Since the 1990s, the morbidity and mortality rate of acute respiratory distress syndrome (ARDS) has seen a significant decrease, but still hovers around 30% [1]. Currently, the incidence and treatment costs of ARDS remain high, and treatment of ARDS is mostly supportive, aiming to improve pulmonary gas exchange and prevent complications, such as preventing nosocomial infections.
In recent years, numerous studies have been devoted to new treatment strategies for ARDS. This article provides a review of new drugs or new uses of drugs in the treatment of ARDS in recent years.
Beta agonists: Some clinical trials have shown that beta agonists can improve the physiological effects of acute lung injury (ALI)/ARDS. for 7 days, and found that the albuterol-treated group showed a reduction in lung water exudation (9 ml/kg vs. 13 ml/kg) and airway plateau pressure (24 cmH2O vs. 30 cmH2O). The effect of inhaled salbutamol was not studied in this trial.
Matthay et al. in another clinical trial randomized 282 patients to the salbutamol inhalation group (5 mg) and the placebo group for 4 h per day for a total treatment period of 10 d. In this trial there was no difference in mean time to deconditioning or morbidity and mortality, and the salbutamol group showed an increased heart rate, but there was no difference in the incidence of arrhythmias in the two groups.
Surface-active substances: The role of endogenous surface-active substances is mainly to maintain the surface tension of the alveoli and to prevent atrophy. In addition, surface active substances promote mucus clearance, scavenge oxygen free radicals, and inhibit the production of inflammatory mediators.
Therapeutic rationale: There are multiple abnormalities of surface active substances in ARDS patients. Changes in many mediators such as oxygen free radicals, proteases, lipases, bioactive lipids, and serum proteins lead to alterations in the components and functions of surface active substances. In animal models of sepsis, alterations in surface active substances precede the onset of lung injury, suggesting that the onset of ARDS may be due to functional inactivation of alveolar surface active substances [7-9].
Alveolar atrophy plays an important role in the physiological changes of intrapulmonary shunts in ARDS, which also leads to an amplification of the degree of lung injury. in ARDS, abnormalities in the surface active substances make some alveolar units susceptible to atrophy, which allows a higher volume of inhaled tidal air to enter compliant normal lung regions, and if ventilator parameters are not adjusted accordingly, it is likely that overexpansion of uninjured lung regions occurs leading to secondary lung injury [10]. The lung in ARDS is referred to as the “baby lung” because only a portion of the lung units are involved in gas exchange. This part of the normal lung is often hyperventilated, which is the basis for the small tidal volume ventilation strategy. Alveolar instability can also lead to periodic alveolar atelectasis (the above mentioned lung units open and close with inhalation and exhalation), resulting in shear forces that lead to secondary lung injury.
Exogenous alveolar surface active substances could theoretically greatly improve these conditions, and therefore there are many studies with great interest in the use of alveolar surface active substances in ARDS.
Clinical application: The application of alveolar surface active protein C, synthetic alveolar surface active substances, and lyophilized powder of animal surface active substances are effective when applied in animal trials. However, when applied to ARDS clinical trials, the results showed poor results despite good compliance, and most of the trials were multicenter, double-blind and placebo-controlled, with evaluation metrics including ventilator duration and mortality.
A total of 448 patients with ARDS were enrolled in two multicenter, randomized, double-blind clinical trials, and patients were randomized to the standard treatment group and the standard treatment combined with alveolar surface active protein C treatment group. All patients were treated within 24 hours of onset, and up to four doses were administered intratracheally in the combination treatment group. The results showed that oxygen sum was significantly higher in the alveolar surfactant treatment group during the first 24 h of treatment (oxygen sum index was the test), but there were no differences between the two groups in terms of ventilator treatment days and mortality. Since the improvement in oxygenation was not sustained in the test group after treatment termination, this also suggests that longer alveolar surfactant treatment may be effective.
Subsequent Meta-analysis of 5 clinical studies showed that alveolar surface-active substances may be able to improve oxygenation in ARDS but not reduce mortality compared to controls, although not statistically significant.
In pediatric clinical trials, intratracheal administration of a specially formulated alveolar surface active substance (calfactant) was able to improve oxygenation more rapidly and also reduced mortality well (19% compared to 33% in the placebo group). clinical trials of calfactant in adults are ongoing [15-16].
