a dose of 200 mg/d. These guidelines
are based on randomized clinical trials5-9 and subsequent
meta-analyses10,11 that found shortened shock duration and
potentially reduced mortality with corticosteroids. However,
the individual clinical trials that demonstrated improved
mortality were limited to interventions that paired hydrocor-
tisone with the mineralocorticoid fludrocortisone,8,9 not trials
comparing hydrocortisone alone with placebo. One random-
ized clinical trial (Combination of Corticotherapy and Inten-
sive Insulin Therapy for Septic Shock [COIITSS])12 showed a
statistically nonsignificant 2.9% lower absolute mortality
among patients randomized to combination hydrocortisone-
fludrocortisone as compared with hydrocortisone alone;
however, the COIITSS trial was underpowered due to under-
estimated control group mortality and a sample size chosen
to detect only a large effect size (12.5% risk difference) gener-
ally not present13,14 in critical care trials.
Given the potential for a clinically significant benefit of
hydrocortisone-fludrocortisone combination therapy as
compared with hydrocortisone alone in septic shock, we used

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 Research Original Investigation Comparative Effectiveness of Fludrocortisone and Hydrocortisone vs Hydrocortisone Alone in Septic Shock
target trial emulation to evaluate the effectiveness of the
addition of fludrocortisone to hydrocortisone vs hydro-
cortisone alone in patients with septic shock admitted to
US hospitals.
Methods
Target Trial
We used observational data to emulate a target trial15,16 (eTable 1
in Supplement 1) that would randomize hospitalized adults
with septic shock who were within 3 days of hospital admis-
sion, and who had initiated hydrocortisone treatment,
to receive fludrocortisone within the same calendar day, or
usual care, in an unblinded fashion. The hypothetical trial
would follow participants until hospital discharge for the pri-
mary composite outcome of hospital mortality or discharge
to hospice care.
Study Population
We used the Premier Healthcare Database 2016-2020, an
enhanced claims-based database designed for measuring
quality and health care utilization that contains claims data
(eg, demographics and International Classification of Dis-
eases diagnosis and procedures codes) and hospital day–
indexed billing information with minimal missing data
(<0.01% of variable fields are missing).17 Preliminary missing
or invalid data received by the database is returned to source
hospitals for correction prior to final data release.18 Approxi-
mately 25% of all US inpatient hospitalizations are included
in the database (because hospitals choose to participate, the
included hospitals represent a nonrandom sample of US hos-
pitals but have characteristics similar to those in the Ameri-
can Hospital Association Database).19 Included patients were
those admitted to intensive care or intermediate care units
with septic shock who received norepinephrine and began
hydrocortisone treatment within 3 days of hospital admis-
sion. We excluded patients younger than 18 years and those
with alternative indications for fludrocortisone (primary
adrenal insufficiency, orthostatic hypotension, and congeni-
tal adrenal hyperplasia). Patients with septic shock were
identified using the International Classification of Diseases,
Tenth Revision (ICD-10) code for septic shock (ie, explicit
septic shock) as the admitting diagnosis or with the present
on admission classifier. We chose to include patients with an
explicit septic shock diagnosis, rather than using other
claims-based strategies to identify septic shock,20 due to the
near 100% specificity and positive predictive value20,21 of
the explicit septic shock definition and because limiting to
patients with explicit septic shock diagnoses results in a
population with high mortality20,22 (ie, patients likely to
benefit from initiation of corticosteroid treatment). There is
moderate correlation (Pearson coefficient, 0.64) between
the explicit septic shock definition and Sepsis-3–based
algorithms.20 Study day 0 was defined as the calendar day in
which hydrocortisone treatment was first initiated (in the
hydrocortisone monotherapy arm), or the day that hydrocor-
tisone and fludrocortisone were co-initiated (in the combi-
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Key Points
Question What is the comparative effectiveness of
fludrocortisone added to hydrocortisone vs hydrocortisone
alone among patients with septic shock?
Findings In this multicenter cohort study among 88 275 patients
with septic shock receiving norepinephrine who initiated
hydrocortisone treatment, the addition of fludrocortisone to
hydrocortisone was associated with a 3.7% lower adjusted
absolute risk difference in the primary composite outcome
of mortality or discharge to hospice compared with initiation
of hydrocortisone alone.
Meaning Among patients with septic shock receiving
norepinephrine who initiated hydrocortisone treatment,
the addition of fludrocortisone was associated with lower rates
of the composite of death or discharge to hospice compared
with hydrocortisone alone.
nation therapy arm). Detailed eligibility criteria are in
eTable 2 in Supplement 1.
Treatment Assignment
Treatment assignment was based on whether enteral fludro-
cortisone treatment was initiated on the same calendar day that
hydrocortisone treatment was initiated (hereafter referred to
as combination “hydrocortisone-fludrocortisone” for those re-
ceiving fludrocortisone and “hydrocortisone-alone” for those
not receiving fludrocortisone). Patients initially started on hy-
drocortisone treatment who then received fludrocortisone on
subsequent days were assigned to the hydrocortisone-only
group consistent with intention-to-treat principles. Unlike prior
clinical trials7,9 that randomized patients to 7 days of cortico-
steroids, the specification of treatment assignment in our study
emulated a hypothetical trial that randomized patients to an
initial corticosteroid strategy without specification of subse-
quent doses or duration. Treatment assignments were ascer-
tained using hospital billing data (eTable 3 in Supplement 1).
Because granularity was limited to the calendar day, the time
from hydrocortisone to fludrocortisone initiation was not
known and included possibilities that fludrocortisone pre-
ceded hydrocortisone (increasing the risk of misclassifica-
tion) or that fludrocortisone was given up to 24 hours after
hydrocortisone (increasing the risk of immortal time bias). Con-
sistent with our assumption that fludrocortisone was given con-
current with or shortly after hydrocortisone, analysis of elec-
tronic health record data (n = 58) from the Medical Information
Mart for Intensive Care Database23 showed a median (IQR) time
from hydrocortisone treatment initiation to fludrocortisone
