Comparative Outcomes of different interventions in ARDS: A systematic review and network meta-analysis

doi:10.21203/rs.3.rs-2439237/v1

OBJECTIVES: Acute respiratory distress syndrome (ARDS) is linked to high rates of morbidity and mortality. Evidence examining commonly used corticosteroids, neuromuscular blocking agents (NMBAs) and inhaled nitric oxide (iNO) remains uncertain. The aim of the study was to compare and rank these three treatments to identify the best one.

DATA SOURCES: We searched Pubmed, Embase, Cochrane Library, and Web of Science from the earliest records to May 1, 2022 for clinic trials.

STUDY SELECTIONT AND DATA EXTRACTION: Clinical trials of three interventions compared with control group for ARDS, no language restricted. Data were extracted by 2 independent reviewers. Frequentist network meta-analyses (NMA) were performed to identify the best intervention and treatments were ranked using the surface under the cumulative ranking (SUCRA) curve. Primary outcome was 28-day mortality. Secondary outcomes varied ventilator-free days at 28 days, ICU mortality, In-hospital mortality and new infection events.

DATA SYNTHESIS: Data were combined from 26 clinical trials which included 5071 patients. Vecuronium bromide was the best strategy to reduce 28-day mortality compared with the conventional treatment, iNO, methylprednisolone and placebo (OR 0.38, 95% CI 0.15-1.00 and OR 0.30, 95% CI 0.10-0.85 and OR 0.25, 95% CI 0.08-0.74 and OR 0.23, 95% CI 0.08-0.65; SUCRA: 96.6%). Dexamethasone was the best treatment option for increasing ventilator-free days at 28 days compared to conventional therapy and cisatracurium (MD 3.60, 95% CI 1.77-5.43 and MD 3.40, 95% CI 0.87-5.92; SUCRA: 93.2%). Methylprednisolone was the most effective treatment option to prevent ICU mortality (SUCRA: 88.5%). Though dexamethasone, cisatracurium, conventional therapy, methylprednisolone and iNO treatment showed no significant superiority of in-hospital mortality protection over placebo, suggesting that it had the highest probability of being the best treatment option (SUCRA: 79.7%) for reducing in-hospital mortality. Dexamethasone treatment showed the highest safety for decreasing the incidence of new infection events compared with placebo and iNO (OR 0.61, 95% CI 0.42-0.88 and OR 0.33, 95% CI 0.19-0.58; SUCRA: 91.8%).

Conclusions: This NMA suggested that corticosteroids are possibly beneficial in the patients with ARDS while application of NMBAs may reduce 28-day mortality, iNO as a therapeutic measure which did not show a prominent beneficial effect.

Study registration:PROSPERO, CRD42022333165

ARDS

Corticosteroids

NMBAs

INO

network meta-analysis

Acute respiratory distress syndrome (ARDS), which identified as a fatal disease worldwide with significant morbidity and mortality, is defined as chronic respiratory failure due to non-hemodynamic pulmonary edema caused by inflammatory cytokines ^{[1, 2]}. Nowadays, ARDS is an important public health problem. The COVID-19 pandemic has led to an increase in ARDS and highlighted the risks posed with the disease, which has an unacceptably high incidence rate and lack of effective drug treatments ^[3]. A global epidemiologic survey reported that 10.4% of intensive care unit admissions and 23.4% of all patients who were intubated had ARDS, with an associated hospital mortality rate of 40% ^[2].

A variety of approaches to its management exist been evaluated and applied clinically ^{[4, 5]}, since the first description of ARDS in 1967 ^[6]. Despite more than 50 years of research, to our knowledge, no of the current available treatments directly address the pathophysiological mechanisms that lead to acute respiratory failure ^[7]. The recent Guidelines ^[8] on the management of ARDS, has decided that the focus should be on effective treatment interventions, and the process for creating guidelines followed that of the National Institute for Health and Care Excellence (NICE). Ten topics, which were chosen based on existing guideline recommendations and the experience of committee members, corticosteroids, neuromuscular blocking agents (NMBAs) and inhaled nitric oxide (iNO) were included.

