◆ Acute respiratory distress syndrome (ARDS) is not a single condition, hence a variety of supportive and therapeutic approaches may be required for optimal management.
◆ The mainstay of ARDS management is the identification and treatment of the pre-disposing condition, together with supportive care, which includes lung-protective ventilation, and even prone ventilation in more severe cases.
◆ Fluid restriction, after patients are appropriately resuscitated, is probably of benefit.
◆ The early, and short-term, use of cisatracurium in more severe ARDS cases may improve outcome over and above lung-protective ventilation.
◆ There are currently no licensed pharmacological therapies for ARDS, although there are a number of novel agents under development.
Acute respiratory distress syndrome (ARDS) is a pathological syndrome characterized by arterial hypoxaemia and bilateral pulmonary infiltrates, in the absence of evidence of left atrial hypertension (see Fig. 109.1a). Histologically, the syndrome features epithelial and endothelial injury, with diffuse alveolar damage, hyaline membrane formation, and infiltration of neutrophils and macrophages into the pulmonary interstitium observed (see Fig. 109.1b), and fibrosis can be prominent. Until recently, the diagnosis of ARDS was made in accordance with the America-European Consensus Conference (AECC) criteria established in 1994, however, an updated ‘Berlin’ definition was produced in 2012 . It is important to remember that almost all clinical studies to date have utilized the AECC criteria, and also that ARDS is not a single disease, but rather a constellation of conditions with similar pathophysiology, and thus there may not be one unifying clinical treatment.
Treatment of predisposing factor and intercurrent infection
The development of ARDS is associated with several risk factors including pneumonia, non-pulmonary sepsis (e.g. peritonitis), aspiration of gastric contents, major trauma, transfusion, and acute pancreatitis. Diagnosis and appropriate treatment of predisposing factors is key to clinical management. It may be necessary, particularly in the immune-compromised host, to undertake invasive diagnostic procedures, such as bronchoscopy, to establish a diagnosis. Furthermore, it has been shown that intercurrent pulmonary infection occurs in 34–70% of patients with ARDS , necessitating vigilance for the subsequent development of infection in ARDS patients.
Lung protective mechanical ventilation
It is well established that mechanical ventilation using tidal volumes of 6 mL/kg predicted body weight (PBW), and a plateau pressure less than 30 cmH2O, confers a mortality benefit, and should be undertaken whenever possible . A trial of high versus low positive end expiratory pressure (PEEP) in patients receiving 6 mL/kg PBW ventilation, with a plateau pressure below 30 cmH2O, did not find any significant difference between groups, suggesting that the level of PEEP may not be as critical as the need for low tidal volume ventilation in all patients with ARDS . However, retrospective subgroup analysis has suggested that higher PEEP levels may be of benefit in severe ARDS.
Non-conventional gas exchange technologies
There has been significant interest in the use of non-conventional gas exchange technologies, including extracorporeal membrane oxygenation (ECMO), extracorporeal carbon dioxide removal (ECCO2R) and oscillatory devices. To date, none of these devices have been proved to be of universal benefit in ARDS, although it is possible that there may be sub-populations of ARDS patients (e.g. H1N1 influenza patients and ECMO ) that derive benefit from these interventions.
Close attention to fluid balance has long been thought to be important in the management of ARDS, and a theoretical case can be made for minimizing the use of fluid therapy, once the patient is adequately resuscitated, to reduce the formation of pulmonary oedema, but the evidence to support this strategy is not conclusive. In 2006, the FACCT study  found that a conservative fluid management strategy (in those patients who had been fully resuscitated) was not associated with decreased 60-day mortality when compared with a more liberal regimen. However, improvements in pulmonary physiological values, and a reduction in the duration of mechanical ventilation and intensive care stay were observed in the conservative fluid group, with no associated increase in renal failure, need for renal replacement therapy, or non-pulmonary organ failures. Subsequently, a retrospective study examined data from patients enrolled in the lung-protective ventilation ARDSnet clinical trial, finding that a cumulative negative fluid balance on day 4 after the diagnosis of ARDS was independently associated with lower hospital mortality, and increased ventilator- and ICU-free days.
Transfusion-related ARDS, or transfusion-related acute lung injury (TRALI), is defined as the development of ARDS during or within 6 hours following transfusion of one or more units of blood or blood components. A recent study identified both recipient (shock, chronic alcohol abuse, liver surgery, current smoking, positive fluid balance before transfusion, and peak airway pressure >30 cmH2O if mechanically ventilated) and transfusion (plasma or whole blood from female donor, volume of HLA class II antibody, and volume of antihuman neutrophil antigen positivity) related risk factors for TRALI. Interestingly, in contrast to previous studies, an increase in the incidence of TRALI associated with older red blood cell units was not observed .
The provision of supportive care involves the administration of nutrition to the ARDS patient. A multicentre study examining the role of trophic (25% of caloric requirement) feeding found no benefit over full standard feeding in terms of ventilator-free days, organ-failure free days, ICU-free days, or incidence of infection . The benefit of dietary supplementation with n-3 fatty acids, gamma-linoleic acid (GLA), and antioxidants on both clinical and physiological outcomes in ARDS has been proposed by several small randomized studies, although a large multicentre double-blinded, placebo-controlled randomized trial to examine the effects of dietary supplementation on ventilator-free days was stopped early on futility grounds, and the intervention group had significantly more reported side effects attributed to the therapy . Currently, there is no evidence to support a specific feeding regimen in ARDS patients, over and above the evidence to suggest that adding parenteral nutrition to enteral nutrition, to facilitate the early meeting of caloric goals, may be detrimental in critically-ill patients.
