Abstract
Background
The clinical benefits of steroid therapy during cardiac arrest (CA) are unclear. Several recent clinical trials have shown that administering corticosteroid therapy during CA may improve patient outcomes. The purpose of the present study was to determine whether providing corticosteroids improves outcomes for patients following CA.
Methods
We searched the PubMed, Embase, Cochrane Library, Web of Science and CNKI databases for randomized controlled trials comparing corticosteroid therapy to placebo during CA.
Results
Eleven relevant studies involving a total of 2273 patients were included in the meta-analysis. The statistical analysis showed that corticosteroid treatment during CA was significantly associated with an increased rate of sustained return of spontaneous circulation (ROSC) (OR: 2.05, 95% CI: 1.24 to 3.37, P < 0.01). Corticosteroid treatment during CA did not show a significant benefit in favorable neurological outcomes (OR: 1.13, 95% CI: 0.81 to 1.58, P = 0.49) or overall survival rate at hospital discharge (OR: 1.29, 95% CI: 0.74 to 2.26, P = 0.38). However, in the subgroup analysis, we found that patients had a significantly increased survival rate and ROSC if the dose of corticosteroid therapy above 100 mg methylprednisolone. The statistical analysis revealed no significant differences in adverse events.
Conclusion
High-dose corticosteroid treatment (above 100 mg methylprednisolone) is associated with better overall survival rate at hospital discharge and ROSC outcomes. However, there is uncertainty regarding whether this treatment results in a benefit or harm to the favorable neurological outcomes at hospital discharge.
1
Introduction
Cardiac arrest (CA) is an important public health problem worldwide. The estimated number of in-hospital cardiac arrests (IHCAs) in the USA alone is approximately 200,000 annually [ ]. Despite advancements in the management of CA over the past decades, the outcome remains dismal [ , ]. The treatment of CA includes basic life support (e.g., chest compressions and ventilations), advanced life support (e.g., defibrillation and drugs), and postcardiac arrest care [ , ]. However, there is limited evidence to support many of the advanced therapies currently used during CA, and there is an unmet need for new pharmacological interventions to improve patient outcomes [ ].
Cardiopulmonary resuscitation (CPR) is an effective treatment to save patients’ lives, but there is still a high incidence of multiple organ dysfunction and neurological damage after resuscitation, which is the result of systemic ischemia–reperfusion and secondary systemic inflammatory response syndrome (SIRS) [ ]. The incidence of SIRS after successful cardiopulmonary resuscitation is approximately 68.3%, and the recovery rate is only 2%–22% [ ]. Glucocorticoids are widely involved in the regulation of physiological functions of various organs and systems in the body with anti-inflammatory, immunosuppressive, antitoxin, anti-shock and other effects.
In recent years, several studies [ ] have explored the use of glucocorticoids in addition to conventional CPR to observe their effect on the success of resuscitation, survival and discharge rate, but the results are still controversial. Andersen et al. found that among adult patients with IHCA, the use of vasopressin and glucocorticoids results in improved return of spontaneous circulation compared to placebo [ ]. Wongtanasarasin et al. also found that steroid administration during CA is associated with better outcomes of resuscitation [ ]. However, Li et al. were unable to reach definitive conclusions due to the inherent limitations of the studies in their review [ ].
In general, it is difficult to assess the efficacy and safety of steroid therapy for the prognosis of CA patients based on the few studies available. Therefore, given the ongoing debate, we evaluated the efficacy and safety of corticosteroid therapy in CA patients by performing a systematic review of randomized controlled trials (RCTs), including survival rate at hospital discharge, sustained return of spontaneous circulation (ROSC) and neurological outcomes at discharge.
2
Methods
2.1
Study protocol
This article was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [ ], and it was registered in INPLASY (DOI: 10.37766/inplasy2023.1.0014 ).
2.2
PICO question
We considered information regarding the effect of corticosteroid therapy (I) on in-hospital cardiac arrest patients (P) with or without a comparator (C). Our goal was to assess the effect of primary treatment outcome (overall survival rate at hospital discharge and rate of sustained ROSC) and secondary outcomes (favorable neurological outcomes at hospital discharge and adverse events, including hyperglycemia, insulin infusion, hypernatremia, infection, gastrointestinal bleeding, new or changing antibiotics, paresis and renal failure) (O).
