ARDS: Acute Respiratory Distress Syndrome

Acute Respiratory Distress Syndrome (ARDS)

• ARDS is a type of acute lung inflammation and diffuse alveolocapillary injury
• Results from direct pulmonary injury or severe systemic inflammation
• 10% of individuals admitted to the ICU and 23% of those requiring mechanical ventilation are diagnosed with ARDS
• ARDS symptoms include acute onset of bilateral infiltrates (pulmonary edema) on chest radiograph and persistent hypoxemia, despite supplemental oxygen
• Predisposing factors include sepsis and multiple trauma, pneumonia, burns, aspiration, cardiopulmonary bypass, pancreatitis, blood transfusions, drug overdose, inhalation of smoke or noxious gases, fat emboli, radiation therapy, and disseminated intravascular coagulation
• Genetic and epigenetic factors can increase susceptibility
• Mortality rate is approximately 30% to 40% despite diagnosis and therapy advances

Pathophysiology of ARDS

• Disorders causing ARDS result in acute inflammatory lung injury
• Characterized by diffuse alveolar damage
• Triggered by direct injury to the lung epithelium and/or indirect biochemical injury to the endothelium
• Within 72 hours, pulmonary capillary endothelial cells and alveolar epithelial cells become damaged
• Endothelial damage activates neutrophils, macrophages, and platelets, releasing inflammatory cytokines
• Capillary membrane permeability, hypercoagulability, and pulmonary arteriolar vasoconstriction increase significantly
• Fluids, proteins, and blood cells leak from the capillary bed into the pulmonary interstitium and flood the alveoli (exudative phase)
• Alveolar ventilation reduces severely, causing V/Q mismatch and severe hypoxemia
• Respiratory rate increases, resulting in initial hypocapnia and respiratory alkalosis
• Epithelial cell damage reduces surfactant production, causing atelectasis
• Lung compliance declines, decreasing tidal volume and developing hypercapnia
• The result of overwhelming inflammatory response by the lungs is acute hypoxemic and hypercapnic respiratory failure
• Resolution of pulmonary edema begins within 4 to 14 days, and the proliferative phase of ARDS starts
• The alveolar exudate turns into cellular granulation tissue, appearing as hyaline membranes that form a diffusion barrier for oxygen exchange, resulting in continued hypoxemia
• Fibrotic stage within 14 to 21 days involves remodeling and lung tissue fibrosis
• Severe cases lead to fibrosis progressively obliterating the alveoli, respiratory bronchioles, and interstitium, resulting in long-term respiratory compromise

Clinical Manifestations of ARDS

• Progressive and include:
  • Dyspnea and hypoxemia with poor response to oxygen supplementation
  • Initial hyperventilation and respiratory alkalosis
  • Decreased tissue perfusion, metabolic acidosis, and organ dysfunction
  • Increased work of breathing, decreased tidal volume, and hypoventilation
  • Hypercapnia, respiratory acidosis, and worsening hypoxemia
  • Respiratory failure, decreased cardiac output, hypotension, multiple organ dysfunction syndrome (MODS) and death

Evaluation and Treatment of ARDS

• Diagnosis is based on history of lung injury, physical examination, blood gas analysis, and chest radiographs
• In 2012, a consensus definition described 3 major criteria for diagnosis:
  • Onset within 1 week of known clinical insult or new/worsening respiratory symptoms
  • Bilateral opacities not fully explained by effusions, lobar/lung collapse, or nodules on chest x-ray or CT
  • Respiratory failure not fully explained by cardiac failure or fluid to exclude hydrostatic edema with no ARDS risk factor
• Serum biomarker measurements (i.e. surfactant proteins, BNP, CRP, interleukins) may aid in the diagnosis and prognosis
• Treatment involves early detection, supportive therapy, and prevention of complications
• Supportive therapy focuses on maintaining oxygenation and ventilation while preventing lung injury and infection
• High flow nasal oxygen and mechanical ventilation, prone positioning, or extracorporeal oxygenation may be required
• Lung-protective ventilation strategies (e.g. lowering tidal volume and driving pressure) are essential due to increasing barotrauma risk as lung compliance decreases
• Corticosteroids continue to be recommended
• New treatment strategies like mesenchymal stem cell and exosome-based therapies show early promise
• COVID-19 related ARDS is treated with antivirals, monoclonal antibodies, corticosteroids, anticoagulants, inhaled vasodilators, bronchodilators, surfactant, and anti-immune therapies

