Pharmacological agents for adults with acute respiratory distress syndrome

Abstract

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. To evaluate the effectiveness of pharmacological agents in adults with ARDS on mortality, mechanical ventilation, and fitness to return to work at 12 months. 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. 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. Two review authors independently assessed studies for inclusion, extracted data, and assessed risks of bias. We assessed the certainty of evidence with GRADE. 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 therapy Corticosteroids 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 therapy We 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 placebo We 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 placebo Statins 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 control Beta‐agonists 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. 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. Drugs to treat acute respiratory distress syndrome in adults We set out to determine, from randomized controlled trials, which drugs improve health outcomes in adults with acute respiratory distress syndrome (ARDS). Background ARDS is a life‐threatening condition caused by injury to the lungs, for example from infections such as pneumonia or sepsis, or from trauma. People with ARDS are cared for in an intensive care unit, and need support with breathing from mechanical ventilation. Many people who survive ARDS suffer from muscle weakness, fatigue, reduced quality of life after hospital discharge, and may not be fit for work 12 months later. Despite improvements in techniques to manage ARDS, death rates are still very high. Drugs may help to repair damage to the lung injury, or limit the body's response to the injury (for example, by reducing any excess fluid that may collect around the injured lungs). Study characteristics The evidence is current to 10 December 2018. We included 48 studies, of 20 different drug types, involving 6299 people who had ARDS. Three studies are awaiting classification (because we did not have enough details to assess them), and 18 studies are still ongoing. We found differences between included studies, such as the severity of ARDS, or potential differences in clinical management and doses. We excluded studies published before 2000, in order to only include up‐to‐date clinical management of people with ARDS (for example, in the pressure applied during mechanical ventilation). However, we found that many studies did not report these management strategies. For the main comparisons in this review, we included five types of drugs: corticosteroids, surfactants, N‐acetylcysteine, statins, and beta‐agonists. These were compared to placebo or to standard care. Key results Although corticosteroids may reduce the number of people who die within the first three months, and beta‐agonists probably slightly increase these early deaths, we found both an increase and a reduction in deaths in our analyses for these drugs. We found no evidence that surfactants, N‐acetylcysteine, or statins made a difference to the number of people who died within three months. Only two studies (one that assessed steroids, and one surfactants) reported deaths later than three months, but evidence for this was uncertain. We found that statins or steroids may make little or no difference to the duration of mechanical ventilation, but we were uncertain about the evidence for steroids. Similarly, we were uncertain whether surfactants reduced the use of mechanical ventilation. We found that steroids may improve the number of days that people do not need mechanical ventilation (ventilator‐free days up to day 28), but that beta‐agonists may not improve ventilator‐free days (although we were uncertain about the evidence for beta‐agonists). We found that statins probably make little or no difference to the number of ventilator‐free days; this was also the case for surfactants (although, again, we were uncertain about the evidence for surfactants). Few studies (and only for surfactants and beta‐agonists) reported whether the study drug was stopped because of serious side effects, and we were uncertain whether either of these drugs led to such serious side effects. No studies reported whether people were fit to return to work 12 months after their illness. Certainty of the evidence Most of the findings were supported by low‐ or very low‐certainty evidence, although we were moderately confident in the evidence for some outcomes when statins and beta‐agonists were used. For some outcomes we found too few studies with few participants, and sometimes there were unexplained differences between the studies in their findings. These factors reduced our certainty (or confidence) in our findings. Also, it was not possible to mask some researchers because the study drug was compared to standard therapy (no drug), which may have biased our findings. Conclusion We found insufficient evidence to determine confidently whether any type of drug was effective at reducing deaths in people with ARDS, or reducing the length of time that they needed mechanical ventilation. No studies reported fitness to return to work at 12 months. We assessed most outcomes to be low or very low certainty, which reduces our confidence in the findings of the review.