One systematic review and meta-analyses (SR/MA) on ARDS has shown that the use of corticosteroids decreases mortality and increases ventilator-free days (VFD) ^[9], another SR/MA suggested that early and longer administration of corticosteroids in patients with ARDS might reduce mortality ^[10]. Meanwhile, one study of NMBAs on ARDS enlightened that use of NMBAs may improve oxygenation, reduce the incidence of ventilator-induced lung injury, and decreases the mortality at 28 days ^[11]. Besides, the role of the iNO in the management of ARDS has been assessed in multiple randomized controlled trials (RCTs), which have been analyzed in subsequent SR/MA. However, and the effect of this treatment is not clear until now and few study evaluated the therapeutic effect of corticosteroids, NMBAs and iNO in the patients with ARDS.

ARDS is particularly relevant globally of ARDS epidemic caused by the outbreak of SARS-CoV-2 affecting millions worldwide, causing the mortality of patients with ARDS to rise rapidly. ^[3]. Therefore, it is of great urgency and significance to synthesise relevant evidence and to put it into the context of current critical care medicine to approach related issues. In this study, we aimed to conduct a NMA of the present high-quality trials to assess the efficacy of these three treatments above in ARDS. Our study may bring great guiding significance for better treatment of ARDS in the future.

Literature Review

The Pubmed, Embase, Cochrane, and Web of Science were systematically searched from the library construction date to May 2022. The search strategy was illustrated in detail in the eAppendix1 in the Supplement. This meta-analysis was composed in strict accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), and has been registered on the PROSPERO (CRD42022333165).

Inclusion and Exclusion criteria

The inclusion criteria of eligible studies were as follows: (I) research objects: adult patients (aged > = 18 years) with ARDS who treated with the three interventions above based on Guidelines on the management of acute respiratory distress syndrome in 2019 ^[8]; (II) interventions: the intervention group was treated with corticosteroids or iNO or NMBAs and the control group was treated with a matched placebo or conventional therapy. Studies were excluded if met the following criteria: (I) the publication type was a letter, a case report, a review, or an editorial; (II) the study design in the literature was an in vitro test or an animal test; (III) the data were insufficient or unavailable. There were no language restrictions.

Data Collection and Outcomes

Two reviewers (Zhiyuan Xu. and Haonan Liu.) independently extracted data using a standardized form. Disagreements arose amicably resolved through consensus, if necessary, consultation with a third reviewer (professor Yan). The primary outcome was 28-day mortality (mortality rate of patients on the 28th day of treatment). The secondary outcomes were ventilator-free days at 28 days (the number of days that the patients did not use a ventilator on the 28th day of treatment), ICU mortality, in-hospital mortality and new infection events.

Risk of Bias Assessment and Quality Assessment

Two reviewers (Zhiyuan Xu. and Haonan Liu.) independently reviewed the articles and assessed potentially eligible studies for inclusion, and discrepancies were resolved by discussion with a third reviewer (professor Yan). The same reviewers used the Cochrane risk of bias assessment tool to assess the following seven domains ^[13]: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete data outcome, selective reporting, and other bias. The risk of bias was graded as low, high, or unclear on the basis above and any disagreements on the assessed quality were resolved with a third reviewer by consensus.

Statistical Analysis

We performed frequentist effects NMA using the mvmeta command in STATA 16.0. We presented all treatment comparisons using a network graph for each outcome. The nodes of the evidence diagram represented different intervention measures, and the lines between them represented different head-to-head comparisons. The dichotomous variables were integrated as risk ratios (OR) with 95% confidence intervals (CI), and continuous variables integrated as mean differences (MD) with 95% CI. Statistical heterogeneity was assessed in each comparison using the I² statistic ^[14]. Given the immense complexity of the analysis, dose differences were ignored.

The random-effect model was adopted when I² > 50%, otherwise the fixed-effect model was adopted ^[15]. We presented all treatment comparisons using a network graph for each outcome, we derived rank probability for each intervention and compared the results of the NMA within a Bayesian framework and decided diagnosis hierarchy using surface under the cumulative ranking curve (SUCRA) ^[16], and higher SUCRA probabilities in each simulation indicate the higher chance of being the best treatment regimen. It is also important to consider the relative risk and corresponding 95% CI for each comparison when interpreting the ranking results. We implemented publication bias in studies contributing to primary outcomes and adverse events by visual inspection of funnel plots performed.

