Surfactant Deficiency

Surfactant is an endogenous mixture of phospholipids and proteins A-D produced by type 2 alveolar cells. It reduces alveolar surface tension, preventing alveolar collapse, and has anti-inflammatory and antimicrobial properties. Exogenous surfactant administration has been successfully used in neonatal respiratory distress syndrome, a condition of reduced surfactant production. Early trials in ARDS demonstrated physiologic improvements ; however, later phase III trials failed to show an improvement in mortality. A meta-analysis of surfactant trials in ARDS reported an increase in oxygenation, without an improvement in duration of ventilation or mortality, at a cost of more frequent complications.

Various reasons have been proposed for these results. Although the neonatal syndrome is due to reduced production, the situation is more complex in ARDS. Surfactant is affected by increased removal, altered composition, reduced efficacy, and reduced production. Potential limitations of these phase III studies include the use of suboptimal surfactant formulation, dose and duration of therapy, inadequate alveolar delivery, and late initiation of therapy. Pending new research, surfactant therapy is not recommended.

Limitation of Generation of Alveolar Edema

Although an increasing appreciation of the endothelial glycocalyx has modified our understanding of microvascular fluid fluxes, alveolar flooding had previously been thought to be primarily dependent on three factors: capillary hydrostatic pressure, oncotic pressure, and alveolar capillary permeability. Capillary permeability is increased in ARDS. Reducing hydrostatic pressure, increasing oncotic pressure, or both have been tested to ameliorate the development of pulmonary edema.

Reducing capillary hydrostatic pressure targeted to pulmonary artery occlusion pressure (PAOP) and central venous pressure may be associated with improved outcome in ARDS, although fluid management guided by a pulmonary artery catheter compared with a central venous catheter offers no advantage in ARDS. A positive fluid balance and increased extravascular lung water (EVLW) are associated with poor outcomes in ARDS. Guiding fluid therapy with EVLW measurement rather than with PAOP may be better.

Hydrostatic pressure may be reduced by restricting fluid intake, increasing fluid output with either diuretics or renal replacement therapy (RRT), or decreasing vasomotor tone with vasodilators. The phase III FACTT (Fluid and Catheters Treatment Trial) study demonstrated improvements in secondary outcomes such as duration of ventilation and intensive care unit (ICU) stay with a restrictive fluid strategy. Fluid balance was dictated by a protocol of diuretic administration based on filling pressures. Total 7-day fluid balance was approximately 0 mL compared with approximately 7000 mL in the liberal fluid strategy. Although there was no difference in mortality, importantly, there was no increase in renal failure or organ hypoperfusion with fluid restriction.

Animal models have demonstrated reduced pulmonary edema through reductions in pulmonary vascular pressures and permeability with RRT. Two small observational studies in humans have provided mixed results. Ten children with ARDS after bone marrow transplantation or chemotherapy who were treated with RRT had an 80% survival rate in contrast to a historic survival of 15%. Thirty-seven adults with renal failure and acute lung injury (ALI)/ARDS who were treated with RRT and a zero fluid balance had no pulmonary improvements within the first 24 hours of treatment. The role of RRT in the management of ARDS remains uncertain.

The choice of fluid for resuscitation in ARDS has been indirectly informed by recent large, multicenter randomized controlled trials on fluid therapy in the critically ill. The traditional Starling forces–based understanding of capillary fluid flux has been challenged, questioning an edema-sparing effect from colloid fluids. With clear signals of harm from hydroxyethyl starches, a lack of safety data for gelatins, and an absence of benefit from albumin over crystalloids, balanced crystalloid solutions are arguably the fluid of choice for all nonexsanguinating patients.

Hypoproteinemia is associated with the development of lung injury and is a marker of weight gain and death. Two small studies have investigated the use of furosemide with albumin infusions in patients with hypoproteinemia who have ALI. Both showed increases in total serum protein and more negative fluid balances with furosemide and albumin administration. This was associated with increased oxygenation but without improving mortality.

