Published April 18, 2023

NEJM Evid 2023; 2 (5)

DOI: 10.1056/EVIDoa2200283

ORIGINAL ARTICLE

Meta-Analysis of Glucocorticoids for Covid-19

Patients Not Receiving Oxygen
Remo Daniel Covello, M.D.,1 Laura Pasin, M.D.,2 Stefano Fresilli, M.D.,3 Krisztina T

oth, M.D.,4 Caterina Damiani, M.D.,3
Ludhmila Abrah~ao Hajjar, M.D., Ph.D., Alberto Zangrillo, M.D., and Giovanni Landoni, M.D.3,6
5 3,6

Abstract
BACKGROUND Glucocorticoids reduce mortality in hospitalized patients with severe and
critical coronavirus disease 2019 (Covid-19), although a possible harm was documented
in patients with Covid-19 not requiring oxygen.

METHODS We searched Embase, BioMed Central, medRxiv, bioRxiv, PubMed, and the
Cochrane Central Register of Controlled Trials for any randomized trial or matched study
ever performed on adult patients with Covid-19 not receiving oxygen therapy treated with
intravenous or oral glucocorticoids versus any comparator (standard therapy or placebo);
there were no restrictions on dose or time of administration. The primary end point was
all-cause mortality at the longest available follow-up.

RESULTS Five randomized trials and one propensity-matched study involving 6634 hospi-
talized patients not on oxygen were finally included (3704 received glucocorticoids and
2930 received standard treatment). The overall mortality of patients treated with gluco-
corticoids was significantly higher than the mortality of patients in the control group
(509 of 3704 [14%] in the glucocorticoid group vs. 294 of 2930 [10%] in the control
group; odds ratio, 1.56 [95% confidence interval, 1.27 to 1.92], with three articles report-
ing mortality events and contributing to the combined odds ratio; P,0.001; number
needed to harm527).

CONCLUSIONS Glucocorticoid use likely increases mortality in hospitalized patients with

Covid-19 not receiving oxygen, with a number needed to harm of 27. (PROSPERO number
CRD42022342996.) Drs. Covello and Pasin
contributed equally to this work.

The author affiliations are listed

at the end of the article.

Dr. Landoni can be contacted at

Introduction landoni.giovanni@hsr.it or at

G
lucocorticoids were the first drugs with a reported survival benefit in hospitalized Department of Anesthesia and
Intensive Care, IRCCS San
patients with severe and critical coronavirus disease 2019 (Covid-19) and are Raffaele Scientific Institute, Via
now the standard of care in these patients.1 Existing guidelines advise against Olgettina, 60–20132, Milan, Italy.