These different results may be a response to different clinical effects brought about by different modes of administration, i.e., different mechanical ventilation strategies and different doses and components of surface active substances may lead to different efficacy. Meta-analyses have been performed here. One analysis showed that the effect of surfactants was independent of the presence of surfactant proteins [17-19], however, the Meta-analysis by Taut FJ et al. showed that surfactants combined with surfactant protein C (SP-C) improved oxygenation and reduced mortality in a subgroup analysis of severe ARDS due to pneumonia or inhalation [20].
Currently, there is no evidence that surface actives cannot be used in clinical trials. However, the data obtained so far suggest that more intensive clinical trials of surface active substance therapy should ideally be fully justified and authorized. In the future, clinical trials on surface-active substances should be adequately designed in terms of mode of administration as well as efficacy, and focus on efficacy on inflammation and fibrosis, which may lead to more desirable results [21].
Inhaled vasodilators: an important hallmark of ARDS is severe hypoxemia due to a dysregulated ventilation/blood flow ratio and intrapulmonary shunts. Inhaled vasodilators, especially nitric oxide (NO) and prostacyclin, can selectively dilate the vasculature in the well ventilated portion of the body, thereby increasing the ventilation/flow ratio, improving oxygenation and lowering pulmonary arterial pressure. Because these vasodilators act locally and have a short half-life, they have few systemic effects and do not cause hypotension.
NO: It is well established that NO inhalation can have a good effect on the treatment of ALI/ARDS.
Clinical outcomes: Inhaled NO can benefit patients with ARDS, but there is little evidence of improvement in important indicators such as mortality. The results of two large Meta-analyses (each with more than 1200 patients enrolled) showed that inhaled NO treatment slowly and temporarily improved oxygenation without reducing mortality and ventilator days compared with placebo or conventional treatment [25-30].
Inhaled NO therapy does not improve oxygenation in all ARDS patients. the results of a retrospective study by Manktelow C et al. showed that patients with septic shock ARDS responded worse to inhaled NO therapy than patients with non-septic or non-shock septic ARDS (33% vs. 64%). the results of another study by Puybasset L et al. showed that patients with pulmonary vascular resistance or a good response to PEEP responded well to inhaled NO.
Inhaled dose: Inhaled NO should be controlled within 1.25-40 ppm and can be applied continuously for several days or even weeks; interruption of treatment may result in decreased oxygenation or pulmonary hypertension. However, there is also evidence from Gerlach H et al. that continuous inhaled NO treatment may be photosensitizing and that the effect of continuous inhaled higher doses of NO does not improve.
Potential efficacy: NO inhalation therapy has a number of effects unrelated to correction of the ventilation/blood flow ratio, which include anti-inflammatory properties, anti-platelet aggregation, and reduced vascular permeability effects.
Potential toxicity: NO inhalation therapy has many potentially harmful properties. Inhaled NO may produce toxic free radicals, but it is unclear which of these toxic free radicals is more harmful than inhaled high concentrations of oxygen; inhaled higher concentrations of NO may produce methemoglobin and NO2, and therefore frequent monitoring of both is required [40]; inhaled NO may cause renal dysfunction; inhaled NO can cause immunosuppression, which may theoretically lead to increased nosocomial infections increase; inhalation of NO may lead to DNA strand breaks and base replacement, which can lead to genetic mutations.
Prostacyclin (PGI2): Inhaled PGI2 has similar physiological effects to NO and does not require complex equipment. As shown in the figure below, many studies have suggested that inhaled PGI2 may increase oxygenation and and lower pulmonary arterial pressure. However, the duration of this effect is short, and it is unclear how clinically significant these effects actually are. Similarly, inhaled PGI2 does not reduce mortality [42-43].
In conclusion, inhaled vasodilators do not reduce mortality in ARDS. Due to the lack of sufficient evidence for their effectiveness, inhaled vasodilators are not a routine treatment for ARDS, but they can be used in refractory cases and in hypoxemia that is difficult to correct by conventional methods. This may be a direction of future research that can demonstrate the effectiveness of inhaled vasodilators [44].
Anti-inflammatory therapy: respiratory failure itself is not the main cause of death in ARDS [45-46], however, respiratory failure prolongs the patient’s stay in the ICU, which leads to complications such as nosocomial infection and multiple organ dysfunction syndrome (MODS), which ultimately lead to These complications eventually lead to the death of the patient.
In ARDS, it is important to control the inflammatory response, otherwise complications such as sepsis or MODS may occur. The persistence of inflammatory response and fibrosis is closely related to the patient’s prognosis. Patients who die of ARDS have higher concentrations of neutrophils and inflammatory factors in the alveolar lavage fluid compared to those who survive. Similarly, low concentrations of anti-inflammatory cytokines such as interleukin-10 and interleukin-1 receptor antagonist (IL-1ra) also predicted a very poor prognosis in ARDS patients [47-50].
