Meta Analysis

Journal of International Medical Research

48(5) 1–11
Steroid use after cardiac ! The Author(s) 2020
Article reuse guidelines:
arrest is associated with sagepub.com/journals-permissions
DOI: 10.1177/0300060520921670
favourable outcomes: journals.sagepub.com/home/imr

a systematic review and

meta-analysis

Bo Liu1,*, Qiang Zhang2,* and Chunsheng Li3

Abstract
Background: The effect of steroid use on outcomes in patients with cardiac arrest (CA)
remains controversial. We systematically reviewed the literature to investigate whether steroid
use after CA increased the return of spontaneous circulation (ROSC) rate and survival to dis-
charge in patients with CA.
Methods: PubMed, Embase, CNKI, and the Cochrane Central Register of Controlled Trials were
searched for randomized controlled trials (RCTs) and observational studies on the effect of
steroid use on outcomes in adults with CA. The outcomes were ROSC and survival to discharge.
Results: Seven studies (four RCTs and three observational studies) were included. Pooled
analysis suggested that steroid use was associated with increased ROSC in patients with CA.
Steroid use was significantly associated with survival to discharge, which was a consistent finding
in RCTs and observational studies. Subgroup analysis based on the time of drug administration
(during cardiopulmonary resuscitation [CPR] vs. after CA) showed that steroid use during CPR
and after CA were significantly associated with an increased rate of ROSC and survival to
discharge.
Conclusion: Current evidence indicates that steroid use after CA could increase ROSC and
survival to discharge in patients with CA. However, high-quality and adequately powered RCTs
are warranted.

*Bo Liu and Qiang Zhang contributed equally to this

article.
1
Department of Emergency Medicine, Beijing Chao-Yang Corresponding author:
Hospital, Capital Medical University, Beijing, China Chunsheng Li, Department of Emergency Medicine,
2
Department of Critical Care Medicine, Peking University Beijing Friendship Hospital, Capital Medical University,
Third Hospital, Beijing, China No. 95 Yong’an Road, Xicheng District, 100050 Beijing,
3
Department of Emergency Medicine, Beijing Friendship China.
Hospital, Capital Medical University, Beijing, China Email: [email protected]

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2 Journal of International Medical Research

Keywords
Steroids, cardiac arrest, meta-analysis, return of spontaneous circulation, survival, cardiopulmo-
nary resuscitation
Date received: 18 October 2019; accepted: 1 April 2020

Introduction Embase, CNKI, and the Cochrane Central

Register of Controlled Trials were searched
Cardiac arrest (CA) is a worldwide health
based on the search strategy from 1 January
problem, with an estimated annual incidence
2000 to 1 March 2019. The search strategy
of 295,000 in the USA.1 Survival of patients
was as follows: (“cardiac arrest” OR “heart
after CA is very low.2 Patients who die after
arrest” OR “ventricular fibrillation” OR
cardiopulmonary resuscitation (CPR) may
“cardiopulmonary resuscitation” OR “CA”
have an inadequate adrenal response.3
OR “CPR”) AND (“steroid”
Other studies have shown that relative adre-
OR “glucocorticoids” OR “adrenal
nal insufficiency is common in patients with
cortex hormones” OR “hydrocortisone”
CA.4–6 Adrenal insufficiency is associated
OR “methylprednisolone” OR
with poor outcome and increased mortality.
“dexamethasone”). We applied language
Several studies suggest that steroid use
restrictions of Chinese and English. Two
after CA could improve the return of
independent investigators performed the ini-
spontaneous circulation (ROSC) rates and
tial search, deleted duplicate records,
long-term survival.7,8 However, Tsai et al.8
screened the titles and abstracts for rele-
conducted a prospective, nonrandomized,
vance, and identified each as excluded or
open-label clinical trial to examine the effect
requiring further assessment. We included
of hydrocortisone on out of hospital cardiac
arrest (OHCA) outcomes. They found no sig- studies that were relevant to our PICO
nificant difference in the rate of survival to search strategy. The US National Institutes
discharge between the hydrocortisone and of Health Ongoing Trials Register
non-hydrocortisone groups.9 To date, studies ClinicalTrials.gov (www.clinicaltrials.gov;
reporting the effect of steroid use on out- March 2019) and World Health
comes after CA have showed conflicting Organization International Clinical Trials
results. Thus, it is necessary to examine the Registry Platform (WHO ICTRP) (apps.
effectiveness of steroid administration in var- who.int/trialsearch/; March 2019) were
ious medical facilities. In the present study, searched for unpublished and ongoing stud-
we conducted a systematic meta-analysis to ies, and the OpenGrey database (www.open
investigate the association between steroid grey.eu; March 2019) was searched for grey
use and outcome in CA patients. literature. The reference sections from all
studies that were retained during data extrac-
tion were searched as well as recent meta-
Materials and methods analyses and reviews on the topic (to
March 2019). We also scanned conference
Literature search and selection criteria proceedings from the American Society of
This study was conducted and reported in Regional Anesthesia, European Society of
accordance with the Preferred Reporting Regional Anaesthesia, European Society
Items for Systematic Reviews and Meta- of Anaesthesiology, and American Society
Analyses (PRISMA) guidelines.10 PubMed, of Anesthesiology up to 2019.
Liu et al. 3