2.3
Search strategy
Two researchers (Zhou FW and Liu C) independently searched the PubMed, Embase, Cochrane Library, Web of Science and China National Knowledge internet (CNKI) databases from inception to October 11, 2022 by using medical subject headings (MeSH), Emtree and text words with no language limitations.
The following keywords were used for the search strategy: “cardiopulmonary resuscitation”, “cardiac arrest”, “asystole”, “heart arrest”, “CPR”, “glucocorticoid”, “corticosteroid”, “dexamethasone”, “hydrocortisone” and “methylprednisolone” (Supplementary Table S1). Reference lists from the identified studies were also searched for potentially eligible articles. Preliminary publications were imported into EndNote X9.1 (Clarivate Analytics, Philadelphia, USA). After removal of duplicate records and irrelevant literature, appropriate studies with detailed classification were compiled.
2.4
Eligibility criteria
Two authors (Zhou FW and Liu C) independently performed the primary review to search for trials that met the inclusion criteria (Supplementary Table S2). Any discrepancy was resolved by discussion and consensus ( Fig. 1 ). The following inclusion criteria were used: 1) the study type was a randomized controlled trial (RCT); 2) the subjects were patients with cardiac arrest caused by various reasons; 3) intervention measures, the experimental group was treated with glucocorticoids in routine cardiopulmonary resuscitation, while the control group was treated with routine cardiopulmonary resuscitation; 4) the statistics and effect values required for meta-analysis or transmissible data were included in the study, and sufficient data were available to evaluate odds ratio (OR) and 95% CI. The exclusion criteria were as follows: 1) for repeated publications, the largest or latest publication was selected; 2) literature with incomplete or unavailable research data as well as abstracts, reviews, systematic reviews, experience summaries, theoretical discussions, case reports and qualitative studies.
2.5
Data extraction
Two reviewers (Zhang Y and Zhou FC) independently extracted data from the same set of publications. The following information was extracted: author, year, sample size, study design, measures of intervention, time of intervention, location of intervention, dose of glucocorticoids and main results (survival rate at hospital discharge, ROSC, neurological outcomes at discharge and adverse events) ( Table 1 ).
| Study | Country | Sample | Average age (year) | Measures of intervention | Time of intervention | Location of intervention | ⁎ Dose of glucocorticoids (original dose) | |||
|---|---|---|---|---|---|---|---|---|---|---|
| T/C | T/C | Treatment | Control | |||||||
| Andersen 2021 | Denmark | 245 | 267 | 71 (13) | 71 (12) | M+ E + V | E | During resuscitation | IH | 40 mg M daily |
| Bolvardi 2016 | Iran | 25 | 25 | 70.2 | 67.64 | M+ E | E | During resuscitation | OH | 125 mg M daily |
| Donnino 2016 | USA | 25 | 25 | 71 (13) | 66 (15) | H+ E | E | After ROSC | OH and IH | 60 mg M daily (300 mg H) |
| Granfeldt 2022 | Denmark | 237 | 264 | 71 (13) | M+ E + V | E | During and after resuscitation | IH | 40 mg M daily | |
| Mentzelopoulos 2009 | Greece | 48 | 52 | 69.2 (17.7) | 65.4 (17.6) | M+ E + V | E | During and after resuscitation | IH | 100 mg M daily (40 mg M + 300 mg H) |
| Mentzelopoulos 2013 | Greece | 130 | 138 | 63.2 (17.6) | 62.8 (18.6) | M+ E + V | E | During and after resuscitation | IH | 100 mg M daily (40 mg M + 300 mg H) |
| Mentzelopoulos 2022 | Greece | 86 | 98 | 76.0 | 76 | M+ E | E | During and after resuscitation | IH | 88 mg M daily (40 mg M + 240 mg H) |
| Mu 2014 | China | 31 | 47 | 58.4 ± 17.3 | 60.8 ± 18.6 | H+ E | E | During resuscitation | IH | 100 mg M daily |
| Paris 1984 | USA | 37 | 46 | Unclear | D + E | E | During resuscitation | OH | 533 mg M daily (100 mg D) | |
| Rafiei 2022 | Netherlands | 171 | 176 | 67.57 ± 17.87 | M+ E | E | During resuscitation | IH | 125 mg M daily | |
| Zhang 2015 | China | 50 | 50 | 65.7 ± 19.6 | M+ E | E | During resuscitation | IH | 40 mg M daily | |
⁎ Glucocorticoids conversion was as follows: 0.75 mg dexamethasone = 4 mg methylprednisolone = 20 mg hydrocortisone.
