US Pharm. 2016;41(7):HS6-HS10.
ABSTRACT: Acute respiratory distress syndrome (ARDS) is a life-threatening condition typically seen in critically ill patients requiring immediate care. In ARDS, enough oxygen is incapable of getting into the lungs and blood. Associated risk factors in ARDS include pneumonia, aspiration of gastric content, sepsis, and sever trauma. To date, no one pharmacologic treatment has been identified to manage ARDS. Instead, supportive care is utilized with agents that include corticosteroids, neuromuscular blocking agents, nitric oxide, surfactants, and beta2-adrenergic agonists.
Acute respiratory distress syndrome (ARDS) is a clinical syndrome characterized by noncardiogenic edema and hypoxic respiratory failure as a result of lung injury. However, since its first appearance, the definition of ARDS has evolved. To date the most recent definition, the Berlin definition, defines ARDS based on the following criteria1,2:
1. Onset within 1 week of a known clinical insult or new or worsening respiratory symptoms
2. Bilateral opacities that are not fully explained by effusions, lobar/lung collapse, or nodules on chest x-ray
3. Respiratory failure that is not fully explained by cardiac failure or fluid overload
4. Impaired oxygenation status based on the PaO2/FiO2 ratio (the ratio of arterial oxygen partial pressure to fractional inspired oxygen). Mild = 200 to 300 mmHg; moderate = 100 to 200 mmHg; and severe = <100 mmHg.
The Berlin definition addresses limitations of the prior accepted American-European Consensus Conference (AECC) definition and has improved feasibility, reliability, predictive validity for morality, and objective evaluation of its use.2
Epidemiology
The incidence of ARDS varies significantly based upon regions around the world, although reasons for this variation are unclear. The estimated incidence of ARDS in the United States ranges from 64 to 79 cases per 100,000 people.3 However, the incidence has declined due to lung protective ventilation and reductions in hospital infections. Death is usually attributed to sepsis and multiorgan failure and not just respiratory failure alone.4,5
It has been noted that African Americans with an acute lung injury have a higher risk of death when compared with Caucasians due to the presence of a T-46C polymorphism in the promoter region of the Duffy antigen/receptor for chemokines (DARC gene), which is associated with a 17% higher 60-day mortality rate.6
Etiology
ARDS results from either a direct (an injury occurring within the lungs) or an indirect injury to the lung (injury occurring to the lungs as a result of an injury to the body, resulting in a systemic inflammatory response syndrome). Among the risk factors (TABLE 1), sepsis is the most commonly associated risk leading to the development of ARDS and is linked to increased rates of mortality. Indeed, the risk of developing ARDS increases with the presence of multiple predisposing factors or in the presence of accompanying chronic alcohol abuse, chronic lung disease, age >60 years, and/or a low serum pH.4 Likewise, signs and symptoms of ARDS include severe shortness of breath, shallow breathing, low blood pressure, confusion, and extreme fatigue and vary in severity depending upon the type of lung injury or stage of the syndrome.
Classification
When classifying ARDS, three distinct phases are utilized: 1) inflammatory, 2) proliferative, and 3) fibrotic (TABLE 2).3,7 The inflammatory phase, described by damage to the alveolar capillary endothelial cells leading to accumulation of fluid in the interstitial and alveolar spaces, usually lasting about 7 days, with symptoms occurring within 12 to 36 hours after lung injury. Symptoms in this stage include dyspnea and tachypnea. Chest x-rays are usually significant for cardiomegaly, pleural effusions, or pulmonary vascular redistribution.
Secondly, the proliferative phase can last up to 21 days with some patients progressing to early pulmonary fibrosis. Signs and symptoms in this stage can include dyspnea, tachypnea, and hypoxemia. Moreover, patients within the inflammatory and proliferative stages often recover with the assistance of mechanical ventilation.3,7
Lastly, the fibrotic phase usually occurs in patients without resolution during the inflamed proliferative phases and is characterized by extensive interstitial and alveolar duct fibrosis. During this phase, morbidity increases and patients require longer ventilation and/or supplemental oxygen therapy.3,7
Pathophysiology
During ARDS, an inflammatory cascade is initiated that stimulates the accumulation of neutrophils to the site of the injury, the activation of nuclear factor-kappa B (NF-KB), and the release of inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and IL-6.7-9 Increased levels of these inflammatory mediators over sustained periods of time can cause resistance to endogenous glucocorticoids, resulting in unopposed inflammatory activity.9 Thus, this proinflammatory state results in an increased permeability of pulmonary vasculature, inactivation and depletion of lung surfactant, and pulmonary edema, which hinders efficient gas exchange and lung compliance.7,8 Besides, in severe cases, fibroblasts may also invade the lungs, causing pulmonary fibrosis.8
Pharmacologic Management
Management of ARDS focuses on treating the underlying cause of lung injury as well as providing supportive care. It has been shown that pharmacologic interventions may provide additional benefit by maintaining adequate oxygenation and ventilation while reducing the duration of ventilator use and decreasing morbidity and mortality.7 To date, corticosteroids, neuromuscular blocking agents, nitric oxide, surfactants, and beta2-adrenergic agonists (beta2-agonists) have been theorized to improve outcomes (TABLE 3), and only a few of the aforementioned drugs have demonstrated significant benefits.