Characteristics and Risk of Bias of the Included Studies

The risk of bias judgments for the studies contributing to the analysis of each outcome are presented in eFigure1 in the Supplement. We identified 7136 reports, of which 26 trials (5071 participants) met the eligibility criteria in this review (Fig. 1). These 26 trials included 24 English documents ^{[17–27,29−35, 37–42]} and 2 Chinese document ^{[28, 36]} with high-quality. Of the included 26 studies, 12 studies ^{[17, 18, 21, 23, 25, 27, 31–33, 35, 37, 40]} involved in ventilator-free days at 28 days, 17 studies ^{[19, 21–23, 27–29, 31, 32, 34–37, 39–42]} provded mortality at 28 days, 10 studies ^{[17, 21, 22, 25, 26, 32–35, 38]} related to ICU mortality, 14 studies ^{[17, 19–21, 24–26, 30–32, 34, 35, 38, 39]} covered in-hospital mortality and 13 studies ^{[17, 18, 20–22, 25–30, 39, 40]} provided new infection events. The baseline characteristics of the included studies are summarized in Table 1.

Table 1

Characteristics of the included studies
Study	Year	Country	Research type	Sample size	Treatment group (PaO2/FiO2, mm Hg)	control group (PaO2/FiO2, mm Hg)	Primary outcome	Secondary outcome	Score of NOS	Score of Jadad
Villar ^[17]	2020	Spain	Randomized controlled trial	277	142.4 ± 37·3	143.5 ± 33.4	Ventilator-free days at 28 days	All-cause mortality 60 days	-	5
Kenneth ^[18]	2006	USA	Randomized controlled trial	180	126 ± 42	126 ± 40	Mortality at 60 days	Ventilator-free days at 28 days	-	5
Liu J ^[19]	2020	China	Retrospective study	774	168 (IQR 99–237)	168 (IQR 99–237)	28-day all-cause mortality.	In-hospital mortality	8	-
Bernard ^[20]	1987	USA	Randomized controlled trial	99	-	-	Mortality at 45 days	New infection events	-	5
Annane ^[21]	2006	France	Retrospective study	177	104 ± 42	108 ± 45	Ventilator-free days at 28 days	Mortality in ICU	7	-
Meduri ^[22]	2018	USA	Retrospective study	180	-	-	Mortality at 28 days	New infection events	8	-
Tongyoo ^[23]	2016	Thailand	Randomized controlled trial	197	175.4 ± 6.9	172.4 ± 6.7	28-day all-cause mortality	Ventilator-free days at 28 days	-	5
HS Lee ^[24]	2005	Korea	Retrospective study	20	142.5 ± 23.7	143.4 ± 23.9	In-hospital mortality	Hospital stay days	7	-
Meduri ^[25]	2007	USA	Randomized controlled trial	91	118.4 ± 51.2	125.9 ± 38.6	Ventilator-free days at 28 days	Mortality in ICU	-	4
Meduri ^[26]	1998	USA	Randomized controlled trial	24	161 ± 14	141 ± 19	Lung function and mortality	MODS scores	-	5
Bruno ^[27]	2020	Brazil	Randomized controlled trial	299	131.1 ± 46.2	132.6 ± 45.7	Ventilator-free days at 28 days	All-cause mortality at 28 days	-	5
Liu L ^[28]	2012	China	Randomized controlled trial	26	138.2 (87.0, 171.0)	157.0 (88.7, 176.3)	Mortality at 28 days	New infection events	-	4
Varpula ^[29]	2000	Finland	Retrospective study	31	126.3 ± 52.4	107 ± 41.4	Mortality at 28 days	New infection events	7	-
Buisson ^[30]	2011	French	Retrospective study	208	101 (73–174)	107 (78–144)	In-hospital mortality	New infection events	9	-
Moss ^[31]	2019	USA	Randomized controlled trial	1006	98.7 ± 27.9	99.5 ± 27.9	In-hospital mortality	Organ dysfunction	-	5
Gainnier ^[32]	2004	France	Randomized controlled trial	56	130 ± 34	119 ± 31	Ventilator-free days at 28 days	Mortality in ICU	-	4
Guervilly ^[33]	2016	France	Randomized controlled trial	24	158 (131; 185)	150 (121; 187)	Ventilator-free days at 28 days	Mortality in ICU	-	5
Forel ^[34]	2006	France	Randomized controlled trial	36	105 ± 22	125 ± 20	Mortality at 28 days	Mortality in ICU	-	4
Papazian ^[35]	2010	France	Randomized controlled trial	340	106.0 ± 36.0	115.0 ± 41.0	The 90-day mortality	The day- 28 mortality	-	5
Lyu ^[36]	2014	China	Randomized controlled trial	96	141.0 ± 26.1	144.3 ± 24.1	Mortality at 28 days	APACHE 1I scores	-	4
Phillip ^[37]	1998	USA	Randomized controlled trial	177	135 ± 41.0	129.0 ± 38.0	Ventilator-free days at 28 days	The day- 28 mortality	-	4
Gerlach ^[38]	2003	Germany	Randomized controlled trial	40	113.0 ± 28.0	104.0 ± 26.0	Duration of ventilation	Mortality in ICU	-	4
Lundin ^[39]	1999	UK	Randomized controlled trial	268	102.8 ± 32.3	100.5 ± 33.0	The day- 28 mortality	New infection events	-	4
Taylor ^[40]	2004	USA	Randomized controlled trial	385	133.0 ± 42.0	138.0 ± 43.0	Ventilator-free days at 28 days	The day- 28 mortality	-	5
Troncy ^[41]	1998	Canada	Randomized controlled trial	30	-	-	The day- 28 mortality	APACHE II scores	-	4
Brian ^[42]	2000	UK	Randomized controlled trial	30	-	-	The day- 28 mortality	APACHE II scores		4

