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Corticosteroids in Sepsis: An Updated Systematic

Review and Meta-Analysis


Bram Rochwerg, MD, MSc1,2; Simon J. Oczkowski, MD, MSc, MHSc1; Reed A. C. Siemieniuk, MD2;
Thomas Agoritsas, MD, PhD2,3,4; Emilie Belley-Cote, MD1,2; Frédérick D’Aragon, MD, MSc5;
Erick Duan, MD, MSc1,2; Shane English, MD, MSc6,7; Kira Gossack-Keenan, BSc1;
Mashari Alghuroba, MSc1; Wojciech Szczeklik, MD, PhD1,8; Kusum Menon, MD, MSc9;
Waleed Alhazzani, MD, MSc1,2; Jonathan Sevransky, MD10; Per Olav Vandvik, MD, PhD11;
Downloaded from http://journals.lww.com/ccmjournal by BhDMf5ePHKbH4TTImqenVHPymkXZPg+VDouM9zDxpsBZRCH+YegZ7y5tzHQlDCcB on 07/06/2018

Djillali Annane, MD, PhD12; Gordon Guyatt, MD, MSc1,2

1
Department of Medicine, McMaster University, Hamilton, ON, Canada. Objective: This systematic review and meta-analysis addresses
2
Department of Health Research Methods, Evidence and Impact, McMas- the efficacy and safety of corticosteroids in critically ill patients
ter University, Hamilton, ON, Canada.
with sepsis.
3
Division of General Internal Medicine, University Hospitals of Geneva,
Data Sources: We updated a comprehensive search of MEDLINE,
Geneva, Switzerland.
EMBASE, CENTRAL, and LILACS, and unpublished sources for ran-
4
Division of Clinical Epidemiology, University Hospitals of Geneva,
Geneva, Switzerland. domized controlled trials that compared any corticosteroid to placebo
5
Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke or no corticosteroid in critically ill children and adults with sepsis.
et Faculté de médecine et des sciences de la santé, Université de Sher- Study Selection: Reviewers conducted duplicate screening of
brooke, Sherbrooke, QC, Canada.
citations, data abstraction, and, using a modified Cochrane risk of
6
Department of Medicine (Critical Care), University of Ottawa, Ottawa,
ON, Canada. bias tool, individual study risk of bias assessment.
7
Clinical Epidemiology Program, Ottawa Hospital Research Institute, Data Extraction: A parallel guideline committee provided input on
Ottawa, ON, Canada. the design and interpretation of the systematic review, including
8
Department of Intensive Care and Perioperative Medicine, Jagiellonian the selection of outcomes important to patients. We assessed
University Medical College, Krakow, Poland. overall certainty in evidence using Grading of Recommendations
9
Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada. Assessment, Development and Evaluation methodology and per-
10
Division of Pulmonary, Allergy and Critical Care, Department of Medi- formed all analyses using random-effect models. For subgroup
cine, Emory University, Atlanta, GA.
analyses, we performed metaregression and considered p value
11
Department of Medicine, Innlandet Hospital Trust-Division, Gjøvik, Norway.
less than 0.05 as significant.
12
Hôpital Raymond Poincaré, Laboratory of Infection and Inflammation,
University of Versailles, Garches, France. Data Synthesis: Forty-two randomized controlled trials including
Supplemental digital content is available for this article. Direct URL cita- 10,194 patients proved eligible. Based on low certainty, cortico-
tions appear in the printed text and are provided in the HTML and PDF steroids may achieve a small reduction or no reduction in the rela-
versions of this article on the journal’s website (http://journals.lww.com/
tive risk of dying in the short-term (28–31 d) (relative risk, 0.93;
ccmjournal).
Drs. Rochwerg and Oczkowski are supported by McMaster University
95% CI, 0.84–1.03; 1.8% absolute risk reduction; 95% CI, 4.1%
Department of Medicine early career research awards. Dr. Siemien- reduction to 0.8% increase), and possibly achieve a small effect on
iuk disclosed off-label product use of corticosteroids (not licensed long-term mortality (60 d to 1 yr) based on moderate certainty (rel-
for treatment of sepsis). Dr. Sevransky’s institution received funding
from the Marcus Foundation, and he received funding from the Society ative risk, 0.94; 95% CI, 0.89–1.00; 2.2% absolute risk reduction;
of Critical Care Medicine (Associate Editor stipend). The remaining 95% CI, 4.1% reduction to no effect). Corticosteroids probably
authors have disclosed that they do not have any potential conflicts result in small reductions in length of stay in ICU (mean difference,
of interest.
–0.73 d; 95% CI, –1.78 to 0.31) and hospital (mean difference,
Address requests for reprints to: Bram Rochwerg, MD, MSc, Department
of Medicine, Division of Critical Care, Juravinski Hospital, 711 Concession –0.73 d; 95% CI, –2.06 to 0.60) (moderate certainty). Corticoste-
St, Hamilton, ON L8V 1C1, Canada. E-mail: rochwerg@mcmaster.ca roids result in higher rates of shock reversal at day 7 (relative risk,
Copyright © 2018 by the Society of Critical Care Medicine and Wolters 1.26; 95% CI, 1.12–1.42) and lower Sequential Organ Failure
Kluwer Health, Inc. All Rights Reserved. Assessment scores at day 7 (mean difference, –1.39; 95% CI,
DOI: 10.1097/CCM.0000000000003262 –1.88 to –0.89) (high certainty). Corticosteroids likely increase the