2.6
Summary of effect size
Odds ratios (ORs) with 95% confidence intervals (CIs) were used as the effect size measures of dichotomous data. The weight of enrolled studies was accounted for by taking into account the size of the treatment group, control group and total sample size. The Z -test was calculated, and therapeutic efficacy was considered significant with a P < 0.05 cutoff [ ].
2.7
Risk of bias
The quality of all trials was evaluated independently by two authors (Zhou FW and Liu C) according to the Cochrane quality criteria (Supplementary Fig. S1). An overall risk of bias assessment was also performed by each reviewer (Supplementary Table S3). Any disagreement between the authors was settled by discussion with a third author (Zhou FC). A weighted kappa value was calculated to examine agreement between reviewers for the overall study risk of bias assessment (Supplementary Table S4). Publication bias was evaluated using Begg’s plots, Egger’s tests and funnel plots.
2.8
GRADE quality assessment
The overall quality of evidence was evaluated by two authors (Zhou FW and Liu C) according to The Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria by evaluating the following evidence [ , ]: 1) study limitations, 2) inconsistency, 3) imprecision, 4) indirectness and 5) publication bias. Any disagreement between the two authors was first resolved by discussion and then by consulting with a third author (Zhang Y) or the senior author (Zhou FC). The results and the overall quality of evidence are presented in (Supplementary Table S5).
2.9
Statistical analysis
STATA 16.0 (Stata Corp LP, College Station, TX, USA) was used to perform statistical analyses. For the remaining circumstances, a random effect model was used to pool the effect size to calculate statistical heterogeneity. Heterogeneity was analyzed by I 2 and χ2 statistics. If there was significant heterogeneity, Galbraith plot was generated to evaluate the consistency and quality of the results. “One-study-removed” sensitivity analyses were conducted to evaluate the stability of meta-analysis results for each outcome. Meta-regression were performed by sample size, time of intervention, location of intervention, measures of intervention, and dose of glucocorticoids for each outcome. For any significant sources of heterogeneity ( P < 0.05), subgroup analyses were conducted.
3
Results
3.1
Study selection
A total of 1250 studies were identified during the initial search after excluding duplicate records ( n = 309). Of those, 891 articles were excluded following screening of the title/abstract to identify the inclusion and exclusion criteria. Thereafter, we read the full text (excluding 39 records) and enrolled 11 RCTs [ ] involving a total of 2273 patients for quantitative synthesis ( Fig. 1 ). The main characteristics of the included RCTs (country, sample size, average age, intervention measures, time of intervention, location of intervention, follow-up and main results) are described in Table 1 .
3.2
Primary outcome
3.2.1
Overall survival rate at hospital discharge
Ten RCTs [ , ] ( n = 1808) were enrolled to estimate the association between steroid use and placebo group with the survival rate at hospital discharge. Statistical analysis showed that there was no significant difference between the corticosteroid group and placebo group (OR: 1.29, 95% CI: 0.74 to 2.26, P = 0.38, I 2 = 49.13%, Fig. 2 ). The meta-regression by bubble plot revealed no significant heterogeneity of the sample size ( P = 0.250, Supplementary Fig. S2) or time of intervention ( P = 0.934, Supplementary Fig. S3) or location of intervention ( P = 0.878, Supplementary Fig. S4) or measures of intervention ( P = 0.949, Supplementary Fig. S5), and dose of glucocorticoids was a potential major source of heterogeneity ( P = 0.003, Supplementary Fig. S6). Therefore, we conducted a subgroup analysis with a dose of 100 mg methylprednisolone as the dividing line in the treatment group and control group. Interestingly, in subgroup studies >100 mg methylprednisolone, the glucocorticoids therapy group had a significantly increased survival rate at hospital discharge. However, the results of subgroup studies <100 mg methylprednisolone showed no significant difference between the glucocorticoids treatment group and the control group (Supplementary Fig. S7). Moreover, after grouping, the heterogeneity within both subgroups was significantly reduced (overall heterogeneity decreased from I 2 = 49.13% to I 2 = 0).
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