28-day mortality

Data regarding the efficiency of corticosteroids, iNO and NMBAs on 28-day mortality were available from 17 trials ^{[19, 21–23, 27–29, 31, 32, 34–37, 39–42]} with 3,930 patients. As shown in Fig. 2 and Fig. 3, vecuronium bromide was the most effective than conventional therapy (OR 0.38, 95% CI 0.15-1.00), iNO (OR 0.30, 95% CI 0.10–0.85), methylprednisolone (OR 0.25, 95% CI 0.08–0.74), and placebo (OR 0.23, 95% CI 0.08–0.65). Dexamethasone was only better than placebo (OR 0.47, 95% CI 0.24–0.93). Cisatracurium was superior to methylprednisolone (OR 0.59, 95% CI 0.38–0.90), placebo (OR 0.53, 95% CI 0.33–0.85). Conventional therapy had an advantage over placebo (OR 0.59, 95% CI 0.38–0.91). No treatment has shown significant advantages over the others during hydrocortisone, iNO, methylprednisolone, and placebo. The effects of all drugs were ranked with SUCRA probabilities (Fig. 4), and vecuronium bromide had the greatest probability (SUCRA 96.6%) for being the best treatment option on reducing 28-day mortality in these patients of ARDS, followed by dexamethasone (SUCRA 73.8%), cisatracurium (SUCRA 67.3%), conventional therapy (SUCRA 57.7%), hydrocortisone (SUCRA 47.4%), iNO (SUCRA 32.4%), methylprednisolone (SUCRA 17.4%) and placebo ranked last (SUCRA 7.4%).

Ventilator-free days at 28 days

Twelve studies ^{[17, 18, 21, 23, 25, 27, 31–33, 35, 37, 40]} involving 3,119 patients evaluated the effect of these drugs on ventilator-free days at 28 days. Compared to placebo, both dexamethasone and methylprednisolone increased ventilator-free days at 28 days (MD 5.50, 95% CI 1.91–9.08) and MD 4.31, 95% CI 2.37–6.26) (Fig. 2 and Fig. 3). Dexamethasone and methylprednisolone also have a significant benefit for ventilator-free days at 28 days (MD 4.97, 95% CI 0.74–9.21) and (MD 3.79, 95% CI 0.94–6.64) compared to iNO group. Compared to conventional therapy and cisatracurium, dexamethasone showed a significant superiority (MD 3.60, 95% CI 1.77–5.43 and MD 3.40, 95% CI 0.87–5.92) in ventilator-free days at 28 days. However, iNO, cisatracurium and hydrocortisone didn't have any superiority of ventilator-free days at 28 days over placebo or conventional therapy. As shown in Fig. 5, dexamethasone had the highest probability of being the best treatment option for increasing ventilator-free days at 28 days (SUCRA 93.2%), followed by methylprednisolone (SUCRA 82.4%). Hydrocortisone (SUCRA 51.6%) and cisatracurium (SUCRA 48.5%) ranked in the third and fourth position before conventional therapy (SUCRA 43.1%), iNO (SUCRA 21.7%) and placebo (SUCRA 9.4%).