Albumin also exerts antioxidant effects via its thiol group. Nonsurvivors of ALI/ARDS have reduced thiol values. The infusion of albumin is associated with increased plasma thiol levels in sepsis and ARDS and decreased markers of oxidant injury. In the recently published ALBIOS (Albumin Italian Outcome Sepsis) study, comparing albumin with crystalloid administration in sepsis, there was no difference in the respiratory SOFA (Sequential Organ Failure Assessment) score between groups.

Lung injury is often heralded by an increase in pulmonary vascular resistance, with an imbalance between pulmonary vasoconstrictors and vasodilators seen in animal endotoxin shock models. Intravenous adenosine reduces EVLW, whereas intravenous nitroprusside and nitroglycerin also reduce pulmonary edema generation but at the expense of increasing ventilation-perfusion mismatch. To date, there is no clear evidence to support the role of vasodilator treatment in ARDS.

Epithelial and Endothelial Repair

Stem cells have the capacity for limitless self-renewal and differentiation. Embryonic stem cells are pluripotent and have the ability to differentiate into any cell type in the body. Adult stem cells are multipotent and have the ability to differentiate into several cell types, including cell types of other organ systems.

Stem cells provide three therapeutic opportunities. First, endogenous stem cells may be stimulated via exogenously administered growth factors. Keratinocyte growth factor (KGF), hepatocyte growth factor, and transforming growth factor-α (TGF-α) have all been shown to reduce the effects of ALI in animal models. Epidermal growth factor, TGF-α, and KGF can all upregulate AFC. KGF has other potentially useful effects, including cytoprotection, augmented surfactant secretion, and an antioxidant effect. A randomized, controlled phase II study of intravenous KGF (palifermin) in ARDS (KARE study) has recently completed with publication imminent. Vascular endothelial growth factor (VEGF) promotes angiogenesis and regulates vascular permeability. Genetic polymorphisms of the VEGF gene are associated with lower levels of VEGF and increased mortality in ARDS. Although VEGF increases alveolar permeability in ARDS, its administration enhances alveolar repair in vitro and in animal models. The role of VEGF in ARDS is currently being studied (NCT00319631).

Second, administration of exogenous stem cells, either embryonic or adult, can provide repair to an injured alveolus. Animal studies have been promising. In a lipopolysaccharide (LPS)–induced ARDS model, bone marrow progenitor cells localized to the site of injury and differentiated into endothelial and epithelial cells. Autologous transplantation of endothelial progenitor cells preserves endothelial function and maintains the integrity of the pulmonary alveolar-capillary barrier, whereas administration of mesenchymal stem cells reduces the severity of ARDS in mice. Patients with pneumonia and ARDS have higher levels of endothelial progenitor cells, and this higher level correlates with improved outcome. Mesenchymal stem cells were originally thought to act as a source of regenerative cells by differentiating into, and locally replacing, lethally injured cells. However, their primary mechanism of action may be through the secretion of growth factors, cytokines, and other signaling molecules causing trophic modulation of inflammation, cell death, fibrosis, and tissue repair.

The third role of stem cells is their ability to deliver gene therapy to the injured lung. Endothelial progenitor cells have been used to deliver vasodilatory genes to the pulmonary vasculature with resultant decreases in pulmonary artery pressures in experimental pulmonary hypertension. In one study, nontransfected mesenchymal stem cells reduced the severity of ARDS in a mouse LPS model, whereas administration of mesenchymal stem cells transfected with the human angiopoietin-1 gene only demonstrated a small additional improvement. Human studies are awaited.

Vasodilators

Nitric oxide (NO) is an endogenous vasodilator produced by the endothelium. When administered by inhalation, it vasodilates the circulation of ventilated alveoli, thus potentially reducing shunt and pulmonary hypertension. Early studies demonstrated physiologic improvements with NO in ARDS ; however, mortality remained unchanged. Two meta-analyses showed no mortality benefit and reported possible harm due to methemoglobinemia, toxic nitrogen compounds, increased pulmonary edema, rebound pulmonary hypertension, and renal failure. Because NO is expensive, possibly harmful, and without a mortality benefit, its routine use is not recommended. It may have a place as salvage therapy for severe hypoxemia given its ability to increase oxygenation, although a recent meta-analysis failed to show a benefit in the most hypoxic patient group.