Corticosteroids: The anti-inflammatory properties of corticosteroids make these medications reasonable pharmacologic options. Corticosteroids exert their anti-inflammatory effect through both genomic and nongenomic mechanisms.9 The two genomic anti-inflammatory mechanisms are described as transrepression and transactivation. Transrepression, occurring within a few hours after corticosteroid administration, directly inhibits NF-KB from migrating to the cell nucleus and transcribing genes for proinflammatory cytokines.9 In contrast, transactivation occurs within days after glucocorticoid administration and involves the activation of glucocorticoid receptor-α. Once activated, the glucocorticoid receptor complex migrates to the cell nucleus and transcribes genes for anti-inflammatory proteins.9 In addition to both of the genomic mechanisms, corticosteroids also prevent neutrophil degranulation and stabilize the cell membrane.
Several trials have aimed to assess the impact of corticosteroid therapy in conjunction with mechanical ventilation in ARDS patients. The effectiveness of corticosteroid therapy depends on a variety of factors, including medication dose, stage of ARDS, and the drug-tapering schedule.9
Meduri et al analyzed the effect of prolonged, low-dose methylprednisolone therapy on patients in early onset ARDS. The patients on corticosteroid therapy were twice as likely to achieve a one-point reduction in lung injury score after 7 days of therapy compared to placebo (69.8% vs. 35.7%; P = .002).10 Patients were also more likely to breathe without assistance by day 7 (54% vs. 25%; P = .01). Although some studies have associated corticosteroid therapy with positive outcomes10, there is evidence that contradicts these findings. Notably, the National Heart, Blood, and Lung Institute analyzed the effect of moderate-dose methylprednisolone on 60-day mortality rate and found similar mortality rates for methylprednisolone and placebo (29.2% and 28.6%, respectively).11
Neuromuscular Blocking Agents (NMBAs): Muscle relaxants have been shown to be beneficial as adjunct therapy to ventilation in the management of ARDS.12 NMBAs work by antagonizing the actions of acetylcholine by binding to cholinergic receptors leading to decreased muscle responsiveness to presynaptic excitation. These agents improve patient-ventilator synchrony, aid with lung-protective ventilation, and improve overall survival rate when used early (within 48 hours) and in severe ARDS (i.e., PaO2/FiO2 150 mmHg). However, limited evidence is available to dictate which specific agent within the class proves more beneficial.12
Guidelines from the Society of Critical Care Medicine outline the use of NMBAs, favoring the use of cisatracurium or atracurium in patients with hepatic or renal dysfunction.12 In contrast, the guidelines discouraged the use of pancuronium in patients who exhibited signs of vagolytic effects. However, many studies have advised that clinicians use their clinical judgment and patient-related factors when choosing an agent.12
Studies involving the use of NMBAs were used in early severe ARDS. Papazian et al conducted a double-blind, randomized, controlled trial comparing cisatracurium to placebo in order to determine its effect on the 90-day in-hospital mortality rate.13 Result findings determined that the 90-day in-hospital mortality of the cisatracurium group was 31.6% compared with that of placebo at 40.7% (HR 0.68; CI: 0.48-0.98; P = .04). Additionally, patients receiving cisatracurium had higher PaO2/FiO2 ratios on day 7 compared with the placebo group, indicating improvement of hypoxemia. Lastly, the cisatracurium group had more ventilator-free days in both the 28-day and 90-day periods, and more days free of organ failure, excluding the lungs.13
In a review article by Roch et al, two studies were evaluated.14 Both trials compared cisatracurium with placebo to determine whether there would be an effect on the PaO2/FiO2 ratio. Patients who underwent cisatracurium therapy had much higher PaO2/FiO2 ratios compared with the placebo group, which further confirms the results from the previously mentioned study by Papazian et al.
