BACKGROUND: Very little direct evidence exists on use of corticosteroids in patients with coronavirus disease 2019 (COVID-19). Indirect evidence from related conditions must therefore inform inferences regarding benefits and harms. To support a guideline for managing COVID-19, we conducted systematic reviews examining the impact of corticosteroids in COVID-19 and related severe acute respiratory illnesses.
METHODS: We searched standard international and Chinese biomedical literature databases and prepublication sources for randomized controlled trials (RCTs) and observational studies comparing corticosteroids versus no corticosteroids in patients with COVID-19, severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS). For acute respiratory distress syndrome (ARDS), influenza and community-acquired pneumonia (CAP), we updated the most recent rigorous systematic review. We conducted random-effects meta-analyses to pool relative risks and then used baseline risk in patients with COVID-19 to generate absolute effects.
RESULTS: In ARDS, according to 1 small cohort study in patients with COVID-19 and 7 RCTs in non-COVID-19 populations (risk ratio [RR] 0.72, 95% confidence interval [CI] 0.55 to 0.93, mean difference 17.3% fewer; low-quality evidence), corticosteroids may reduce mortality. In patients with severe COVID-19 but without ARDS, direct evidence from 2 observational studies provided very low-quality evidence of an increase in mortality with corticosteroids (hazard ratio [HR] 2.30, 95% CI 1.00 to 5.29, mean difference 11.9% more), as did observational data from influenza studies. Observational data from SARS and MERS studies provided very low-quality evidence of a small or no reduction in mortality. Randomized controlled trials in CAP suggest that corticosteroids may reduce mortality (RR 0.70, 95% CI 0.50 to 0.98, 3.1% lower; very low-quality evidence), and may increase hyperglycemia.
INTERPRETATION: Corticosteroids may reduce mortality for patients with COVID-19 and ARDS. For patients with severe COVID-19 but without ARDS, evidence regarding benefit from different bodies of evidence is inconsistent and of very low quality.
INTRODUCTION: Acute respiratory distress syndrome (ARDS) is a rapidly progressing inflammatory lung disease with a high mortality rate without specific pharmacological therapy.
OBJECTIVES: We conducted a systematic review and meta-analysis on corticosteroid use in ARDS.
METHODS: A search of four medical literature databases was conducted. We retained randomized trials (RCTs) of corticosteroids in hospitalized adults with ARDS in a search up to February, 2020. Two reviewers identified eligible studies, independently extracted data, and assessed risk of bias. Authors assessed the certainty of the evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach.
RESULTS: We included seven RCTs (n=851 patients). Corticosteroids reduced all-cause mortality (risk ratio [RR] 0.75, 95% CI: 0.59 to 0.95, p=0.02, moderate certainty) and duration of mechanical ventilation (mean difference [MD] -4.93 days, 95% CI: -7.81 days to -2.06 days, p<0.001, low certainty), and increased ventilator-free days (VFD) (MD 4.28 days, 95% CI: 2.67 days to 5.88 days, p<0.001, moderate certainty), when compared to placebo. Corticosteroids also increased the risk of hyperglycemia (RR 1.12%, 95% CI: 1.01 to 1.24, p=0.03, moderate certainty), and the effect on neuromuscular weakness was unclear (RR 1.30, 95% CI 0.80 to 2.11, p=0.28, low certainty).
CONCLUSIONS: These results suggest that systemic corticosteroids may potentially improve mortality, ventilator duration, and VFD in patients with ARDS. However, the studies included different corticosteroid classes and initiated the corticosteroid doses at different times, as well as different dosing regimens. Thus caution in the actual clinical application of these results is recommended.
INTRODUCCIÓN: la publicación reciente de los resultados preliminares de un ensayo aleatorizado multicéntrico, que informan sobre la efectividad del tratamiento con dexametasona en pacientes con infección grave por SARS-CoV-2, plantea la necesidad de hacer una revisión de la literatura e identificar y valorar de manera crítica la evidencia sobre la efectividad y seguridad de esta intervención. METODOS: se realizó una búsqueda amplia, no sistemática. Se utilizó la metodología GRADE para la evaluación de la certeza en la evidencia incluida. Se conformó un equipo multidisciplinario para elaborar un informe de evaluación de tecnología sanitaria. RESULTADOS: el uso de glucocorticoides (dexametasona en dosis de 6 mg/día por 10 días) en pacientes con neumonía por SARS-CoV-2 mostró reducir la mortalidad global a los 28 días (riesgo relativo [RR]: 0,83; intervalo de confianza del 95% [IC95%]: 0,75-0,93), con un número necesario a tratar (NNT) de 33 (confianza alta). En pacientes con neumonía grave con requerimientos de asistencia ventilatoria mecánica (AVM) se observó una disminución de la mortalidad (RR: 0,64; IC95%: 0,51-0,81; NNT: 8,5) (confianza moderada). En pacientes con neumonía grave con requerimientos de oxígeno sin AVM también se informa una reducción de la mortalidad (RR: 0,82; IC95%: 0,72-0,94) (confianza moderada). En pacientes con neumonía sin requerimientos de oxígeno (RR: 1,19; IC95%: 0,91-1,55) no se evidenció beneficio con el uso de esta intervención (confianza baja). No se describieron efectos adversos en los pacientes críticos con el uso de corticoides en las dosis utilizadas. DISCUSIÓN: se recomienda la administración de dexametasona en dosis de 6 mg/día (dosis bajas) durante 10 días en los pacientes con neumonía grave por SARS-CoV-2 y requerimientos de oxigenoterapia o AVM.