Studies meeting the following criteria The GRADE approach

were included: (1) population: adult
The Grading of Recommendations
patients with CA, with no exclusion for
Assessment, Development, and Evaluation
the cause of CA, and thus, trauma patients (GRADE) approach was applied to provide
were among some of the included studies; an overall assessment of the evidence relat-
(2) intervention: steroid use after CA; ing to all of the outcomes. A summary of
(3) comparison: no steroid use; (4) outcome: findings was developed using the
ROSC and survival to discharge; and GRADEpro software (ims.cochrane.org/
(5) design: randomized controlled trials revman/other-resources/gradepro).
(RCTs) and observational studies (prospec-
tive or retrospective cohort studies). In Statistical analysis
accordance with the CPR guidelines, epi-
nephrine was used in both the experimental Review Manager (version 5.3; Copenhagen:
The Nordic Cochrane Centre, The Cochrane
and control groups, and thus, in both study
Collaboration, 2014) was used for statistical
types, experimental groups received both
analysis. Differences were expressed as the
drugs (steroids and epinephrine) and con-
relative risk (RR) with the 95% confidence
trol groups received epinephrine. In addi-
interval (CI). Heterogeneity across studies
tion, each group may have received other was tested using the I2 statistic, which is a
drugs such as vasopressin. We excluded quantitative measure of inconsistency across
case reports, case series, review articles, studies. Studies with an I2 statistic of 25% to
and non-human studies. 50% were considered to have low heteroge-
neity, those with an I2 statistic of 50% to
75% were considered to have moderate het-
erogeneity, and those with an I2 statistic of
Data extraction and quality assessment >75% were considered to have high hetero-
Data extraction was performed by Q.Z. geneity. Considering the large clinical het-
and confirmed independently by B.L. erogeneity of included patients, a random
The following information was extracted effects model was used to explain the sub-
from each study: first author, year of pub- stantial clinical heterogeneity between stud-
lication, country, study design, patient ies. Potential publication bias was assessed
characteristics, number of patients by visual assessment of constructed funnel
enrolled, intervention, and outcome data. plots. A p-value <0.05 was considered to
When the same patients were reported in be significant. This study did not receive or
several publications, we retained only the require ethics approval and informed con-
sent was not required because it was a
largest study to avoid duplication of the
meta-analysis.
information. Discrepancies were resolved
by discussion between the two investiga-
tors. The primary outcome was ROSC. Results
The secondary outcome was survival to
discharge. Two reviewers (Q.Z. and B.L.) Study search and selection
independently assessed the methodological A flowchart of our search strategy and the
quality of each study using the Newcastle– reasons is shown in Figure 1. After identifi-
Ottawa scale11 for prospective studies and cation and screening, 210 full-text studies
the Cochrane Collaboration tool for were read for further evaluation and,
RCTs.11 among them, 203 were excluded because
4 Journal of International Medical Research

Figure 1. Flowchart of the search strategy.

they did not report predefined outcomes or used steroids in combination with atropine
meet our inclusion criteria. Finally, seven and epinephrine. Overall, there were 9414
studies were included in our analysis. patients included in the meta-analysis
(3647 patients in the steroid group and
Study characteristics and quality 5767 patients in the non-steroid group).