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the use of glucocorticoids outside of these conditions,2,3
mainly because of the results of the Randomised Evaluation
of COVID-19 Therapy (RECOVERY) trial,1 which showed no
effect and a trend toward harm in hospitalized patients not
receiving oxygen treated with glucocorticoids. The best tim-
ing of — and severity threshold for — administering gluco-
corticoids in patients with Covid-19 has been a main issue
in clinical practice since the beginning of the pandemic.
Covid-19 is a systemic disease whose clinical manifestations
range from asymptomatic infection or only mild symptoms
in most of the population to severe viral pneumonia that
may require oxygen support in a minority of patients.
Among all anti-inflammatory and immunosuppressive drugs
tested in Covid-19, glucocorticoids are a low-cost, globally
available, easily accessible therapy. At the beginning of the
pandemic, glucocorticoids were either “contraindicated” or
“not recommended” by most of the Covid-19 treatment
guidelines, mainly in light of enhanced viral replication,
decreased viral clearance, and poor outcomes in previous
viral infections such as severe acute respiratory syndrome,
Middle East respiratory syndrome, and influenza.4-8
In the RECOVERY trial, 6425 hospitalized patients were
randomly allocated to receive either standard therapy or
standard therapy plus dexamethasone.1 Overall mortality
of patients treated with dexamethasone was significantly
lower than mortality of patients in the control group
(22.9% in the dexamethasone group vs. 25.7% in the con-
trol group). However, mortality rates varied significantly,
depending on the level of respiratory support at randomiza-
tion; in patients not receiving any respiratory support, there
was a nonsignificant trend toward harm (17.8% mortality in
the dexamethasone group vs. 14% in the control group; rela-
tive risk 1.30; 95% confidence interval [CI], 0.99 to 1.72).
In September 2020, the World Health Organization updated
its guidance on the use of glucocorticoids in Covid-19 to
reflect these data, with the recommendation “not to use sys-
temic corticosteroids in the treatment of patients with non-
severe Covid-19,” whereas in cases of “severe and critical
Covid-19” patients it is recommended to use it.2 This caution
against glucocorticoids may seem overstated in clinical prac-
tice, and glucocorticoids are often prescribed with a low
threshold in patients not receiving oxygen support even out-
side the hospital setting.9 This is a result of the unproven
belief that early administration of glucocorticoids could
modify the natural history of the illness and because of their
perceived safety. It is interesting to note that in the face
of the widespread use of glucocorticoids in outpatients,
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randomized controlled trials (RCTs) evaluating the role of
glucocorticoids in the very early phase of Covid-19 are
lacking; the data are mainly limited to case series and
observational studies, with a low level of evidence and
inconsistent results.10-18 In a previous meta-analysis of
RCTs evaluating the effects of glucocorticoids on the
survival of patients with Covid-19 receiving various types
of respiratory support, we documented increased mortality
in patients not receiving oxygen therapy treated with glu-
cocorticoids; only two trials were included, however, and
significance was borderline.19 To test the hypothesis that
glucocorticoids could be detrimental in patients not on
oxygen therapy, we performed an updated meta-analysis
of all randomized or matched trials that compared gluco-
corticoids versus placebo or standard treatment in patients
with Covid-19 not on oxygen.
Methods
SEARCH STRATEGY
Electronic searches were independently performed in
Embase, BioMed Central, medRxiv, bioRxiv, PubMed, and
the Cochrane Central Register of Controlled Trials by four
investigators (last update, January 7, 2023). The full search
strategies aimed to include any RCT, cluster crossover
trial, and matched or paired observational data study ever
performed with glucocorticoids in patients with Covid-19
and are presented in the Supplementary Appendix (Table
S1). No language restriction was imposed. In addition,
hand searches were conducted among the reference lists
of eligible primary reports and relevant review articles.
Moreover, international experts were contacted in search
of additional publications.
ARTICLE SELECTION
The reports retrieved during the searches were screened
for relevance, and those considered as potentially eligible
were evaluated based on the inclusion/exclusion criteria
and rejected or selected for this meta-analysis, as appro-
priate. Inclusion criteria for potentially relevant reports
were RCTs or cluster crossover trials; matched or paired
studies in which patients were selected to receive intrave-
nous or oral glucocorticoids versus any comparator (stan-
dard therapy or placebo), with no restrictions on dose or
time of administration; and trials and studies involving
adult patients with Covid-19 not receiving oxygen therapy.
The exclusion criteria were reports involving patients
receiving oxygen supplementation and/or any kind of
2
respiratory support (invasive or noninvasive ventilation);
reports in which patients received inhaled glucocorticoids;
reports involving pediatric patients; more than one publi-
cation describing a study or trial (in this case, we extracted
data from the publication with the longest follow-up avail-
able); and reports lacking data on the primary outcome.
References were examined at the title/abstract level inde-
pendently by four investigators and, if potentially suitable
for inclusion, were retrieved as complete articles.
DATA ABSTRACTION
Data from the chosen articles were extracted indepen-
dently by four reviewers using an extraction form that was
constructed before the study or trial article review. The
primary end point of our analysis was all-cause mortality
at the longest available follow-up. Secondary end points
were intubation rate, intensive care unit admission, length
of intensive care unit stay, and length of hospital stay.
Incidence of adverse events was also recorded. At least
two email attempts to contact the corresponding author of
articles with missing data on primary outcome were made.
INTERNAL VALIDITY AND RISK OF BIAS ASSESSMENT
Risk of bias was assessed by using the Cochrane Risk of
Bias tool for RCTs. This tool included the following
items: blinding of participants and personnel, allocation
sequence generation, incomplete outcome data, allocation
concealment, blinding of outcome assessment, selective
outcome reporting, for-profit bias, and overall risk of bias.20
The quality assessment was completed by two researchers
independently, who reached a consensus before moving to
the next step. Any discrepancies between them were resolved
through discussions with a third reviewer. Subgroup analysis
including only RCTs was performed. Publication bias was
assessed by visually inspecting funnel plots.
DATA ANALYSIS AND SYNTHESIS
This meta-analysis was registered on PROSPERO (CRD
42022342996) and follows the guidelines of The Cochrane
Collaboration and Preferred Reporting Items for Systematic
Reviews and Meta-Analyses.20,21 All the analyses were per-
formed with ReviewManager version 5.4 (Nordic Cochrane
Centre, Cochrane Collaboration). Data were synthesized by
using a random-effects model, which better accommodates
statistical and clinical variations compared with the fixed-
effects model. Pooled relative risk or odds ratios and their
95% CIs were estimated for categorical outcomes, whereas
pooled mean differences and their 95% CIs were estimated
for continuous outcomes. The double-arm-zero-event trials
or studies were discarded from the analyses, and a fixed
value of 0.5 was added to trials or studies with no events in