Prostacylins are derivatives of arachidonic acid and have potentially beneficial effects, including vasodilation, inhibition of platelet aggregation, reduction of neutrophil adhesion, and inhibition of macrophage and neutrophil activation. Inhaled prostaglandin I ₂ (PGI ₂ , or prostacyclin) has been compared with inhaled NO in ARDS. PGI ₂ has similar efficacy, and some advantages including minimal systemic effects, absence of platelet dysfunction, easy administration, harmless metabolites, and no requirement for monitoring. A small study published in 2013 showed nebulized PGI ₂ (iloprost) selectively decreases pulmonary hypertension and improves myocardial diastolic dysfunction but without a significant effect on oxygenation in ARDS.

Intravenous prostacyclin in the form of prostaglandin E ₁ (PGE ₁ ) has also been investigated in ARDS. Although vasodilatory effects can cause hypotension and increase pulmonary shunting, prostacyclin is anti-inflammatory and can increase both cardiac output and oxygen delivery and improve oxygen extraction during reduced oxygen delivery. Early studies in ARDS showed no significant benefit, although the dose delivered was questioned. PGE ₁ was reformulated as liposomal PGE ₁ to increase pulmonary drug delivery and minimize side effects. Again, despite a promising preclinical study, results of subsequent studies were negative.

Endothelin-1 is a potent vasoconstrictor that has been implicated in the pathophysiology of lung injury. Tezosentan, an endothelin receptor antagonist, has been investigated in animal models of lung injury with mixed results thus far.

Vasoconstrictors

Almitrine is a pulmonary vasoconstrictor that may increase hypoxic pulmonary vasoconstriction and reduce shunt. In a small ARDS study, oxygenation was improved with minimal increase in pulmonary vascular pressures. The combination of intravenous almitrine to decrease blood flow to hypoxic lung units and inhaled NO to increase blood flow to ventilated lung units has been investigated in experimental lung injury and a small clinical study. Both found the combination superior to either therapy alone at increasing the partial pressure of oxygen in arterial blood (Pa o ₂ ) with minimal increase in pulmonary artery pressure. Further research is required.

Coagulation

An imbalance between fibrinogenesis and fibrinolysis in ARDS results in widespread fibrin deposition in the alveolar airspace, interstitium, and blood vessels. Pulmonary intravascular thrombosis and vasoconstriction can lead to the development of increased pulmonary vascular dead space, an independent predictor of mortality in ARDS. Several anticoagulants have been proposed as potential therapies in ARDS and have undergone investigation in animal models. Tissue factor pathway inhibitor (TFPI), factor VIIai, heparin, antithrombin III, activated protein C (APC), and thrombomodulin have all been shown to have beneficial effects at this level of investigation.

Protein C levels are lower in patients with ARDS than in normal controls, and the level of protein C correlates with clinical outcome. However, a small randomized controlled trial of APC in ARDS did not reduce either duration of ventilation or mortality, although pulmonary vascular dead space was decreased. A further small study investigating APC in inflammatory and infectious ARDS also failed to demonstrate benefit. After the disappointing results of the PROWESS-SHOCK (Prospective Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis and Septic Shock) study, recombinant APC (Xigris) has been withdrawn from the market. A phase II trial of recombinant TFPI demonstrated improvements in lung dysfunction score and survival.

The pathophysiologic role played by platelets, as both proinflammatory and prothrombotic effectors, could potentially allow for a therapeutic effect for antiplatelet agents. Aspirin is currently being examined in a human preclinical ARDS model (NCT01659307) and an ARDS prevention clinical study (NCT01504867). Therapeutic modulation of the hemostatic system is not currently recommended in ARDS.