treatment initiation of 120 (0-840) minutes among patients
with septic shock (eMethods in Supplement 1).
Outcomes
Outcomes were ascertained from study day 0 (start of hydro-
cortisone or hydrocortisone-fludrocortisone) until hospital dis-
charge. The primary outcome was the composite of hospital
death or discharge to hospice. Secondary outcomes were hos-
pital death, vasopressor-free days, and hospital-free days by
day 28. “Free day” outcomes were calculated as 28 minus the
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 Comparative Effectiveness of Fludrocortisone and Hydrocortisone vs Hydrocortisone Alone in Septic Shock
number of days of therapy (vasopressor use or hospitaliza-
tion during the index hospitalization), with patients who died
in the hospital assigned 0 “free days.” We calculated the pro-
portion of patients who developed hypernatremia and health
care–associated infection in each treatment arm to assess for
potential complications of corticosteroid treatment.
Covariates
We used directed acyclic graphs24 (eFigure 1 in Supplement 1)
to identify 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; vali-
dated measures of comorbidity burden25 and acute organ
dysfunction26,27; major surgery28; history of congestive heart
failure or connective tissue disease; pneumonia present on
admission; resuscitative fluid volume; enteral administra-
tion of medications other than fludrocortisone (as the receipt
of enteral medications may reflect lower severity of acute ill-
ness); 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 hospi-
tal; and hospital teaching status, size, caseload, and US cen-
sus region. We used the most recent value for covariates with
more than 1 entry. Variable definitions are shown in eTable 3
in Supplement 1.
Statistical Analysis
Covariate balance was assessed using absolute standardized
mean differences (SMDs) between treatment assignments.
Unadjusted survival curves were constructed using the
Kaplan-Meier estimator.29 Unadjusted proportions and risk
differences were calculated by treatment assignment.
We calculated adjusted absolute risk differences (adjusted
mean differences for continuous outcomes) and 95% CIs
using doubly robust targeted maximum likelihood estima-
tion (TMLE) 30 and an ensemble machine learner (Super
Learner). 31,32 Targeted maximum likelihood estimation
provides semiparametric, locally efficient substitution esti-
mators and yields valid estimates of the treatment effect
when models estimating the probability of treatment assign-
ment or the probability of the outcome are correctly speci-
fied (doubly robust). We conducted subgroup analyses
stratified by age, sex, history of congestive heart failure,
and days from hospital admission to initiation of corticoste-
roid treatment.
Analyses were performed with R software, version 4.0.5
(R Foundation for Statistical Computing). Alpha was 2-sided
and set at .05 for the primary outcome TMLE analysis. We did
not adjust for multiple comparisons; thus, all analyses other
than the primary outcome should be viewed as hypothesis
generating. The protocol for this study was previously depos-
ited in an online repository.33 This study was designated as not
human participants research by Boston University’s Institu-
tional Review Board (#H-41795). The design of this study
followed the Strengthening the Reporting of Observational
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Original Investigation Research
Studies in Epidemiology (STROBE) guidelines.34 Additional
analysis details are included in the eMethods in Supplement 1.
Sensitivity Analyses
We conducted multiple additional analyses to assess the ro-
bustness of the findings under alternative assumptions and to
assess the risk of bias (see eMethods in Supplement 1 for ad-
ditional details). Briefly, we calculated E-values to estimate
the strength of association between unmeasured confound-
ers, treatment assignment, and the primary outcome that
would be needed to bring the association between treatment
assignment and outcome to zero.35,36 We conducted a nega-
tive control analysis using an outcome of blood transfusion to
assess the risk of residual confounding.37 We repeated analy-
ses after excluding patients discharged in 2020 to minimize
effects from the COVID-19 pandemic. To minimize the poten-
tial for immortal time bias,38 we repeated analyses among
patients who met inclusion criteria only on hospital day 1.
To assess the robustness of results to possible covariate mis-
classification, we repeated analyses among patients who met
inclusion criteria on hospital day 2 or 3 and classified covari-
ates using variables from the day prior to treatment assign-
ment. Last, we explored the robustness of findings to potential
residual confounding by indication, secular changes in sepsis
treatment, and patient illness severity, using the difference-
in-differences method39 that compared changes in outcomes
before and after hospital-level adoption of fludrocortisone
following the March 2018 publication of the Activated Protein
C and Corticosteroids for Human Septic Shock (APROCCHSS)
trial9—the largest clinical trial showing mortality benefit
of combination hydrocortisone-fludrocortisone compared
with placebo.
Results
Study Population and Baseline Characteristics
Among the 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 (Figure 1). Among included patients,
85 995 (97.4%) were treated with hydrocortisone alone
(median [IQR] age, 67 [57-76] years; 42 136 female; 43 859
male), and 2280 (2.6%) were treated with combination
hydrocortisone-fludrocortisone (median [IQR] age, 64 [54-
73] years; 1041 female; 1239 male). The median (IQR) time
from norepinephrine initiation 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 charac-
teristics related to admission hospital also differed between
treatment assignments (Table 1).
Primary Outcome
The median (IQR) number of days of follow-up was 6 (2-13)
in patients treated with hydrocortisone-fludrocortisone and
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 Research Original Investigation Comparative Effectiveness of Fludrocortisone and Hydrocortisone vs Hydrocortisone Alone in Septic Shock

Figure 1. Study Flow Diagram

11 927 084 Step-down and ICU encounters in

the enhanced claims-based Premier
Healthcare Database, 2016-2020

384 394 Patients with septic shock diagnosis

present on admission and
receiving norepinephrine

96 861 Received hydrocortisone within

3 d of admission

8586 Excluded
459 Age <18 y
8127 Alternative indications for
fludrocortisone present
on admission

88 275 Final cohort Among the 287 533 patients

85 995 Received hydrocortisone alone 2280 Received addition of fludrocortisone
(combination hydrocortisone-fludrocortisone)
with septic shock who received
norepinephrine but who did
not receive hydrocortisone,
101 611 (35.3%) died. ICU indicates
intensive care unit.