BACKGROUND: Very little direct evidence exists on use of corticosteroids in patients with coronavirus disease 2019 (COVID-19). Indirect evidence from related conditions must therefore inform inferences regarding benefits and harms. To support a guideline for managing COVID-19, we conducted systematic reviews examining the impact of corticosteroids in COVID-19 and related severe acute respiratory illnesses.
METHODS: We searched standard international and Chinese biomedical literature databases and prepublication sources for randomized controlled trials (RCTs) and observational studies comparing corticosteroids versus no corticosteroids in patients with COVID-19, severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS). For acute respiratory distress syndrome (ARDS), influenza and community-acquired pneumonia (CAP), we updated the most recent rigorous systematic review. We conducted random-effects meta-analyses to pool relative risks and then used baseline risk in patients with COVID-19 to generate absolute effects.
RESULTS: In ARDS, according to 1 small cohort study in patients with COVID-19 and 7 RCTs in non-COVID-19 populations (risk ratio [RR] 0.72, 95% confidence interval [CI] 0.55 to 0.93, mean difference 17.3% fewer; low-quality evidence), corticosteroids may reduce mortality. In patients with severe COVID-19 but without ARDS, direct evidence from 2 observational studies provided very low-quality evidence of an increase in mortality with corticosteroids (hazard ratio [HR] 2.30, 95% CI 1.00 to 5.29, mean difference 11.9% more), as did observational data from influenza studies. Observational data from SARS and MERS studies provided very low-quality evidence of a small or no reduction in mortality. Randomized controlled trials in CAP suggest that corticosteroids may reduce mortality (RR 0.70, 95% CI 0.50 to 0.98, 3.1% lower; very low-quality evidence), and may increase hyperglycemia.
INTERPRETATION: Corticosteroids may reduce mortality for patients with COVID-19 and ARDS. For patients with severe COVID-19 but without ARDS, evidence regarding benefit from different bodies of evidence is inconsistent and of very low quality.
BACKGROUND: Acute respiratory distress syndrome (ARDS) is a life-threatening condition caused by direct or indirect injury to the lungs. Despite improvements in clinical management (for example, lung protection strategies), mortality in this patient group is at approximately 40%. This is an update of a previous version of this review, last published in 2004.
OBJECTIVES: To evaluate the effectiveness of pharmacological agents in adults with ARDS on mortality, mechanical ventilation, and fitness to return to work at 12 months.
SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and CINAHL on 10 December 2018. We searched clinical trials registers and grey literature, and handsearched reference lists of included studies and related reviews.
SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing pharmacological agents with control (placebo or standard therapy) to treat adults with established ARDS. We excluded trials of nitric oxide, inhaled prostacyclins, partial liquid ventilation, neuromuscular blocking agents, fluid and nutritional interventions and medical oxygen. We excluded studies published earlier than 2000, because of changes to lung protection strategies for people with ARDS since this date.
DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, extracted data, and assessed risks of bias. We assessed the certainty of evidence with GRADE.