Based on the above observations, the application of inflammatory inhibitors in ARDS may promote lung repair and ultimately affect its prognosis. For this reason, corticosteroids, prostaglandin E1 and arachidonic acid metabolite inhibitors have all been used in the treatment of ARDS.
Corticosteroids: The systemic application of corticosteroids in ARDS has been extensively studied and used. However, it is now very clear that corticosteroids work well only in those patients with ARDS who have a good hormonal response (e.g., acute eosinophilic pneumonia), and their application in most ARDS is not certain [51].
Throughout the 1970s and early 1980s, empirical hormone therapy was very common in the treatment of ARDS. However, subsequent studies have found that hormone therapy in ARDS may not be effective or may even have adverse consequences for patients [52].
Since then, most studies have focused on the fibroproliferative phase of ARDS, with occasional studies looking at refractory ARDS and advanced ARDS. the fibroproliferative phase of ARDS is characterized by fever, purulent secretions, and pulmonary exudate without inflammatory manifestations. The ability of corticosteroids to reduce the inflammatory response in the lungs has also allowed for continued research on the therapeutic use of hormones in ARDS [53-54].
In a randomized, double-blind clinical trial organized by the ARDS Network, 180 patients with refractory ARDS (disease duration 7-28 days) were randomized to receive methylprednisolone or placebo for 21 days [55]. The results showed no difference in 60-day and 180-day mortality rates (29.2% versus 28.6% and 31.5% versus 31.9%, respectively); further counting patients with a disease duration of 7-13 days after the onset of ARDS, the methylprednisolone-treated group showed a decrease in 60-day and 180-day mortality rates (27% versus 36% and 27% versus 39%, respectively), but it was not statistically significant; in In patients who had been ill for more than 14 days after the onset of ARDS, the 60- and 180-day mortality rates were significantly higher in the methylprednisolone group (35% versus 8% and 44% versus 12%, respectively).
Methylprednisolone may increase oxygenation and improve pulmonary compliance, reduce ventilator use and days in shock, and raise blood pressure, but it also promotes the development of neuromuscular weakness in patients.
In another double-blind clinical trial, patients with early ARDS (72 h duration) were randomized in a 2:1 ratio to receive corticosteroids (63 patients) and placebo (28 patients). The corticosteroid treatment group was given methylprednisolone treatment 1 mg/kg for up to 28 days. Inflammation and neuromuscular weakness were the key monitoring indicators in this trial. The results showed that corticosteroid treatment reduced the duration of mechanical ventilation, the duration of ICU stay and the mortality rate in the ICU (21% vs. 42%). The results of this trial are encouraging but less convincing due to the small sample [56].
Several Meta-analyses and retrospective studies have contradicted each other regarding the outlook of corticosteroid hormone therapy for ARDS [57-58]. The debate has focused on the timing of hormone therapy, the duration of treatment, whether a gradual taper is required, and how to interpret the results of some small samples of trials. Although many studies suggest that early administration of hormone therapy in ARDS especially before 2 weeks may improve survival, more conflicting findings suggest that more clinical trials should be conducted to determine the effectiveness of corticosteroids in treating ARDS.
Statins: In an animal model of acute lung injury, statins, hydroxymethyl coenzyme à (HMG-CoA) reductase inhibitors, were shown to attenuate serum inflammatory cytokines TNF-α and IL-1β, thereby reducing inflammatory exudation in the interstitial lung and improving survival. treatment groups, applied until cessation of ventilator therapy or 14 days. The simvastatin-treated group showed significant but not statistically significant improvements in oxygenation (PaO2/FiO2 increased to 48 mmHg versus 25 mmHg) and mean airway pressure (Pplat decreased to 9.5 cmH2O/kPa versus 1.5 cm H2O/kPa), and there was no difference in mortality between the two groups. A large number of clinical trials are still needed to determine the role of statins in the treatment of ARDS [59].
Prostaglandin E1 (PGE1): PGE1 is an endogenous and potent anti-inflammatory mediator and vasodilator that, under certain conditions, inhibits neutrophil actions such as peroxidation, phagocytosis and chemotaxis. Some test results suggest that PGE1 (e.g., prostilbestrol, epoprostenol, etc.) can increase oxygen supply by increasing cardiac output [60].
