Version May 2024
INTRODUCTION — Therapy for patients with acute respiratory distress syndrome (ARDS) is supportive, aimed at improving gas exchange and preventing complications while the underlying condition that precipitated ARDS is addressed. Several potential ARDS-specific pharmacotherapies are being evaluated, although none are recommended as routine therapy because patient-important effects are uncertain [1].
Investigational and ineffective medical therapies for ARDS are reviewed here. The pathogenesis of ARDS as well as mechanical ventilation strategies and supportive care for ARDS are discussed in separate topics. (See "Acute respiratory distress syndrome: Epidemiology, pathophysiology, pathology, and etiology in adults" and "Acute respiratory distress syndrome: Fluid management, pharmacotherapy, and supportive care in adults" and "Acute respiratory distress syndrome: Ventilator management strategies for adults".)
CLINICAL TRIALS LINK — Numerous trials investigate novel medical therapies and ventilatory interventions for patients with ARDS. These trials have frequent status updates and can be readily accessed at the US National Institute of Health.
THERAPIES FOR PREVENTION — Few trials have rigorously examined strategies to prevent ARDS. Aspirin has no proven benefit, and trials of inhaled glucocorticoids and beta-2 agonist combinations are awaited.
Aspirin — Preclinical and clinical observational studies of aspirin, as an antiplatelet and anti-inflammatory agent, have suggested a potential role for it in the prevention and treatment of ARDS [2-7]. However, in a randomized trial (LIPS-A) of 390 patients at risk of developing ARDS, aspirin was reported to be of no benefit in preventing ARDS [8]. Aspirin was administered at 325 mg followed by 81 mg daily for seven days following presentation to the emergency department and compared with placebo and had no effect on the incidence of ARDS at one week (approximately 10 percent in each group). However, the lower-than-expected rate of ARDS in this study suggested a more modest severity of illness than anticipated, which may have limited the ability to detect a study drug effect.
Further trials are required before we can consider aspirin as a preventive therapy for those at risk for developing ARDS.
The role of aspirin in patients with COVID-19-related ARDS is discussed separately. (See "COVID-19: Management in hospitalized adults", section on 'Statins and aspirin'.)
Combined inhaled glucocorticoids and beta agonists — While human studies of short-acting inhaled and systemic beta-2 agonists have shown no efficacy for the treatment of ARDS, a phase IIa trial of a long-acting inhaled beta-2 agonist (formoterol) combined with an inhaled steroid (budesonide) improved oxygenation compared with placebo [9]. Further trials are needed.
THERAPIES FOR TREATMENT — Despite preclinical studies that are encouraging, agents that enhance lung repair (eg, granulocyte macrophage colony-stimulating factor, stem cell therapy) and agents that reduce inflammation (eg, systemic glucocorticoids, macrolide antibiotics, aspirin) have no proven benefit and are not routinely administered in patients with ARDS [1].
Antioxidant supplementation of enteral feeds has proven not beneficial. Most clinicians do not use dietary oil supplementation that contain antioxidants such as omega-3 fatty acids due to a lack of proven benefit and potential harm. This is discussed separately. (See 'Ineffective or harmful therapies' below and "Nutrition support in intubated critically ill adult patients: Enteral nutrition".)
A trial of vitamin D used to treat critically ill patients who were vitamin D-deficient showed no impact on 90-day mortality, post-randomization incidence of ARDS, or other non-fatal outcomes [10].
Enhancing lung repair
Granulocyte macrophage colony-stimulating factor — Granulocyte macrophage colony-stimulating factor (GM-CSF) has not become a routine therapy for adults with ARDS, because the evidence is still inconclusive.
GM-CSF plays an important role in repairing injured lung and enhancing alveolar macrophage function [11,12]. Preclinical studies suggest that GM-CSF in the bronchoalveolar lavage fluid of humans with ARDS is associated with better survival [13]. However, human therapeutic trials have shown mixed results:
●In one randomized trial of 131 patients with ARDS, compared with placebo, intravenous GM-CSF for 14 days was associated with a nonsignificant reduction in mortality (17 versus 23 percent) and increase in organ failure-free days (15.7 versus 12.8 days) [14]. However, a meta-analysis of pharmacotherapies for patients with ARDS reported no effect of GM-CSF on mortality [1], and another single center randomized trial also showed no difference in mortality, organ failure-, or ventilator-free days [14].
●The use of inhaled GM-CSF in a small group of patients with pneumonia-associated ARDS demonstrated improvement in oxygenation, lung compliance, and severity of illness scores compared with untreated patients [15]. Further study of inhaled GM-CSF is underway NCT02595060.
Stem cells — Preclinical studies suggest that treatment with exogenously administered mesenchymal stem cells (MSCs) may help to attenuate lung injury and promote repair [16-18]. In animal models, MSCs appear to secrete growth factors and cytokines capable of modulating local inflammation and promoting tissue repair, improve bacterial clearance, and potentially differentiate into mature cells to replace those that have been injured.
A phase I randomized trial enrolled 12 patients with ARDS to evaluate the safety and feasibility of using systemically administered allogeneic adipose-derived MSCs [19]. Infusion of MSCs was well tolerated. Compared with placebo, patients treated with MSCs had lower levels of surfactant protein-D on day 5, suggesting amelioration of epithelial cell injury. No significant differences were demonstrated in levels of inflammatory cytokines. The study was not sufficiently powered to assess the impact of treatment on clinically important outcomes, such as survival or duration of mechanical ventilation. A second phase I trial reported similar results [20].