5 (1-12) in those treated with hydrocortisone alone. The
median (IQR) duration of treatment was 3 (1-4) days in the
hydrocortisone-fludrocortisone group and 3 (2-6) in the hy-
drocortisone alone group. The median (IQR) total dose
of hydrocortisone on study day 0 was 225 (200-300) mg
among patients who received hydrocortisone-
fludrocortisone and 200 (100-300) mg among patients who
received hydrocortisone alone. The median (IQR) total dose
of fludrocortisone was 0.1 (0.1-0.1) mg. Among patients who
received hydrocortisone-fludrocortisone, 1076 (47.2%) died
or were discharged to hospice vs 43 669 (50.8%) for those
who received hydrocortisone alone. Figure 2 shows unad-
justed survival curves by treatment assignment. In the
adjusted TMLE analysis, receipt of hydrocortisone-
fludrocortisone was associated with an adjusted absolute
risk difference of −3.7% (95% CI, −4.2% to −3.1%; P < .001;
E-value, 1.37) in hospital mortality or discharge to hospice
compared with hydrocortisone alone (Table 2, eFigure 2 in
Supplement 1). Results were similar in the sensitivity analy-
ses (eTables 4-6 in Supplement 1, Table 2). There was no dif-
ference by treatment assignment for the negative control
outcome of blood transfusion after study day 0 (hydrocorti-
sone-fludrocortisone: 28.3%; hydrocortisone alone: 29.9%;
adjusted risk difference, −0.3%; 95% CI, −0.8% to 0.1%). The
direction of effect favored hydrocortisone-fludrocortisone in
all prespecified subgroups (eTable 7 in Supplement 1).
Secondary Outcomes
The rate of hospital death was 39.3% among patients who
received hydrocortisone-fludrocortisone and 42.7% among
patients who received hydrocortisone (adjusted risk differ-
ence, −3.7%; 95% CI, −4.2% to −3.3%). Vasopressor-free days
and hospital-free days were higher among patients who
received hydrocortisone-fludrocortisone (Table 3). The
adjusted mean difference in vasopressor-free days and
hospital-free days comparing patients treated w ith
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. The proportions of patients with incident
hypernatremia (8872 of 78 484 [11.3%] for hydrocortisone
a l o n e ; 2 3 6 o f 2 0 6 6 [ 1 1 . 4% ] f o r hyd r o c o r t i s o n e -
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.
Difference-in-Differences
We identified 3521 patients admitted to future fludrocorti-
sone “adopter” hospitals (ie, those in the top quartile of
hospitals that increased their use of hydrocortisone-
fludrocortisone after APROCCHSS) and 7510 admitted to
control hospitals prior to publication of APROCCHSS,9 and
5464 admitted to adopter hospitals and 9784 admitted to
control hospitals after publication of APROCCHSS. The per-
centage of patients who received fludrocortisone in addition
to hydrocortisone increased from 0.4% pre-APROCCHSS to
12.6% post-APROCCHSS among patients admitted to adopter
hospitals and remained stable (0.3% to 0.3%) among
patients admitted to control hospitals. There was no evi-
dence (interaction term β, 0.0006; 95% CI, −0.0010 to
0.0030) that outcome trends between adopter and control
hospitals were different in the pre-APROCCHSS period (eFig-
ure 3 in Supplement 1). Hospital death or discharge to
hospice occurred in 51.6% of patients admitted to adopter
hospitals and 49.0% of patients admitted to control hospi-
tals pre-APROCCHSS and 52.6% (+1.0%) in adopter hospitals
and 52.2% (+3.2%) of patients in controls post-APROCCHSS,
resulting in an adjusted difference-in-difference estimator of
−2.0% (−3.9% to −0.2%), a lower probability of hospital
death or discharge to hospice for patients admitted to flu-
drocortisone adopter hospitals after public ation of
APROCCHSS9 compared with patients admitted to control

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 Comparative Effectiveness of Fludrocortisone and Hydrocortisone vs Hydrocortisone Alone in Septic Shock Original Investigation Research