Glucocorticoids for patients with Covid-19 not receiving oxygen

4003
Identification

Articles retrieved
from database screening and manual
searches

3963 Articles not pertinent to the study question and duplicate

articles

40 Articles eligible for inclusion

Screening

and detailed assessment to the

selection criteria

34 Articles excluded:
–1 No matched pair trial
–6 Inhaled glucocorticoids
–23 Missing data on patients without oxygen supplementation
–4 Patients with oxygen or respiratory support
Included

6 Articles finally included

in the analysis

Figure 1. Flowchart.
Covid-19 denotes coronavirus disease 2019.

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 NEJM EVIDENCE
Table 1. Characteristics of the Included Reports.*

No. of Patients No. of Duration

Receiving Control Glucocorticoid of Longest
Study Year Design Glucocorticoids Patients Setting Primary Outcome Type and Dose Treatment Comparator Follow-up
Crothers et al.22 2021 Propensity 3124 1800 Ordinary 90-Day mortality At least 1 dose of Any Standard 90 d
ward dexamethasone, duration treatment
prednisone, prednisolone,
methylprednisolone, and/or
hydrocortisone, any dosage
Kocks et al.26 2022 RCT 4 3 Out-of- Development of Oral dexamethasone 6 mg 10 days Home-based 28 d
hospital severe Covid-19 once daily disease monitoring
requiring under usual care
hospitalization
Les et al.25 2022 RCT 34 37 Ordinary Treatment failure Intravenous 120 mg 3 days Placebo 1 28 d
ward (death, ICU methylprednisolone once standard treatment
admission, IMV, daily

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or clinical
worsening)
Prado 2020 RCT 30 42 Ordinary 28-Day mortality Intravenous 5 days Placebo 1 28 d
Jeronimet al.24 ward methylprednisolone standard treatment
(0.5 mg/kg) twice daily

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RECOVERY Trial1 2020 RCT 501 1034 Ordinary 28-Day mortality Oral or intravenous Up to 10 Standard 28 d
ward dexamethasone 6 mg days (or treatment
once daily hospital

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discharge)

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Tang et al.23 2021 RCT 11 14 Ordinary Clinical Intravenous 7 days Placebo 1 Hospital
ward deterioration methylprednisolone standard treatment discharge
1 mg/kg daily
* Covid-19 denotes coronavirus disease 2019; ICU, intensive care unit; IMV, intermittent mechanical ventilation; and RCT, randomized controlled trial.

4
 Table 2. Outcomes.*

No. of Included No. of Glucocorticoid No. of Control P Value for

Outcome Reports Patients Patients Odds Ratio 95% CI Effect I2 (%)
Overall population 6 3704 2930
Mortality† 6 509/3704 (14%) 294/2930 (10%) 1.56‡ 1.27–1.92‡ <0.001‡ 20
RCTs only 5 90/580 (16%) 145/1130 (13%) 1.34§ 1.00–1.78§ 0.05§ 0
Mechanical ventilation¶ 4 98/550 (18%) 160/1088 (15%) 1.32k 1.00–1.74k 0.05k 0
* CI denotes confidence interval; and RCTs, randomized controlled trials. Bold type indicates statistical significance.
† Additional data were provided through personal correspondence (C.M. Prado Jeronimo, K. Crothers, J. Kocks, and X. Tang).
‡ Overall effect size estimate based on three reports (6531 patients).
§ Overall effect size estimate based on two trials (1607 patients).
¶ Additional data were provided through personal correspondence (J. Kocks and X. Tang).
k Overall effect size estimate based on two trials (1542 patients).

one arm. Moreover, a continuity correction method was
applied to all double-arm-zero-event trials or studies by add-
ing a fixed value of 1. Statistical significance was set at the
two-tailed 0.05 level for hypothesis testing. Unadjusted P
values are reported throughout.
of Recommendations, Assessment, Development and Eval-
uation) approach was used to assess the certainty of evi-
dence related to each outcome.

