Acute Respiratory Distress Syndrome (ARDS)

History

  • In 1967, Ashbaugh Introduced the Term “Respiratory Distress Syndrome” to Describe a Clinical Syndrome with Defined Features
    • Acute Onset of Tachypnea
    • Hypoxemia (see Hypoxemia)
    • Diffuse Pulmonary Infiltrates
    • Decreased Lung Compliance
    • High Short-Term Adult Mortality Rates

Epidemiology

Prevalence

  • LUNG SAFE Global Observational Study of ARDS in 50 Countries (JAMA, 2016) [MEDLINE]
    • Epidemiology
      • Approximately 10.4% of ICU Admissions Fulfilled ARDS Criteria
      • Approximately 23.4% of Mechanically Ventilated Patients Met ARDS Criteria
    • Clinical
      • Clinical Recognition of ARDS Ranged from 51.3% in Mild ARDS to 78.5% in Severe ARDS
    • Therapy
      • Less Than 66% of the Patients Received Tidal Volume <8 mL/kg
      • Proning was Used in Only 16.3% of Patients with Severe ARDS
    • Hospital Mortality Rates
      • Mild ARDS: 34.9%
      • Moderate ARDS: 40.3%
      • Severe ARDS: 46.1%
    • Conclusions
      • ARDS Recognition and Management Has Room for Potential Clinical Improvement

Risk Factors

Prediction of Acute Respiratory Distress Syndrome Using Clinical Factors

  • Lung Injury Prediction Score (LIPS) Study (Am J Respir Crit Care Med, 2011) [MEDLINE]: multicenter observational cohort study (n = 5,584 patients at risk)
    • Acute Lung Injury Occurred at a Median of 2 Days in 6.8% of Patients
    • Acute Lung Injury Can Be Predicted Early in the Course of Illness Using Clinical Parameters
      • Aspiration: LIPS points +2 pts
      • High-Risk Surgery (add 1.5 pts if emergency surgery)
        • Aortic/Vascular: +3.5 pts
        • Cardiac: +2.5 pts
        • Acute Abdomen: +2 pts
        • Orthopedic Spine: +1 pt
      • High-Risk Trauma
        • Traumatic Brain Injury: +2 pts
        • Smoke Inhalation: +2 pts
        • Near Drowning: +2 pts
        • Lung Contusion: +1.5 pts
        • Multiple Fractures: +1.5 pts
      • Pneumonia: +1.5 pts
      • Shock: +2 pts
      • Sepsis: +1 pt
      • Negative Risk Modifiers (Decrease the Risk of Acute Lung Injury)
        • Diabetes Mellitus: -1 pt (only if sepsis)
        • Note: Diabetes Mellitus is the Only Risk factor Which Decreases the Risk of Developing ARDS
      • Positive Risk Modifiers (Increase the Risk of Acute Lung Injury)
        • FIO2 >35%: +2 pts
        • pH <7.35: +1.5 pts
        • Tachypnea with RR >30: +1.5 pts
        • Alcohol Abuse: +1 pts
        • Obesity with BMI >30: +1 pt
        • Hypoalbuminemia: +1 pt
        • Chemotherapy: +1 pt
        • SpO2 <95%: +1 pt
    • Scoring
      • Over 4 points (Optimal Cutoff Point in the Study Based on the Area Under the Curve Analysis): 69% sensitivity and 78% specificity for the prediction of development of ARDS

Prediction of Acute Respiratory Distress Syndrome Using Clinical Factors Present in the Emergency Department

  • Emergency Department Lung Injury Prediction Score Study (EDLIPS)/LIPS-1 Study (Int J Emerg Med, 2012) [MEDLINE]
    • Incidence of Acute Lung Injury was 7%
    • EDLIPS (Obtained Early in ED Course) Discriminated Patients Who Developed Acute Lung Injury Better than APACHE II Scoring and Similar to Original LIPS Score

Age

  • Prospective Multicenter Observational Cohort Study of Hospitalized Patients at Risk of Developing ARDS (from 3/09-8/09) (J Intensive Care Med. 2019 May 8:885066619848357. doi: 10.1177/0885066619848357 [MEDLINE]: n = 5,584 (22 hospitals)
    • Approximately 6.8% of the Patients Developed ARDS
    • After Adjusting for Severity of Illness and the Risk of ARDS Development Attributable to Other Factors, Older Adult Patients Had a Lower Incidence of ARDS, as Compared to Younger Patients (Odds Ratio: 0.28, 95% Confidence Interval: 0.18-0.42)

Corticosteroids (see Corticosteroids)

  • Restrospective Study Examining the Effect of Preadmission Oral Corticosteroid on the Risk of Development of Acute Respiratory Distress Syndrome in ICU Patients with Sepsis (Crit Care Med, 2017) [MEDLINE]: n = 1080
    • Preadmission Oral Corticosteroid Use Decreases the Risk of Early Acute Respiratory Distress Syndrome (Within 96 hrs of ICU Admission) in ICU Patients with Sepsis (35%), as Compared to Patients Who Had Not Received Preadmission Corticosteroids (42%)
    • Higher Corticosteroid Doses (Prednisone 30 qday) were Associated with Lower Risk of ARDS (Odds Ratio 0.53) than were Lower Corticosteroid Doses (Prednisone 5 mg qday)
    • Preadmission Oral Corticosteroid Use Did Not Impact the In-Hospital Mortality Rate, ICU Length of Stay, or Ventilator-Free Days

Etiology

Infection

General

  • Sepsis (see Sepsis)
    • Epidemiology
      • Sepsis is the Most Common Etiology of ARDS
    • Risk Factors for the Development of Sepsis-Associated ARDS
      • Acute Abdomen (Ann Intensive Care, 2017) [MEDLINE]
      • Acute Pancreatitis (Ann Intensive Care, 2017) [MEDLINE]
      • Alcohol Abuse (Crit Care Med, 2003) [MEDLINE] and (Crit Care Med, 2008) [MEDLINE]: ethanol may decrease glutathione concentrations in the epithelial lining fluid, increasing the risk of oxidative injury to the lung
      • Delayed Antibiotics (Crit Care Med, 2008) [MEDLINE]
      • Delayed Goal-Directed Resuscitation (Crit Care Med, 2008) [MEDLINE]
      • Diabetes Mellitus (Crit Care Med, 2008) [MEDLINE]
      • Higher APACHE II Score (Ann Intensive Care, 2017) [MEDLINE]
      • Higher Intravenous Fluid Resuscitation within the First 6 hrs (Ann Intensive Care, 2017) [MEDLINE]: in stratified analysis, the total fluid infused within the first 6 hrs was a risk factor in the non-shock group, but not in the shock group
      • Increased Baseline Respiratory Rate (Crit Care Med, 2008) [MEDLINE]
      • Older Age (Ann Intensive Care, 2017) [MEDLINE]
      • Pneumonia as the Site of Infection (Ann Intensive Care, 2017) [MEDLINE]
      • Recent Chemotherapy (Crit Care Med, 2008) [MEDLINE]
      • Shock (Ann Intensive Care, 2017) [MEDLINE]
      • Transfusion (Crit Care Med, 2008) [MEDLINE]

