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Acute Respiratory Distress Syndrome

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Acute Respiratory Distress Syndrome, Adult Respiratory Distress Syndrome, Acute Lung Injury, ARDS, Traumatic Wet Lung, Shock Lung, Congestive Atelectasis, PaO2/FIO2 Ratio

  • Definitions
  1. Acute Respiratory Distress Syndrome (ARDS)
    1. Acute onset of Dyspnea, Tachypnea, Hypoxemia, and bilateral Interstitial Infiltrates
    2. Rapidly progresses to Respiratory Failure
    3. Non-cardiogenic pulmonary edema (contrast with Congestive Heart Failure)
  2. Acute Lung Injury (ALI)
    1. Slightly less severe form of ARDS in hospitalized patients with less severe Hypoxemia than ARDS
  • Epidemiology
  1. Incidence
    1. Acute Lung Injury (ALI)
      1. Adults: Up to 86 cases per 100,000 person years
      2. Children: 9.5 cases per 100,000 person years
    2. Acute Respiratory Distress Syndrome (ARDS)
      1. Adults: Up to 64 cases per 100,000 person years
      2. Children: 12.8 cases per 100,000 person years (18 to 27% mortality)
      3. ARDS results in 10% of U.S. ICU admissions, and 23% of Mechanical Ventilations
  2. References
    1. Rubenfeld (2005) N Engl J Med 353(16): 1685-93 [PubMed]
    2. Zimmerman (2009) Pediatrics 124(1): 87-95 [PubMed]
  • Pathophysiology
  1. Acute, bilateral, complete lung inflammation
    1. Onset 24-48 hours after major Trauma or severe illness
    2. Variant of multi-system organ failure (e.g. Acute Tubular Necrosis, Disseminated Intravascular Coagulation)
  2. Exudative Phase: Neutrophil mediated endothelial damage
    1. Duration: 7-10 days
    2. Alveolar Macrophages release mediators triggering an inflammatory cascade
    3. Inflammatory mediator proliferation leads to Neutrophil accumulation within the lung microcirculation
      1. Neutrophils activate and cross the vascular endothelium and the alveolar epithelium
      2. Neutrophils release proteases, Cytokines, and reactive oxygen species
    4. Inflammatory mediator cause local destruction
      1. Vascular permeability increases to protein rich fluid
      2. Gaps form at the alveolar epithelial barrier
      3. Alveolar cell (type I and II) necrosis
      4. Intravascular coagulation with microthrombi formation
    5. Local tissue effects ultimately decrease lung compliance and interfere with gas exchange
      1. Low-pressure pulmonary edema
      2. Surfactant loss
      3. Hyaline membrane formation (accumulation of necrotic cells and debris within the alveoli)
        1. Decreased pulmonary compliance
        2. Decreased gas exchange
  3. Fibrotic Phase (Ongoing Inflammation and Edema)
    1. Not universally present in ARDS, and confers worse prognosis
    2. May be provoked by Mechanical Ventilation (may be reduced by lung protective strategy)
    3. Fibroblasts infiltrate region of inflammation
      1. Ongoing inflammation and edema persists, and basement membrane destroyed
      2. Collagen deposition
      3. Intra-alveolar and Interstitial Fibrosis
      4. Disease progression
  4. Proliferative Phase (Recovery)
    1. Duration: 14-21 days
    2. Neutrophils are deactivated by anti-inflammatory Cytokines
      1. Neutrophils undergo apoptosis and later Phagocytosis
    3. Alveolar cells proliferate
      1. Type II alveolar cells proliferate
      2. Type II alveolar cells differentiate into type I alveolar cells
    4. Osmotic gradient reverses
      1. Alveolar ion channels and aquaporins expressed
      2. Draws fluid out of alveoli and back into lymphatics and lung microcirculation
      3. Endothelial cells reestablish vascular supply
    5. Macrophage and alveolar cell activity
      1. Remove debris and protein depositions from the alveoli
  5. Models of pathogenesis
    1. ARDS is analogous to other system failures
      1. Disseminated Intravascular Coagulation (DIC)
      2. Acute Tubular Necrosis (ATN)
    2. Surfactant disorder
      1. Neonatal Respiratory Distress Syndrome
    3. Fibrosis
      1. Idiopathic Pulmonary Fibrosis (chronic)
    4. Granulation
      1. Healing superficial Skin Wound
    5. Microatelectasis
  • Risk Factors
  1. Chronic lung disease
  2. Alcoholism
  3. Age over 65 years
  4. ICU admission (7% develop ALI or ARDS)