Obstructive Lung Diseases

• Characterized by narrowed airways, causing worse airway obstruction with expiration
• Requires more force to expire air, increasing work of breathing and use of accessory muscles
• Slowed emptying of the lungs is measured by decreased forced expiratory volume in 1 second (FEV1)
• Air is trapped in the lungs, decreasing tidal volume and leading to hypoventilation and hypercapnia
• Changes in alveolar ventilation cause V/Q mismatching and hypoxemia
• Unifying symptom is dyspnea, and the unifying sign is wheezing
• Common obstructive diseases are asthma, chronic bronchitis, and emphysema
• Chronic bronchitis and emphysema often are called chronic obstructive pulmonary disease (COPD)

Asthma

• As defined by GINA; a "heterogenous disease, usually characterized by chronic airway inflammation"
• Respiratory symptoms such as wheeze, shortness of breath, chest tightness, and cough that vary over time and in intensity, combined with variable expiratory airflow limitation
• Chronic inflammation causes bronchial hyperresponsiveness, constriction of the airways, and reversible variable airflow obstruction
• Limitation may become persistent with disease progression
• Affects 7% of children and 8% (approx. 20 million) of adults in the United States
• More prevalent in women and individuals below the poverty level
• Familial disorder involving more than 120 genes
• Gene expressions may impart associated phenotypes such as allergic asthma, non-allergic asthma, adult-onset asthma, asthma with persistent airflow limitation, and asthma with obesity

Pathology of Asthma

• Allergic asthma is most common
• Classified into endotypes (clinical characteristics, biomarkers, lung physiology, histopathology, epidemiology, and treatment response)
• Risk factors include allergen exposure, urban residence, indoor and outdoor air pollution, tobacco smoke, recurrent viral infections, obesity, acetaminophen use, and GERD impact gene expression (epigenetics)
• Exposure to high allergen levels increases the risk for allergic asthma in sensitized individuals by promoting more type 1 hypersensitivity
• Decreased exposure to certain infectious microorganisms creates an immunologic imbalance
• Exposure to common respiratory viruses (e.g., RSV) increases the risk of asthma
• Diet, immunization, antibiotic use, and indoor/outdoor activity patterns are linked to asthma development
• Upper gastrointestinal microorganisms influence the airway microbiota through aspiration
• Dysbiosis of the gut can lead to dysbiosis in the lung via microorganisms traveling through the bloodstream
• Exposure to inhaled irritants causes neutrophil activation, inflammation, and airway damage
• Obesity is associated with a chronic inflammatory state sensitizing the bronchial mucosa to allergen and irritant exposure
• Acetaminophen depletes glutathione levels, leading to oxidative stress, inflammation, and bronchoconstriction
• GERD stimulates the vagus nerve, releasing acetylcholine (ACh), causing bronchoconstriction

Pathophysiology of Allergic Asthma

• Airway epithelial exposure to antigen initiates both an innate and an adaptive immune response in sensitized individuals
• Immune response includes dendritic cells (antigen-presenting macrophages), T-helper 2 (Th2) lymphocytes, B lymphocytes, mast cells, neutrophils, eosinophils, and basophils
• There is an immediate and a late (delayed) asthmatic response
• Early asthmatic response:
  • Antigen exposure activates bronchial epithelium dendritic cells, presenting antigen to T-helper cells
  • T-helper cells differentiate into Th2 cells, releasing IL-4, IL-5, IL-13, and IL-33
  • Plasma cells produce antigen-specific IgE, which binds to mast cells
  • Subsequent cross-linking of IgE molecules with the antigen causes mast cell degranulation and release of inflammatory mediators
  • Inflammation also leads to increased ACh release by the pulmonary parasympathetic nervous system. ACh binds to the muscarinic 3 (M3) receptor, further contributing to bronchospasm and mucus secretion
  • Eosinophils release toxic neuropeptides that contribute to increased bronchial hyperresponsiveness
• Late asthmatic response begins 4 to 8 hours after the early response
  • Chemotactic recruitment causes a release of inflammatory mediators, inciting bronchospasm, edema, and mucus secretion with obstruction to airflow
  • Leakage contributes to prolonged smooth muscle contraction
  • Eosinophils cause direct tissue injury with fibroblast proliferation and airway scarring
  • Damage to ciliated epithelial cells contributes to mucus and cellular debris accumulation, forming plugs in the airways
  • Untreated inflammation can lead to long-term airway damage causing subepithelial fibrosis and smooth muscle hypertrophy (airway remodeling)