Viral Pneumonia

Bacterial Pneumonia

Fungal Pneumonia

Parasitic Pneumonia

Aspiration

Trauma/Surgery

  • Burns (see Burns
  • Blast Injury
    • Explosion
    • Lightning
  • Fat Embolism (see Fat Embolism)
  • Head Trauma/Traumatic Brain Injury (TBI) (see Traumatic Brain Injury)
  • Pulmonary Contusion (see Pulmonary Contusion)
  • Surgery
    • Systematic Review/Meta-Analysis of Morbidity/Mortality in Post-Operative Acute Lung Injury (Lancet Respir Med, 2014) [MEDLINE]
      • Incidence of Acute Lung Injury was Similar Following Both Thoracic and Abdominal Surgery
      • Risk Factors for Post-Operative Acute Lung Injury
        • Higher American Society of Anesthesiology (ASA) Score
        • Higher Prevalence of Pre-Existing Sepsis or Pneumonia
        • Older Age
        • Receipt of Blood Transfusions
        • Receipt of High Tidal Volume Ventilation and/or Low PEEP During Surgery
      • Post-Operative Acute Lung Injury Increased ICU Length of Stay and Hospital Length of Stay
      • Overall Attributable Mortality Rate for Post-Operative Acute Lung Injury: 19%
        • Attributable Mortality Rate for Post-Operative Acute Lung Injury Following Thoracic Surgery: 26.5%
        • Attributable Mortality Rate for Post-Operative Acute Lung Injury Following Abdominal Surgery: 12.2%
      • Risk of In-Hospital Mortality was Independent of the Ventilation Strategy
  • Other Trauma

Mechanical Pulmonary Edema

Hemodynamic Disturbance

Hematologic Disorder

Neurogenic Pulmonary Edema (see Neurogenic Pulmonary Edema)

Rheumatologic Disease

Lung Transplant Rejection/Dysfunction (see Lung Transplant Rejection)

Drug

Toxin

  • Acetic Acid Inhalation (see Acetic Acid)
    • Inhalational Exposure
  • Acetic Anhydride Inhalation (see Acetic Anhydride)
    • Inhalational Exposure
  • Acrolein Inhalation (see Acrolein)
    • Inhalational Exposure
  • Acute Beryllium Exposure (see Beryllium)
    • Inhalational Exposure
  • Amitrole Inhalation (see Amitrole)
    • Inhalational Exposure
  • Ammonia Inhalation (see Ammonia)
    • Inhalational Exposure
  • Bromine/Methyl Bromide Inhalation (see Bromine-Methyl Bromide)
    • Inhalational Exposures
      • Bromine Liquid (Readily Vaporizes): used in chemical synthesis and water purification
      • Methyl Bromide Gas (Bromomethane): used as industrial fumigant
  • Carboxyhemoglobinemia (see Carboxyhemoglobinemia)
    • Inhalational Exposure
  • Chlorine Inhalation (see Chlorine)
    • Inhalational Exposure
  • Chloropicrin Gas Inhalation (see Chloropicrin Gas)
    • Inhalational Exposures
      • Chemical Manufacturing
      • Fumigant
      • World War I Wartime Exposure
  • Chromic Acid Inhalation (see Chromic Acid)
    • Inhalational Exposures: used in electroplating
  • Contaminated Rapeseed Oil (see Contaminated Rapeseed Oil)
  • Copper Dust/Fume Inhalation (see Copper)
    • Inhalational Exposure
  • Cyanide Intoxication (see Cyanide)
    • Dermal, Ingestion, and Inhalational Exposures
      • Fire/Smoke Inhalation (see Smoke Inhalation): smoke inhalation is the most common etiology of cyanide intoxication in industrialized countries
      • Industrial Exposure: jewelry electroplating, plastic and rubber manufacturing, metal extraction during mining, photography, hair removal from hides, rodent pesticide and fumigant use
      • Medical Administration: amygdalin (laetrile), nitroprusside (nipride)
      • Dietary Ingestion: Rosaceae family seeds
      • Other: during illicit synthesis of phencyclidine, as a result of terrorist attack, ingestion of acetonitrile nail polish remover, tobacco abuse
  • Diazomethane Inhalation (see Diazomethane)
    • Inhalational Exposure
  • Diborane Gas Inhalation (see Diborane Gas)
    • Inhalational Exposure During Microelectronics Manufacturing
  • Dinitrogen Tetroxide Inhalation (see Dinitrogen Tetroxide)
    • Inhalational Exposure to Rocket Propellant
  • Ethylene Oxide Gas Inhalation (see Ethylene Oxide Gas)
    • Inhalational Exposure During Medical Disinfection and Sterilization
  • Formic Acid Inhalation (see Formic Acid)
    • Inhalational (Aerosol, Vapor) Exposures
      • Leather Tanning
      • Limescale Remover
      • Rubber Manufacturing
      • Textile Industry
      • Toilet Bowl Cleaner
      • Treatment of Livestock Feed: due to to its antibacterial properties
  • Glyphosate Ingestion (see Glyphosate)
    • Ingestion Exposure to Herbicide (Roundup, etc)
  • Heavy Metal Fume Inhalation
  • Hydrocarbons (see Hydrocarbons)
    • Ingestion/Aspiration Exposure
  • Hydrofluoric Acid Inhalation (see Hydrofluoric Acid)
    • Inhalational Exposure
  • Hydrogen Sulfide Gas Inhalation (see Hydrogen Sulfide Gas)
    • Inhalational Exposure
  • Isopropanol Intoxication (see Isopropanol)
  • Lycoperdonosis (see Lycoperdonosis)
    • Inhalational Exposure to Puffball Mushroom (Lycoperdon) Spore, Resulting in Allergic Bronchioloalveolitis
  • Methamphetamine Intoxication (see Methamphetamine)
  • Methyl Isocyanate Inhalation (see Methyl Isocyanate)
    • Inhalational Exposure
  • Methyl Isothiocyanate Inhalation (see Methyl Isothiocyanate)
    • Inhalational Exposure
  • Nitric Acid Inhalation (see Nitric Acid)
    • Inhalational Exposure
  • Nitrogen Dioxide Inhalation (see Nitrogen Dioxide)
    • Inhalational Exposure
  • Nitrogen Mustard Gas Inhalation (see Nitrogen Mustard Gas)
    • Inhalational Exposure
  • Osmium Tetroxide Inhalation (see Osmium Tetroxide)
    • Inhalational Exposure
  • Ozone Inhalation (see Ozone)
    • Inhalational Exposure
  • Palytoxin (see Palytoxin)
    • Epidemiology
      • Palytoxin Rarely is Associated with ARDS
    • Inhalational Exposure to Microalgae (Ostreopsis Ovate, Ostreopsis Siamensis), Corals, and Sea Anemones
  • Paraquat Intoxication (see Paraquat)
    • Ingestion Exposure
  • Phosgene Gas Inhalation (see Phosgene Gas)
    • Inhalational Exposure
  • Phosphine Gas Inhalation (see Phosphine Gas)
    • Inhalational Exposure
  • Polytetrafluoroethylene (PTFE, Teflon) Inhalation (see Polytetrafluoroethylene)
    • Inhalational Exposure
  • Rattlesnake Bite (see Rattlesnake Bite)
  • Smoke Inhalation (see Smoke Inhalation)
    • Inhalational Exposure to Fire (Especially in an Enclosed Space)
  • Sodium Azide Inhalation (see Sodium Azide)
    • Inhalational Exposure During Automobile Airbag Deployment
  • Sulfur Dioxide Inhalation (see Sulfur Dioxide)
    • Inhalational Exposure
  • Sulfuric Acid Inhalation (see Sulfuric Acid)
    • Inhalational Exposure
  • Sulfur Mustard Gas Inhalation (see Sulfur Mustard Gas)
    • Inhalational Exposure
  • Tear Gas Inhalation (see Tear Gas)
    • Inhalational Exposure to Tear Gas Used by Police/Military for Crowd Control
  • White Phosphorus Inhalation (see White Phosphorus)
    • Inhalational Exposure to Firework/Incendiary Explosion
  • Zinc Chloride Gas Inhalation (see Zinc Chloride Gas)
    • Inhalational Exposure to Smoke Bomb