PGE1 also has some side effects, including hypotension, fever, thrombocytopenia, diarrhea, arrhythmias, and may also worsen oxygenation and, presumably, due to a dysregulated V/Q ratio.Patients with ARDS tend to be hemodynamically unstable, which limits the use of PGE1 [61].
Holcroft JW et al. conducted a randomized, double-blind, placebo-controlled clinical trial with 41 patients with ARDS and showed that 7 days of continuous PGE1 injections significantly improved patient survival at 30 days (71% versus 35%) [62]. Unfortunately, however, a subsequent clinical trial with a 100-case sample failed to replicate these results.
A new dosage form packages PGE1 in a double layer of liposomes that can be applied directly into the alveoli, thus avoiding the side effects of systemic application. In a phase 2 clinical trial with 25 patients, there was a substantial increase in the 8-day extubation rate in patients who applied PGE1 liposomes [63]. at the time of the phase 3 clinical trial, the improvement in oxygenation was significant in patients who applied PGE1 liposomes, but there was no reduction in the duration of ventilator application and no increase in survival. There was no systemic application of PGE1 in the above-mentioned trials [64].
PGE1 nebulizer therapy has similar effects to inhaled NO or prostacyclin, but experience with its application is scarce. All of these drugs lack conclusive evidence of prognostic impact in ARDS [65].
Neutrophil elastase inhibitors: neutrophil elastase inhibits the action of α1 antitrypsin, and its excessive release during the inflammatory response can lead to tissue damage. Neutrophil elastase is thought to play an important role in facilitating endothelial damage and increased vascular permeability during acute lung injury [66].
Cevilostat is a competitive inhibitor of neutrophil elastase. It was shown to improve the prognosis of acute lung injury in both early animal and human trials. However, in a multicenter, randomized, controlled trial with 492 mechanically ventilated ARDS patients, there were no differences in 28-day mortality, duration of mechanical ventilation, or respiratory mechanics between the sevelamerestat-treated and placebo groups [67-68].
Arachidonic acid inhibitors: several lipid mediators, such as thromboxanes, leukotrienes, platelet-activating factors, and multiple prostaglandins have been implicated in the pathogenic mechanisms of ARDS. Inhibition of these mediators themselves, inhibition of metabolism or activation of their components could theoretically be more effective, but the lack of theoretical research on biochemical metabolic disorders in ARDS has hindered clinical screening of these drugs.
Ketoconazole: Ketoconazole is an antifungal agent and thromboxane A2 inhibitor. It inhibits the expression of several of these mediators including thromboxane B2 and leukotriene B4. Several studies suggest that prophylactic application of ketoconazole can reduce the incidence of ARDS. A randomized, double-blind, placebo-controlled clinical trial of 71 critically ill surgical patients found that prophylactic ketoconazole reduced the incidence of ARDS from 31% to 6%. In another similar trial with 54 patients with sepsis, prophylactic ketoconazole reduced the incidence of ARDS from 64% to 15% and mortality from 39% to 15%. All of this evidence strengthens confidence in the use of ketoconazole as a guideline medication to prevent the development of ARDS in multiple studies [69-71].
In contrast, a subsequent multicenter study randomizing 234 patients who recognized the possibility of acute lung injury within 36 hours to ketoconazole treatment and placebo treatment groups did not find differences in mortality, duration of ventilator use, or duration of illness between the two groups and therefore did not support ketoconazole as a therapeutic agent for early ARDS [72].
Ibuprofen: In a swine model of sepsis, application of ibuprofen was able to reduce the formation of pulmonary edema and improve hemodynamic parameters and oxygenation [73]. However, in a randomized, double-blind, placebo-controlled clinical trial of 455 patients with sepsis, Bernard GR et al. applied ibuprofen did not reduce the incidence and duration of ARDS, and 30-day survival did not differ between the two groups. For these reasons, there are few studies interested in the use of ibuprofen or similar drugs in ARDS [74].
Antioxidants: superoxide, hydroxyl radicals, hydrogen peroxide, hypochlorous acid, and other products of these oxygen metabolites play a large role in the development and progression of ARDS. These toxic oxidants, produced by neutrophils, macrophages, and endothelial cells of the lung, may have an adverse effect on oxygen supply. Toxicity to cells includes DNA strand breaks, lipid peroxidation reactions, protein denaturation, and can also promote neutrophil activation.
Glutathione: This antioxidant appears to decrease in ARDS, with a rapid decrease in intracellular glutathione. The depletion of antioxidants increases the susceptibility of the lung to oxidative damage, so restoring antioxidant concentrations in the body becomes an eye-catching strategy when treating ARDS. Two drugs are currently useful in restoring glutathione, N-acetylcysteine (NAC) and procysteine, which have also been extensively studied [75].