Table 1. Baseline Covariates for Patients With Septic Shock Receiving Norepinephrine Who Received Hydrocortisone Treatment
Hydrocortisone and Absolute SMD after
Hydrocortisone alone fludrocortisone Absolute inverse probability of
Variable (n = 85 995) (n = 2280) SMD treatment weighting
Age, median (IQR), y 67 (57-76) 64 (54-73) 0.20 0.06
Sex, No. (%)
Female 42 136 (49.0) 1041 (45.7)
0.07 0.05
Male 43 859 (51.0) 1239 (54.3)
Health insurance type, No. (%)
Commercial 12 479 (14.5) 318 (13.9)
Medicaid 12 000 (14.0) 427 (18.7)
Medicare 56 551 (65.8) 1389 (60.9) 0.15 0.08
Self-pay 2692 (3.1) 94 (4.1)
Other 2273 (2.6) 52 (2.3)
Elixhauser comorbidity score POA, median (IQR) 6 (4-7) 6 (4-7) 0.04 0.05
CHF POA, No. (%) 31 663 (36.8) 848 (37.2) 0.01 0.02
Connective tissue disease POA, No. (%) 6461 (7.5) 117 (5.1) 0.10 0.08
Pneumonia POA, No. (%) 32 306 (37.6) 899 (39.4) 0.04 0.02
Major surgery per HCUP on or before day 8380 (9.7) 148 (6.5) 0.12 0.10
of hydrocortisone initiation, No. (%)
Acute organ dysfunction, No. (%)
Respiratory 36 518 (42.5) 1123 (49.3) 0.14 0.02
Hematologic 26 125 (30.4) 724 (31.8) 0.03 0.06
Hepatic 10 906 (12.7) 291 (12.8) 0.00 0.07
Renal 60 416 (70.3) 1621 (71.1) 0.02 0.01
Time from hospital admission
to hydrocortisone initiation, No. (%)
0d 45 835 (53.3) 1052 (46.1)
1d 32 576 (37.9) 1029 (45.1) 0.15 0.02
2d 7584 (8.8) 199 (8.7)
Time from norepinephrine initiation
to hydrocortisone treatment, No. (%)
0d 60 262 (70.1) 1434 (62.9)
1d 22 431 (26.1) 771 (33.8) 0.17 0.02
2d 3302 (3.8) 75 (3.3)
Volume of resuscitative fluids on day 2000 (0-4500) 2500 (500-5000) 0.16 0.02
of hydrocortisone initiation, median (IQR), mL
Enteral medication administration 51 974 (60.4) 1895 (83.1) 0.52 0.29
other than fludrocortisone on day
of hydrocortisone initiation, No. (%)
Serum cortisol measured on day 14 130 (16.4) 321 (14.1) 0.07 0.02
of hydrocortisone initiation, No. (%)
Cosyntropin administered on day 392 (0.5) 5 (0.2) 0.04 0.06
of hydrocortisone initiation, No. (%)
Etomidate use on or before day 22 652 (26.3) 710 (31.1) 0.11 0.03
of hydrocortisone initiation, No. (%)
Kidney replacement therapy on or before day 7301 (8.5) 216 (9.5) 0.04 0.02
of hydrocortisone initiation, No. (%)
Vasopressor use on day
of hydrocortisone initiation, No. (%)
Dopamine 5715 (6.6) 74 (3.2) 0.16 0.09
Epinephrine 17 987 (20.9) 483 (21.2) 0.01 0.03
Phenylephrine 21 445 (24.9) 565 (24.8) 0.00 0.02
Vasopressin 45 077 (52.4) 1551 (68.0) 0.32 0.09
Vasopressor count on day 2 (1-3) 2 (1-3) 0.13 0.01
of hydrocortisone initiation, median (IQR)
Invasive mechanical ventilation on day 50 981 (59.3) 1491 (65.4) 0.13 0.00
of hydrocortisone initiation, No. (%)
US Census region, No. (%)
Midwest 18 548 (21.6) 480 (21.1)
Northeast 10 954 (12.7) 388 (17.0)
0.17 0.13
South 39 823 (46.3) 897 (39.3)
West 16 670 (19.4) 515 (22.6)

(continued)

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 Research Original Investigation Comparative Effectiveness of Fludrocortisone and Hydrocortisone vs Hydrocortisone Alone in Septic Shock

Table 1. Baseline Covariates for Patients With Septic Shock Receiving Norepinephrine Who Received Hydrocortisone Treatment (continued)
Hydrocortisone and Absolute SMD after
Hydrocortisone alone fludrocortisone Absolute inverse probability of
Variable (n = 85 995) (n = 2280) SMD treatment weighting
Teaching hospital status, No. (%) 44 347 (51.6) 1640 (71.9) 0.43 0.18
Hospital bed number, No. (%)
0-99 2912 (3.4) 62 (2.7)
100-199 11 286 (13.1) 177 (7.8)
200-299 14 549 (16.9) 311 (13.6)
0.29 0.13
300-399 14 199 (16.5) 280 (12.3)
400-499 10 792 (12.5) 342 (15.0)
≥500 32 257 (37.5) 1108 (48.6)
Hospital caseload, median (IQR) 232 (119-394) 370 (189-503) 0.42 0.15
Surgical care unit, No. (%) 3221 (3.7) 175 (7.7) 0.17 0.03
Discharge quarter/y, No. (%)
1/2016 3709 (4.3) 10 (0.4)
2/2016 3435 (4.0) 8 (0.4)
3/2016 3363 (3.9) 13 (0.6)
4/2016 3673 (4.3) 16 (0.7)
1/2017 4336 (5.0) 13 (0.6)
2/2017 4198 (4.9) 9 (0.4)
3/2017 3967 (4.6) 10 (0.4)
4/2017 4340 (5.0) 15 (0.7)
1/2018 4929 (5.7) 35 (1.5)
2/2018 4297 (5.0) 233 (10.2)
0.95 0.31
3/2018 4212 (4.9) 191 (8.4)
4/2018 4659 (5.4) 189 (8.3)
1/2019 5204 (6.1) 237 (10.4)
2/2019 4786 (5.6) 194 (8.5)
3/2019 4525 (5.3) 182 (8.0)
4/2019 4916 (5.7) 164 (7.2)
1/2020 5078 (5.9) 224 (9.8)
2/2020 4116 (4.8) 201 (8.8)
3/2020 4000 (4.7) 180 (7.9)
4/2020 4252 (4.9) 156 (6.8)

Abbreviations: CHF, congestive heart failure; HCUP, Healthcare Cost and Utilization Project; POA, present on admission; SMD, standardized mean difference.