Other


Physiology

Factors Which Promote or Exacerbate Acute Respiratory Distress Syndrome (ARDS)

  • High Tidal Volume (VT)
  • Plateau Pressure >30 cm H2O
  • High Respiratory Rate: due to high frequency of stretch
  • High Rate of Stretch: due to rapid lung inflation

Monocyte Activation

  • Substudy of LIPS-A Trial Examining Monocyte Activation in ARDS (Am J Respir Crit Care Med, 2018) [MEDLINE]
    • Biomarkers of Intravascular Monocyte Activation in At-Risk patients were Associated with the Development of ARDS

Pathology

Pathologic Stages of Acute Respiratory Distress Syndrome (ARDS)

  • Early Exudative Stage (Characterized by Diffuse Alveolar Damage): first 7-10 days
    • Diffuse Alveolar Damage is a Nonspecific Reaction to Lung Injury by a Number of Insults (see Diffuse Alveolar Damage)
      • Diffuse Alveolar Damage is Characterized by Interstitial Edema, Acute/Chronic Inflammation, Type II Cell Hyperplasia, and Hyaline Membrane Formation
    • In Patients with Confirmed ARDS by the Berlin Definition, Approximately 45% Had Diffuse Alveolar Damage on Autopsy (Am J Respir Crit Care Med, 2013) [MEDLINE]
  • Fibroproliferative Stage: lasts 14-21 days
    • Resolution of Pulmonary Edema
    • Type II Alveolar Cell Proliferation
    • Squamous Metaplasia
    • Interstitial Infiltration by Myofibroblasts
    • Early Collagen Deposition
  • Fibrotic Stage
    • Destruction of Normal Lung Architecture
    • Variable Degree of Fibrosis
    • Cyst Formation

Diagnosis

History and Physical Exam Elements Which Should Be Explored in the Patient

  • Cardiac Disease (Which May Suggest Cardiogenic Pulmonary Edema)
    • Chest Pain
    • Dyspnea
    • History of Congestive Heart Failure (CHF)
    • History of Coronary Artery Disease (CAD)
    • Orthopnea (see Orthopnea)
    • Peripheral Edema (see Peripheral Edema)
    • Weight Gain (see Weight Gain)
  • Dermatologic Disease
  • Gastrointestinal/Hepatic Disease
  • Hematologic Disease
  • Infectious Disease
    • Animal Exposures
    • Fever (see Fever)
    • History of Recent Dental Procedures
    • History of Recent Travel (Especially Foreign Travel)
    • History of Tick Exposure (Example: Hiking, Camping, etc)
    • History of Unusual Food Ingestion (Example: Unpasteurized Milk Products, etc)
    • Sick Contacts
  • Malignancy
  • Pulmonary Disease
    • Abnormal Lung Sounds (Crackles, Wheezing, Egophony, etc)
    • Cough/Sputum Production (see Cough)
    • Dyspnea (see Dyspnea)
    • Hemoptysis (see Hemoptysis)
    • History of Choking/Aspiration (see Aspiration Pneumonia)
    • History of Lung Disease (Asthma, Bronchiectasis, Chronic Obstructive Pulmonary Disease)
    • Hypoxemia (see Hypoxemia)
  • Reproductive Disease
    • Abdominal Pain
    • History of Pelvic Inflammatory Disease
    • Pregnancy or Recent Vaginal Delivery/C-Section
    • Vaginal Discharge
  • Rheumatologic Disease
  • Surgery/Trauma
    • Burns (see Burns)
    • Recent Surgery
    • Trauma
  • Medication Use
    • Change in Prescribed Medications
    • New Prescribed Medications
  • Illicit Drug Use
  • Toxin Exposure

Standard Blood Testing

  • Arterial Blood Gas (ABG) (see Arterial Blood Gas)
    • Standardly Utilized to Assess for Hypoxemia and Hypercapnia
      • Arterial Blood Gas is Especially Useful in Patients in Whom SpO2 May Not Correlate Well with the Arterial pO2 (i.e. Patients in Whom the Oxygen-Hemoglobin Dissociation Curve May Be Shifted Either Left or Right, Creating an Unexpected Disparity Between the SpO2 and Arterial pO2)
  • Complete Blood Count (CBC) (see Complete Blood Count)
  • Serum Chemistry with Liver Function Tests (LFT’s) (see Serum Chemistry and Liver Function Tests)
    • Standardly Utilized to Evaluate for Electrolyte Disturbance, Acid-Base Disturbance Abnormality, Abnormal Hepatic Function, and Abnormal Renal Function
  • Serum Amylase and Lipase (see Serum Amylase and Serum Lipase) Serum Amylase is Useful to Evaluate for Acute Pancreatitis in a Patient with Abdominal Pain
  • Coagulation Tests
  • Serum Lactate (see Serum Lactate)
    • Serum Lactate is Standardly Utilized to Evaluate for Sepsis: since sepsis is the most common etiology of ARDS

Infectious Workup

Blood Culture (see Blood Culture)