Neuromuscular Blockade

Ventilator-induced lung injury can be a significant problem for patients with ARDS, with levels of mechanical ventilation required for maintenance of adequate gas exchange producing volutrauma, barotrauma, and biotrauma. Inhibition of skeletal muscle activity attenuates numerous pathophysiologic mechanisms, such as elevated airway pressures, regional hyperventilation, reduced compliance, and patient-ventilator dyssynchrony. Two small randomized controlled trials demonstrated improved oxygenation and decreased pulmonary inflammation, leading to a large multicenter randomized controlled trial in 340 patients with severe ARDS investigating early paralysis for 48 hours with cisatracurium. Neuromuscular blockade was associated with improved adjusted 90-day mortality, with no difference in rates of ICU-acquired weakness.

Glucocorticoids

Steroids possess a myriad of anti-inflammatory properties, stretching from the genome to the macrophage. In the 1980s, several trials unsuccessfully examined the role of short-course, high-dose methylprednisolone in preventing the development of ARDS in high-risk patients. A trial of high-dose steroids early in the course of ARDS had negative results, but a recent study in 91 patients with prolonged low-dose methylprednisolone showed reduced inflammation and organ dysfunction, plus reduced duration of mechanical ventilation and ICU stay.

Excessive alveolar fibrosis is a feature of established ARDS, and the antifibrotic properties of steroids have been investigated in this setting. Observational studies showed promising results and were followed by a small randomized controlled trial that suggested a beneficial effect on outcome. However, the ARDSnet Late Steroid Rescue Study demonstrated no overall effect on mortality, with increased mortality when steroids were commenced 7 days after the onset of ARDS. A meta-analysis and systematic review concluded that steroids have no role in preventing ARDS but that they may have a role in treating ARDS. Further studies are required to definitively answer this question.

Proinflammatory Mediator Inhibition

Eicosanoids are derivatives of arachidonic acid and act as proinflammatory mediators. They are produced via the activity of either 5-lipoxygenase to produce the leukotrienes or cyclooxygenase to produce prostanoids.

Ketoconazole is an imidazole antifungal agent with anti-inflammatory properties, specifically an ability to block leukotriene and thromboxane A ₂ synthesis, and an antimacrophage effect by which proinflammatory cytokine secretion is reduced. Small studies reported positive results for the prevention of ARDS in high-risk patients. A large subsequent study by the ARDSnet group of ketoconazole in 234 patients with ARDS demonstrated no beneficial effects.

Ibuprofen is a nonsteroidal anti-inflammatory agent that inhibits cyclooxygenase. In a large sepsis study of 448 patients, ibuprofen diminished prostanoid production and was associated with a trend toward decreased duration of pulmonary dysfunction and ARDS, but this did not reach statistical significance. Modulation of other inflammatory mediators has also been investigated, but to date no treatment has been shown to effectively reduce mortality.

Complement can contribute to ARDS by the generation of C3a and C5a, which attract neutrophils to the lungs and activate them. Complement can also cause cellular injury through the production of the membrane attack complex, C5b-9. Complement receptor 1 is a cell surface receptor on erythrocytes and leukocytes that can inhibit classic and alternative complement pathways. Animal studies have provided a basis for further investigation, and a human phase I study in 24 patients with ARDS has demonstrated the safety of recombinant soluble cytokine receptor 1 and its ability to inhibit the complement cascade. Further studies are awaited.

Interferon β-1a may reduce lung endothelial barrier dysfunction and minimize lung edema through the generation of adenosine, which reduces vascular permeability. An open-label phase II study investigating this intervention reported increased lung CD73 expression, which produces adenosine, and lessened mortality in ARDS. Anti-inflammatory therapy for ARDS is not recommended pending further research.