  5. Mechanical Ventilation (16% develop ALI or ARDS)
  6. Direct lung injury (see causes below)
  • Causes
  1. Direct lung injury
    1. Pneumonia (highest risk of ARDS, responsible for 60% of ARDS cases)
    2. Respiratory Syncytial Virus
    3. Corona Virus 19 (COVID-19, SARS-CoV2)
    4. Gastric acid Aspiration Pneumonia
    5. Pulmonary Contusion
    6. Fat embolism
    7. Toxic Inhalation Injury
      1. Smoke Inhalation
      2. Chlorine
      3. Nitrogen dioxide
      4. Phosgene
      5. Ammonia
      6. Cocaine
      7. Clove Cigarettes
    8. Near-drowning (high risk)
    9. Severe Pulmonary Hemorrhage
    10. Oxygen Toxicity
  2. Indirect lung injury
    1. Non-Pulmonary Sepsis (responsible for 16% of ARDS cases)
    2. Multiple Trauma (high risk)
    3. Disseminated Intravascular Coagulation
    4. Cardiopulmonary bypass (CABG)
    5. Burn Injury
    6. Acute Pancreatitis
    7. Drug Overdose (Heroin, Cocaine)
    8. Transfusion Reaction
    9. Ingestion
      1. Hydrocarbon Ingestion
      2. Ethchlorvynol (Placidyl)
    10. Non-cardiac pulmonary edema
      1. High Altitude Pulmonary Edema
      2. Neurogenic pulmonary edema
      3. Heroin-induced pulmonary edema
    11. Infection (often in immunocompromised patients)
      1. Miliary Tuberculosis
      2. Diffuse fungal infection
        1. Histoplasmosis
        2. Blastomycosis
        3. Coccidioidomycosis
        4. Cryptococcosis
      3. Parasitic Infections
        1. Babesia species (Babesiosis)
        2. Pneumocystis carinii
        3. Plasmodium species (Malaria)
        4. Strongyloides stercoralis (Threadworm)
  • Symptoms
  1. Onset within 24-72 hours of triggering event
  2. Progressive Dyspnea
  1. Critical for assessment
  2. Most sensitive for identifying ARDS early
  3. Large A-a Gradient
  4. See PaO2/FIO2 under diagnosis below
  • Imaging
  1. Chest XRay
    1. Early: Diffuse, bilateral Interstitial Infiltrates
    2. Later: Diffuse fluffy infiltrates (pulmonary edema)
    3. No cardiomegaly or Pleural Effusions
  2. Chest CT
    1. Acute Phase
      1. Bilateral alveolar opacities
      2. Air Bronchograms
      3. Bullae
      4. Pleural Effusions
    2. Fibroproliferative stage
      1. Bilateral reticular opacities
      2. Decreased Lung Volume
      3. Large bullae
  • Diagnosis
  1. Criteria (Berlin)
    1. Acute onset within one week of known clinical disorder or new or worsening respiratory status
    2. Identifiable cause from above list
    3. Pulmonary Edema not fully explained by Congestive Heart Failure or Fluid Overload
      1. Pulmonary artery wedge pressure <19 mmHg or
      2. No signs of left atrial Hypertension
    4. Hypoxemia despite Supplemental Oxygen
      1. See PaO2 to FIO2 ratios below
    5. Bilateral Pulmonary Infiltrates on Chest XRay
      1. Not fully explained by effusions, lobar or lung collapse or Nodules
  2. Classification: Spectrum of lung injury based on PaO2/FIO2
    1. Interpretation regardless of PEEP
    2. Normal patient PaO2/FIO2: 500 mmHg
    3. ARDS PaO2/FIO2: <300 mmHg with PEEP or CPAP >=5 cm H2O
      1. Mild ARDS <300 mmHg (27-35% mortality)
      2. Moderate ARDS <200 mmHg (32-40% mortality)
      3. Severe ARDS <100 mmHg (45-60% mortality)
  3. Resources
    1. Life in the Fast Lane
      1. https://lifeinthefastlane.com/ccc/pao2fio2-ratio/
  4. References
    1. Bernard (1994) Am J Respir Crit Care Med 149:818-24 [PubMed]
    2. (2012) JAMA 307(23):2526-33 +PMID:22797452 [PubMed]
  • Differential Diagnosis
  1. See Hypoxia
  2. Congestive Heart Failure (CHF)
    1. ARDS is non-cardiogenic pulmonary edema
    2. Critical to distinguish ARDS from CHF, as CHF management is not effective in ARDS
      1. ARDS is managed with supportive care
      2. Avoid Furosemide and ACE Inhibitors in ARDS
    3. ARDS, in contrast to CHF
      1. Heart size is typically normal in ARDS (often difficult to distinguish)
      2. Left atrial Hypertension or volume overload are typically absent in ARDS
    4. Congestive Heart Failure is often accompanied by
      1. Edema
      2. Jugular Venous Distention
      3. S3 gallup
      4. Increased ntBNP
  3. Pneumonia
    1. Pneumonia often has typical features
      1. Fever
      2. Pleuritic Chest Pain
      3. Productive cough