  • Useful to Rule Out an Infectious Etiology of ARDS

Sputum Culture (see Sputum Culture)

  • Useful to Rule Out Pneumonia an Etiology of ARDS

Bronchoscopy (see Bronchoscopy)

  • Indications
    • Diagnose Aspiration Pneumonia (see Aspiration Pneumonia): food material in the airways may suggest aspiration as the etiology
    • Diagnose Lipoid Pneumonia (see Lipoid Pneumonia): lipid-laden macrophages may suggest the diagnosis (although lung biopsy is usually required ton confirm the diagnosis)
    • Diagnose Uncommon (or Less Easily Diagnosed) Infectious Etiologies
    • Diagnose Malignancy
    • Diagnose Eosinophilic Pneumonias
    • Diagnose Diffuse Alveolar Hemorrhage (DAH) (see Diffuse Alveolar Hemorrhage)
  • Clinical Efficacy
    • Bacterial Pneumonia May Be Diagnosed by Bronchoscopy Even When it is Not Suspected Clinically
      • Autopsy Study Demonstrated Presence of Bacterial Pneumonia in 58% of ARDS Cases, While Only 20% of These Cases were Clinically Suspected Antemortem (Chest. 1981) [MEDLINE]

Lung Biopsy (see Video-Assisted Thoracoscopic Lung Biopsy)

  • May Be Useful in Cases Where Other Diagnostic Testing Has Been Negative/Inconclusive (and Patient is Clinically Worsening or Not Improving)
  • Clinical Efficacy
    • Open Lung Biopsy Can Be Performed Safely in Select Patients with ARDS and Often Reveals an Unsuspected Diagnosis, Leading to an Alteration in Therapy (Chest, 2004) [MEDLINE]: unsuspected diagnoses in the study included infection (n = 8), alveolar hemorrhage (n = 5), and bronchiolitis obliterans organizing pneumonia (n = 5)
    • Diffuse Alveolar Damage is Present in Most Patients with Unresolving ARDS and its Frequency is the Same Regardless of the Stage of ARDS (Mild, Moderate, Severe) (Intensive Care Med, 2015) [MEDLINE]: authors concluded that steroid therapy is not recommended
    • Meta-Analysis of Utility of Open Lung Biopsy in ARDS Demonstrated that Biopsy Revleaed a Wide Range of Diagnoses and was Associated with a Change in Therapy in 78% of Cases (Ann Am Thorac Soc, 2015) [MEDLINE]
      • The Most Common Diagnoses were “Fibrosis/Pneumonitis” (n = 155, 25%; 95% CI: 14-37%) and Infection (n = 113, 20%; 95% CI: 15-27%): viruses were the most common infectious agents (accounted for 50% of infectious cases)
      • Diffuse Alveolar Damage was Present in Only 16% of Specimens
      • Procedure-Related Complications Occurred in 29% of Patients: most commonly persistent air leak

Thoracentesis (see Thoracentesis)

  • Useful to Establish an Infectious Etiology of ARDS (When a Pleural Effusion is Present)

Urinalysis with Urine Culture (see Urinalysis and Urine Culture)

  • Useful to Rule Out Urinary Tract Infection as an Etiology of ARDS

Wound Culture

  • Useful to Establish an Infectious Etiology of ARDS (When a Wound is Present)

GenMark ePlex Respiratory Pathogen Panel (see GenMark ePlex Respiratory Pathogen Panel)

Urinary Legionella Antigen (see Urinary Legionella Antigen)

  • Useful to Evaluate ARDS When Pneumonia is the Inciting Etiology

Urinary Pneumococcal Antigen (see Urinary Pneumococcal Antigen)

  • Useful to Evaluate ARDS When Pneumonia is the Inciting Etiology

Urinary Histoplasma Antigen (see Urinary Histoplasma Antigen)

  • Useful to Evaluate ARDS When Pneumonia is the Inciting Etiology

Human Immunodeficiency Virus (HIV) Test (see Human Immunodeficiency Virus)

  • Useful When HIV is a Diagnostic Consideration

Hantavirus Serology (see Hantavirus Cardiopulmonary Syndrome and Hemorrhagic Fever with Renal Syndrome)

  • Useful When Hantavirus Infection is a Diagnostic Consideration as the Etiology of ARDS

Leptospirosis Serology (see Leptospirosis)

  • Useful When Leptospirosis is a Diagnostic Consideration as the Etiology of ARDS

Respiratory Specimen Testing with rRT-PCR For Middle East Respiratory Syndrome Coronavirus

Severe Acute Respiratory Syndrome Serology and RT-PCR

Coccidioidomycosis Serology (see Coccidioidomycosis Serology)

  • Useful When Coccidioidomycosis is a Diagnostic Consideration as the Etiology of ARDS (see Coccidioidomycosis)

Lung Imaging

Lung Imaging Modalities

  • Chest X-Ray (CXR) (see Chest X-Ray)
    • Presence of Bilateral Pulmonary Infiltrates is Required for the Diagnosis of ARDS
    • Dependent Atelectasis May Be Present
  • Chest Computed Tomography (CT) (see Chest Computed Tomography)
    • Presence of Bilateral Pulmonary Infiltrates is Required for the Diagnosis of ARDS
    • Dependent Atelectasis May Be Present
  • CT Pulmonary Artery Angiogram (see Computed Tomography Pulmonary Artery Angiogram)
    • Occasionally Useful to Exclude Acute Pulmonary Embolism (May Mimic ARDS in Some Cases)
  • Thoracic Ultrasound (see Thoracic Ultrasound)
    • May Be Useful to Evaluate for Pleural Effusion, B-Lines (Which are Believed to Represent Thickened Interlobular Septae), etc