Airway Obstruction

• Increases resistance to airflow and expiratory flow rates
• Decreased expiratory flow causes air trapping, hyperinflation, and increased work of breathing
• Uneven distribution of inspired air causes V/Q mismatch and hypoxemia
• Hyperventilation is triggered by lung receptors responding to airway obstruction and increased lung volume
• Early hypoxemia with decreased PaCO2 and increased pH (respiratory alkalosis) result
• Progressive obstruction of expiratory airflow worsen the air trapping, the lungs and thorax become hyperexpanded, positioning the respiratory muscles at a mechanical disadvantage leading to decreased tidal volume, hypoventilation, increased PaCO2, and respiratory acidosis
• Respiratory acidosis signals respiratory failure

Clinical Manifestations of Asthma

• Individuals are usually asymptomatic between attacks, and pulmonary function tests are normal
• Begins with chest constriction, expiratory wheezing, dyspnea, nonproductive cough, prolonged expiration, accessory muscle use, tachycardia, and tachypnea
• A pulsus paradoxus (decrease in systolic blood pressure during inspiration of >10 mm Hg) may be noted
• Peak flow measurements should be obtained
• Arterial blood gas tensions should be measured if oxygen saturation falls below 90% as blood-gas alterations are difficult to evaluate clinically
• If bronchospasm is not reversed by treatment measures, status asthmaticus is considered which is life-threatening
• Status asthmaticus continues to develop with hypoxemia worsens and respiratory acidosis develops as the PaCO2 level begins to rise
• Ventilation may cease altogether
• A silent chest and PaCO2 greater than 70 mm Hg are ominous signs of impending death

Evaluation and Treatment of Asthma

• Diagnosis is based on history of symptom patterns and evidence of variable and reversible airflow limitation
• Supported by history of allergies and recurrent episodes of wheezing, dyspnea, and cough/exercise intolerance
• Symptoms are at their worst at night, vary over time/intensity, and triggered by allergens/irritants
• Physical examination findings are often normal between episodes
• Spirometry is used to document reversible decreases in FEV1 during an induced attack
• Critical assessment is necessary for correct diagnosis since conditions may be mistaken for asthma, including heart disease, cystic fibrosis, vocal cord dysfunction, and medication-related cough
• Allergy testing may be performed once diagnosed, asthma is classified by severity
• Acute asthma attack evaluation needs assessment of arterial blood gases and expiratory flow rates (using peak expiratory flow meter) and underlying triggers like infection
• Hypoxemia and respiratory alkalosis are expected early an in acute attacks
• Hypercapnia development with repiratory acidosis signals mechanical ventilation
• Management of acute asthma attack is on severity based on peak flow messurements
• Immediate administration of oxygen, inhaled short acting b-agonist bronchodilators, and systemic corticosteroids in individuals with severe exacerbation
• Monitors gas exchange and patency determines hospitilization
• Exhaled nitric oxide (FeNO) levels Increasingly used to follow therapy response and can be used when other diagnostic modalities are inconclusive
• Antibiotics are against acute asthma unless there is a documented bacterial infection
• Asthma management consists of allergy and irritant avoidance
• Education is important, including peak flow meter use and adherence to an action plan
• A 2020 Focused Updates on Asthma Management Guidelines are from the National Asthma Education and Prevention Program Coordinating Committee
• Stepwise approach for persistent asthma treatment is recommended
• Use of continuous dose inhaled corticosteriods with of without long-acting beta-agonist (LABA) managing symptoms
• Short-acting beta-agonists (SABAs) and Intermittent asthma symptoms must be reserved
• New recommendations include use of needed low doses for older corticosteriods with formoterol as an option
• Continuous administration of for corticosteroids is a form of therapy
• Biologic that block the cytokine that are responsible foe hypersensitivity, bronchospasm, and inflammatory.
• Immunitherepy is also available when the other methods are ineffective and the patient has allergy shots
• Immunotherapy is also given sublingually