Effectiveness of Glucocorticoids on acute respiratory distress syndrome: An umbrella review

Management of Acute Respiratory Distress Syndrome is a very challenging critical illness in ICU with high morbidity and mortality worldwide.The review was intended to provide evidence on the effectiveness of Glucocorticoid treatment for acute respiratory distress syndrome Method A comprehensive search strategy was conducted on PubMed/Medline, Cochrane Library, Science direct, LILACS, and African Online Journal. Data extraction was carried out with two independent authors with customized checklist. The quality of each systemic review was assessed by two independent authors using AMSTAR tool and the overall quality of evidence was generated with online GRADEpro GDT software for primary and secondary outcomes. The umbrella review included nine systemic reviews and meta-analysis and one narrative review with eight thousand four hundred ninety one participants. The methodological quality of the included studies was moderate to high quality. The overall quality of evidence and recommendation varied form high to very low.


Abstract
Background Management of Acute Respiratory Distress Syndrome is a very challenging critical illness in ICU with high morbidity and mortality worldwide.The review was intended to provide evidence on the effectiveness of Glucocorticoid treatment for acute respiratory distress syndrome Method A comprehensive search strategy was conducted on PubMed/Medline, Cochrane Library, Science direct, LILACS, and African Online Journal. Data extraction was carried out with two independent authors with customized checklist. The quality of each systemic review was assessed by two independent authors using AMSTAR tool and the overall quality of evidence was generated with online GRADEpro GDT software for primary and secondary outcomes.

Result
The umbrella review included nine systemic reviews and meta-analysis and one narrative review with eight thousand four hundred ninety one participants. The methodological quality of the included studies was moderate to high quality. The overall quality of evidence and recommendation varied form high to very low.

Conclusion
There is high to moderate quality evidence on the initiation of early low dose prolonged glucocorticoid for reduction of mortality for ARDS. However, randomized controlled trials with large sample sizes to address ventilator-free days, the incidence of infection and other glucocorticoid associated adverse events is required as the quality of evidence with these secondary outcomes were low to very low 3 Background Acute respiratory distress syndrome (ARDS) is an acute inflammatory lung process associated with increased pulmonary vascular permeability, increased lung weight, and hypoxemic respiratory failure which results in significant morbidity and mortality worldwide 1 − 6 . The first clinical description of ARDS was traced back to 1967 by AShbaugh et al on 12 patients having refractory cyanosis due to hypoxemia respiratory failure requiring mechanical ventilation 5  The Kigali modification defined ARDS without the PEEP, as the presence of bilateral opacities on the chest radiograph or lung ultrasound and hypoxia defined as SpO2/FIO2 less than or equal to 315 8− 11 . A study by Riviello et al published on incidence of ARDS with a Kigali modification of the Berlin definition which is applicable in resource-limited set up where Arterial blood gas analysis is not available 11 . The Kigali modification defined ARDS as the presence of bilateral opacities on the chest radiograph or lung ultrasound, hypoxia defined as SpO2/FIO2 less than or equal to 315 and without the requirement of PEEP which is validated to be employed in resource-limited setup 8 .
ARDS is a clinical syndrome associated with respiratory failure due to pulmonary and nonpulmonary insults 3,6,12 . A number of pulmonary risk factors of ARDS have mentioned in the literature and from which pneumonia accounted for more than fifty percent followed by aspiration of gastric content and pulmonary contusion whereas as sepsis, noncardiogenic shock and massive blood transfusion are the most common nonpulmonary causes of ARDS 1,12 .
Despite a number of observational and Randomized Clinical trials, the Incidence of ARDS is still very high. A large observational study (LUNG SAFE) with 50 high and middle-income countries including 459 Intensive Care Unit ( ICU) centers revealed that the incidence of ARDS was 10.4% with patient mortality of around fifty percent in severe cases 4 . However, the incidence and mortality were very high in low and middle-income countries with resource-limited setups 6,13 .
Management of Acute Respiratory Distress Syndrome is a very challenging critical illness in ICU with high morbidity and mortality. Recent studies revealed that low tidal volume ventilation (6 ml/kg ideal body weight), prone positioning (16-20hrs), airway recruiting maneuvers, Extra-corporeal Membrane Oxygenation (ECM) and lung stem cell provision decrease patient mortality, decrease ventilator-free days and ICU discharge. However, glucocorticoid administration for prevention and/or treatment didn't show conclusive evidence 14,15 .
Three systemic reviews and meta-analysis of Randomized Controlled Trails(RCTs) revealed that early and prolonged administration of methylprednisolone reduced mortality and duration of mechanical ventilation 16− 18 . On the other hand, five Meta-analyses of randomized trials failed to show conclusive evidence on mortality benefit of glucocorticoids in a patient with Acute Respiratory Distress Syndrome 19 − 23 . A systemic review by Curtis failed to show a significant benefit of glucocorticoids for the late stages of ARDS 24 . Therefore, this umbrella review is aimed to provide evidence on the efficacy of glucocorticoids on the treatment and prevention of acute respiratory distress syndrome.