Clinical Efficacy

  • Study of Interobserver Variability in the Radiographic Diagnosis of ARDS (Chest, 1999) [MEDLINE]
    • The Radiographic Criterion used in the Current AECC Definition for ALI/ARDS Showed High Interobserver Variability when Applied by Expert iInvestigators in the Fields of Mechanical Ventilation and ARDS
  • Study of Comparative Accuracy of Chest X-Ray vs Chest CT in the Diagnosis of ARDS (J Crit Care, 2013) [MEDLINE]
    • Chest X-Ray (as Compared to Chest CT)
      • Sensitivity: 73%
      • Specificity: 70%
      • Positive Predictive Value: 88%
      • Negative Predictive Value: 47%
    • Female Sex was Associated with Higher Sensitivity and Lower Specificity
  • Retrospective, Observational Study of Chest CT in Diagnosing ARDS (Respir Care, 2016) [MEDLINE]
    • In Patients with ARDS, the Most Common Pathologic Findings of the Lung Parenchyma were Consolidation (94.1% of Cases) and Ground-Glass Infiltrates (85.3% of Cases)
      • Other CT Scan Findings
        • Pleural Effusions (80.4%)
        • Mediastinal Lymphadenopathy (66.7%)
        • Signs of Right Ventricular Strain and Pulmonary Hypertension (53.9%)
        • Pericardial Effusion (37.3%)
        • Subcutaneous Emphysema (12.3%)
        • Pneumothorax (11.8%)
        • Pneumomediastinum (7.4%)
        • Pulmonary Embolism (2.5%)
    • Results of Chest CT Scans Led to Changes in Management in 26.5% of ARDS Cases
  • Study of Chest X-Ray Diagnosis of Acute Respiratory Distress Syndrome (Crit Care Med, 2018) [MEDLINE]: n = 463
    • Radiographic Criteria for Acute Respiratory Distress Syndrome Have Been Criticized for Poor Reliability
    • Only 56% of Observers Correctly Identified ARDS on Chest X-Ray Studies
    • An Educational Intervention Did Not Improve the Rate of Successful Identification (58%)
    • Overall Agreement Between Raters was 0.296 for the Educational intervention Group and 0.272 for the Control Group (p < 0.001)

Other Imaging

  • Abdominal/Pelvic CT (see Abdominal-Pelvic Computed Tomography)
    • May Be Useful to Evaluate Abdominal Pain in the Setting of ARDS: especially for diagnoses such as abdominal abscess, acute pancreatitis, etc

Specific Testing to Rule Out the Alternative Diagnosis of Cardiogenic Pulmonary Edema (see Pulmonary Edema)

  • General Comments
    • Some of the Same Etiologies Which Cause ARDS (Such as Sepsis) May Also Cause Cardiomyopathy (Eur Heart J, 2012) [MEDLINE]
  • Electrocardiogram (EKG) (see Electrocardiogram)
    • Often Useful to Rule Out Cardiac Etiology of Cardiogenic Pulmonary Edema
  • Serum Brain Natriuretic Peptide (BNP) (see Serum Brain Natriuretic Peptide
    • Often Useful to Rule Out Cardiac Etiology of Cardiogenic Pulmonary Edema: however, it is probably not useful in isolation
    • Prospective Study of BNP in Sepsis (Crit Care Med, 2006) [MEDLINE]
      • In patients with Severe Sepsis/Septic Shock, BNP and N-Terminal Pro-BNP Values are Highly Elevated and (Despite Significant Hemodynamic Differences) Comparable with Those Found in Acute Heart Failure Patients
    • Prospective Cohort Study of Diagnostic Value of BNP in Critically Ill Patients with Pulmonary Edema (Crit Care, 2008) [MEDLINE]: n= 54
      • BNP Level Drawn within 48 hrs of ICU Admission Do Not Reliably Distinguish ARDS from Cardiogenic Pulmonary Edema, Do Not Correlate with Invasive Hemodynamics, and Daily Measurements Do Not Track Predictably with Volume Status
      • BNP<100 pg/mL Identified ARDS with Sensitivity of 27%/Specificity of 95%
  • Serum Troponin (see Serum Troponin)
    • Often Useful to Rule Out Cardiac Etiology of Cardiogenic Pulmonary Edema
  • Echocardiogram (see Echocardiogram)
    • Often Useful to Rule Out Cardiac Etiology of Cardiogenic Pulmonary Edema
  • Swan-Ganz Catheter (see Swan-Ganz Catheter)
    • May Be Useful in Select Cases to Rule Out Cardiac Etiology (of Cardiogenic Pulmonary Edema)
    • Clinical Efficacy
      • Study of Pulmonary Capillary Wedge Pressure in Acute Respiratory Distress Syndrome (Intensive Care Med, 2002) [MEDLINE]
        • Median PCWP was 16.6 mm Hg in ARDS Patients
        • Patients Who Met Standard Criteria for ARDS Were More Likely to Have a High PCWP
        • PCWP >18 mm Hg was a Strong Predictor of Mortality in ARDS Patients (After Correction of Baseline Differences)
      • Study of Swan-Ganz Catheter to Guide Treatment of Acute Respiratory Distress Syndrome (N Engl J Med, 2006) [MEDLINE]
        • Swan-Ganz Catheter-Guided Therapy Did Not Improve Mortality Rate or Organ Function, But was Associated with More Complications than Central Venous Catheter-Guided Therapy
      • Study of Swan-Ganz Catheter in Shock and ARDS (JAMA, 2003) [MEDLINE]
        • Early Use of Swan-Ganz Catheter Did Not Improve Morbidity or Mortality in Patients with Shock and/or ARDS
    • Recommendations (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]
      • Swan-Ganz Catheter is Not Routinely Recommended in the Management of Sepsis-Associated ARDS (Strong Recommendation, High Quality of Evidence)
  • FloTrac (see FloTrac)

Specific Testing to Rule Out the Alternative Diagnosis of Venous Thromboembolism (see Deep Venous Thrombosis and Acute Pulmonary Embolism)

Other


Clinical: Berlin Definition of Acute Respiratory Distress Syndrome (ARDS) (JAMA, 2012) [MEDLINE]

Criteria for the Diagnosis of ARDS

  • Timing: within 1 week of a known clinical insult or worsening respiratory symptoms
  • Chest Imaging: bilateral pulmonary infiltrates (on chest x-ray or chest CT) which are not fully explained by effusions, lobar/lung collapse, or lung nodules
  • Origin of Edema: not due to cardiac origin or fluid overload
    • Objective Assessment (Echocardiogram, Swan, etc): required in the absence of risk factors for ARDS
  • Oxygenation: using pO2/FIO2 ratio (pO2 in mm Hg, FIO2 in decimal)
    • General Comments
      • In Cases Where ABG Cannot Be Obtained, Nonlinear Imputation of PaO2/FIO2 from the SpO2/FIO2 Ratio Could Alternatively Be Used (Crit Care Med, 2017) [MEDLINE]
    • Mild ARDS: pO2/FIO2 ratio 200-300 with PEEP/CPAP ≥5 cm H20
    • Moderate ARDS: pO2/FIO2 ratio 100-200 with PEEP/CPAP ≥5 cm H20
    • Severe ARDS: pO2/FIO2 ratio ≤100 with PEEP/CPAP ≥5 cm H20

Clinical Manifestations

Cardiovascular Manifestations

Gastrointestinal Manifestations

  • Elevated Liver Function Tests (LFT’s) (see Elevated Liver Function Tests)
    • Epidemiology
      • Variably Present
    • Clinical
      • Transaminitis