ICU mortality

ICU mortality was reported from a total of 10 studies ^{[17, 21, 22, 25, 26, 32–35, 38]} of 1,244 patients. Methylprednisolone significantly decreased the mortality in ICU compared with placebo (OR 0.48, 95% CI 0.33–0.72) as shown in Fig. 2 and Fig. 3. The therapy of methylprednisolone, cisatracurium and dexamethasone were superior to conventional therapy in reducing ICU mortality (OR 0.34, 95%CI 0.13–0.90 and OR 0.46, 95%CI 0.21–0.99 and OR 0.58, 95%CI 0.34-1.00). The therapy of iNO had no advantages in reducing mortality in ICU over other treatments. Our results (Fig. 6) suggested that, regarding prevention of ICU mortality, methylprednisolone (SUCRA 88.5%) was most effective, followed by cisatracurium (SUCRA 69.4%), dexamethasone (SUCRA 53.7%), iNO (SUCRA 42.3%), placebo (SUCRA 33.6%), conventional therapy (SUCRA 12.4%).

In-hospital mortality

Fourteen studies ^{[17, 19, 20, 21, 24–26, 30–32, 34, 35, 38, 39]} with 3,327 participants involved in in-hospital mortality. As shown in Fig. 2 and Fig. 3, compared with the conventional treatment or placebo, dexamethasone, cisatracurium, methylprednisolone and iNO showed no significant advantages in reducing hospital mortality. For all that, as shown in Fig. 7, dexamethasone reduced the incidence of in-hospital mortality at the top-ranking position (SUCRA 79.7%), followed by cisatracurium (SUCRA 72.1%), conventional therapy (SUCRA 47.6%), methylprednisolone (SUCRA 45.6%), iNO (SUCRA 42.1%), placebo (SUCRA 13.0%).

New infection events

Data regarding new infection events were available from 13 trials ^{[17, 18, 20–22, 25–30, 39, 40]} with 2,157 patients. Dexamethasone significantly decreased the rate of new infection events compared with hydrocortisone and iNO (OR 0.46, 95% CI 0.24–0.89 and OR 0.25, 95% CI 0.10–0.59) as seen in Fig. 2 and Fig. 3. Methylprednisolone had advantages of new infection events protection over placebo and iNO (OR 0.61, 95% CI 0.42–0.88 and OR 0.33, 95% CI 0.19–0.58). Conventional therapy also had a significant benefit for reducing new infection events (OR 0.59, 95% CI 0.35-1.00 and OR 0.32, 95% CI 0.15–0.69) compared to hydrocortisone and iNO. In addition, placebo significantly decreased the rate of new infection events compared with iNO (OR 0.53, 95% CI 0.34–0.83). For decreasing the incidence of new infection events, dexamethasone showed the highest safety ranking (Fig. 8, SUCRA 91.8%), followed by methylprednisolone (SUCRA 72.3%) and conventional therapy (SUCRA 70.9%), placebo (SUCRA 32.5%) and hydrocortisone (SUCRA 31.2%) ranked in the fourth and fifth position, iNO ranked last (SUCRA 1.2%).

Publication bias

Funnel plots were used to assess publication bias for each arm of the comparison, and further statistical analysis of funnel plot asymmetry was planned if there were more than 10 trials in each arm. Visual inspection of the Begg funnel plot did not identify substantial asymmetry, and there was no obvious publication bias in primary outcome (Fig. 9).

This is the first NMA direct compare the efficacy and safety of corticosteroids, iNO and NMBAs in adult patients with ARDS. Our results suggested vecuronium may be the best treatment to reduce the mortality at 28 days of patients with ARDS, although it has no significant effect compared with dexamethasone, cisatracurium and hydrocortisone. Meanwhile, dexamethasone and methylprednisolone also had a significant benefit for ventilator-free days at 28 days in patients with ARDS. Besides, methylprednisolone, cisatracurium and dexamethasone had significant efficacy in reducing ICU mortality in patients with ARDS, and methylprednisolone ranked highest. Furthermore, dexamethasone and methylprednisolone were effective in preventing the complications of new infections in patients with ARDS. No intervention was superior to any other in reducing In-hospital mortality.