Neuromuscular blockade is often used in ARDS to permit lung-protective ventilation, although concerns have been raised about the potential of these agents to induce ICU-acquired weakness. A multicentre double-blinded placebo-controlled randomized trial of short-term cisatracurium therapy showed a decrease in the adjusted 90-day mortality of more severe ARDS patients, i.e. those with a PaO2/FiO2 ratio below 150 mmHg, who received lung-protective ventilation . Paralysis was commenced within 48 hours of patients fulfilling study entry criteria, and was continued for 48 hours according to a standardized protocol. No increase in the incidence of ICU-acquired weakness was observed between the study groups. It remains to be seen in further planned trials, whether the improved mortality seen was due to the effect of neuromuscular blockade, or a specific effect of cisatracurium.
Pharmacological therapies for acute lung injury
Hydroxymethyglutaryl-coenzyme A reductase inhibition (statin therapy)
Hydroxymethyglutaryl-coenzyme A reductase inhibitors, or statins, have been shown to have pleotropic immunomodulatory effects, in addition to their cholesterol-reducing action. Hence, interest has developed in their use as potential anti-inflammatory agents in ARDS. Observational studies examining the impact of prehospital statin use have produced conflicting results, with some suggesting prehospital statin use was associated with a reduced risk of developing ARDS and/or severe sepsis, and others reporting no effect. A single centre, double-blinded placebo-controlled randomized trial of simvastatin showed no significant reduction in pulmonary oedema (extravascular lung water, EVLW), or improvement in pulmonary physiological variables over 14 days, and no improvement in clinical outcomes, although the study was under-powered to detect clinical outcome differences . Furthermore, a multicentre randomized controlled trial (RCT) of rosuvastatin in sepsis-induced ARDS (SAILS; ClinicalTrials.gov: NCT00979121) has recently been stopped, on grounds of futility, after the recruitment of 745 patients. Currently, there is no evidence to support the clinical use of statins in ARDS, particularly as the latest multicentre, HARP2, has shown no benefit (ISTCTN 88244364).
Due to the inflammatory nature of ARDS there has been much interest in the use of corticosteroid therapy. Several studies have shown no benefit from the use of high-dose short-course corticosteroids early in the clinical course of ARDS, and a double-blinded placebo RCT in patients diagnosed with ARDS for at least 7 days prior enrolment found no benefit of methylprednisolone, and in fact a significantly increased mortality amongst patients diagnosed with ARDS at least 14 days prior to commencing corticosteroid therapy . However, interest remains in the use of low-dose corticosteroids for established ARDS, with several clinical trials planned.
Beta-adrenergic receptor agonists
Alveolar fluid clearance has been shown to be defective in ARDS. Previous studies demonstrating the ability of beta-adrenergic receptor agonists to improve the resolution of pulmonary oedema led to multicentre randomized controlled trials of both intravenous  and aerosolized  salbutamol in ARDS. Both studies were stopped early, the aerosolized study on grounds of futility, and the intravenous study due to a significantly increased 28-day mortality in the intervention arm. The lack of benefit of beta-adrenergic agonist therapy on mortality and ventilator-free days was consistent between the two studies, with both concluding that the routine use of this therapy in ARDS patients cannot be recommended. Furthermore, there is evidence that intravenous salbutamol usage in ARDS may be associated with worsened outcomes.
Decreased surfactant levels and altered surfactant composition have been identified in the lungs of patients with ARDS. Clinical trials of replacement therapy with synthetic surfactants have not proved successful, despite significant improvements in oxygenation and a multicentre RCT of large volume natural porcine surfactant replacement, within 36 hours of the onset of ARDS, showed no benefit and a trend towards increased mortality and adverse events in the treatment group .
Inhaled nitric oxide
The ventilation–perfusion mismatch, and pulmonary hypertension, often observed in ARDS has led to clinical trials of inhaled nitric oxide therapy. Nitric oxide is a potent pulmonary vasodilator, and also has anti-inflammatory properties. Unfortunately, meta-analysis has shown that inhaled nitric oxide, whilst associated with improved oxygenation in ARDS patients, does not lead to shortened duration of mechanical ventilation, or improved survival .
Adenosine is a key regulator of endothelial cell permeability. Preclinical studies have suggested that using interferon beta to induce CD73, a cell surface enzyme that de-phosphorylates AMP to adenosine, may be of benefit in ARDS by improving endothelial barrier function . Interferon beta therapy is currently undergoing phase III clinical trials in ARDS.
The accumulation of activated platelets and neutrophils within the pulmonary vasculature has been demonstrated to be a key step in the pathogenesis of ARDS. Preclinical studies show that platelet inhibition with aspirin leads to improved outcomes in animal models of ARDS . Clinical trials of aspirin therapy are underway in both Europe and the United States (Clinicaltrials.gov: NCT01504867 and NCT02326350).
Recently, much interest has developed within the pharmaceutical industry for new therapies for ARDS, leading to the development of novel agents, such as a domain antibody to inhibit the p55 TNF receptor .
A multicentre phase one clinical trial to investigate the role of allogeneic bone marrow-derived mesenchymal stem cells (MSCs) for the treatment of ARDS is currently underway in the United States (ClinicalTrials.gov: NCT01775774). However, engraftment in the lung does not seem to be the major therapeutic effect of MSCs, rather the effect derives from their capacity to secrete paracrine factors that modulate immune responses and alter the host responses to injury. Preclinical work has shown that clinical-grade, cryopreserved allogeneic human MSC are therapeutic in a human, ex vivo, E. coli pneumonia model, but the antimicrobial effects of the MSCs could be largely duplicated by KGF, a major paracrine product of MSCs . A phase II trial investigating the efficacy and safety of intravenous KGF in ARDS is currently also under way (ISRCTN95690673).
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