MAIN RESULTS: We included 48 RCTs with 6299 participants who had ARDS; two included only participants with mild ARDS (also called acute lung injury). Most studies included causes of ARDS that were both direct and indirect injuries. We noted differences between studies, for example the time of administration or the size of dose, and because of unclear reporting we were uncertain whether all studies had used equivalent lung protection strategies.We included five types of agents as the primary comparisons in the review: corticosteroids, surfactants, N-acetylcysteine, statins, and beta-agonists. We included 15 additional agents (sivelestat, mesenchymal stem cells, ulinastatin, anisodimine, angiotensin-converting enzyme (ACE) inhibitor, recombinant human ACE2 (palifermin), AP301, granulocyte-macrophage colony stimulating factor (GM-CSF), levosimendan, prostacyclins, lisofylline, ketaconazole, nitroglycerins, L-2-oxothiazolidine-4-carboxylic acid (OTZ), and penehyclidine hydrochloride).We used GRADE to downgrade outcomes for imprecision (because of few studies and few participants), for study limitations (e.g. high risks of bias) and for inconsistency (e.g. differences between study data).Corticosteroids versus placebo or standard therapyCorticosteroids may reduce all-cause mortality within three months by 86 per 1000 patients (with as many as 161 fewer to 19 more deaths); however, the 95% confidence interval (CI) includes the possibility of both increased and reduced deaths (risk ratio (RR) 0.77, 95% CI 0.57 to 1.05; 6 studies, 574 participants; low-certainty evidence). Due to the very low-certainty evidence, we are uncertain whether corticosteroids make little or no difference to late all-cause mortality (later than three months) (RR 0.99, 95% CI 0.64 to 1.52; 1 study, 180 participants), or to the duration of mechanical ventilation (mean difference (MD) -4.30, 95% CI -9.72 to 1.12; 3 studies, 277 participants). We found that ventilator-free days up to day 28 (VFD) may be improved with corticosteroids (MD 4.09, 95% CI 1.74 to 6.44; 4 studies, 494 participants; low-certainty evidence). No studies reported adverse events leading to discontinuation of study medication, or fitness to return to work at 12 months (FTR).Surfactants versus placebo or standard therapyWe are uncertain whether surfactants make little or no difference to early mortality (RR 1.08, 95% CI 0.91 to 1.29; 9 studies, 1338 participants), or whether they reduce late all-cause mortality (RR 1.28, 95% CI 1.01 to 1.61; 1 study, 418 participants). Similarly, we are uncertain whether surfactants reduce the duration of mechanical ventilation (MD -2.50, 95% CI -4.95 to -0.05; 1 study, 16 participants), make little or no difference to VFD (MD -0.39, 95% CI -2.49 to 1.72; 2 studies, 344 participants), or to adverse events leading to discontinuation of study medication (RR 0.50, 95% CI 0.17 to 1.44; 2 studies, 88 participants). We are uncertain of these effects because we assessed them as very low-certainty. No studies reported FTR.N-aceytylcysteine versus placeboWe are uncertain whether N-acetylcysteine makes little or no difference to early mortality, because we assessed this as very low-certainty evidence (RR 0.64, 95% CI 0.32 to 1.30; 1 study, 36 participants). No studies reported late all-cause mortality, duration of mechanical ventilation, VFD, adverse events leading to study drug discontinuation, or FTR.Statins versus placeboStatins probably make little or no difference to early mortality (RR 0.99, 95% CI 0.78 to 1.26; 3 studies, 1344 participants; moderate-certainty evidence) or to VFD (MD 0.40, 95% CI -0.71 to 1.52; 3 studies, 1342 participants; moderate-certainty evidence). Statins may make little or no difference to duration of mechanical ventilation (MD 2.70, 95% CI -3.55 to 8.95; 1 study, 60 participants; low-certainty evidence). We could not include data for adverse events leading to study drug discontinuation in one study because it was unclearly reported. No studies reported late all-cause mortality or FTR.Beta-agonists versus placebo controlBeta-blockers probably slightly increase early mortality by 40 per 1000 patients (with as many as 119 more or 25 fewer deaths); however, the 95% CI includes the possibility of an increase as well as a reduction in mortality (RR 1.14, 95% CI 0.91 to 1.42; 3 studies, 646 participants; moderate-certainty evidence). Due to the very low-certainty evidence, we are uncertain whether beta-agonists increase VFD (MD -2.20, 95% CI -3.68 to -0.71; 3 studies, 646 participants), or make little or no difference to adverse events leading to study drug discontinuation (one study reported little or no difference between groups, and one study reported more events in the beta-agonist group). No studies reported late all-cause mortality, duration of mechanical ventilation, or FTR.
AUTHORS' CONCLUSIONS: We found insufficient evidence to determine with certainty whether corticosteroids, surfactants, N-acetylcysteine, statins, or beta-agonists were effective at reducing mortality in people with ARDS, or duration of mechanical ventilation, or increasing ventilator-free days. Three studies awaiting classification may alter the conclusions of this review. As the potential long-term consequences of ARDS are important to survivors, future research should incorporate a longer follow-up to measure the impacts on quality of life.
OBJECTIVE: Corticosteroids have important effects on intermediate outcomes in critically ill patients, but their effect on survival is unknown. The objective of this meta-analysis was to analyze the effect on mortality of corticosteroids in critical and perioperative settings.
DESIGN: A meta-analysis of randomized trials.