A post hoc trial sequential analysis was performed to Results

assess whether the data were convincing enough to
prove the effect. The required information size was esti-
mated with the choice of an a priori relative risk reduction
of 25%, based on the results of the RECOVERY trial
(17.0% vs. 13.2% mortality). We defined a type I error of
5% and a statistical power of 80%. The GRADE (Grading
STUDY CHARACTERISTICS
Database screening, manual searches, and contacts with
experts yielded a total of 4003 articles. Excluding dupli-
cates and unsuitable titles or abstracts, we retrieved in
complete form and assessed 40 trials and studies

Glucocorticoids Control Odds Ratio Odds Ratio Risk of Bias

Study or Subgroup Events Total Events Total Weight M–H, Random (95% Cl) M–H, Random (95% Cl) A B C D E F G
Crothers, 2022 419 3,124 149 1,800 62.0% 1.72 (1.41 to 2.09) – – – – + +
Kocks, 2022 0 4 0 3 Not estimable – – + +
Les, 2022 0 34 0 37 Not estimable + + + + + + +
Prado Jeronimo, 2020 1 30 0 42 0.4% 4.32 (0.17 to 109.79) + + + + + +
RECOVERY trial, 2020 89 501 145 1,034 37.6% 1.32 (0.99 to 1. 77) + + – – + +
Tang, 2021 0 11 0 14 Not estimable + + – + + +

Total (95% Cl) 3,704 2,930 100.0% 1.56 (1.27 to 1.92)

Total events 509 294
Heterogeneity: Tau2 =0.01; χ2 =2.49, df =2 (P=0.29); I2 =20%
Test for overall effect: Z=4.25 (P<0.0001)
0.005 0.1 1 10 200
Risk of bias legend Favors glucocorticoids Favors control
(A) Random sequence generation (selection bias)
(B) Allocation concealment (selection bias)
(C) Blinding of participants and personnel (performance bias)
(D) Blinding of outcome assessment (detection bias)
(E) Incomplete outcome data (attrition bias)
(F) Selective reporting (reporting bias)
(G) Other bias

Figure 2. Forest Plot of Overall Mortality.

This illustration compares glucocorticoid use versus control treatment in patients with coronavirus disease 2019 who were not
receiving oxygen support or any kind of ventilation support at the beginning of the treatment. Boldface indicates subgroup headings and
summary estimates. CI denotes confidence interval; and M–H, Mantel–Haenszel statistic.

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 according to the overall inclusion selection criteria (Fig. 1).

509/3704 (14%) 294/2930 (10%) 1.56 higher (1.27–1.92)

98/550 (18%) 160/1088 (15%) 1.32 higher (1.00–1.74)

Glucocorticoids, Odds
According to our prespecified exclusion criteria, 34 articles

Relative Effect with

* CI denotes confidence interval; GRADE, Grading of Recommendations, Assessment, Development and Evaluation; PM, propensity-matched study; and RCTs, randomized controlled trials.
Ratio (95% CI)
were then excluded. Details of the excluded articles are
presented in Table S2.