Immunonutrition

Nutrition has been suggested to play various roles in the management of ARDS. The use of a feed high in fat and low in carbohydrate can reduce carbon dioxide (CO ₂ ) production and thus ventilatory requirements. Enteral nutrition can stimulate gut and lung immunoglobulin A defense mechanisms. The omega-3 polyunsaturated fatty acids found in fish oil, eicosapentaenoic acid, γ-linolenic acid, and docosahexaenoic acid can reduce the production of arachidonic acid from membrane phospholipids, with potential effects on inflammation. On the basis of these findings, several recent studies in ARDS and general ICU populations have investigated various elements of nutrition such as intensity, feeding route, and formulation, including pharmaconutrition. The EDEN (Early vs. Delayed Enteral Feeding) study compared early enteral trophic feeding with full enteral feeding in 1000 patients with ARDS and found that trophic feeding was associated with reduced gastrointestinal intolerance but no improvement in ventilator-free days, infections, or 60-day mortality. The very recently completed CALORIES trial demonstrated no difference in duration of advanced respiratory support in 2388 critically ill patients randomized to either early enteral or parenteral nutrition. Three major pharmaconutrition studies (OMEGA in an ARDS population, as well as REDOX [Reducing Deaths due to Oxidative Stress] and METAPLUS in non-ARDS, mechanically ventilated populations) all reported harm from a range of interventions.

Despite various purported physiologic advantages, including reductions in pulmonary neutrophil infiltration, microvascular permeability, and pulmonary vascular resistance, numerous clinical studies of omega-3 fatty acids in ARDS have failed to clearly show benefit from this intervention, a finding confirmed in separate meta-analyses of enteral and parenteral administration studies.

Antiadhesion Molecule Therapy

The adhesion of immune cells to the endothelium to facilitate diapedesis is a vital step in the accumulation of neutrophils in the alveolus. The blockage of adhesion molecules is a potential therapeutic target in ARDS. Blockage of CD18, a neutrophil adhesion molecule, has been shown to attenuate the development of experimental lung injury. To date, there are no human studies.

Effector Cell Inhibition

Pentoxifylline is a phosphodiesterase inhibitor with anti-inflammatory effects, acting against neutrophils and macrophages. A small phase I study of pentoxifylline in six ARDS patients did not show any advantage in either gas exchange or hemodynamic parameters.

Lisofylline is a pentoxifylline derivative with slightly differing anti-inflammatory mechanisms. Although it also inhibits neutrophil accumulation and downregulates proinflammatory cytokines, it additionally has an effect on reducing levels of oxidized free fatty acids. Animal studies of lisofylline in the treatment of ARDS were promising, but again a large multicenter study by the ARDSnet group in 235 patients with ARDS had negative results.

Granulocyte-macrophage colony stimulating factor (GM-CSF) is involved in the development and homeostasis of alveolar macrophages. It also plays a role in the prevention of alveolar epithelial apoptosis. A small study of 10 patients with ALI demonstrated an improvement in oxygenation with GM-CSF over a 5-day period. A further study of GM-CSF in 130 patients with ARDS failed to demonstrate benefit, although it was underpowered, with nonsignificant signals of benefit evident.

Activated neutrophils release neutrophil elastase, which plays a key role in alveolar injury leading to increased vascular permeability and alveolar flooding. EPI-hNE-4 is a neutrophil elastase inhibitor that improved pulmonary compliance without affecting immune function during Pseudomonas aeruginosa –induced pneumonia in rats. A phase III multicenter trial of depelestat (EPI-hNE-4) in ARDS has completed and is awaiting publication (NCT 00455767). Sivelestat is a reversible, competitive inhibitor of neutrophil elastase. After promising animal studies, sivelestat underwent a phase III study in which it improved pulmonary function and reduced duration of ICU stay, with trends toward a reduction in duration of mechanical ventilation and mortality. However, the international STRIVE (Sivelestat Trial in ALI Patients Requiring Mechanical Ventilation) study in 492 ALI patients was prematurely stopped after an increase in 180-day all-cause mortality was noted. No pulmonary improvements occurred, and 28-day mortality was not reduced.