The main characteristics of the included

studies are shown in Table 1, and the out- Quality assessment
come data from each included study are The risk of bias of the RCTs ranged from
shown in Table 2. We included seven stud- low to high (two were low, two were
ies7,8,12–16 in our analysis. These studies medium, and one was high). Sources with
were published between 2001 and 2019. a high risk of bias included sequence gener-
Among the included studies, three stud- ation, allocation concealment, and other
ies7,8,12 were published in English, and potential threats to validity. All five RCTs
among these three studies, the steroid had a low risk for blinding of participants,
group received a combination of steroids personnel, and outcome assessors. A low
with vasopressin and/or epinephrine. The risk of selective outcome reporting was
other four studies were published in achieved in five RCTs. A high risk of spe-
Chinese.13–16 Two studies8,12 were cohort cific methodology for allocation conceal-
studies, and the other five studies were ment was described in three RCTs. A low
RCTs.7,13–16 Among these studies, Zhang risk of sequence generation was found in
et al.13 used steroids and epinephrine in two RCTs. Based on the Newcastle-
the steroid group, while the other studies Ottawa Scale to assess the risk of bias in
Table 1. Baseline characteristics of the included studies.
Epinephrine
Study Year Country/ Region Study Design Cause of CA Age Gender (male) Endpoint dosage Vasopressin Range year Finding

Tsai et al. 2019 Taiwan Retrospective Nontraumatic Steroid 67.66 y; Steroid 59.19%; Survival to dis- Steroid 5.68
5.27; Steroid 0.35%; 2004–2011 Steroid use was associated
observational OHCA, IHCA Non-steroid Non-steroid charge, 1-year Non-steroid Non-steroid with better survival to
single centre 67.51 y 59.5% survival 5.72
5.23 0.4% hospital discharge
Zhang et al. 2015 China mainland RCT Single centre Nontraumatic 65.7
19.6 y 35% ROSC, Survival to Steroid 9.03; Non- – 2011–2014 Glucocorticoid use during
OHCA, IHCA discharge steroid 9.05 CPR was associated
with ROSC
Niimura et al. 2017 Japan Retrospective OHCA Steroid 51.43
Steroid 62%; Survival to dis- – Steroid 8%; Non- January 2005 and The results demonstrate a
observational 14.17 y; Non- Non-steroid charge, ROSC steroid 1% May 2014 correlation between
single centre steroid 73% hydrocortisone admin-
51.30
13.19 y istration and the high
rate of survival to
discharge.
Mentzelopoulos 2013 Greece RCT single centre OHCA, IHCA Steroid 63.2 y; Steroid 63.8%; Survival to dis- – – September 1, Combined vasopressin–
et al. Non-steroid Non-steroid charge, ROSC 2008, to epinephrine and meth-
62.8 y 73.1% October 1, ylprednisolone during
2010 CPR resulted in
improved survival to
hospital discharge
Yang et al. 2002 China mainland RCT, single centre OHCA 26–76 y Steroid 57%; ROSC – – – Combined vasopressin–
IHCA Non-steroid epinephrine and meth-
52% ylprednisolone during
resuscitation improved
ROSC
Mu et al. 2014 China mainland Retrospective Nontraumatic – – ROSC – – October 2004 to Administration of hydro-
observational OHCA July 2005 cortisone during resus-
Single centre citation, particularly
within 6 minutes after
ED arrival, may be
associated with
improved ROSC rate in
OHCA patients
Wei et al. 2001 China mainland RCT, single centre Nontraumatic – – – – Combined vasopressin–
OHCA, IHCA epinephrine and meth-
ylprednisolone during
CPR improved ROSC

RCT, randomized controlled trial; ROSC, return of spontaneous circulation; OHCA, out of hospital cardiac arrest; IHCA, in hospital cardiac arrest.
6 Journal of International Medical Research

Table 2. Outcome data from included studies.