Summary of Findings Five randomized trials and one propensity-matched study

involving 6634 patients were finally included (3704 patients

Evidence Glucocorticoids Glucocorticoids

received glucocorticoids, and 2930 patients received standard
treatment).1,22-26 Characteristics of the included trials and
No. of Study Event Rates

Without

study are presented in Table 1. Clinical heterogeneity was

mostly due to type of glucocorticoid, setting, dosage, and
duration of administration. Overall risk of bias of the included
trials and study was considered moderate (Table S3).
With

⨁⨁⨁ represents a moderate quality of evidence in a scale ranging from ⨁⨁⨁⨁ to ⨁ (from high to very low quality of evidence). QUANTITATIVE DATA SYNTHESIS
Overall mortality of patients treated with glucocorticoids
Certainty of

Moderate

Moderate
⨁⨁⨁

⨁⨁⨁
Overall

was significantly higher than mortality of patients in the con-

trol group (509 of 3704 [14%] in the glucocorticoid group vs.
294 of 2930 [10%] in the control group; odds ratio, 1.56
[95% CI, 1.27 to 1.92]; P for effect ,0.001; number needed
Publication

None

None
Bias

to harm527; relative risk increase, 36%) (Table 2; Fig. 2).

This statistically significant mortality increase with the use
of glucocorticoids was confirmed in the subgroup analysis
Not serious Not serious

Not serious Not serious

Indirectness Imprecision

† Most of the information is from trials at low or moderate risk of bias (one study at high risk of bias).

including only RCTs and applying the continuity correction

Certainty Assessment

method for zero-event reports (Table 2; Figs. S1 and S2).

Given the presence of moderate risk of bias, the quality
Table 3. GRADE Summary of Findings for Mortality and Need for Mechanical Ventilation.*

of evidence was evaluated as moderate (Table 3). Visual

inspection of funnel plots was limited by the small num-
ber of included trials and study but did not identify a
skewed or asymmetrical shape for the primary end point
(Fig. S3).
‡ Most of the information is from reports at low or moderate risk of bias.
Inconsistency
Not serious

Not serious

Patients treated with glucocorticoids had a trend toward a

higher risk of need for mechanical ventilation than control
subjects (98 of 550 [18%] in the glucocorticoid group vs.
Risk of Bias
Moderate†

Moderate‡

160 of 1088 [15%] in the control group; odds ratio, 1.32

[95% CI, 1.00 to 1.74]; P for effect50.05) (Table 2;
Fig. 3). Results were confirmed when applying the conti-
nuity correction method for zero-event trials (Fig. S4).
No. of Participants

Visual inspection of the funnel plot was limited by the small

6634 (5 RCTs and
(No. of Reports)

1638 (4 RCTs)

number of included trials but did not identify a skewed or

asymmetric shape for a secondary end point (Fig. S5). Given
the presence of moderate risk of bias, this quality of evi-
1 PM)

dence was evaluated as moderate (Table 3). No data on

length of intensive care unit or hospital stay were available.
mechanical
Type of Study

ventilation
Mortality

Need for

No clinically relevant adverse events were reported

(Table S4). The trial sequential analysis revealed that the
cumulative Z-curve crossed the trial sequential monitoring

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 Favors Glucocorticoids Need MV control Odds Ratio Odds Ratio Risk of Bias
Study or Subgroup Events Total Events Total Weight M–H, Random (95% Cl) M–H, Random (95% Cl) A B C D E F G
Tang, 2021 0 11 0 14 Not estimable + + – + + +
Les, 2022 0 34 0 37 Not estimable + + + + + + +
Kocks, 2022 1 4 0 3 0.6% 3.00 (0.09 to 102.05) – – + +
RECOVERY trial, 2020 97 501 160 1,034 99.4% 1.31 (0.99 to 1.73) + + – – + +

Total (95% Cl) 550 1,088 100.0% 1.32 (1.00 to 1.74)

Total events 98 160
Heterogeneity: Tau2 =0.00; χ2 =0.21, df =1 (P = 0.65); I2 =0%
Test for overall effect: Z=1.95 (P=0.05)
0.005 0.1 1 10 200

Risk of bias legend Favors glucocorticoids Favors control

(A) Random sequence generation (selection bias)
(B) Allocation concealment (selection bias)
(C) Blinding of participants and personnel (performance bias)
(D) Blinding of outcome assessment (detection bias)
(E) Incomplete outcome data (attrition bias)
(F) Selective reporting (reporting bias)
(G) Other bias

Figure 3. Forest Plot of the Incidence of MV.