Objectives
The objective of this umbrella review was to provide evidence on the effectiveness of Glucocorticoid treatment for acute respiratory distress syndrome.

Research question
Do we have high-quality evidence on the effectiveness of glucocorticoids for acute respiratory distress syndrome?
When should glucocorticoids be initiated for acute respiratory distress syndrome?
Is low dose regimen of glucocorticoids more effective than high dose regimen glucocorticoids for acute respiratory distress syndrome?

Types of studies
All systemic reviews of Randomized Controlled Trials and Cohort study designs comparing the effects of glucocorticoids on acute respiratory syndrome without language and date restriction were included. This umbrella review was registered in Prospero international prospective register of systemic reviews (CRD42019130539).

Types of participants
All Systemic reviews incorporating adult ICU patient with ARDS receiving glucocorticoid and placebo were considered The intervention was any type of glucocorticoids administered to patients with acute respiratory distress syndrome.

Comparator
The control was patients who took a placebo or other form of treatment with the purpose of comparing it with glucocorticoids.

Types of outcomes
The primary outcomes were hospital mortality and the number of mechanical ventilatorfree days. The secondary outcomes were duration of ICU stay and glucocorticoid related adverse effects including the incidence of infection, hyperglycemia, and neuromuscular dysfunction.

Inclusion criteria
The umbrella review included all systemic reviews with or without meta-analysis comparing the effectiveness of glucocorticoids on acute respiratory disease syndrome either for treatment or prevention strategies.

Exclusion criteria
The overview view excluded systemic reviews assessing the effectiveness of glucocorticoid on pediatrics acute respiratory syndrome, a systemic review of crosssectional studies and clinical reviews.

Search strategy
The search strategy was intended to explore all available published and unpublished systemic reviews on the effectiveness of glucocorticoids for treatment or prevention of acute respiratory distress syndrome. A three-phase search strategy was employed in this umbrella review. An initial search on PubMed/Medline, Cochrane Library, Science direct, LILACS, and African Online Journal was carried out followed by an analysis of the text words contained in Title/Abstract and indexed terms. A second search was undertaken by combining free text words and indexed terms with Boolean operators. The third search was conducted with the reference lists of all identified reports and articles for additional studies. Finally, an additional and grey literature search was conducted on Google scholars up to ten pages. The result of the search strategy was presented with the Prisma flow chart (figure-1). The search strategy conducted in PubMed was presented in appendix 1.

Methodological Quality Assessment
The methodological quality of each included systemic review was evaluated with the AMSTAR tool (Assessing the Methodological quality of systemic reviews) by two independent authors 25 . A score was given for each included systemic review from the sum of all positive points to the checklist items and the inconvenience between the two authors was resolved by the third author. The included systemic reviews were classified based on the AMSTAR scores as high quality 8-11, moderate quality 4-7 and low quality 0-3 score values (Table 1). Table 1 Assessment of Methodological quality The AMSTAR tool (Assessing the Methodological Grading the quality of evidence The overall qualities of evidence for the studied outcome were evaluated using the GRADE system (Grading of Recommendations Assessment, Development, and Evaluation) 28,29 .
The system incorporates study quality (risk of bias), inconsistency (comparison of effect estimates across studies), indirectness (applicability of the population, intervention, comparator and outcomes to the clinical decision), imprecision (certainty of confidence interval) and high probability of publication bias. The overall quality of evidence was categorized as follows by evaluating and combing the above five parameters for mortality, mechanical ventilator free days and incidence of infection.
Effective interventions: indicated that the review found high-quality evidence of effectiveness for an intervention.
Possibly effective interventions: indicated that the review found moderate-quality evidence of effectiveness for an intervention, but more evidence is needed.
Ineffective interventions: indicated that the review found high-quality evidence of lack of effectiveness (or harm) for an intervention.
Probably ineffective interventions: indicated that the review found moderate-quality evidence suggesting a lack of effectiveness (or harm) for an intervention, but more evidence is needed.
No conclusions possible: indicated that the review found low or very low-quality evidence, or insufficient evidence to comment on the effectiveness or safety of an intervention.

Description of included studies
The search strategy identified 272 systemic reviews and meta-analysis from different databases as described in the methodology section. Thirty systemic reviews and metaanalysis were selected for further evaluation after the successive screening. Finally, ten systemic reviews and meta-analysis with 8491 participants were included for the umbrella review (Table 2) and the rest were excluded with reasons ( Table 3). The systemic reviews and meta-analysis included in the umbrella review were published from 2008 to 2018 with participant size varied from 567 to 1474. The methodological quality of included systemic reviews was ranged from low to high quality. Four systemic reviews were rated as high quality while another four were moderate quality. There was only one systemic review scored low with the methodological assessment.    One systemic review reported neuromyopathy, lung injury score, multiorgan dysfunction syndrome score, and all major adverse events as a secondary outcome 17 .