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Rochwerg et al

risk of hypernatremia (relative risk, 1.64; 95% CI, 1.32–2.03) and parallel clinical practice guideline (http://www.magicapp.org/
hyperglycemia (relative risk, 1.16; 95% CI, 1.08–1.24) (moderate public/guideline/EZ1w8n).
certainty), may increase the risk of neuromuscular weakness (rela-
tive risk, 1.21; 95% CI, 1.01–1.52) (low certainty), and appear to
METHODS
have no other adverse effects (low or very low certainty). Subgroup
The protocol for this systematic review was registered on
analysis did not demonstrate a credible subgroup effect on any of
PROSPERO (CRD42017058537) and published in full (13).
the outcomes of interest (p > 0.05 for all).
Substantive deviations from the published protocol are high-
Conclusions: In critically ill patients with sepsis, corticosteroids
lighted with an accompanying explanation.
possibly result in a small reduction in mortality while also possibly
increasing the risk of neuromuscular weakness. (Crit Care Med
Rapid Recommendation Guideline Panel
2018; XX:00–00)
According to the Rapid Recommendations process, the guide-
Key Words: corticosteroids; immune response; meta-analysis;
line panel provided critical oversight and identified populations,
sepsis; systematic review
subgroups, and outcomes of interest for this review (14). The
panel included content experts, methodologists, and patients
or caregivers of patients with lived experience of sepsis. Patients

S
epsis—life-threatening organ dysfunction caused by received personal training and support to optimize contributions
a dysregulated host immune response to infection throughout the guideline development process. The patients on
(1)—can result in systemic hypoperfusion and end- the panel led the interpretation of the results based on what they
organ dysfunction, and is associated with frequent morbidity expected the typical patient values and preferences to be, as well
and mortality in the ICU (2). The mainstays of treatment are as the variation between patients. The four patients who were full
early antibiotics and restoration of perfusion (IV fluids and members of the guideline panel contributed to the selection and
vasopressor therapy) (3); despite early and aggressive therapy, prioritization of outcomes, values and preferences assessments,
mortality in septic shock remains as high as 30–40% (4). and critical feedback to the protocol for the systematic review.
Because the pathology of sepsis is characterized by a maladap-
tive host response to infection, experts have hypothesized that Data Sources and Searches
immunomodulatory therapies may provide effective treatment We performed a comprehensive search of MEDLINE, EMBASE,
(5). Exogenous glucocorticoids are an attractive candidate given CENTRAL, and LILACS for RCTs from December 1, 2014, to
their widespread availability, relatively low cost, and their demon- January 10, 2018. As this was an updated systematic review, to
strated ability to dampen the inflammatory cascade (5). In combi- ensure adequate overlap, we searched from 3 months before the
nation with mineralocorticoids, they may also address the relative last review (6) (supplemental electronic material 1, Supple-
deficiency of cortisol that can occur in states of extreme stress (5). mental Digital Content 1, http://links.lww.com/CCM/D757,
Despite the physiologic rationale, clinical data examining the presents the MEDLINE search strategy). Keyword search terms
effect of corticosteroids in sepsis have remained inconsistent, included corticosteroids, sepsis, and septic shock in a search that
leading to substantial variation in clinical practice worldwide. The did not apply any language restrictions. We searched conference
most recent Cochrane meta-analysis suggested that corticoste- proceedings and abstracts from the last 3 years (2014–2017)
roids may reduce 28-day mortality in sepsis (relative risk [RR], from the following societal meetings: The Society of Critical
0.87; 95% CI, 0.76–1.00), although there was only low certainty Care Medicine Congress, The American Thoracic Society, and
in the evidence, limited by imprecision, inconsistency, and the The European Society of Intensive Care Medicine.
potential for publication bias (6). Results from this review sug-
gested that patients with septic shock and those treated with a low Study Selection
dose and a long course of corticosteroids had the highest likeli- We performed all screening in duplicate with disagreements
hood of benefit. Another review showed a similar point estimate, resolved by discussion and third party adjudication as required.
but wider CI, and concluded no effect of corticosteroids in those After implementation of the search strategy, reviewers worked
with sepsis (RR, 0.87; trial sequential analysis adjusted 95% CI, in pairs to screen all potentially relevant citations and references.
0.74–1.08) (7). Since these reviews, a number of large randomized Reviewers performed screening in two stages, initially assessing
controlled trials (RCTs) addressing the topic have been published titles and abstracts, and then full articles for those possibly eligible.
(8, 9), establishing the need for an updated systematic review. We captured reasons for exclusion at the full article review stage.
This systematic review is part of the Rapid Recommendations We included all RCTs comparing the use of corticosteroids
project, a collaborative effort from the Making GRADE the (including but not limited to hydrocortisone, methylpredniso-
Irresistible Choice (MAGIC) research and innovation pro- lone, betamethasone, fludrocortisone, and dexamethasone)
gram (www.magicproject.org) (10). The aim of the project is with a corticosteroid-free comparator group in critically ill
to respond to new potentially practice-changing evidence and patients with sepsis, excluding case reports, case series, and
provide trustworthy practice guidelines in a timely manner. In observational studies. The population of interest included all
light of the two recently published large RCTs of 5,042 criti- adults and children, excluding neonates, diagnosed with sep-
cally ill patients with sepsis (11, 12), we updated the previous sis, severe sepsis, or septic shock, according to accepted criteria
systematic review and meta-analysis (6) in order to inform a (15–17). We included data from trials enrolling patients with