Hematologic Manifestations

  • Coagulopathy (see Coagulopathy)
    • Epidemiology
      • While Coagulopathy May Occur in ARDS, Disseminated Intravascular Coagulation (DIC) is Uncommon, Except When Sepsis or Malignancy is Present
    • Clinical
      • Elevated Partial Thromboplastin Time (PTT)
      • Elevated Prothrombin Time (PT)
  • Elevated Plasma D-Dimer (see Elevated Plasma D-Dimer)
    • Epidemiology
      • Variably Present
  • Leukocytosis with/without Bandemia (see Leukocytosis)
    • Epidemiology
      • Variably Present
  • Leukopenia (see Leukopenia
    • Epidemiology
      • Variably Present

Pulmonary Manifestations

Bilateral Pulmonary Infiltrates

  • Epidemiology
    • By Definition, Bilateral Pulmonary Infiltrates are a Required Diagnostic Feature of ARDS
    • Radiographic Pulmonary Infiltrates Generally Appear Between 6-72 hrs Following an Inciting Event
  • Physiology
    • Alveolar Filling Process
  • Diagnosis
    • Decreased Lung Compliance: static and dynamic compliance can be measured on the ventilator
    • Increased Dead Space/Tidal Volume (VD/VT) Ratio
    • Chest X-Ray (see Chest X-Ray)
      • Alveolar Infiltrates (with/without Dependent Atelectasis)
      • Atelectasis: may also be present
    • Chest CT (see Chest Computed Tomography)
      • Alveolar Filling/Consolidation
      • Ground-Glass Infiltrates
      • Atelectasis: may also be present
  • Clinical
    • Cough (see Cough)
    • Crackles
    • Cyanosis (see Cyanosis): may occur in severe cases
    • Dyspnea (see Dyspnea)
    • Increased A-a Gradient Hypoxemia (see Hypoxemia)
      • Epidemiology
        • Type I-Hypoxemic Respiratory Failure: most commonly observed
        • Type II-Hypoxemic, Hypercapnic Respiratory Failure: may be observed in cases with severe ARDS (and usually requires mechanical ventilation)
    • Respiratory Alkalosis (see Respiratory Alkalosis)
    • Tachypnea (see Tachypnea)

Bronchospasm (see Obstructive Lung Disease)

  • Epidemiology
    • Variably Present
  • Clinical
    • Increased Peak Inspiratory Pressure-Plateau Pressure Difference (>5 cm H2O) on Ventilator
    • Wheezing (see Wheezing)

Diffuse Alveolar Hemorrhage (DAH) (see Diffuse Alveolar Hemorrhage)

  • Epidemiology
    • While Low-Grade Diffuse Alveolar Hemorrhage May Occur in Some Cases of ARDS, the Presence of Significant Hemoptysis Requires that Diffuse Alveolar Hemorrhage is Ruled Out as a Primary Disorder
  • Diagnosis
    • Bronchoscopy (see Bronchoscopy: routinely used to evaluate hemoptysis in the setting of ARDS
  • Clinical

Pulmonary Hypertension (see Pulmonary Hypertension)

  • Physiology
    • Hypercapnia-Induced Pulmonary Vasoconstriction (see Hypercapnia) (J Appl Physiol, 2003) [MEDLINE]
      • Hypercapnic Vasoconstriction May Be Responsive to Nitric Oxide
      • When Associated with High PEEP in the Setting of ARDS, Hypercapnic Vasoconstriction May Result in RV Dysfunction (Intensive Care Med, 2009) [MEDLINE]
    • Hypoxemia-Induced Pulmonary Vasoconstriction (see Hypoxemia)
      • Hypoxic Vasoconstriction is Enhanced by Acidosis

Other Manifestations

  • Fever (see Fever)
    • Presence of Fever (or Hypothermia) is Associated with Delayed Liberation from Mechanical Ventilation
      • Analysis of Prospective Cohort Study Evaluating the Impact of Fever on Ventilator Weaning in Patients with Acute Respiratory Distress Syndrome (Ann Am Thorac Soc, 2013) [MEDLINE]: n = 450 (from 13 ICU’s at 4 hospitals in Baltimore, Maryland)
        • Only 12% of Patients were Normothermic During the First 3 Days After Onset of Acute Respiratory Distress Syndrome
        • Fever was Associated with Delayed Liberation from Mechanical Ventilation
        • During the First Week Post-Acute Respiratory Distress Syndrome, Each Additional Day of Fever Resulted in a 33% Reduction in the Likelihood of Successful Ventilator Liberation (95% Confidence Interval for Adjusted Hazard Ratio, 0.57-0.78; P<0.001
        • Hypothermia was Associated with Delayed Liberation from Mechanical Ventilation and Increased Mortality Rate
        • Hypothermia was Independently Associated with Decreased Ventilator-Free Days (Hypothermia During Each of the First 3 Days: Reduction of 5.58 Days, 95% CI: -9.04 to -2.13; P = 0.002)
        • Hypothermia was Independently Associated with Increased Mortality (Hypothermia During Each of the First 3 Days: Relative Risk, 1.68; 95% CI: 1.06-2.66; P = 0.03)

Complications

Infectious Complications

  • Central Line-Associated Blood Stream Infection (CLABSI) (see Central Venous Catheter)
    • Epidemiology
      • May Occur as a Complication When a Central Venous Catheter Has Been Previously Placed as a Component of Either Sepsis or ARDS Therapy
  • Sepsis (see Sepsis)
    • Epidemiology
      • May Occur as a Complication in a Critically Ill Patient with Portals for Entry (Endotracheal Tube, Central Venous Catheter, etc)

Gastrointestinal Complications

  • Clostridium Difficile Colitis (see Clostridium Difficile)
    • Epidemiology
      • May Occur as a Complication When Antibiotics Have Been Previously Utilized in the Treatment of ARDS
  • Impaired Nutrition
    • Epidemiology
      • May Occur as a Complication in a Critically Ill Patient

Vascular Complications

  • Deep Venous Thrombosis (DVT) (see Deep Venous Thrombosis)
    • Epidemiology
      • May Occur as a Complication in an Immobilized, Critically Ill Patient

Neurologic Complications

  • Delirium (see Delirium)
    • Epidemiology
      • Delirium is a Common Complication in Critical Illness (Both as a Component of the Primary Disease Process and as a Result of Treatments Such as Sedation, etc)
        • BRAIN-ICU Study (NEJM, 2013) [MEDLINE]: in a study of patients with respiratory failure or shock in the medical or surgical intensive care unit (n = 821), 74% of cases had delirium
  • Intensive Care Unit (ICU)-Acquired Weakness (see Intensive Care Unit-Acquired Weakness)
    • Epidemiology
      • Generalized Weakness is a Common Complication of Critical Illness with Prolonged Immobilization
        • Study of Vasoactive Medications in Mechanically-Ventilated Patients (Chest, 2018) [MEDLINE]: in mechanically-ventilated patients, the use of vasoactive medications was associated with an increased risk of ICU-acquired weakness
  • Sleep Disturbance
    • Epidemiology
      • May Occur as a Complication in a Critically Ill Patient