Survival to discharge ROSC

Study Steroid Non-steroid Steroid Non-steroid

Tsai et al. (2019) 828/3248 618/3248 N N

Mentzelopoulos et al. (2013) 18/130 7/138 109/130 91/138
Niimura et al. (2017) 10/46 214/1771 15/61 325/2172
Zhang et al. (2015) 7/50 2/50 31/50 8/50
Mu et al. (2014) N N 18/31 19/47
Yang et al. (2002) N N 32/42 26/42
Wei et al. (2001) N N 65/85 42/71
ROSC, return of spontaneous circulation.

the cohort studies, two studies were rated as an increased rate of ROSC (RR 1.42; 95%
having a total score of >5, indicating a low CI 1.13–1.77, P < 0.0001). One study [12]
risk of bias. Two studies7,16 achieved low reported drug administration during CPR
risk, two studies13,15 achieved medium and five studies7,13–16 reported drug admin-
risk, and one study14 achieve high risk. istration after CPR for the ROSC. Two
studies7,12 reported drug administration
Primary outcome: ROSC during CPR and two studies8,13 reported
drug administration after CPR for the
Six studies7,12–16 examined the association
result of survival to discharge.
between steroid use and ROSC. Among
these six studies, four studies were RCTs
and two were cohort studies. The overall
Secondary outcomes: Survival to
effect size (RR 1.44; 95%CI 1.17–1.76; discharge
P ¼ 0.02) demonstrated a significant associ- Four studies7,8,12,13 reported the association
ation between steroid use and ROSC. between steroid use and the outcome sur-
A subgroup analysis (RCTs vs. cohort stud- vival to discharge. When the four groups
ies) was also conducted. RCTs and cohort were pooled together (Figure 3), the effect
studies both revealed a significant associa- size analysis (RR 1.67; 95% CI 1.16–2.40,
tion between steroid use and ROSC (RCT: P < 0.005) indicated that steroid use was
RR 1.43; 95%CI: 1.10–1.86, P ¼ 0.008; significantly associated with an increased
cohort studies: RR 1.54; 95%CI 1.12– rate of survival to discharge. A subgroup
2.12, P ¼ 0.009). There was no significantly analysis suggested that steroid use was asso-
statistical heterogeneity between the sub- ciated with a significantly increased rate of
groups based on a test of interaction survival to discharge in both the RCTs
(I2 ¼ 0; Figure 2). (RR, 2.89; 95% CI, 1.39–6.03, P ¼ 0.005)
A subgroup analysis based on the time of and the observational studies (RR, 1.36;
steroid administration (during CPR vs. 95% CI, 1.21–1.52, P < 0.0001).
after CA) showed that steroid use during Subgroup analysis based on the time of
CPR was significantly associated with an drug administration (during CPR vs after
increased rate of ROSC (RR 1.64; 95% CA) showed that use of steroid during
CI 1.05–2.58, P < 0.005). Steroid use after CPR was significantly associated with
CA was also significantly associated with increased rate of survival to discharge
Liu et al. 7

Figure 2. Forest plot of the pooled effects of steroid use on ROSC in cardiac arrest patients.
df, degrees of freedom; M-H, Mantel–Haenszel; Experimental, steroid group; control, non-steroid group.

Figure 3. Forest plot of the pooled effects of steroid use on survival to discharge in cardiac arrest patients.
df, degrees of freedom; M-H, Mantel–Haenszel; Experimental, steroid group; control, non-steroid group.

(RR 2.16; 95% CI 1.33–3.49, P < 0.05), use significant publication bias based on inspec-
of steroid after CA was significantly associ- tion of the funnel plot (Figure 4).
ated with increased rate of survival to dis-
charge (RR 1.35; 95% CI 1.23–1.48,
P < 0.05). GRADEpro summary of findings
The quality of evidence was assessed for
Publication bias ROSC and survival to discharge and there
For the meta-analysis of the effect of ste- was no difference in the risk of bias for
roid use on ROSC, there was no evidence of these parameters.
8 Journal of International Medical Research

Figure 4. a: Funnel plot of the effects of steroid use on ROSC in cardiac arrest patients. b: Funnel plot of
the effects of steroid on survival to discharge in cardiac arrest patients.