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Review Article

acute respiratory distress syndrome (ARDS) as long as the data and the arcsine test for dichotomous outcomes. Funnel plots
from patients with sepsis were reported separately. and small study effect testing were performed using Stata 15
We included the following outcomes: short-term mortality up to (StataCorp, College Station, TX).
31 days, long-term mortality (60 d to 1 yr), shock reversal at day 7 We assessed for heterogeneity between studies using the chi-
(defined as stable hemodynamic status for > 24 hr after withdrawal square test for homogeneity, the I2 statistic, and visual inspection
of vasopressors), organ dysfunction at day 7 (using total Sequential of the forest plots. We considered the magnitude and direction of
Organ Failure Assessment [SOFA] score [18]), ICU length of stay, heterogeneity when considering whether to rate down our cer-
hospital length of stay, quality of life at 1 year using a validated index, tainty in the evidence for inconsistency. We explored prespecified
stroke, myocardial infarction, and adverse events including neu- subgroups with random-effects metaregression using Stata 15 and
romuscular weakness, gastrointestinal bleeding, neuropsychiatric present interaction p values. Subgroups assessed included the fol-
effects (including delirium, confusion, mania, and others), hyperna- lowing: high RoB versus low RoB hypothesizing that corticosteroids
tremia, superinfection, and hyperglycemia. Our published protocol would be more effective in trials with high RoB; patient subpopu-
further separated short-term mortality into two separate endpoints, lation (sepsis without shock vs septic shock, respiratory [ARDS/
28–31 days and 90 days. Given that all studies that reported 28- to community-acquired pneumonia (CAP)] vs no respiratory illness)
31-day mortality also reported 90-day mortality, we deviated slightly hypothesizing that corticosteroids would be more effective in those
from our protocol and included both endpoints from these studies with septic shock and pneumonia/ARDS; dose and duration of
separately in our analysis. The short-term mortality from these stud- corticosteroids (high dose/short course vs low dose/long course)
ies was grouped with the other studies that also reported this 28- to hypothesizing that corticosteroids would be more effective with
31-day endpoint, whereas the longer 90-day mortality data were lower doses and when used for a longer duration; and corticoste-
grouped with the 1-year mortality data. To assess for any difference roid molecule (hydrocortisone vs hydrocortisone plus fludrocor-
in long-term mortality between studies reporting at 60–180 days and tisone vs methylprednisolone or prednisolone or prednisone vs
those that reported at 1 year, we performed subgroup analysis. dexamethasone) hypothesizing that corticosteroids would be more
effective using agents with more mineralocorticoid effect. The pro-
Data Extraction and Quality Assessment tocol (13) included these subgroup analyses and a plan for assess-
Reviewers performed data extraction independently and in ment for credible subgroup effect (22).
duplicate using predefined data abstraction forms. A third We performed two additional metaregression subgroup analyses
reviewer resolved disagreements. Abstracted data included study that were not predefined but were requested by the linked Rapid
title, first author, demographic data, details of the intervention Recommendations panel: impact of the mortality rate in the control
and control, primary and secondary outcome data, and risk of group and year of study publication (as a continuous variable) on
bias (RoB) for each study. We performed our own data abstrac- the effect of corticosteroids on mortality. The panel hypothesized
tion only for studies not included in the prior review (6), and for that corticosteroids would be more effective in trials with a higher
outcomes or subgroups that were not previously reported. mortality rate in the control group and in older studies. Although
RoB was assessed, independently and in duplicate, for each we planned for subgroup analysis based on age of patients (adults
outcome of individual studies using a modified Cochrane RoB vs children) and presence of critical illness–related corticosteroid
tool (19) that classifies RoB as “low,” “probably low,” “probably insufficiency, there was insufficient evidence examining these sub-
high,” or “high” for each of the following domains: sequence groups for metaregression. We also performed three additional
generation, allocation sequence concealment, blinding, selec- sensitivity analyses at the request of peer reviewers: we examined
tive outcome reporting, and other bias. We rated the overall the effect of corticosteroids on short-term mortality in those only
RoB as the highest risk attributed to any criterion. We assessed treated with long-course and low-dose corticosteroids, the effect of
the overall certainty of evidence for each outcome using the short-term mortality only in the last two published RCTs (11, 12),
Grading of Recommendations Assessment, Development and and the effect of corticosteroids in only studies at low or probably
Evaluation (GRADE) framework (20). Disagreements for RoB low RoB. Absolute effects were calculated using the pooled baseline
and GRADE assessments were resolved by discussion. GRADE prevalence from the control arm of included studies.
assessments were also agreed upon with the linked British
Medical Journal Rapid Recommendation guideline panel.
RESULTS
Data Analysis Description of Eligible Studies
We used DerSimonian and Laird random-effects models in The 2015 Cochrane review contributed 30 eligible studies
Rev-Man 5.3 (The Cochrane Collaboration, Copenhagen, Den- (n = 3,623) (23–52). Of the 7,202 citations identified in our
mark) to conduct the meta-analyses. Study weights were gen- updated search, we reviewed the full text of 33, of which 12
erated using the inverse of the variance. We present results as new RCTs ultimately proved eligible (7–9, 11, 53–60) for a total
RRs for dichotomous outcomes and as mean difference (MD) of 42 RCTs (Fig. 1).
for continuous outcomes, both with 95% CI. We examined the Supplementary Table 1 (Supplemental Digital Content 2,
potential for small study effects using a funnel plot if evidence http://links.lww.com/CCM/D758) presents a detailed descrip-
included more than 10 trials per outcome, using the Egger test tion of eligible trials, 20 of which were multicenter (7–9, 11,
to detect funnel plot asymmetry for continuous outcomes (21) 23, 24, 26, 27, 31–33, 37, 38, 42, 44, 46, 49, 54, 57) and the

Critical Care Medicine www.ccmjournal.org 3


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Rochwerg et al

of corticosteroid administered
varied, although most (n = 37;
9,283 patients) used what we
defined as low dose (< 400 mg/d
of hydrocortisone or equiva-
lent) and used them over a short
course of therapy (< 3 d) (7–9,
11, 24–26, 28–35, 37–42, 45, 46,
48–53, 55–60).
Supplemental material 2
(Supplemental Digital Content
1, http://links.lww.com/CCM/
D757) presents individual study
RoB. Approximately half of the
included studies were judged to
be at low (n = 10) (7–9, 11, 24,
38, 46, 49, 57, 59) or probably
low RoB (n = 11) (23, 25, 27, 28,
32, 35, 37, 45, 51, 52, 60).