Pulmonary Complications Associated with the Use of Invasive Mechanical Ventilation (see Invasive Mechanical Ventilation-Adverse Effects and Complications)

Renal Complications

  • Acute Kidney Injury (AKI) (see Acute Kidney Injury)
    • Epidemiology
      • AKI Occurs in Approximately 68% of ARDS Patients (After ARDS Onset) (Ann Intensive Care, 2019) [MEDLINE]
    • Retrospective Study of Risk Factors for the Development of AKI in Patients with ARDS (Ann Intensive Care, 2019) [MEDLINE]: n = 357
      • Approximately 24.6% of Patients had Stage I AKI, 27% had stage II AKI, and 48.4% had Stage III AKI
      • Median Time of AKI Onset for Stage I AKI was 2 Days (Interquartile Range: 1.5–5.5), While Stage II and III AKI was 4 Days
      • Risk Factors
        • Acidosis (on Day 1 of ARDS): subdistribution hazard ratio per 0.1 units decrease was 1.18 (95% CI: 1.05–1.32)
        • Age: subdistribution hazard ratio 1.01 (95% CI: 1.00–1.02)
        • Higher Severity of Illness (SOFA Score): subdistribution hazard ratio 1.16 (95% CI: 1.12–1.21)
        • History of Diabetes Mellitus (see Diabetes Mellitus): subdistribution hazard ratio 1.42 (95% CI: 1.07–1.89)

Prevention

General Comments

  • Prevention of ARDS is an Important Clinical Goal, Since the Radiographic Identification of the Findings of ARDS is Generally Unreliable (Crit Care Med, 2018) [MEDLINE]

Aspirin (see Acetylsalicylic Acid)

  • LIPS-A (Phase 2b) Trial of Aspirin to Prevent ARDS in Patients Presenting to the ED Who are At-Risk for ARDS (JAMA, 2016) [MEDLINE]
    • Aspirin Administered to At-Risk Patients in the Emergency Department Had No Clinical Benefit in the Prevention of ARDS at 7 Days

Low Tidal Volume Ventilation

  • IMPROVE Trial of Low Tidal Volume Ventilation in Abdominal Surgery Patients at Risk for ARDS (N Engl J Med, 2013) [MEDLINE]
    • As Compared with Nonprotective Mechanical vVentilation, the Lung Protective Ventilation in Intermediate/High-Risk Patients Undergoing Major Abdominal Surgery was Associated with Improved Clinical Outcomes and Decreased Health Care Utilization
    • Meta-Analysis of Low Tidal Volume Ventilation in Patients without ARDS (Intensive Care Med, 2014) [MEDLINE]
    • Use of Lower Tidal Volumes in Patients without ARDS at the Onset of Mechanical Ventilation Could Be Associated with a Shorter Duration of Ventilation
    • Use of Lower Tidal Volumes Seems No to Affect Sedation or Analgesia Needs, But This Must Be Confirmed in a Robust, Well-Powered Randomized Controlled Trial
  • Meta-Analysis of Efficacy of Intraoperative Low Tidal Volume Ventilation in Preventing Postoperative Pulmonary Complications (Ann Surg, 2016) [MEDLINE]: n = 1054 (16 studies)
    • Intraoperative Low Tidal Volume Ventilation in Conjunction with PEEP and Recruitment Maneuvers Improved Clinical Pulmonary Outcomes (Atelectasis, Lung Infection, Acute Lung Injury) and Decreased Hospital Length of Stay in Otherwise Healthy Patients Undergoing General Surgery
  • PReVENT Trial Comparing Low (7 mL/kg PBW) vs Intermediate (9 mL/kg PBW) Tidal Volume Ventilation in ICU Patients at Risk for ARDS (JAMA, 2018) [MEDLINE]: n = 961 (6 centers)
    • Study Design
      • The Majority of Patients were Randomized within 1 hr of Start of Mechanical Ventilation
      • Only Patients Who were Not Expected to Be Extubated within 24 hrs of Randomization were Included in the Trial
      • Low Tidal Volume Group Used Higher Tidal Volume (7 mL/kg PBW) than in Other Similar Studies (Which Generally Used 6 mL/kg PBW), Because Pressure Support was Used More Frequently in this Group
        • By Day 1, 58% of Patients in the Low Tidal Volume Group were Receiving Pressure Support Ventilation (Which Allowed Large Spontaneous Tidal Volumes if the Patients were on Minimal Ventilatory Support)
        • On Day 1, 59% of Patient in the Low Tidal Volume Group Received a Tidal Volume >6 mL/kg PBW and 14% of Patients Received a Tidal Volume >9.5 mL/kg PBW
        • On Days 1 and 2, Respectively, Estimates Suggest that Only 25% and 25% of Patients in the Intermediate Tidal Volume Group Received Tidal Volumes >10 mL/kg PBW
    • In ICU Patients without ARDS, There was No Difference Between Low Tidal Volume Ventilation Strategy (7 mL/kg PBW) and Intermediate Tidal Volume Ventilation Strategy (9 mL/kg PBW), in Terms of Ventilator-Free Days at Day 28
    • In ICU Patients without ARDS, There was No Difference Between Low Tidal Volume Ventilation Strategy (7 mL/kg PBW) and Intermediate Tidal Volume Ventilation Strategy (9 mL/kg PBW), in Terms of ICU Length of Stay, Hospital Length of Stay, 90-Day Mortality, Incidence of ARDS, Incidence of Pneumonia, Incidence of Severe Atelectasis, and Incidence of Pneumothorax
    • Possible Explanations for Lack of Effect of the Low Tidal Volume Ventilation Strategy
      • The Low Tidal Volume Ventilation Strategy was Associated with Respiratory Acidosis, Which Might Have Influenced the Duration of Ventilation
      • Driving Pressure in the Intermediate Volume Ventilation Strategy was Still within a Protective Range for Patients without ARDS
    • Critique
      • Some Experts Have Suggested that the PReVENT Trial Demonstrates that a Negative Trial May Be the Result of Inadequate Separation Between Interventions

Treatment

General Comments

Summary of Strategies to Improve Oxygenation in the Mechanically Ventilated Patient with Acute Respiratory Distress Syndrome (ARDS)