Two recent studies ^{[10, 43]} showed that corticosteroids may reduce short term mortality and duration of mechanical ventilation in all patients with ARDS. Due to their anti-inflammatory properties, maintenance of endothelial integrity, reduction of pro-inflammatory cytokines and nitric oxide synthases included, corticosteroids are effective in a variety of inflammatory diseases ^[10]. They also inhibit fibroblast growth and collagen deposition, thus having antifibrotic properties ^[44]. Another study ^[45] suggested that the effect of steroids on the outcome in patients with ARDS might vary on the type of the medication drug they were administered, which was consistent with our results. It has long been hypothesized that therapy of corticosteroids, may be beneficial to patients with ARDS ^{[18, 26]}. The results of our NMA were exactly to support this hypothesis. This NMA showed that corticosteroids reduce short-time mortality and duration of mechanical ventilation in patients with ARDS. Therefore, clinicians can choose to use corticosteroids to reduce the short-term life risk of patients with ARDS and reduce the incidence of infection. Meanwhile, corticosteroids can reduce the duration that patients use the ventilator, which is of great benefit to recovery of spontaneous breathing and improvement of lung function.

Clinicians also often use muscle relaxation therapy to treat moderate to severe ARDS, which is one of the common non-ventilatory strategies ^[35]. Benefits from neuromuscular blocking agents (NMBAs) could be attributed to its direct pharmacological action to control tidal volume and prevent ventilator desynchrony ^[46]. NMBAs have been suggested as solution to this problem because they can relax skeletal muscles and joint better patient ventilation and tidal volume control ^[47]. The benefit of NMBAs for ARDS is widely recognized. Dozens of studies found that NMBAs could reduce lung injury caused by ventilator by improving man-machine synchronization and reduce oxygen consumption and possible indirect anti-inflammatory effects. Over the past two decades, several clinical studies have been conducted to evaluate the role of NMBAs in the management of ARDS ^{[32–36, 48]}. However, the results have been conflicting making clinical judgement difficult on NMBAs use in ARDS cases. This study found that NMBAs can effectively reduce 28-day mortality and ICU mortality of patients with ARDS. our outcomes were more innovative than some previous studies ^[11,49−52].

Nitric oxide was first reported to be an endogenousvasodilator in 1987 ^[53]. After this discovery, iNO was applied to treat pulmonary hypertension and lung diseases ^{[54, 55]}. At present, iNO has become an important treatment for pulmonary hypertension, ARDS and hypoxic respiratory failure in children ^[56–58]. Unlike the above two treatment measures for ARDS, the treatment of ARDS patients with iNO has been controversial for a long time. In 2007, Adhikari et al. reported that iNO was associated with renal insufficiency ^[59], their study included ARDS trials only, revealed that iNO was associated with limited improvement in metabolism in patients with ARDS but may cause harm. In 2014 ^[60], Adhikari et al. got the similar conclusions: nitric oxide does not reduce mortality in adults or children with ARDS. Our NMA found that iNO does not improve the mortality and ventilator days of ARDS patients, which is consistent with the above studies. There are several possible reasons why iNO is not linked to improved mortality. On the one hand, the prolonged fixed-dosing scheme used in most trials may weaken the benefits over time because the sensitivity increases ^[38], inhibiting the benefits of oxygenation while continuing to expose patients to possible toxic effects, such as oxidative damage ^[61]. On the other hand, even in the most severe cases of hypoxemia, they may die from primary respiratory failure rather than multiple non-pulmonary organ failure, the small improvement in oxygenation from iNO may be overwhelmed by the harmful effects of mechanical ventilation strategies used in most trials that do not strictly limit tidal volume or airway pressure.

Strengths and limitations of the study

This NMA was the first study to directly compare three different treatments for the effectiveness and safety of ARDS patients. On the basis of many previous studies, we included new relevant studies and eliminated unqualified or low-quality studies, which will show clinicians and relevant people a new and more comprehensive evidence-based medical evidence for the treatment of ARDS.