Outcomes
Table 1 shows summary of find-
ings for all outcomes, based on
the meta-analysis of identified
trials, and includes the certainty
of the evidence and the rea-
sons for rating down certainty.
Interactive tables summariz-
ing the findings are available
at http://www.magicapp.org/
public/guideline/EZ1w8n. Fig-
ures 2 and 3 and supplemental
material 3–18 (Supplemental
Digital Content 1, http://links.
lww.com/CCM/D757) pres-
ent forest plots, metaregression
results, and funnel plots for all
outcomes including sensitivity
Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram demonstrating analysis.
study selection for inclusion in the quantitative meta-analysis. RCT = randomized controlled trial.
The pooled point estimates
suggest that corticosteroids may
remainder single center. Twenty-four of the RCTs examined result in a small reduction or no reduction in short-term mortality
patients with septic shock (8, 9, 11, 24–26, 28–30, 32–34, 39, 43, (RR, 0.93; 95% CI, 0.84–1.03; 1.8% absolute risk reduction; 95% CI,
46–48, 50, 53–58); five included patients with both CAP and 4.1% reduction to 0.8% increase, low certainty) (Fig. 2 and Table 1)
sepsis (28, 35, 39, 42, 46) and four enrolled patients with the and possibly a small reduction in long-term mortality (RR, 0.94;
ARDS and sepsis (32, 34, 37, 57). Three of the included studies 95% CI, 0.89–1.00; 2.2% absolute risk reduction; 95% CI, 4.1%
enrolled only children (41, 47, 55) and one enrolled both adult reduction to no effect, moderate certainty) (Fig. 3 and Table 1).
and children, but reported the two groups separately (33). Pooled estimates suggest that corticosteroids probably result
The majority of studies used hydrocortisone (n = 27; 6,922 in small reductions in ICU length of stay (MD, –0.73 d; 95%
patients) (7–9, 11, 25, 26, 28, 29, 31–35, 39, 41, 42, 47, 48, 50, 53– CI, –1.78 to 0.31; 12.40 vs 13.13 d, moderate certainty) and
60); others used methylprednisolone (n = 6; 859 patients) (23, hospital length of stay (MD, –0.73 d; 95% CI, –2.06 to 0.60;
27, 36, 37, 40, 49), prednisolone (n = 3; 308 patients) (45, 51, 52), 31.30 vs 32.03 d, moderate certainty). Patients randomized to
or dexamethasone (n = 3; 333 patients) (30, 38, 44). Two stud- receive corticosteroids had higher rates of shock reversal at day
ies used hydrocortisone in addition to fludrocortisone (1,541 7 (RR, 1.26; 95% CI, 1.12–1.42; 12.1% absolute risk increase;
patients) (11, 24), and two studies included both dexamethasone 95% CI, 5.6–19.5% increase, high certainty) and lower SOFA
and methylprednisolone groups (231 patients) (43, 47). The dose scores at day 7 (MD, –1.39 points; 95% CI, –1.88 to –0.89; 6.22

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Review Article

Summary of Findings Table Including Relative Effect Measure, Absolute Effect


TABLE 1.
Measure, Certainty of Evidence, and Narrative Plain Text Summary
Absolute Effect Estimates
Certainty in Effect
Outcome Study Results No Estimates (Quality Plain Text
Timeframe and Measurements Corticosteroids Corticosteroids of Evidence) Summary

Mortality Relative risk: 0.94 371/1,000 349/1,000 Moderate Corticosteroids


longer term (95% CI, 0.89–1.0) possibly achieve a
(60 d to 1 Based on data from Difference: 22 fewer per 1,000 Due to serious small reduction in
yr) 6,438 patients in (95% CI, 41 fewer to 0 fewer) imprecisiona long-term mortality.
nine studies
Mortality Relative risk: 0.93 254/1,000 236/1,000 Low Corticosteroids may
short term (95% CI, 0.84–1.03) Due to serious achieve a small
(28–31 d) Based on data from Difference: 18 fewer per 1,000 imprecision, border- or no reduction in
9,433 patients in 36 (95% CI, 41 fewer to 8 more) line inconsistency, short-term mortality.
studies and publication
biasb
Shock reversal Relative risk: 1.26 464/1,000 585/1,000 High Corticosteroids
(1 wk) (95% CI, 1.12–1.42) increase shock
Based on data from Difference: 121 more per 1,000 reversal in the first
2,802 patients in 13 (95% CI, 56 more to 195 more) week.
studies
Neuromuscular Relative risk: 1.21 250/1,000 303/1,000 Low Corticosteroids may
weakness (95% CI, 1.01–1.45) Due to serious impre- result in a small
Based on data from Difference: 53 more per 1,000 cision and indirect- increase in neuro-
6,178 patients in (95% CI, 3 more to 130 more) ness and borderline muscular weakness.
seven studies inconsistencyc
Gastrointestinal Relative risk: 1.09 35/1,000 38/1,000 Low Corticosteroids may
bleeding (95% CI, 0.86–1.38) Due to serious indi- have little or no dif-
Based on data from 4,243 Difference: 3 more per 1,000 rectness and ference on gastroin-
patients in 17 studies (95% CI, 5 fewer to 13 more) imprecisiond testinal bleeding
Neuropsychiatric Relative risk: 0.58 59/1,000 34/1,000 Low Corticosteroids may
events (95% CI, 0.33–1.03) Due to serious impre- achieve a small
Based on data from Difference: 25 fewer per 1,000 cision and serious reduction in neu-
1,004 patients in five (95% CI, 40 fewer to 2 more) indirectnesse ropsychiatric events.
studies
Hypernatremia Relative risk: 1.64 36/1,000 59/1,000 Moderate Corticosteroids proba-
(95% CI, 1.32–2.03) Due to serious bly increase the risk
Based on data from 5,015 Difference: 23 more per 1,000 indirectnessf of hypernatremia.
patients in six studies (95% CI, 12 more to 37 more)

Superinfection Relative risk: 1.02 161/1,000 164/1,000 Low Corticosteroids may


(95% CI, 0.89–1.18) Due to serious impre- have little or no
Based on data from 4,519 Difference: 3 more per 1,000 cision and serious impact on superin-
patients in 21 studies (95% CI, 18 fewer to 29 more) indirectnessc fection.
Stroke Relative risk: 2.07 5/1,000 10/1,000 Very low Whether or not corti-
(95% CI, 0.45–9.61) Due to serious indi- costeroids impact
Based on data from Difference: 5 more per 1,000 rectness and very the risk of stroke is
1,105 patients in three (95% CI, 3 fewer to 43 more) serious imprecisiong uncertain.
studies
Myocardial Relative risk: 0.91 30/1,000 27/1,000 Very low Whether or not corticos-
infarction (95% CI, 0.45–1.82) Due to serious indi- teroids impact the risk
Based on data from 1,080 Difference: 3 fewer per 1,000 rectness and very of myocardial infarc-
patients in three studies (95% CI, 16 fewer to 25 more) serious imprecisiong tion is uncertain.
Hyperglycemia Relative risk: 1.16 181/1,000 210/1,000 Moderate Corticosteroids prob-
(95% CI, 1.08–1.24) Due to serious indi- ably increase the
Based on data from 7,563 Difference: 29 more per 1,000 rectnessh incidence of
patients in 15 studies (95% CI, 14 more to 43 more) hyperglycemia.
(Continued )