hospitals. There was no evidence of bias from the blood
transfusion falsification test (difference-in-difference esti-
mator, 1.3%; 95% CI, −0.4% to 2.9%).
Discussion
In this cohort study, we used a large, multicenter, enhanced
claims-based database to emulate a clinical trial that would
compare the effectiveness of fludrocortisone added to hydro-
cortisone vs hydrocortisone alone among patients with sep-
tic shock. We found that fludrocortisone added to hydrocor-
tisone was associated with increased hospital survival, shorter
length of stay, and decreased shock duration compared with
hydrocortisone alone. The primary outcome effect estimate
was similar to the risk reduction of the COIITSS clinical trial
(−2.9% absolute risk reduction),12 a previous and potentially
underpowered randomized clinical trial that also compared
hydrocortisone-fludrocortisone to hydrocortisone alone.
Findings provide additional evidence that the addition of
fludrocortisone to hydrocortisone may be superior to hydro-
cortisone alone among patients with septic shock.
Despite the findings of prior clinical trials8,9 that showed
reduced mortality w ith combined hydrocortisone-
fludrocortisone as compared with placebo, guidelines 4
recommend hydrocortisone alone in patients with septic
shock with persistent vasopressor requirements. Rationale
fo r re c o m m e n d at i o n s to u s e hyd ro c o r t i s o n e a l o n e
during septic shock include the “negative” (ie, statistically
nonsignificant) findings from the COIITSS clinical trial 12
and potentially adequate mineralocorticoid effects of
hydrocortisone. However, published mineralocorticoid
equivalences are based on sodium-retaining potency40,41
and do not account for pleotropic mineralocorticoid
effects, including activation of innate immunity and facilita-
tion of clearance of increased alveolar fluid (a hallmark
of acute respiratory distress syndrome, a common comor-
bidity in patients with septic shock) by alveolar epithelial
cells.42-44 We speculate that differences in these pleotropic
effects between fludrocortisone and hydrocortisone

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 Comparative Effectiveness of Fludrocortisone and Hydrocortisone vs Hydrocortisone Alone in Septic Shock Original Investigation Research

Figure 2. 28-Day Survival Among Patients With Septic Shock Treated With Hydrocortisone-Fludrocortisone
or Hydrocortisone Alone

1.00

Overall survival probability

0.75
+

Combination hydrocortisone-
fludrocortisone
0.50

Hydrocortisone alone
0.25

Shown are unadjusted Kaplan-Meier

0
0 5 10 15 20 25 survival curves for the composite
Days outcome of hospital death or
No. at risk discharge to hospice for patients in
Hydrocortisone alone 85 995 46 364 26 760 15 456 9205 5718 the 28 days after initiation of
Combination hydrocortisone-fludrocortisone 2280 1378 828 491 286 181 corticosteroid treatment among
adult patients with septic shock.

Table 2. Primary and Sensitivity Targeted Maximum Likelihood Estimation Analyses for Hospital Death or Discharge to Hospice
Hydrocortisone
Hydrocortisone alone and fludrocortisone
Hospital death or discharge Unadjusted risk Adjusted risk
to hospice No. patients with events/total No. of patients (%) difference (95% CI) difference (95% CI) P value
Primary analysis (n = 88 275) 43 669/85 995 (50.8) 1076/2280 (47.2) −3.6 (−5.7 to −1.5) −3.7 (−4.2 to −3.1) <.001
Sensitivity analyses
Met inclusion criteria on 22 303/45 835 (48.7) 452/1052 (43.0) −5.7 (−8.7 to −2.6) −5.2 (−5.8 to −4.6) <.001
hospital day 1 (n = 46 887)
Met inclusion criteria on 21 366/40 160 (53.2) 624/1228 (50.8) −2.4 (−5.2 to 0.4) −2.2 (−3.2 to −1.3) <.001
hospital day 2 or 3 with
covariates ascertained
on the day before treatment
assignment (n = 41 388)
Excluding 2020 (n = 70 068) 34 072/68 549 (49.7) 696/1519 (45.8) −3.9 (−6.4 to −1.3) −4.0 (−4.6 to −3.5) <.001

may explain the lower mortality associated with combina- tion with treatment assignment and outcome (E-value, 1.37),
tion hydrocortisone-fludrocortisone vs hydrocortisone the observational nature of our study increases the risk of
alone. residual unmeasured confounding as compared with a ran-
Our results inform the feasibility of future studies and domized trial. Although we used validated scores to esti-
clinical care. Based on our results and assuming 50% mortal- mate severity of acute organ dysfunction with similar
ity among patients given hydrocortisone alone, a 1:1 random- performance to the sequential organ failure score 27 and
ized clinical trial comparing hydrocortisone alone to adjusted for admission hospital to account for between-
hydrocortisone-fludrocortisone would need to enroll 5724 center practice pattern variation, the Premier Healthcare
participants to have 80% power (α = .05) to detect a differ- Database does not contain comprehensive electronic
ence at least as large as that identified in our study. In addi- medical record physiological/vital sign data or vasopressor
tion, future Bayesian network meta-analyses seeking to doses that, because not included in models, may increase
compare hydrocortisone to hydrocortisone-fludrocortisone the risk of unmeasured cofounding. However, a difference-
using existing placebo-controlled randomized clinical trials in-differences design sensitivity analysis less subject to
should consider using our observational effect estimates to residual confounding by individual patient characteristics
inform prior probabilities. Last, in absence of these future yielded complementary results showing that higher vs
studies, our results suggest that clinicians seeking to opti- lower hospital-level adoption of fludrocortisone after publi-
mize the use of corticosteroids in septic shock should con- c ation of the APROCCHSS trial 9 was associated with
sider adding fludrocortisone when initiating hydrocortisone improved outcomes. Last, there are several limitations
treatment. related to the Premier Healthcare Database having granular-
ity only to the level of the calendar day. First, in our primary
Limitations analysis we classified covariates that were present on
Our study has limitations. Although results were robust to study day 0 as preexposure (rather than postexposure), an
sensitivity analyses, were similar to those from a prior assumption that is unverifiable based on the limited granu-
clinical trial,12 and would only be altered in the presence of larity of the data set. However, a sensitivity analysis limited
an unmeasured confounder with a 37% or greater associa- to patients who met inclusion criteria and were assigned