Nitric Oxide: The mechanism by which nitric oxide (NO) exerts its pharmacologic action makes it a preferred option for management of ARDS. Inhaled NO enhances perfusion in the lungs by targeting the lungs directly and reduces systemic effects due to its short half-life. NO works by selectively dilating the pulmonary vasculature in ventilated alveoli, resulting in improvement of blood flow by enhancing ventilation-perfusion matching (i.e., V/Q ratio). By improving this ratio, hypoxemia is reversed and the pulmonary arterial pressure is lowered.14,15
Studies have shown that the use of NO at low doses provided improvement in oxygenation; however, inhaled NO was not able to reduce mortality or the amount of ventilator-free days.7 In a systematic review and meta-analysis of 12 studies utilizing NO, inhaled NO was associated with a modest improvement of the PaO2/FiO2 ratio, but it had no effect on mean pulmonary pressure, survival, or duration of mechanical ventilation. In the studies, this improvement of oxygenation was transient and was not seen when NO was used for more than 1 to 2 days.7 Thus, the use of routine NO in patients with sepsis-related ARDS should be reserved for use as rescue therapy.15
Surfactant: Depletion and inactivation of lung surfactant occurs during the progression of ARDS. The role of a surfactant is to reduce surface tension, prevent alveolar damage, and decrease inflammation.16 In the pediatric population, administration of bovine lung surfactant significantly reduced 28-day mortality rates.15 In contrast, clinical studies in adults have shown that administration of exogenous surfactant improves oxygenation but has no effect on mortality or ventilator-free days.15,16 This may be due to several variables, including dose and type of surfactant administered.15 Therefore, surfactants may be useful for a transient improvement in oxygenation for adults with ARDS.
Beta2-Agonists: These agents are theorized to aid in ARDS by reducing pulmonary edema via fluid reabsorption. Beta2-agonists upregulate the Na+/K+ ATPase pump, which transports electrolytes, accompanied by water, across the epithelial membrane. Additionally, beta2-agonists minimize the permeability of pulmonary vasculature.15,16 In randomized controlled trials, salbutamol (known as albuterol in the U.S.) was poorly tolerated and did not improve mortality.15
Investigational Therapies
Statins: These drugs exhibit anti-inflammatory properties in addition to their cholesterol-lowering effects.16 The anti-inflammatory action of statins have allowed them to be used in organ transplantations and neurologic diseases and have made them an area of research for ARDS therapy.15,16 Statins have not been associated with any beneficial ARDS-related outcomes in randomized controlled trials and are currently not recommended for ARDS management.
Angiotensin-Converting Enzyme (ACE) Inhibitors: This enzyme is a novel target for ARDS. Hypoxia is believed to stimulate angiotensin II receptors, leading to an increase in vascular permeability and pulmonary edema.15 In mice models, blocking the effects of the angiotensin II receptor led to decreased vascular permeability. Additional studies are needed to further evaluate the efficacy of ACE inhibitors in ARDS treatment.
Anticoagulants and Antiplatelets: Multiorgan failure is a common cause of ARDS-related mortality and is mainly attributed to excessive coagulation. Hence, anticoagulants have been theorized to improve mortality in ARDS by inhibiting the coagulation cascade. However, clinical trials involving anticoagulation have not yielded any benefit in ARDS management.15,17
The role of aspirin therapy is also being researched. An observational trial has revealed a possible association between aspirin use and decreased incidence of ARDS.18 Prospective studies must be conducted to fully evaluate the advantages of aspirin administration in ARDS management.
Conclusion
Mechanical ventilation and fluid administration are first-line options for the management of ARDS. Adjunctive pharmacologic therapy may improve ARDS outcomes in more severe cases by limiting duration of required mechanical ventilation, improving oxygenation, and reducing mortality and morbidity. As participants in a multidisciplinary team, pharmacists play a vital role in the management of ARDS by helping to improve patient outcomes and survival. Many pharmacologic options are associated with severe adverse effects and, as medication experts, pharmacists can aid in selecting appropriate agents. Consequently, pharmacists are able to provide expertise when navigating adverse effects, pharmacokinetic monitoring and adjustments, drug toxicities, and other individualized patient-related factors.
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