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Rochwerg et al

TABLE 1. (Continued). Summary of Findings Table Including Relative Effect Measure,


Absolute Effect Measure, Grading of Recommendations Assessment, Development and
Evaluation Certainty of Evidence, and Narrative Plain Text Summary
Absolute Effect Estimates
Certainty in Effect
Outcome Study Results No Estimates (Quality Plain Text
Timeframe and Measurements Corticosteroids Corticosteroids of Evidence) Summary

ICU length of Measured by: days 13.13 d 12.4 d Moderate Corticosteroids prob-
stay Based on data from 7,463 Due to serious impre- ably achieve a small
patients in 20 studies MD: 0.73 fewer (95% CI, 1.78 cisioni reduction in the
fewer to 0.31 more) duration of initial
ICU stay.
Hospital length Measured by: days 32.03 d 31.3 d Moderate Corticosteroids prob-
of stay Based on data from Due to serious impre- ably achieve a small
7,706 patients in MD: 0.73 fewer (95% CI, 2.06 cisionj reduction in the
18 studies fewer to 0.6 more) duration of hospitali-
zation.
Organ dysfunc- Measured by: Sepsis Organ 7.61 points 6.22 points High Corticosteroids
tion (1 wk) Failure Assessment decrease organ
score MD: 1.39 lower (95% CI, 1.88 dysfunction at 7 d.
Scale: 0–24 lower better lower to 0.89 lower)
Based on data from 1,986
patients in nine studies
Quality of life Not reported in any of the included studies
MD = mean difference.
a
Note that all studies that reported 90-d to 1-yr mortality also reported 28- to 30-day mortality: the 95% CI, around the pooled effect for short-term mortality
also excludes no effect: relative risk, 0.91 (95% CI, 0.84–0.98).
b
There is borderline inconsistency (I2 = 37%). There was also borderline publication bias (some visual asymmetry in the funnel plot), but statistical tests (Egger
test and the Trim and Fill method) did not detect statistically significant small study effects (p = 0.12).
c
Variable time of assessment. Variable assessment tool used. Varying magnitude. All decrease our certainty in this effect estimate. CI includes no difference.
d
Variable definition of gastrointestinal bleeding. Varying magnitude/clinical significance of gastrointestinal bleeding. All decrease our certainty in this effect
estimate. CI includes no difference.
e
Variable time of assessment. Variable assessment tool used. Varying magnitude. All decrease our certainty in this effect estimate.
Variable time of assessment. Variable assessment tool used. Varying magnitude. All decrease our certainty in this effect estimate. CI includes important harm.
f

g
Unclear how this outcome was abstracted or ascertained. Unclear clinical impact of these stroke or myocardial infarction events. Very few events and only two
studies.
h
Unclear how this outcome was abstracted or ascertained. Unclear clinical impact of these stroke or MI events. Very few events and only one study.
Variable time of assessment. Variable assessment tool used. Varying magnitude. All decrease our certainty in this effect estimate.
i

CI includes no difference.
j

vs 7.61 points, high certainty). None of the studies reported are very uncertain about the effect of steroids on stroke (RR, 2.07;
quality of life outcomes. 95% CI, 0.45–9.61; 0.5% absolute risk increase; 95% CI, 0.3–4.3%
increase, very low certainty) or myocardial infarction (RR, 0.91;
Adverse Effects 95% CI, 0.45–1.82; 0.3% absolute risk reduction; 95% CI, 1.6%
Corticosteroids likely increase the rates of hypernatremia decrease to 2.5% increase; very low certainty) (Table 1).
(RR, 1.64; 95% CI, 1.32–2.03; 2.3% absolute risk increase; 95%
CI, 1.2–3.7% increase, moderate certainty) and hyperglycemia Subgroup Analyses
(RR, 1.16; 95% CI, 1.08–1.24; 2.9% absolute risk increase; 95% Subgroup analyses did not demonstrate a credible effect
CI, 1.4–4.3% increase, moderate certainty). Corticosteroids may for any of the predefined subgroups and on any of the out-
increase the risk of neuromuscular weakness (RR, 1.21; 95% comes of interest (p > 0.05 for all outcomes) (Supplemen-
CI, 1.01–1.52; 5.3% absolute risk increase; 95% CI, 0.3–13.0% tary Material 19, Supplemental Digital Content 1, http://
increase, low certainty). Results did not demonstrate a convincing links.lww.com/CCM/D757). Metaregression examining the
effect on other adverse effects including gastrointestinal bleeding effect of control group mortality on short-term mortality
(RR, 1.09; 95% CI, 0.86–1.38; 0.3% absolute risk increase; 95% did not demonstrate a credible subgroup effect (p = 0.26).
CI, 0.5% decrease to 1.3% increase, low certainty), superinfection There was also no effect based on year of study publication
(RR, 1.02; 95% CI, 0.89–1.18; 0.3% absolute risk increase; 95% CI, (p = 0.89). Although we had planned for subgroup analysis
1.8% decrease to 2.9% increase, low certainty), and neuropsychi- examining the effect of corticosteroids on adults when com-
atric outcomes (RR, 0.58; 95% CI, 0.33–1.03; 2.5% absolute risk pared with children, insufficient data precluded this analysis
reduction; 95% CI, 4.0% fewer to 0.2% more, low certainty). We for any of the outcomes of interest.

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Review Article

Figure 2. Forest plot for short-term mortality. df = degrees of freedom, M-H = Mantel-Haenszel.