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 Research Original Investigation Comparative Effectiveness of Fludrocortisone and Hydrocortisone vs Hydrocortisone Alone in Septic Shock

Table 3. Secondary Outcomes Using Targeted Maximum Likelihood Estimation

Hydrocortisone
Hydrocortisone alone and fludrocortisone
Unadjusted risk Adjusted risk
Outcome (n = 88 275) No. patients with events/total No. of patients (%) difference (95% CI) difference (95% CI) P value
Hospital death 36 713/85 995 (42.7) 896/2280 (39.3) −3.4 (−5.5 to −1.3) −3.7 (−4.2 to −3.3) <.001
Blood transfusion negative 25 716/85 995 (29.9) 645/2280 (28.3) −1.6 (−3.5 to 0.3) −0.3 (−0.8 to 0.1) .12
control outcome
Unadjusted risk Adjusted risk P value
Mean days (95% CI) difference (95% CI) difference (95% CI)
Vasopressor-free days 12.9 (12.9 to 13.0) 13.8 (13.3 to 14.4) 0.9 (0.3 to 1.5) 0.9 (0.8 to 1.1) <.001
Hospital-free days 8.4 (8.3 to 8.4) 8.7 (8.3 to 9.1) 0.3 (−0.1 to 0.7) 0.7 (0.6 to 0.8) <.001

treatment status on hospital day 2 or 3, with covariates
defined based on values on the day prior to treatment
assignment, yielded similar results to the primary analysis,
suggesting that primary results were not fully explained
by covariate misclassification. Second, it is possible that ini-
tiation of fludrocortisone treatment did not occur concur-
rently 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 unadjusted survival
curve showing separation between treatment assignments
starting on study day 0 could suggest evidence of immortal
time bias, although the treatment arms continue to separate
through study day 4, a time period consistent with survival
curve separation in the APROCCHSS trial. 9 In addition,
analysis of the separate MIMIC-IV database23 suggested that
the median time from hydrocortisone to fludrocortisone
initiation is only 2 hours.
Conclusions
In this multicenter observational effectiveness cohort study
of patients with septic shock who were started on hydrocor-
tisone treatment, the addition of fludrocortisone was supe-
rior to hydrocortisone alone across multiple patient out-
comes, including mortality. These results, among more than
88 000 patients, showed similar absolute risk reduction esti-
mates to a previous clinical trial and provide additional
evidence for combination hydrocortisone-fludrocortisone
therapy for patients with septic shock for whom clinicians
choose to initiate corticosteroid therapy.

ARTICLE INFORMATION
Accepted for Publication: January 28, 2023.
Published Online: March 27, 2023.
doi:10.1001/jamainternmed.2023.0258
Author Contributions: Dr Bosch had full access to
all of the data in the study and takes responsibility
for the integrity of the data and the accuracy of the
data analysis.
Concept and design: Bosch, Teja, Law, Pang, Walkey.
Acquisition, analysis, or interpretation of data: Teja,
Law, Jafarzadeh, Walkey.
Drafting of the manuscript: Bosch, Teja, Law,
Pang, Walkey.
Critical revision of the manuscript for important
intellectual content: Bosch, Teja, Law, Jafarzadeh,
Walkey.
Statistical analysis: Bosch, Law, Jafarzadeh.
Obtained funding: Bosch.
Administrative, technical, or material support: Pang.
Supervision: Walkey.
Conflict of Interest Disclosures: Dr Bosch
reported grants from Department of Defense
(DOD), National Heart, Lung, and Blood Institute
(NHLBI), and Gilead Sciences outside the submitted
work. Dr Law reported grants from Doris Duke
outside the submitted work. Dr Walkey reported
grants from Gilead and Agency for Healthcare
Research and Quality outside the submitted work.
No other disclosures were reported.
Funding/Support: This study was supported by
National Institutes of Health (NIH) National Center
for Advancing Translational Sciences (NCATS) grant
number 1KL2TR001411, 1UL1TR001430, and the
Boston University Chobanian & Avedisian School of
Medicine Department of Medicine Career
Investment Award. Dr Bosch is supported by the
NIH/NHLBI, the NIH/NCATS, and the DOD. Dr Teja
is supported by the Canadian Institutes of Health
Research. ACL is supported by the NIH/NHLBI and
the Doris Duke Charitable Foundation. Dr Law is
supported by the NIH/NHLBI, the Agency for
Healthcare Research and Quality, and the DOD.
Role of the Funder/Sponsor: The funders had no
role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Disclaimer: This study’s contents are solely the
responsibility of the authors and do not necessarily
represent the official views of the NIH or Boston
University.
Data Sharing Statement: See Supplement 2.
REFERENCES
1. Rhee C, Dantes R, Epstein L, et al; CDC
Prevention Epicenter Program. Incidence and
trends of sepsis in US hospitals using clinical vs
claims data, 2009-2014. JAMA. 2017;318(13):
1241-1249. doi:10.1001/jama.2017.13836
2. Liu V, Escobar GJ, Greene JD, et al. Hospital
deaths in patients with sepsis from 2 independent
cohorts. JAMA. 2014;312(1):90-92. doi:10.1001/
jama.2014.5804
3. Bauer M, Gerlach H, Vogelmann T, Preissing F,
Stiefel J, Adam D. Mortality in sepsis and septic
shock in Europe, North America and Australia
between 2009 and 2019—results from a systematic
review and meta-analysis. Crit Care. 2020;24(1):239.
doi:10.1186/s13054-020-02950-2
4. Evans L, Rhodes A, Alhazzani W, et al. Surviving
Sepsis Campaign: international guidelines for
management of sepsis and septic shock 2021. Crit
Care Med. 2021;49(11):e1063-e1143. doi:10.1097/
CCM.0000000000005337
5. Gordon AC, Mason AJ, Thirunavukkarasu N, et al;
VANISH Investigators. Effect of early vasopressin vs
norepinephrine on kidney failure in patients with
septic shock: the VANISH randomized clinical trial.
JAMA. 2016;316(5):509-518. doi:10.1001/jama.2016.
10485
6. Sprung CL, Annane D, Keh D, et al; CORTICUS
Study Group. Hydrocortisone therapy for patients
with septic shock. N Engl J Med. 2008;358(2):111-124.
doi:10.1056/NEJMoa071366
7. Venkatesh B, Finfer S, Cohen J, et al; ADRENAL
Trial Investigators and the Australian–New Zealand
Intensive Care Society Clinical Trials Group.
Adjunctive glucocorticoid therapy in patients with
septic shock. N Engl J Med. 2018;378(9):797-808.
doi:10.1056/NEJMoa1705835
8. Annane D, Sébille V, Charpentier C, et al. Effect
of treatment with low doses of hydrocortisone and
fludrocortisone on mortality in patients with septic
shock. JAMA. 2002;288(7):862-871. doi:10.1001/
jama.288.7.862
9. Annane D, Renault A, Brun-Buisson C, et al;
CRICS-TRIGGERSEP Network. Hydrocortisone plus
fludrocortisone for adults with septic shock. N Engl
J Med. 2018;378(9):809-818. doi:10.1056/
NEJMoa1705716