SETTING: PubMed, Embase, BioMed Central, Google Scholar, and the Cochrane Central Register of Controlled Trials were searched to February 1, 2018, for randomized trials comparing corticosteroids with placebo or standard care.
PARTICIPANTS: Critically ill or surgical adult patients.
INTERVENTIONS: Corticosteroids compared with placebo or standard care.
MEASUREMENTS AND MAIN RESULTS: A total of 44,553 patients from 135 studies were included. Overall, mortality in the corticosteroid group and in the control group were similar (16% v 16%; p = 0.9). Subanalyses identified a beneficial effect of corticosteroids on survival in patients with respiratory system diseases (9% v 13%; p < 0.001) and bacterial meningitis (28% v 32%; p= 0.04), and a detrimental effect on survival in patients with traumatic brain injury (22% v 19%; p < 0.001). No differences in mortality were found in patients with cardiac diseases (7% v 6%; p = 0.7), in patients undergoing cardiac surgery (2.8% v 3.2% p = 0.14), and when treatment duration or patient age were considered.
CONCLUSIONS: This meta-analysis documents the safety of corticosteroids in the overall critically ill population with the notable exception of brain injury patients, a setting where the authors confirmed their detrimental effect on survival. A possible beneficial effect of corticosteroids on survival was found among patients with respiratory diseases and in patients with bacterial meningitis.
BACKGROUND: The benefits and adverse effects of corticosteroids in the treatment of severe community-acquired pneumonia (CAP) have not been well assessed. The aim of this systematic review of the literature and meta-analysis was to evaluate the clinical efficacy of adjuvant corticosteroid therapy in patients with severe CAP.
METHODS: The following databases were searched: PubMed, the Cochrane database, Embase, Wanfang, the China National Knowledge Infrastructure (CNKI), and the WeiPu (VIP) database in Chinese. Published randomized controlled clinical trial results were identified that compared corticosteroid therapy with conventional therapy for patients with severe CAP, up to November 2016. The relative risk (RR), weighted mean difference (WMD), and 95% confidence interval (CI) were evaluated. Statistical analysis was performed using STATA 10.0. The quality of the published studies was evaluated using the Oxford quality scoring system (Jadad scale).
RESULTS: Ten randomized controlled trials (RCTs) were identified that included 729 patients with severe CAP. Data analysis showed that corticosteroid therapy did not have a statistically significant clinical effect in patients with severe CAP (RR: 1.19; 95% CI: 0.99-1.42), mechanical ventilation time (WMD: -2.30; 95% CI: -6.09-1.49). However, corticosteroids treatment was significantly associated with reduced in-hospital mortality (RR: 0.49; 95% CI: 0.29-0.85), reduced length of hospital stay (WMD: -4.21; 95% CI: -6.61 to -1.81).
CONCLUSION: Corticosteroids adjuvant therapy in patients with severe CAP may reduce the rate of in-hospital mortality, reduce the length of hospital stay, and reduce CRP levels.
Previous clinical trials have investigated the effect of glucocorticoid therapy in acute respiratory distress syndrome (ARDS), with controversial results, particularly with regard to the early administration of low dose glucocorticoid. The present meta-analysis aimed to assess whether the application of glucocorticoid was able to reduce mortality in patients with ARDS. A literature search was performed using online databases, including MEDLINE, Embase, Cochrane and CNKI regardless of whether the studies were published in English or Chinese. Following assessment via inclusion and exclusion criteria, two reviewers screened controlled randomized trials which investigated glucocorticoid therapy in ARDS patients and independently extracted data. The quality of all of the included trials was evaluated based on blinding, randomization and other methods. A total of 14 studies with 1,441 patients met the inclusion criteria. The results of the meta-analysis demonstrated that glucocorticoid significantly reduced the overall mortality of patients with ARDS [relative ratio (RR), 0.68; 95% confidence interval (CI), 0.50-0.91; P<0.05], particularly with a low-dose of glucocorticoid (RR, 0.57; 95% CI, 0.39-0.84; P<0.05) at the early phase of ARDS (RR, 0.37; 95% CI, 0.16-0.86; P<0.05), and a longer duration of steroids (RR, 0.44; 95% CI, 0.30-0.64; P<0.05). Administration of steroids also significantly increased the number of days that patients remained alive and were off mechanical ventilation (RR, 3.08; 95% CI, 1.49-4.68; P<0.05) without significantly increasing the novel infection rate (RR, 1.00; 95% CI, 0.44-2.25; P<0.05). Due to inconsistencies and other limitations, the quality of the studies used for the meta-analysis of the effect of glucocorticoid on mortality was low. In conclusion, early use of low dose glucocorticoid may effectively reduce mortality in patients with ARDS. However, this conclusion may be affected by the limited quality of the studies included in the present meta-analysis.