Antioxidant Therapy

Activated neutrophils and macrophages partly exert their injurious effects through the generation of reactive oxygen species. Pulmonary glutathione, an antioxidant, is reduced in ARDS. N -acetylcysteine and procysteine are precursors for glutathione, and their administration can replete pulmonary glutathione levels in ARDS. Small studies of N -acetylcysteine in ARDS reported mixed results, whereas a study of procysteine in ARDS was halted in 1998 because of increased mortality (unpublished data). N -acetylcysteine can also downregulate nuclear factor-κB with resultant reduction in neutrophil chemoattractant mRNA and alveolitis in a rat model of lung injury.

In a study of critically ill surgical patients, vitamin C and E administration reduced the duration of mechanical ventilation and ICU stay without decreasing the incidence of ARDS. The more recent REDOX study reported no efficacy from antioxidant administration in a general ICU population, whereas a high-protein enteral diet enriched with pharmaconutrients including antioxidants also failed to demonstrate efficacy.

Statins

Statins were introduced into clinical practice as cholesterol-lowering agents through the inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase and have since been shown to possess pleotropic actions both dependent and independent of HMG CoA reductase inhibition. Statins exert beneficial effects on inflammation and coagulation as well as epithelial, endothelial, and immune cell function. Several retrospective studies have demonstrated that prior statin therapy is associated with improved survival in sepsis, including pneumonia. In a healthy-volunteer, inhaled LPS-induced model of lung injury, pretreatment with a statin reduced pulmonary markers of inflammation Despite this promising background, two large, multicenter randomized controlled trials published in 2014 did not demonstrate any advantage to statin therapy in ARDS. The American SAILS (Statins for Acutely Injured Lungs from Sepsis) study, investigating rosuvastatin, reported no mortality benefit and possible renal harm, whereas the Irish Critical Care Trials Group HARP-2 (Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction) study, examining simvastatin, showed no statistically significant improvement in ventilator-free days, although it was potentially underpowered to detect a small difference in mortality.

Angiotensin-Converting Enzyme Inhibitors

The severe acute respiratory syndrome epidemic led to the discovery of a novel coronavirus, the receptor for which is a variant of the angiotensin-converting enzyme (ACE), implicating the renin-angiotensin system (RAS) in ARDS. ACE converts angiotensin I into angiotensin II, and angiotensin II, acting through the angiotensin-1 receptor (AT1R), mediates vasoconstriction, alveolar permeability, and lung injury. ACE2 degrades angiotensin II; therefore excessive ACE activity or ACE2 deletion is associated with worse lung injury.

Genetic observational studies in humans have supported the concept that the RAS is important in the development and outcome of ARDS. The ACE DD genotype is associated with increased ACE activity and worse outcome in ARDS. A retrospective study has shown that prior treatment with an ACE inhibitor was associated with decreased mortality in patients requiring hospitalization for community-acquired pneumonia. Therapeutic modulation of the RAS with recombinant ACE2, ACE inhibition, and AT1R blockade with losartan attenuate pulmonary inflammation in rodent models of LPS-induced ARDS and ventilator-induced lung injury. Human studies are awaited.

Induced Hypothermia

Hypothermia decreases metabolism by 25% at 33° C, reducing oxygen consumption and CO ₂ production and thus ventilatory demand. It also decreases proinflammatory gene transcription and exerts an anti-inflammatory effect. In animal models, induced hypothermia reduces the expression of intracellular adhesion molecule-1, interleukin-1β levels, the pulmonary accumulation of neutrophils, and histologic lung damage. Several case reports have documented the successful use of hypothermia (33 to 34° C) for severe ARDS. To date, there has been only one small study of 19 patients with sepsis-associated severe ARDS treated with induced hypothermia. Mortality was reduced by 33% at a mean temperature of 33.7° C. The reduction in body temperature was associated with a reduction in alveolar-arterial oxygen gradient, heart rate, and cardiac index and an increase in oxygen extraction, although oxygen consumption interestingly remained unchanged. Further research is required.