E8 JAMA Internal Medicine Published online March 27, 2023 (Reprinted) jamainternalmedicine.com

© 2023 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ by a HEMOCE User on 03/27/2023

 Comparative Effectiveness of Fludrocortisone and Hydrocortisone vs Hydrocortisone Alone in Septic Shock
10. Rygård SL, Butler E, Granholm A, et al.
Low-dose corticosteroids for adult patients with
septic shock: a systematic review with
meta-analysis and trial sequential analysis. Intensive
Care Med. 2018;44(7):1003-1016. doi:10.1007/
s00134-018-5197-6
11. Rochwerg B, Oczkowski SJ, Siemieniuk RAC,
et al. Corticosteroids in sepsis: an updated
systematic review and meta-analysis. Crit Care Med.
2018;46(9):1411-1420. doi:10.1097/CCM.
0000000000003262
12. Annane D, Cariou A, Maxime V, et al; COIITSS
Study Investigators. Corticosteroid treatment and
intensive insulin therapy for septic shock in adults:
a randomized controlled trial. JAMA. 2010;303
(4):341-348. doi:10.1001/jama.2010.2
13. Harhay MO, Wagner J, Ratcliffe SJ, et al.
Outcomes and statistical power in adult critical care
randomized trials. Am J Respir Crit Care Med. 2014;
189(12):1469-1478. doi:10.1164/rccm.201401-0056CP
14. Abrams D, Montesi SB, Moore SKL, et al.
Powering bias and clinically important treatment
effects in randomized trials of critical illness. Crit
Care Med. 2020;48(12):1710-1719. doi:10.1097/
CCM.0000000000004568
15. Hernán MA, Robins JM. Using big data to
emulate a target trial when a randomized trial is not
available. Am J Epidemiol. 2016;183(8):758-764.
doi:10.1093/aje/kwv254
16. Hernán MA. Methods of public health
research—strengthening causal inference from
observational data. N Engl J Med. 2021;385(15):
1345-1348. doi:10.1056/NEJMp2113319
17. Lindenauer PK, Pekow P, Wang K, Mamidi DK,
Gutierrez B, Benjamin EM. Perioperative
beta-blocker therapy and mortality after major
noncardiac surgery. N Engl J Med. 2005;353(4):
349-361. doi:10.1056/NEJMoa041895
18. Schneeweiss S, Seeger JD, Landon J,
Walker AM. Aprotinin during coronary-artery
bypass grafting and risk of death. N Engl J Med.
2008;358(8):771-783. doi:10.1056/NEJMoa0707571
19. Premier Healthcare Database White Paper.
Data that informs and performs. Published online
March 2, 2020. Accessed November 9, 2021.
https://products.premierinc.com/downloads/
PremierHealthcareDatabaseWhitepaper.pdf
20. Rhee C, Jentzsch MS, Kadri SS, et al;
Centers for Disease Control and Prevention (CDC)
Prevention Epicenters Program. Variation in
identifying sepsis and organ dysfunction using
administrative versus electronic clinical data and
impact on hospital outcome comparisons. Crit Care
Med. 2019;47(4):493-500. doi:10.1097/CCM.
0000000000003554
21. Iwashyna TJ, Odden A, Rohde J, et al.
Identifying patients with severe sepsis using
jamainternalmedicine.com
© 2023 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ by a HEMOCE User on 03/27/2023
administrative claims: patient-level validation
of the angus implementation of the international
consensus conference definition of severe sepsis.
Med Care. 2014;52(6):e39-e43. doi:10.1097/MLR.
0b013e318268ac86
22. Whittaker SA, Mikkelsen ME, Gaieski DF,
Koshy S, Kean C, Fuchs BD. Severe sepsis cohorts
derived from claims-based strategies appear to be
biased toward a more severely ill patient
population. Crit Care Med. 2013;41(4):945-953.
doi:10.1097/CCM.0b013e31827466f1
23. Johnson A, Bulgarelli L, Pollard T, Horng S, Celi
LA, Mark R. MIMIC-IV (version 0.4). PhysioNet.
doi:10.13026/A3WN-HQ05
24. Shrier I, Platt RW. Reducing bias through
directed acyclic graphs. BMC Med Res Methodol.
2008;8(1):70. doi:10.1186/1471-2288-8-70
25. Elixhauser A, Friedman B, Stranges E.
Septicemia in US hospitals, 2009: Statistical Brief
#122. In: Healthcare Cost and Utilization Project
(HCUP) Statistical Briefs. Agency for Healthcare
Research and Quality (US); 2006. Accessed