      4. Localized Pulmonary Infiltrate
    2. Many of these features can also be present in ARDS, but a constellation of these symptoms suggests Pneumonia
      1. Pneumonia is also the most common cause of ARDS so may be difficult to distinguish from ARDS
      2. Hypoxia that does not improve wtih Supplemental Oxygen suggests ARDS
  4. Atypical infection
    1. Tuberculosis
    2. Fungal Pneumonia (e.g. Blastomycosis or Coccidioidomycosis)
    3. Pneumocystis Pneumonia
  • Management
  • General (Supportive care)
  1. See Ventilatory Support below
  2. Identify and treat underlying cause
    1. Example: Treat site-specific infections (e.g. Pneumonia)
  3. Maximize nutritional status and fluid balance
    1. Conservative fluid therapy titrated down to lower Central Venous Pressures (shortens ICU stay)
    2. Eicosapentaenoic Acid (fish oil extract) effective
    3. Enteral Nutrition started within 24 to 48 hours of ICU admission (if intubation >3 days anticipated)
      1. See Enteral Nutrition for Intubated Patients,
  4. Inotropic pressure support may be required
  5. Pulmonary artery catheters (and central venous catheters) are not routinely indicated
    1. Choose selectively in complicated fluid status, and then only by experienced clinicians
    2. Higher risk of complications without significantly improved outcomes
  6. Maintain adequate sedation and analgesia
  7. Stress Ulcer prophylaxis
    1. Proton Pump Inhibitor (e.g. Protonix 40 mg IV) or
    2. Sucralfate 1 gram orally or via Nasogastric Tube four times daily or
    3. Ranitidine (e.g. Ranitidine 50 mg IV every 8 hours)
  8. Deep Vein Thrombosis Prevention
    1. Enoxaparin 40 mg SQ daily or
    2. Unfractionated Heparin 5000 units SQ twice daily or
    3. Fondaparinux (Arixtra)
  9. Prone position reduces dependent consolidation
    1. Prone patient for 12 to 16 hours per day
    2. Results in greater lung, alveolar recruitment and improves ventilation-perfusion matching
    3. Prone position requires adequate sedation, and is labor intensive to turn patient
    4. Prone position does not alter hemodynamic parameters
  10. Inhaled Beta Agonists appear effective
    1. Reduce Ventilatory pressures and increase oxygenation
  11. Corticosteroids have mixed outcome results
    1. Consult with a medical intensivist about use
    2. Hydrocortisone is a part of Sepsis protocols in fluid and Vasopressor refractory hemodynamic instability
    3. Older studies showed no consistent benefit in mortality reduction
    4. Some studies show Corticosteroids (e.g. Dexamethasone) decreases days on mechanical Ventilator and mortality
      1. Villar (2020) Lancet Respir Med 8(3):267-76 [PubMed]
  12. Extracorporeal Membrane Oxygenation (ECMO)
    1. Supported as of 2020, in formal guidelines for severe ARDS management
    2. However, ECMO is not uniformly effective in severe ARDS
      1. Most indicated as an emergency rescue measure when Mechanical Ventilation is failing
      2. Combes (2018) N Engl J Med 378(21): 1965-75 +PMID:29791822 [PubMed]
  13. Measures not proven effective
    1. Inhaled nitric oxide
      1. Has been used in severe ARDS, prior to ECMO
      2. No strong evidence of benefit and may be harmful
      3. Gebistorf (2016) (6):CD002787 Cochrane Database Syst Rev +PMID: 27347773 [PubMed]
    2. Aerosolized surfactant replacement
    3. N-Acetylcysteine (Mucomyst)
    4. Vasodilators (e.g. Nitroprusside, Hydralazine)
    5. Prophylactic antibiotics
    6. Prophylactic Chest Tubes
  14. Measures used in Congestive Heart Failure will not be effective in ARDS
    1. Furosemide will not be effective in ARDS
    2. ACE Inhibitors will not be effective for ARDS
    3. Nitroglycerin will not be effective for ARDS
  15. Experimental methods under current evaluation
    1. Liquid ventilation (lung filled with perfluorocarbon)
    2. Surfactant is not recommended for ARDS (outside the perinatal period)
    3. Sarkar (2014) Anesth Essays Res 8(3): 277-82 +PMID: 25886321 [PubMed]
  16. Tracheostomy Tube
    1. Consider Tracheostomy for prolonged intubation (anticipated >8 to 10 days)
  17. Mobilization therapy
    1. Encourage range of motion Exercises and even sitting and standing
    2. Reduces days on Ventilator as well as days in ICU