This illustration compares glucocorticoid use versus control treatment in patients with coronavirus disease 2019 who were not receiving
oxygen support or any kind of ventilation support at the beginning of the treatment. Boldface indicates subgroup headings and summary
estimates. M–H denotes Mantel–Haenszel statistic; and MV, mechanical ventilation.

boundary for harm, and the required information size of
3646 patients was achieved (Fig. S6).
Discussion
Our meta-analysis suggests that the use of glucocorticoids
increases mortality in hospitalized patients with Covid-19
not receiving oxygen, with a number needed to harm of
27. A prior meta-analysis of RCTs evaluating the effects
of glucocorticoids on the survival of subgroups of patients
with Covid-19 receiving various levels of respiratory
support showed increased mortality in the subgroup of
patients not receiving oxygen, with a number needed to
harm of 19.19 The conclusion was not strong because only
1607 patients were included in the analysis, statistical
significance was fragile, and only two trials reported
events.22,25 In the current meta-analysis, instead of analyz-
ing all trials and studies in this area, as previous meta-
analyses had done, we specifically focused on reports
involving patients with Covid-19 not using oxygen at the
time of enrollment. Our findings are also in line with
recent observational evidence that reported poor out-
comes in terms of disease progression or mortality in
patients with Covid-19 who had early or mild disease and
who received glucocorticoids.27-29
Our findings increase the evidence for what had been only
presumed in previous reports; that is, administration of
glucocorticoids to patients not receiving supplemental
oxygen may be harmful. This is of public health impor-
tance because the total number of documented severe
acute respiratory syndrome coronavirus 2–positive patients
worldwide is more than 600 million; even a small detri-
mental effect of glucocorticoids on survival could translate
into thousands of potentially preventable deaths.30 Gluco-
corticoids seem to elicit distinct clinical outcomes in
patients with Covid-19, depending on the timing and the
inflammatory milieu when they are administered.10 We
speculate that in patients who are sick enough to receive
oxygen treatment, the anti-inflammatory actions of glucocor-
ticoids, as opposed to the delay in viral clearance effects,
lead to the selective beneficial effects we observed. Con-
versely, under physiological conditions, glucocorticoid treat-
ment may lead to endothelial dysfunction by decreasing
vascular nitric oxide availability and the adverse outcomes
observed in our meta-analysis.31,32
We acknowledge that our meta-analysis has several
limitations. We included only one, very small trial, per-
formed on patients outside the hospital setting.26 There-
fore, selection bias cannot be excluded, and our findings
cannot be simply extrapolated to the wider community

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because our analysis includes almost only hospitalized
patients with an observed mortality rate of 10 to 14%.
Moreover, because we focused on RCTs and a single
propensity-matched study, the number of included reports
is low, and the final results were primarily driven by the
RECOVERY trial1 and the observational study of Crothers
et al.,22 accounting for .90% of the included patients. In
addition, the type of glucocorticoid used for treatment, dose,
duration of administration, and tapering modes were not
investigated; we also did not include reports on inhaled glu-
cocorticoids. In conclusion, our meta-analysis shows that
administering glucocorticoids in hospitalized patients with
Covid-19 not receiving oxygen is likely associated with worse
clinical outcomes.
Disclosures
Author disclosures and other supplementary materials are available at
evidence.nejm.org.
A data sharing statement provided by the authors is available at evidence.
nejm.org.
We thank Giacomo Maiucci (Department of Anesthesia and Intensive
Care, IRCCS San Raffaele Scientific Institute, Milan, Italy) for his help
and insights. We sincerely thank Drs. Prado Jeronimo, Crothers, Tate,
Kocks, Kerkhof, and Tang for providing additional data.
Author Affiliations
1 roid therapy in elderly patients with early Covid-19. Aging Clin Exp
Busto Arsizio Hospital, Busto Arsizio, Lombardia, Italy
2 Res 2022;34:2585-2590. DOI: 10.1007/s40520-022-02181-1.
Anesthesia and Intensive Care, Azienda Ospedale-Universita di Padova,
Padova, Italy
3
Department of Anesthesia and Intensive Care, IRCCS San Raffaele
Scientific Institute, Milan
4 14. Ordinola Navarro A, Lopez Luis BA. Corticosteroids prescription
Doctoral School of Theoretical and Translational Medicine, Semmelweis
University, Budapest, Hungary
5
InCor, Hospital das Cl
ınicas da Faculdade de Medicina, Universidade de
S~
ao Paulo, S~
ao Paulo
6
Faculty of Medicine, Vita-Salute San Raffaele University, Milan
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