Data synthesis
The primary objective of this umbrella review was to provide quality evidence on the effectiveness of glucocorticoids on acute respiratory distress syndrome. The methodological quality of each systemic review was assessed with the AMSTAR tool and the overall quality evidence for the outcomes such as mortality, a number of mechanical ventilator-free days and incidence of infection were evaluated with online GRADEpro software. The primary outcome quality of evidence was provided with the GRADEpro summary table (Tables 4 and 5). The provision of glucocorticoids and its impact on patients with ARDS are themed as follows: Early glucocorticoid therapy There are discrepancies among systemic reviews on early initiation of glucocorticoids (less than 7 days) for the mortality benefit of patients with ARDS. One systemic review with high quality of evidence showed 67% reduction in mortality (OR = 0.37, 95% confidence interval (CI) 0.16 to 0.86, 8 studies, 501participants) 21 . Another moderate quality of evidence systemic review revealed that early glucocorticoid therapy reduced mortality by 32% (RR = 0.68, 95% confidence interval (CI) 0.57 to 0.82, 9 studies, 766 participants) 16 .
One low quality systemic review showed 38% mortality reduction (RR = 0.62, 95% confidence interval (CI) 0.43 to 0.91, 5 cohort and 4 RCTs, 648 participants) 17 . However, two low-quality systemic reviews and one very low-quality systemic review didn't show any significant difference in mortality between glucocorticoid and control 23,32,33 .
Low to moderate quality of evidence showed that low incidence of infection and longer duration of mechanical ventilator-free days was observed in a patient with early low dose glucocorticoid when compared with controls 16

Prolonged glucocorticoids
Prolonged low dose glucocorticoid initiated at least one week revealed certain mortality reduction in low to moderate quality evidence systemic reviews 16,18

Discussion
Acute respiratory distress syndrome is the most challenging critical illness in the Intensive Care Unit with significant mortality and morbidity. Glucocorticoid has been employed for the management of ARDS in different dosage, duration and timing. Despite plenty of randomized controlled trials and systemic reviews, there is no conclusive evidence on the effectiveness of glucocorticoids for ARDS. The aim of this umbrella review is to assess the quality of evidence of available systemic reviews and meta-analysis on the effectiveness of glucocorticoids for ARDS.
High-quality evidence of effectiveness High-quality evidence showed a reduction in mortality and prolonged numbers of mechanical ventilator-free days in a patient with acute respiratory distress syndrome taking early low dose prolonged glucocorticoid therapy 21 .
Moderate quality evidence of effectiveness Moderate quality of evidence showed early low dose glucocorticoid reduced mortality 16,20 .
Moderate quality of evidence also revealed that early low dose glucocorticoid decreased incidence of infection and prolonged numbers of mechanical ventilator-free days 17,20,21 .
Moderate quality of evidence failed to show mortality benefit in late phase ARDS initiation of glucocorticoids 26 . A prolonged administration of glucocorticoids showed a reduction in mortality as depicted with moderate quality of evidence systemic reviews 16,18,21 .
Moderate quality of evidence failed to show a significant difference in mortality in patients taking high dose short term glucocorticoid treatment 21 .
Low to a very low quality of evidence Low to a very low quality of evidence didn't show a significant difference in mortality in a patient who was on early low dose glucocorticoid when compared to control 17,19,23,26 . Low quality of evidence showed that prolonged glucocorticoid reduced mortality and prolonged number of mechanical ventilator-free days 26 . Low quality of evidence failed to show a significant difference in mortality and incidence of infection in a patient who was on preventive glucocorticoids 20 .

Limitation of the overview
The umbrella review incorporated ten systemic reviews with high to a very low quality of evidence. The majority of systemic reviews had moderate to a very low quality of evidence and strong recommendation on the effectiveness of glucocorticoids which is indeed affected with time to initiation, duration of therapy and dosage could be a challenge.
Besides, some of the systemic reviews didn't report the relevant information for the GRADE evidence profile.

Conclusion
This umbrella review summaries the evidence from systemic review and meta-analysis of randomized controlled trials and cohort studies to address the effects of glucocorticoids for acute respiratory distress syndrome. The finding of this review is valuable for clinicians, researchers, and policy-makers for decision making and evidence translation.
There is high-quality evidence from one systemic review and meta-analysis of randomized controlled trials regarding the mortality benefit of early and low dose glucocorticoid for greater than one week for acute respiratory distress syndrome. Moderate to low-quality evidence showed early low dose glucocorticoids decrease mortality; prolong a number of mechanical ventilator days and incidence of infection. However, moderate-quality evidence failed to show a significant benefit of the administration of glucocorticoid in the late phase of acute respiratory distress.
Low to a very low quality of evidence from systemic reviews failed to show a significant benefit of glucocorticoid initiated in the late phase of acute respiratory distress syndrome.
number of mechanical ventilator-free days and rates of infection with preventive glucocorticoid for severe and unresolved acute respiratory distress syndrome.
Despite strong recommendation on the initiation of early low dose prolonged glucocorticoid for reduction of mortality for ARDS, randomized controlled trials with large sample sizes to address ventilator-free days, the incidence of infection and other glucocorticoid associated adverse events as the quality of evidence with these secondary outcomes were low to very low.  prisma_checklists.doc