Discussion maintain vascular tone and enhance the

effects of administered vasopressors.7
This meta-analysis compares steroid use
CA causes severe shock, and the inter-
with placebo/no steroid use. In this study,
ruption of blood flow leads to disruption
we found that steroid use compared with no
of oxygen and metabolic substrate delivery,
steroid use was associated with an
which affects every system including the
improved ROSC rate and survival to dis- immune system. CA patients present with
charge in patients with CA. a “sepsis-like” syndrome, which is charac-
Various studies have shown that steroid teristic of the high levels of circulating cyto-
supplementation during CPR may be bene- kines and the presence of endotoxin in
ficial by maintaining hemodynamic stability plasma.19 Immune dysregulation is an
and enhancing myocardial function, there- important feature of OHCA patients after
by improving ROSC rates.17,18 ROSC.19 Steroids could work through both
The recovery of ROSC in CA patients immunologic and hemodynamic mecha-
leads to the global ischemia–reperfusion nisms, and steroids modulate the systemic
(I/R) injury, which includes excess free rad- inflammatory response.23 Previous animal
ical production, systemic inflammatory studies have shown that steroids may pre-
response, and an activated apoptosis path- serve myocardial function and improve
way.19,20 Studies have shown that a low arterial reactivity.24,25 They also help to
serum cortisol level was associated with maintain cardiovascular stability by inhibit-
unstable hemodynamics after ROSC and a ing catecholamine reuptake, enhancing vas-
shorter survival duration.21 Steroids also cular response to vasopressors, and
help to maintain cardiovascular stability decreasing nitric oxide-mediated vasodila-
by inhibiting catecholamine reuptake and tion.22,26 Steroids have been reported to
the enhancing vascular response to vaso- decrease oxidative stress,27 which was
pressors.22 The use of vasopressors increase increased after CA.28 Previous studies
the plasma cortisol concentration by have shown that myocardial apoptosis and
improving perfusion to the adrenal cortex lymphocyte apoptosis occur after CA.29,30
and medulla,17 which in turn helps to However, steroids could reduce apoptosis,31
Liu et al. 9

and thus ameliorate post-resuscitation myo- additional subgroup analyses were not pos-
cardial dysfunction.32 CA also leads to cere- sible. Fourth, the largest study included in
bral injury,33 and studies have shown that the present analysis was Tsai et al.,8 which
steroids could reduce cerebral injury.34 enrolled more patients than the all remain-
Steroids modulate the immune system, ing studies combined. However, the prima-
and they could theoretically affect the ry outcome of the present analysis did not
post-CA inflammatory response. include that study. This may have led to
In this study on the effects of steroid use bias in the primary outcome.
on ROSC in CA patients, the overall het-
erogeneity was low, but the subgroup het-
Conclusion
erogeneity (RCTs vs. cohort studies) was
high. The effect of steroid use on survival Current evidence indicates that steroid use
to discharge was investigated in this meta- increases the rate of ROSC and survival to
analysis, and the total heterogeneity was discharge in patients with CA. Steroid use
high, but the subgroup heterogeneity may remain an acceptable option for
(RCTs vs. cohort studies) was low. The dif- patients with CA; however, high-quality
ference between RCTs and cohort studies and adequately powered RCTs are
may explain the heterogeneity. Thus, it is warranted.
critical to improve the methodological qual-
ity of observational studies in future Declaration of conflicting interest
research. Among the included studies, the The authors declare that there is no conflict of
combination of steroids with different interest.
drugs and the drug dose may lead to sub-
stantial clinical heterogeneity. Additionally, Funding
further studies are required to uncover
This research received no specific grant from any
potential mechanisms of steroids in CA.
funding agency in the public, commercial, or
However, more well-designed, randomized,
not-for-profit sectors.
double-blind, placebo-controlled trials are
required.
ORCID iD
Chunsheng Li https://orcid.org/0000-0002-
Limitations 3161-4457
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