    3. Improved functional status after Extubation
    4. May require reduced sedation
  1. See Mechanical Ventilation
  2. Overall strategy
    1. Limiting Barotrauma decreases mortality in ARDS
  3. Start with Tidal Volume at 4-6 ml/kg initially
    1. Much lower than Tidal Volume in other conditions (typically 6-8, up to 8-10 ml/kg)
    2. Base Tidal Volume on Ideal Weight for height
  4. Lower FIO2 to avoid alveolar toxicity
    1. Titrate FIO2 down to 0.60 to keep O2 Sat at 88-95%
    2. PaO2 goal 55 to 85 mmHg
  5. Set PEEP for maximal alveolar recruitment
    1. Start with PEEP 5 cm H20 and ideally titrate PEEP >12 cm H2O
    2. See PEEP Table (adjust in concert with FIO2)
    3. Monitor for reduced Cardiac Output
  6. Allow some hypercapnia to reduce Barotrauma risk (permissive hypercapnia)
    1. Lower minute volumes (lower Tidal Volume and rate)
    2. Titrate to PaCO2 up to 50 mmHg (permissive hypercapnia)
      1. PaCO2 >50 mmHg is associated with increased mortality
      2. Nin (2017) Intensive Care Med 43(2): 200-8 [PubMed]
    3. Titrate to pH of 7.20 to 7.30
  7. Maintain plateau pressure (inspiratory pressure) <30 cm H2O
  8. Other settings
    1. Inspiratory to expiratory ratio of 1:2 to 1:3
    2. Respiratory Rate up to 35 breaths per minute
  9. Weaning criteria
    1. Meeting oxygen requirements with non-invasive methods
    2. Hemodynamically stable
    3. Minute ventilation is 15 Liters or less
    4. Positive End-Expiratory Pressure (PEEP) is 5 cm H2O or less
    5. Tolerates 1-2 hour trials of spontaneous breathing
      1. Protects airway
      2. No Agitation
      3. Remains hemodyanmically stable
      4. Oxygen Saturation maintained at 90% or greater
      5. Respiratory frequency to Tidal Volume ratio maintained at 105 or less
      6. Respiratory Rate does not exceed 35 breaths per minute
  • Complications
  1. Nosocomial infection
  2. Pneumothorax (Barotrauma related) in up to 41% of cases
  3. Gastrointestinal Bleeding (Stress Ulcer)
  4. Thromboembolism
  • Course
  1. ARDS presents within 12-24 hours of antecedent event
  2. ARDS patients intubated within 72 hours in 90% cases
  3. High mortality rate
    1. Short-term mortality (ICU: 37%, overall: 42%)
      1. Most deaths are due to multi-organ failure
      2. Refractory Hypoxemia accounts for 16% of deaths
    2. Long-term mortality in the first 3 years following ALI or ARDS
      1. Mechanical Ventilation was required: 57% three year mortality
      2. ICU admission not requiring ventilation: 38% three year mortality
      3. No ICU admission or ventilation: 15% three year mortality
      4. Wunsch (2010) JAMA 303(9): 849-56 [PubMed]
  4. Typical hospital course
    1. ICU stay averages 16 days
    2. Hospital stay averages 26 days
  5. Predictors of better prognosis
    1. Those who survive first 2 weeks have better prognosis
    2. Trauma related ARDS
    3. Best outcomes are at high volume centers where ARDS is commonly treated
    4. Age under 55 years
      1. Children under age 15 years have an overall mortality rate of 18% (contrast with 42% in adults)
      2. Zimmerman (2009) Pediatrics 124(1): 87-95 [PubMed]
  6. Predictors of poor prognosis
    1. Elderly (especially over age 70 years)
    2. Immunocompromised patients
    3. Chronic Liver Disease
    4. Increased dead space fraction
    5. Worsening multiorgan dysfunction
    6. Acute Physiology and Chronic Health Evaluation II (APACHE II Score) high
  • Management
  • Follow-Up ICU Stay
  1. Applies to over 100,000 survivors of ARDS in United States annually
  2. See Post-ICU Ambulatory Care
  3. See Myopathy Following ICU Admission
  4. Anticipate cognitive Impairment
  5. Anticipate lower quality of life
  6. Anticipate delayed return to work
  7. Anticipate decreased functional status (decreased walk distance)
  8. Anticipate prolonged respiratory recovery period
    1. Even at 5 years, some residual pulmonary function deficit persists
  9. Mortality in first 3 years is very high (see above)
  10. Higher morbidity with prolonged Mechanical Ventilation and ICU stay
  11. Psychiatric illness is common following ARDS episode
    1. Major Depression: Up to 43% of patients
    2. Anxiety Disorder: Up to 48% of patients
    3. Posttraumatic Stress Disorder: Up to 35% of patients