DISCUSSION in ICU and hospital length of stay (Table 1). Our results fail to
Our systematic review demonstrates that the use of cortico- demonstrate an impact of corticosteroids on gastrointestinal
steroids in sepsis may result in a small absolute reduction in bleeding, superinfection, neuropsychiatric effects, stroke, or
mortality of approximately 2%. In this most comprehensive myocardial infarction (Table 1). Based on low certainty evi-
review to date, including several new large trials, the precision dence, corticosteroids may result in a small increase in the risk
of the pooled point effect estimates has increased substantially of neuromuscular weakness. Corticosteroids did increase the
(6, 7, 61). The CI around the pooled effect on mortality over risk of hyperglycemia and hypernatremia although the stud-
the short, but not the long term, includes a small risk of harm ies failed to provide information regarding whether these find-
(moderate quality for the latter because the upper boundary of ings required intervention or resulted in patient-important
the CI is 1.0) (Table 1). sequelae. Ascertainment of these adverse outcomes in the
Subgroup analyses failed to identify credible effect modifi- included studies was also variable, further contributing to the
cation in patient population, study RoB, control group mor- lower certainty in evidence.
tality (severity of illness), corticosteroid dose, duration, or Strengths of this review include a comprehensive literature
molecule, or year of publication. Most of the evidence comes search including unpublished sources, a published protocol
from studies that used hydrocortisone with or without fludro- to which we adhered (13), application of GRADE methodol-
cortisone over a long course (> 2 d) and at a low dose (under ogy to assess certainty in pooled estimates of effect, a priori
400 mg/d of hydrocortisone or equivalent). Results showed specification of possible effect modifiers including direction
that it is likely that corticosteroids result in small reductions of effect and subsequent metaregression to explore the effect

Critical Care Medicine www.ccmjournal.org 7


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Rochwerg et al

Figure 3. Forest plot for long-term mortality. df = degrees of freedom.

modification, and specification of both relative and absolute demonstrated a small reduction in 90-day mortality with
effects. Content experts as well as methodologists and patients corticosteroids (RR, 0.88; 95% CI, 0.78–0.99) (11). The
or caregivers with personal experience with sepsis as part of the Adjunctive Glucocorticoid Therapy in Patients with Septic
Rapid Recommendation process provided critical input to our Shock (ADRENAL) trial enrolled 3,800 patients with septic
protocol and assessment of the synthesized evidence. shock from 69 medical-surgical ICUs, and there was no effect
Limitations include significant clinical heterogeneity over on 90-day mortality (odds ratio, 0.95; 95% CI, 0.82–1.10). The
studies conducted over a period of 60 years. Our exploration of results of both trials are consistent with our pooled estimates
subgroup hypotheses, including the era in which the studies were of effect and the associated CIs (9).
conducted, and the failure to identify any effect modification, Based on the results of this review, our best estimates suggest
markedly diminishes this concern. All included studies enrolled a small absolute reduction in mortality with corticosteroids in
patients based on previous sepsis diagnostic criteria, although sepsis based on low-to-moderate certainty evidence. This abso-
we have no reason to believe that using the new Sepsis-3 criteria lute reduction in death will be highest in the sickest patients
would change the efficacy or harms of corticosteroids (16). (e.g., those with septic shock); however, the relative effects of
Although the demonstrated mortality effect may be impor- corticosteroids appear consistent across all studied subgroups.
tant, the certainty is limited by imprecision. Our review dem- Previous clinical practice guidelines, before the publication of
onstrates that the use of corticosteroids in septic shock is ADRENAL and APROCCHSS, have made conditional recom-
associated with faster shock reversal and less organ dysfunc- mendations against corticosteroids in sepsis and conditional
tion at day 7 when compared with those that do not receive recommendations for corticosteroids in the setting of septic
corticosteroids. Both outcomes are best viewed as surrogates shock (3, 7). The results of this systematic review and meta-
for mortality and, on the basis of evidence that persistent analysis will inform a Rapid Recommendation (19) exam-
organ dysfunction and shock may be associated with worse ining the role of corticosteroids in patients with sepsis and
long-term quality of life, for quality of life. Despite previous septic shock.
suggestions that sicker patients might derive greater benefit
from corticosteroids in sepsis, we found no support for this CONCLUSIONS
hypothesis in our subgroup analyses examining patients with The additional recent evidence from large trials has established
septic shock and study control group mortality rate. Harms that if steroids do have on effect on mortality, that effect is
associated with the long-term use of corticosteroids (62) are small. The most compelling evidence is of a 6% relative reduc-
well documented; our review suggests, however, that adverse tion in long-term mortality, translating to a 2% absolute risk
effects may be minimal with the short-term use of corticoste- reduction, but the CI around the estimate includes no effect.
roids in critically ill patients with sepsis. Point estimates suggest a reduction in length of stay in hospital
The results of this meta-analysis reflect results of the recent and ICU, but these effects are also small—less than a day—and
large RCTs. The Activated Protein C and Corticosteroids for CIs include a possible increase in length of stay. Harms, how-
Human Septic Shock (APROCCHSS) trial enrolled 1,241 ever, are minimal, and informed individuals may as a result
patients with septic shock from 34 centers in France and conclude that net benefit is likely.