February 23, 2021. https://www.ncbi.nlm.nih.gov/
books/NBK65391/
26. Angus DC, Linde-Zwirble WT, Lidicker J,
Clermont G, Carcillo J, Pinsky MR. Epidemiology of
severe sepsis in the United States: analysis of
incidence, outcome, and associated costs of care.
Crit Care Med. 2001;29(7):1303-1310. doi:10.1097/
00003246-200107000-00002
27. Bosch NA, Law AC, Rucci JM, Peterson D,
Walkey AJ. Predictive validity of the sequential
organ failure assessment score versus claims-based
scores among critically ill patients. Ann Am Thorac
Soc. 2022;19(6):1072-1076. doi:10.1513/AnnalsATS.
202111-1251RL
28. Healthcare Cost & Utilization Project.
Procedure classes refined for ICD-10-PCS.
Accessed June 8, 2022. https://hcup-us.ahrq.gov/
toolssoftware/procedureicd10/procedure_icd10.
jsp#elements
29. Kaplan EL, Meier P. Nonparametric estimation
from incomplete observations. J Am Stat Assoc.
1958;53(282):457-481. doi:10.1080/01621459.1958.
10501452
30. van der Laan MJ, Rubin D. Targeted maximum
likelihood learning. Int J Biostat. 2006;2(1).
doi:10.2202/1557-4679.1043
31. van der Laan MJ, Polley EC, Hubbard AE. Super
learner. Stat Appl Genet Mol Biol. 2007;6(1):e25.
doi:10.2202/1544-6115.1309
32. Gruber S, van der Laan M. tmle: An R package
for targeted maximum likelihood estimation. J Stat
Softw. 2012;51:1-35. doi:10.18637/jss.v051.i13
33. Bosch N. Comparative effectiveness of
fludrocortisone and hydrocortisone to
(Reprinted) JAMA Internal Medicine Published online March 27, 2023
Original Investigation Research
hydrocortisone in patients with septic shock:
a target trial emulation. Published online June 9,
2022. Accessed June 28, 2022. https://osf.io/gkrqn/
34. von Elm E, Altman DG, Egger M, Pocock SJ,
Gøtzsche PC, Vandenbroucke JP; STROBE Initiative.
The Strengthening the Reporting of Observational
Studies in Epidemiology (STROBE) statement:
guidelines for reporting observational studies.
J Clin Epidemiol. 2008;61(4):344-349. doi:10.1016/
j.jclinepi.2007.11.008
35. Mathur MB, Ding P, Riddell CA,
VanderWeele TJ. Web site and R package for
computing E-values. Epidemiology. 2018;29(5):
e45-e47. doi:10.1097/EDE.0000000000000864
36. VanderWeele TJ, Ding P. Sensitivity analysis in
observational research: introducing the E-value.
Ann Intern Med. 2017;167(4):268-274. doi:10.7326/
M16-2607
37. Lipsitch M, Tchetgen Tchetgen E, Cohen T.
Negative controls: a tool for detecting confounding
and bias in observational studies. Epidemiology.
2010;21(3):383-388. doi:10.1097/EDE.
0b013e3181d61eeb
38. Vail EA, Gershengorn HB, Wunsch H,
Walkey AJ. Attention to immortal time bias in
critical care research. Am J Respir Crit Care Med.
2021;203(10):1222-1229. doi:10.1164/rccm.202008-
3238CP
39. Zhou H, Taber C, Arcona S, Li Y.
Difference-in-differences method in comparative
effectiveness research: utility with unbalanced
groups. Appl Health Econ Health Policy. 2016;14(4):
419-429. doi:10.1007/s40258-016-0249-y
40. Brunton LL, Hilal-Dandan R, Knollmann BC.
Goodman & Gilman’s: The Pharmacological Basis of
Therapeutics. 13th ed. McGraw Hill Medical; 2018.
Accessed June 27, 2022. https://accessmedicine.
mhmedical.com/book.aspx?bookid=2189
41. Kaufman DA. Glucocorticoid therapy in septic
shock in adults. In: UpToDate. Wolters Kluwer;
2022. Accessed June 27, 2022. https://www.
uptodate.com/contents/glucocorticoid-therapy-in-
septic-shock-in-adults#H1330646853
42. Heming N, Sivanandamoorthy S, Meng P,
Bounab R, Annane D. Immune effects of
corticosteroids in sepsis. Front Immunol. 2018;9:1736.
doi:10.3389/fimmu.2018.01736
43. Annane D. Why my steroid trials in septic shock
were “positive”. Crit Care Med. 2019;47(12):
1789-1793. doi:10.1097/CCM.0000000000003889
44. Suzuki S, Tsubochi H, Suzuki T, et al.
Modulation of transalveolar fluid absorption by
endogenous aldosterone in adult rats. Exp Lung Res.
2001;27(2):143-155. doi:10.1080/
019021401750069384
E9