Nevertheless, our research still has several limitations. First, the network meta-analysis relied on the assumption that population and intervention characteristics were substantially similar in the included studies. Therefore, the analysis of trials involving the use of different PaO2/FIO2 ratios (severity of ARDS) thresholds for patient recruitment was biased. For example, Herwig Gerlach only enrolled patients with severe ARDS. Second, the adverse effects of treatments were limited because of the nature of different interventions. We only assessed new infection, and there were differences in definition of infection in each trial. Third, though short-term mortality was only evaluated by our team, we believe this approach is theoretically sound, as the main rationale for most of the interventions studied is to reduce ventilator-induced lung damage and more immediate death. Future studies should include assessment of long-term mortality and functional outcomes. Fourth, our research involved a wide range of regions, such as the United States, Britain, France, China and so on, patients in different countries or of different ages do not have the same tolerance and sensitivity to drug therapy. For example, 50-year-old patients with ARDS can be more immune than 60-year-old patients, the efficacy of drug treatment of ARDS may also be different. Fifth, due to the broadness of our research, some studies that are not RCTs were included, and clinicians and investigators completing the outcome assessment were aware of the group allocation. These problems might cause selection and performance bias. Sixth, because some participants in the included trials had severe sepsis or septic shock with ARDS, the results of our analysis may have been partially influenced by the beneficial effects of corticosteroids on septic shock. Seventh, because of the complexity of the study and the nature of different treatments, we did not perform sub-group analysis for therapies, for example, the dose of drugs, the start time and duration of drug treatment. These problems may might cause some impact on our research. One study with individual patient data may be desirable to further separate the effectiveness of each intervention and explore outcomes in important patient subgroups.

Based on the findings of this NMA, the application of corticosteroids in patients with ARDS can improve short-term survival, increase ventilator-free days and reduce the incidence of infection. NMBAs may have the ability to reduce the mortality at 28 days, while, iNO might has no benefit on ARDS. We therefore recommend the use of corticosteroids or NMBAs in ARDS. However, there are issues that need to be addressed, such as beneficial effects on long-term survival outcomes, differences in effects between different causes of ARDS, or the type, amount and duration of corticosteroids or NMBAs used. These questions should be elucidated in future trials.

Ethics approval and consent to participate: Not applicable

Consent for publication: Not applicable

Availability of data and materials: Data and materials can be obtained from Raw Data.xlsx, for more information, please consult the corresponding authors.

Competing interest: We solemnly declare that there is no conflict of interest in our manuscripts and research results.

Funding: This research was supported by The Excellent Teaching Team of "Qinglan Project" in Jiangsu, Xuzhou National Clinical Key Specialty Cultivation Project (2018ZK004), Jiangsu Provincial Commission of Health and Family Planning (LGY2019085), The excellent young and middle-age talents project of the affiliated hospital of Xuzhou medical university (2019128009), National keypoint research and invention program (2020YFC151270).

Authors' contributions:

Composition and typesetting of this manuscript: Zhiyuan Xu, Haonan Liu and Shuaishuai Zhou

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Zhiyuan Xu, Haonan Liu, Ruiqi Zhang and professor Xianliang Yan.

Critical revision of the manuscript for important intellectual content: Shengli Li, Xiao Liu, Xianliang Yan

Statistical analysis: professor Shengli Li

Obtained funding: professor Xiao Liu and professor Xianliang Yan.

Administrative, technical, or material support: professor Xianliang Yan

Supervision: professor Xiao Liu and professor Xianliang Yan.

Acknowledgements: We thank professor Xianliang Yan for administrative, technical, or material support; we thank professor Shengli Li for statistical analysis.

Author details (optional): Professor Shengli Li: senior Statistician; doctor of medical statistics

E-mail: [email protected]

Professor Xiao Liu: Ph.D.; Doctor of Medicine (M.D.)

E-mail: [email protected]

*Professor Xianliang Yan: Ph.D.; Doctor of Medicine (M.D.)

E-mail: [email protected]

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No competing interests reported.

Comparative Outcomes of different interventions in ARDS: A systematic review and network meta-analysis

Status:

Version 1

Abstract

Figures

Introduction

Materials And Methods

Inclusion and Exclusion criteria

Data Collection and Outcomes

Risk of Bias Assessment and Quality Assessment

Statistical Analysis

Results

Characteristics and Risk of Bias of the Included Studies

28-day mortality

Ventilator-free days at 28 days

ICU mortality

In-hospital mortality

New infection events

Publication bias

Discussion

Strengths and limitations of the study

Conclusions

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1