8 www.ccmjournal.org XXX 2018 • Volume XX • Number XXX

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Review Article

ACKNOWLEDGMENTS 20. Guyatt GH, Oxman AD, Vist GE, et al: GRADE: An emerging consen-
sus on rating quality of evidence and strength of recommendations.
We would like to express our gratitude to Jean Maragno and BMJ 2008; 336:924–926
Lois Cottrel for their guidance in designing and carrying out 21. Higgins JP, Altman DG, Gotzsche PC, et al: The Cochrane
our search strategy. Collaboration’s tool for assessing risk of bias in randomised trials.
BMJ 2011; 343:d5928
22. Sun X, Briel M, Busse JW, et al: Credibility of claims of subgroup
REFERENCES effects in randomised controlled trials: Systematic review. BMJ 2012;
1. Seymour CW, Liu VX, Iwashyna TJ, et al: Assessment of clinical cri- 344:e1553
teria for sepsis: For the Third International Consensus Definitions for 23. The Veterans Administration Systemic Sepsis Cooperative Study Group:
Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315:762–774 Effect of high-dose glucocorticoid therapy on mortality in patients with
2. Rhee C, Dantes R, Epstein L, et al; CDC Prevention Epicenter clinical signs of systemic sepsis. N Eng J Med 1987; 317:659–665
Program: Incidence and trends of sepsis in US hospitals using clini- 24. Annane D, Sébille V, Charpentier C, et al: Effect of treatment with low
cal vs claims data, 2009-2014. JAMA 2017; 318:1241–1249 doses of hydrocortisone and fludrocortisone on mortality in patients
3. Rhodes A, Evans LE, Alhazzani W, et al: Surviving sepsis campaign: with septic shock. JAMA 2002; 288:862–871
International Guidelines for Management of Sepsis and Septic Shock: 25. Arabi YM, Aljumah A, Dabbagh O, et al: Low-dose hydrocortisone
2016. Intensive Care Med 2017; 43:304–377 in patients with cirrhosis and septic shock: A randomized controlled
4. Shankar-Hari M, Phillips GS, Levy ML, et al; Sepsis Definitions Task trial. CMAJ 2010; 182:1971–1977
Force: Developing a new definition and assessing new clinical criteria 26. Bollaert PE, Charpentier C, Levy B, et al: Reversal of late septic shock
for septic shock: For the Third International Consensus Definitions for with supraphysiologic doses of hydrocortisone. Crit Care Med 1998;
Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315:775–787 26:645–650
5. Annane D, Pastores SM, Arlt W, et al: Critical illness-related cortico- 27. Bone RC, Fisher CJ Jr, Clemmer TP, et al: A controlled clinical trial of
steroid insufficiency (CIRCI): A narrative review from a Multispecialty high-dose methylprednisolone in the treatment of severe sepsis and
Task Force of the Society of Critical Care Medicine (SCCM) and the septic shock. N Engl J Med 1987; 317:653–658
European Society of Intensive Care Medicine (ESICM). Intensive 28. Briegel J, Forst H, Haller M, et al: Stress doses of hydrocortisone
Care Med 2017; 43:1781–1792 reverse hyperdynamic septic shock: A prospective, randomized,
6. Annane D, Bellissant E, Bollaert PE, et al: Corticosteroids for treating double-blind, single-center study. Crit Care Med 1999; 27:723–732
sepsis. Cochrane Database Syst Rev 2015; (12):CD002243 29. Chawla K, Kupfer Y, Goldman I, et al: Hydrocortisone reverses refrac-
7. Volbeda M, Wetterslev J, Gluud C, et al: Glucocorticosteroids for sep- tory septic shock. Crit Care Med 1999; 27:Supplement page 33A
sis: Systematic review with meta-analysis and trial sequential analysis. 30. Cicarelli DD, Vieira JE, Benseñor FE: Early dexamethasone treatment
Intensive Care Med 2015; 41:1220–1234 for septic shock patients: A prospective randomized clinical trial. Sao
8. Keh D, Trips E, Marx G, et al; SepNet–Critical Care Trials Group: Paulo Med J 2007; 125:237–241
Effect of hydrocortisone on development of shock among patients 31. Confalonieri M, Urbino R, Potena A, et al: Hydrocortisone infusion
with severe sepsis: The HYPRESS randomized clinical trial. JAMA for severe community-acquired pneumonia: A preliminary randomized
2016; 316:1775–1785 study. Am J Respir Crit Care Med 2005; 171:242–248
9. Gordon AC, Mason AJ, Thirunavukkarasu N, et al; VANISH 32. Gordon AC, Mason AJ, Perkins GD, et al: The interaction of vasopres-
Investigators: Effect of early vasopressin vs norepinephrine on kidney sin and corticosteroids in septic shock: A pilot randomized controlled
failure in patients with septic shock: The VANISH randomized clinical trial. Crit Care Med 2014; 42:1325–1333
trial. JAMA 2016; 316:509–518 33. Group CS: The effectiveness of hydrocortisone in the management of
10. Siemieniuk RA, Agoritsas T, Macdonald H, et al: Introduction to BMJ severe infections. JAMA 1963; 183:462–465
Rapid Recommendations. BMJ 2016; 354:i5191 34. Hu B, Li JG, Liang H, et al: The effect of low-dose hydrocortisone
11. Venkatesh B, Finfer S, Cohen J, et al: Adjunctive glucocorticoid on requirement of norepinephrine and lactate clearance in patients
therapy in patients with septic shock. N Engl J Med 2018; 378: with refractory septic shock. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue
797–808 2009; 21:529–531
12. Annane D, Renault A, Brun-Buisson C, et al; CRICS-TRIGGERSEP 35. Liu L, Li J, Huang YZ, et al: The effect of stress dose glucocorticoid
Network: Hydrocortisone plus fludrocortisone for adults with septic on patients with acute respiratory distress syndrome combined with
shock. N Engl J Med 2018; 378:809–818 critical illness-related corticosteroid insufficiency. Zhonghua Nei Ke
13. Rochwerg B, Oczkowski S, Siemieniuk RA, et al: Corticosteroids in Za Zhi 2012; 51:599–603
sepsis: An updated systematic review and meta-analysis (protocol). 36. Luce JM, Montgomery AB, Marks JD, et al: Ineffectiveness of high-
BMJ Open 2017; 7:e016847 dose methylprednisolone in preventing parenchymal lung injury and
14. Guyatt GH, Oxman AD, Kunz R, et al: GRADE guidelines: 2. Framing improving mortality in patients with septic shock. Am Rev Respir Dis
the question and deciding on important outcomes. J Clin Epidemiol 1988; 138:62–68
2011; 64:395–400 37. Meduri GU, Golden E, Freire AX, et al: Methylprednisolone infusion
15. Levy MM, Fink MP, Marshall JC, et al: 2001 SCCM/ESICM/ACCP/ in early severe ARDS: Results of a randomized controlled trial. Chest
ATS/SIS International Sepsis Definitions Conference. Critical Care 2007; 131:954–963
Med 2003; 31:1250–1256 38. Meijvis SC, Hardeman H, Remmelts HH, et al: Dexamethasone and
16. Singer M, Deutschman CS, Seymour CW, et al: The Third International length of hospital stay in patients with community-acquired pneu-
Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). monia: A randomised, double-blind, placebo-controlled trial. Lancet
JAMA 2016; 315:801–810 2011; 377:2023–2030
17. Bone RC, Balk RA, Cerra FB, et al: Definitions for sepsis and organ 39. Oppert M, Schindler R, Husung C, et al: Low-dose hydrocortisone
failure and guidelines for the use of innovative therapies in sepsis. improves shock reversal and reduces cytokine levels in early hyperdy-
The ACCP/SCCM Consensus Conference Committee. American namic septic shock. Crit Care Med 2005; 33:2457–2464
College of Chest Physicians/Society of Critical Care Medicine. Chest 40. Rezk N, Ibrahim A: Effects of methylprednisolone in early ARDS.
1992; 101:1644–1655 Egypt J Chest Dis Tuberc 2013; 62:167–172
18. Minne L, Abu-Hanna A, de Jonge E: Evaluation of SOFA-based mod- 41. Rinaldi S, Adembri C, Grechi S, et al: Low-dose hydrocortisone dur-
els for predicting mortality in the ICU: A systematic review. Crit Care ing severe sepsis: Effects on microalbuminuria. Crit Care Med 2006;
2008; 12:R161 34:2334–2339
19. Guyatt GH, Busse J: Evidence Partners. 2013. Available at: http:// 42. Sabry N, Omar EED: Corticosteroids and ICU course of community
distillercer.com/resources/methodological-resources/risk-of-bias- acquired pneumonia in Egyptian settings. Pharmacol Pharm 2011;
commentary/. Accessed September 6, 2013 2:73–81