Several trials are studying the role of mesenchymal or bone marrow-derived human stem cells (NCT01775774; NCT02804945) as a treatment for ARDS.
Anti-inflammatory therapies — Mortality is higher among patients with ARDS who have large quantities of neutrophils and proinflammatory cytokines [21,22] and/or low levels of anti-inflammatory cytokines [23]. Based upon these observations, it has been hypothesized that anti-inflammatory medications might improve the outcome of ARDS. However, data have not shown convincing benefit from anti-inflammatory agents including macrolide antibiotics or aspirin. Data favor the administration of glucocorticoids. This is discussed separately. (See "Acute respiratory distress syndrome: Fluid management, pharmacotherapy, and supportive care in adults", section on 'Glucocorticoids'.)
Macrolide antibiotics — Macrolide antibiotics have both antimicrobial and anti-inflammatory effects. Animal models suggest that these agents may have a beneficial effect in ARDS [24,25].
To evaluate the effects of macrolide antibiotics in humans with ARDS, an observational study was conducted using data from the Lisofylline and Respiratory Management of Acute Lung Injury (LARMA) trial [26]. Patients with ARDS who received a macrolide antibiotic within the initial 24 hours (n = 47) were compared with patients who did not receive a macrolide antibiotic (n = 188) [27]. There was a trend toward lower 180-day mortality among patients who received a macrolide antibiotic (23 versus 36 percent); after adjusting for potential confounders (eg, patients who received a macrolide antibiotic were less likely to have received low tidal volume ventilation), the lower 180-day mortality became statistically significant (hazard ratio [HR] 0.46, 95% CI 0.23-0.92). Follow-up studies investigating the role of macrolides to treat ARDS have not been performed.
Aspirin — Aspirin is a powerful antiplatelet and anti-inflammatory agent that has been studied as a preventative agent in patients with ARDS. However, no trial has been published demonstrating a role for it in the treatment of ARDS, although one trial registered at the was terminated because of slow recruitment (NCT02326350). (See 'Aspirin' above.)
Other anti-inflammatory agents — Carbon monoxide (CO) is thought to have anti-inflammatory or antioxidant properties in low doses. Two studies investigating CO are underway, which will examine the role of CO in treating patients with ARDS. One of which is actively recruiting patients (NCT03799874), and one is scheduled to begin enrollment in 2022 (NCT04870125).
Lung transplantation — One retrospective series described outcomes in 14 Korean patients with severe ARDS (partial arterial pressure of oxygen:fraction of inspired oxygen ratio <100 mmHg) who were listed for lung transplantation (LTPL) [28]. Most of the patients had inhalation injury from disinfectant and were without end-stage lung disease. Among the 14 listed, nine underwent LTPL as a salvage therapy for ARDS. The number of patients who survived was greater in those who received LTPL compared with those who did not undergo LTPL (89 versus 20 percent); similarly, the median survival was higher in those who underwent LTPL (1996 versus 49 days). A retrospective study evaluating 39 ARDS patients who underwent LTPL showed 87.2 percent 90-day survival, 82.1 percent one-year survival, and 69.2 percent three-year survival, which was similar to results seen in a propensity-matched control group of patients with restrictive lung disease [29]. Further studies are required to examine the effects of LTPL on outcomes and to delineate suitable criteria for LTPL before it can be accepted as an option in patients with severe ARDS.
INEFFECTIVE OR HARMFUL THERAPIES — A number of potential therapies for ARDS were once regarded as promising but have since proven to be either ineffective or harmful. They include the following:
●Antioxidant preparations (N-acetylcysteine, procysteine [L-2-oxothiazolidine-4-carboxylate], glutamine, omega-3 fatty acids, selenium, beta carotene, zinc, vitamin E and C, lisofylline) [26,30-34]
●Intravenous prostaglandin E1 [35,36]
●Neutrophil elastase inhibitors [37]
●Activated protein C [39]
●Statins [45-48]
●Surfactant [49-57]
●Short-acting beta-2 agonists (inhaled and systemic) [58-60]
●Keratinocyte growth factor [61]
●Interferon-beta-1a [62]
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Acute respiratory distress syndrome (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Therapy for patients with acute respiratory distress syndrome (ARDS) is supportive, aimed at improving gas exchange and preventing complications while the underlying condition that precipitated ARDS is addressed. Potential ARDS-specific pharmacotherapies are being evaluated, although none are recommended as routine therapy, because patient-important effects are uncertain. (See 'Introduction' above.)
●Few trials have rigorously examined strategies to prevent ARDS; thus far, no treatment studied has been shown to be effective. (See 'Therapies for prevention' above.)
●Despite preclinical studies that are encouraging, the benefits of agents that enhance lung repair (eg, granulocyte macrophage colony-stimulating factor, stem cell therapy) and agents that reduce inflammation (eg, macrolide antibiotics, aspirin) remain uncertain and require further study before they can be recommended for routine administration in patients with ARDS. (See 'Therapies for treatment' above and "Acute respiratory distress syndrome: Fluid management, pharmacotherapy, and supportive care in adults", section on 'Glucocorticoids'.)
●A number of potential therapies were once regarded as promising in patients with ARDS but have since proven to be either ineffective or harmful. These include various antioxidant preparations (N-acetylcysteine, procysteine, glutamine, omega-3 fatty acids, selenium, beta carotene, zinc, vitamin E and C, lisofylline), intravenous prostaglandin E1, neutrophil elastase inhibitors, ibuprofen, activated protein C, ketoconazole, statins, surfactant, short-acting beta-2 agonists, keratinocyte growth factor, and interferon-beta-1a. (See 'Ineffective or harmful therapies' above.)
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