The results of human trials of glutathione supplementation are complex compared to the encouraging results of animal trials.The results of a randomized, double-blind, placebo-controlled trial of 66 patients with ARDS by Jepsen S et al. showed that NAC treatment did not improve oxygenation and reduce mortality. Subsequent studies showed that NAC repaired glutathione levels in neutrophils but did not prevent peroxide production. Finally, Laurent T et al. compared the effects of NAC, procysteine, and placebo in a prospective, randomized, double-blind, placebo-controlled clinical trial in 46 patients with ARDS. The results showed that both NAC and procysteine were effective in restoring glutathione levels and reducing the duration of lung injury, but there was no difference in survival, a result that is now one of the incentives to continue research on this class of drugs. Of course, due to the small sample of this trial, the conclusions drawn are for reference only [76-77].
Lisophylline (Lisophylline): levels of circulating free fatty acids (FFAs) are increased exponentially in ARDS patients. Some FFAs, especially linoleic acid, may be oxidized and become inflammatory mediators during the inflammatory response. Lysostaphine (1-[5R-hydroxyhexyl]-3,7-dimethylxanthine) reduces FFAs levels both in animal models of ARDS or sepsis and in healthy volunteers. In addition, lisocyanine reduced the release of pro-inflammatory mediators such as TNFα, IL-1β, and IL-6 from monocytes.
Although the safety and efficacy of lisotretinoin were assured in animal trials, a randomized, controlled trial in 235 patients with ALI or ARDS was discontinued midway through because the outcome analysis showed no difference between the two groups in terms of survival or other clinical endpoints. Interestingly, there was also no difference in the levels of FFAs between these two groups [78].
Edible oil supplementation: there is evidence that ARDS patients can benefit from edible oil supplementation, perhaps due to the ability of anti-inflammatory substances to benefit from arachidonic acid metabolism.
Gadek JE et al. In a clinical trial of 98 patients with ARDS, patients were randomized to receive standard intranasal or combined eicosapentaenoic acid (EPA) and gamma-linolenic acid (GLA) therapy. The results showed better oxygenation, lower levels of leukocytes in continuous alveolar lavage fluid, and shorter length of stay in the ICU and ventilator treatment in the combination treatment group [79].
In another trial of the same 100 patients, the combination therapy group was also found to have significant improvements in static lung compliance and ventilator duration [80].
Unfortunately, however, recent studies have shown little improvement in ARDS patients with edible oil supplementation [81]. Further trials are needed in the future to investigate whether these conflicting results are due to differences in trial design, treatment combinations, or supplementation doses.
Summary.
Approaches to the control of ARDS are supportive and aim to ensure oxygenation and and prevent complications. Some specific approaches with potential for ARDS treatment have also been studied a lot, however, there is not sufficient evidence for their clinical effectiveness and, therefore, they are not recommended for routine treatment.
Intravenous salbutamol reduces pulmonary water and airway pressure. However, before beta agonists are formally recommended for the treatment of ARDS, many important clinical indicators such as mortality, duration of mechanical ventilation, and ICU length of stay require additional clinical trials to confirm their effectiveness.
Exogenous alveolar surface-active substances, inhaled NO or prostacyclin, can improve physiological parameters (e.g. oxygenation and), however they again do not have sufficient evidence for their clinical efficacy (e.g. reduction of mortality, etc.).
Current studies do not yet prove that the application of corticosteroids increases survival in patients with ARDS. However, the role of glucocorticoids in ARDS may be related to the duration of therapy, dose, and timing of application. Further studies are necessary to determine the role of glucocorticoids in the treatment of ARDS.
Subsequent trials have failed to replicate earlier studies to confirm that application of prostaglandin E1, neutrophil elastase inhibitors, supplemental glutathione drugs, or arachidonic acid inhibitors improve survival, among other clinically important outcomes in ARDS.
Numerous studies have suggested that supplementation with edible oils may play a role in anti-inflammation, improving oxygenation, respiratory mechanics, and reducing the duration of mechanical ventilation in ARDS patients, but further studies are needed to confirm these findings and to determine what role they may play.
It is important to note that none of the treatments for ARDS reviewed in this article currently have a lasting and definitive effect. Studies of treatments for ARDS are subject to uncertainty due to many factors, such as differences in disease severity, patient heritability, and ARDS pretreatment, all of which seriously confound the reliability of clinical trials, even when they are completely randomized.