Critical Care Medicine www.ccmjournal.org 9


Copyright © 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
Rochwerg et al

43. Schumer W: Steroids in the treatment of clinical septic shock. Ann 53. Branco RG, Amoretti CF, Garcia PCR, et al: Corticosteroid replace-
Surg 1976; 184:333–341 ment in sepsis induces lymphopenia: Results of a randomized con-
44. Slusher T, Gbadero D, Howard C, et al: Randomized, placebo-con- trolled trial. Pediatr Crit Care Med 2014; 15(4 Suppl):12
trolled, double blinded trial of dexamethasone in African children with 54. De Graaf H, Ramakrishnan KA, Pappachan J, et al: Evaluation of cortico-
sepsis. Pediatr Infect Dis J 1996; 15:579–583 steroid replacement therapy in children with severe septic shock - a ran-
45. Snijders D, Daniels JM, de Graaff CS, et al: Efficacy of corticosteroids domised intervention trial. Pediatr Crit Care Med 2014; 15(4 Suppl):141
in community-acquired pneumonia: A randomized double-blinded 55. El-Nawawy A, Khater D, Omar H, et al: Evaluation of early cortico-
clinical trial. Am J Respir Crit Care Med 2010; 181:975–982 steroid therapy in management of pediatric septic shock in pediatric
46. Sprung CL, Annane D, Keh D, et al; CORTICUS Study Group: intensive care patients: A randomized clinical study. Pediatr Infect Dis
Hydrocortisone therapy for patients with septic shock. N Engl J Med J 2017; 36:155–159
2008; 358:111–124 56. Lv QQ, Gu XH, Chen QH, et al: Early initiation of low-dose hydrocor-
47. Sprung CL, Caralis PV, Marcial EH, et al: The effects of high-dose tisone treatment for septic shock in adults: A randomized clinical trial.
corticosteroids in patients with septic shock. A prospective, con- Am J Emerg Med 2017; 35:1810–1814
trolled study. N Engl J Med 1984; 311:1137–1143 57. Menon K, McNally D, O’Hearn K, et al; Canadian Critical Care Trials
48. Tandan SM, Guleria R, Gupta N: Low dose steroids and adreno- Group: A randomized controlled trial of corticosteroids in pediatric septic
cortical insufficiency in septic shock: A double-blind randomized shock: A pilot feasibility study. Pediatr Crit Care Med 2017; 18:505–512
controlled trial from India. In: Proceedings of the American Thoracic 58. Mirea L, Ungureanu R, Pavelescu D, et al: Continuous administration
Society Meeting, New York, NY, 2005:A24 of corticosteroids in septic shock can reduce risk of hypernatremia.
49. Torres A, Sibila O, Ferrer M, et al: Effect of corticosteroids on treat- Crit Care 2014; 18(Suppl 1):P239
ment failure among hospitalized patients with severe community- 59. Tongyoo S, Permpikul C, Mongkolpun W, et al: Hydrocortisone treat-
acquired pneumonia and high inflammatory response: A randomized ment in early sepsis-associated acute respiratory distress syndrome:
clinical trial. JAMA 2015; 313:677–686 Results of a randomized controlled trial. Crit Care 2016; 20:329
50. Valoor HT, Singhi S, Jayashree M: Low-dose hydrocortisone in pediat- 6 0. Meduri G, Golden E, Freire A, et al: Randomized clinical trial evalu-
ric septic shock: An exploratory study in a third world setting. Pediatr ating the effects of low-dose prolonged hydrocortisone infusion on
Crit Care Med 2009; 10:121–125 resolution of MODS in severe sepsis. Chest 2009; 136(Suppl):154
51. Yildiz O, Doganay M, Aygen B, et al: Physiological-dose steroid ther- 61. Gibbison B, López-López JA, Higgins JP, et al: Corticosteroids in sep-
apy in sepsis [ISRCTN36253388]. Crit Care 2002; 6:251–259 tic shock: A systematic review and network meta-analysis. Crit Care
52. Yildiz O, Tanriverdi F, Simsek S, et al: The effects of moderate-dose 2017; 21:78
steroid therapy in sepsis: A placebo-controlled, randomized study. J 62. Oray M, Abu Samra K, Ebrahimiadib N, et al: Long-term side effects
Res Med Sci 2011; 16:1410–1421 of glucocorticoids. Expert Opin Drug Saf 2016; 15:457–465

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