  • Increase Inspired Oxygen Fraction (FIO2)
    • Physiology
      • Increasing FIO2 Increases the Alveolar pO2
  • Treat Factors Which Increase Oxygen Consumption
    • Factors
      • Anxiety/Agitation (see Anxiety and Agitation): anxiety/agitation increase respiratory muscle work
        • Treat with Sedation, Analgesia, and Paralytics (if required)
      • Fever (see Fever): fever increases the metabolic rate
        • Treat with Antipyretics (Acetaminophen, etc)
      • Pain: pain can increase respiratory muscle work
        • Treat with Analgesia
  • Treat Acidosis (see Metabolic Acidosis-General)
  • Treat Airway Obstruction (see Obstructive Lung Disease)
    • Physiology
      • Bronchodilators Improve V/Q Matching and Decrease Lung Water
  • Address Patient-Ventilator Dyssynchrony (If Present) (see Ventilator Mechanics)
    • Physiology
      • Improving Ventilator Synchrony Decreases the Work of Breathing, Resulting in Improved Oxygenation and Decreased Risk of Barotrauma
  • Optimize Fluid Status
    • Physiology
      • Decreasing Lung Water Enhances Pulmonary Gas Exchange
  • Increase Positive End-Expiratory Pressure (PEEP) (see Invasive Mechanical Ventilation-General)
    • Physiology
      • See Below
  • Proning
    • Physiology
      • See Below
  • Change in Ventilator Mode
  • Venovenous Extracorporeal Membrane Oxygenation (VV-EMCO) (see Venovenous Extracorporeal Membrane Oxygenation)

Treatment of Fever (see Fever)

Rationale

  • Fever Undesirably Increases Oxygen Consumption
  • Fever Exacerbates the Development of Lung Injury (in Animal Studies)

Clinical Efficacy

  • Rabbit Study of Treatment of Fever in Lung Injury (Crit Care Med, 2004) [MEDLINE]
    • Hyperthermia Augmented the Development of Lung Injury in a Rabbit Model, as Compared to Hypothermia: effects were not due to cardiovascular factors or consequences of heating non-pulmonary organs

Bronchodilators

Agents

Clinical Efficacy

  • BALTI and BALTI-2 Trials (Am J Respir Crit Care Med, 2006) [MEDLINE] (Health Technol Assess, 2013) [MEDLINE]
    • BALTI Trial Indicated that Intravenous Salbutamol May Decrease Extravascular Lung Water and Plateau Pressure
    • BALTI-2 Indicated that Treatment with Intravenous Salbutamol Early in the Course of ARDS is Poorly Tolerated, Unlikely to Be Beneficial, and Could Worsen Outcomes
  • National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network Study of Inhaled β2-Agonists (Am J Respir Crit Care Med, 2011) [MEDLINE]
    • Aerosolized Albuterol Did Not Improve Clinical Outcome in Acute Lung Injury: therefore, routine use of β2-agonist therapy in mechanically ventilated patients with ALI is not recommended

Recommendations for Patients with ARDS Associated with Sepsis (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]

  • In the Absence of Bronchospasm, β2-Agonists are Not Recommended in Sepsis-Associated ARDS (Strong Recommendation, Moderate Quality of Evidence)

Management of Ventilator-Induced Lung Injury (VILI)/Barotrauma

Management of Patient-Ventilator Dyssynchrony

Corticosteroids (see Corticosteroids)

Clinical Efficacy

  • National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network Corticosteroids in Persistent ARDS Study (NEJM, 2006) [MEDLINE]: RCT (n = 180) ARDS patients of at least 7 days duration
    • Corticosteroid Use in ALI/ARDS Did Not Alter the Mortality Rate, Sepsis Rate, Renal Dysfunction Rate, or Hepatic Dysfunction Rate
    • Starting Methylprednisolone Therapy >2 wks After the Onset of ARDS May Increase the Risk of Death
    • Corticosteroids Facilitated Ventilator Withdrawal in ARDS, But Increased Reintubation Rates
  • Meta-Analysis of Corticosteroids in ARDS (Respirology, 2007) [MEDLINE]
    • Corticosteroids Had No Benefit in Either Early or Late ARDS
  • Meta-Analysis of Corticosteroids in ARDS (BMJ, 2008) [MEDLINE]
    • Corticosteroids Had Unclear Benefit in ARDS
    • Preventative Corticosteroids Possibly Increased the Risk of ARDS in Critically Ill Patients
  • Meta-Analysis of Glucocorticoids in ARDS (Intensive Care Med, 2008) [MEDLINE]
    • Prolonged Glucocorticoids Improved Patient-Centered Outcome Variables and Had a Survival Benefit When Initiated Before Day 14 of ARDS
  • Consensus Statement from the American College of Critical Care Medicine (Crit Care Med, 2008) [MEDLINE]
    • Moderate-Dose Glucocorticoids Should Be Considered in the Management Strategy of Patients with Early Severe ARDS and Before Day 14 for Patients with Unresolving ARDS (Weak 2b Recommendation, Moderate Quality Evidence)
  • Systematic Review and Meta-Analysis of Corticosteroids in ALI/ARDS (Crit Care Med, 2009) [MEDLINE]
    • Low-Dose Corticosteroids Were Associated with Improved Mortality and Morbidity Outcomes Without Increased Adverse Reactions in ALI/ARDS: however, the mortality benefits in early ARDS should be confirmed by an adequately powered randomized trial
  • Effect of Corticosteroids on the Development of Delirium in ALI/ARDS (Crit Care Med, 2014) [MEDLINE]: prospective cohort study
    • After Adjusting for Other Risk Factors, Systemic Corticosteroids Were Significantly Associated with the Development of Delirium in ALI/ARDS
  • Study of the Role of Open Lung Biopsy in Unresolving ARDS (Intensive Care Med, 2015) [MEDLINE]
    • Diffuse Alveolar Damage is Present in Most Patients with Unresolving ARDS and its Frequency is the Same Regardless of the Stage of ARDS (Mild, Moderate, Severe): on this basis, authors concluded that corticosteroid therapy is not recommended
  • Meta-Analysis of Corticosteroids in ARDS (Intensive Care Med, 2016) [MEDLINE]
    • Prolonged Methylprednisolone Accelerated the Resolution of ARDS, Decreased Hospital Mortality (20% vs 33%), and Increased ICU-Free Days: analysis of the data suggests that any benefit is likely limited to patients in whom corticosteroid treatment is initiated prior to day 14
    • Methylprednisolone Did Not Increase the Risk for Infection

General Recommendations

  • Glucocorticoids Should Not Routinely Be Administered to Patients with ARDS
    • Glucocorticoids Used Early in the Course of ARDS (<14 Days): glucocorticoids have unclear benefit
    • Glucocorticoids Used Late in the Course of ARDS (≥14 Days): glucocorticoids are not beneficial

Recommendations for Critically Ill Patients (American College of Critical Care Medicine Consensus Statement on the Diagnosis and Management of Corticosteroid Insufficiency in Critically Ill Adult Patients, Crit Care Med, 2008) [MEDLINE]

  • General Comments: involved a multi-disciplinary, multi-specialty group from the membership of the Society of Critical Care Medicine, the European Society of Intensive Care Medicine, and international experts in endocrinology
  • Agents
    • Methylprednisolone (1 mg/kg/day for ≥14 Days) is Recommended in Patients with Severe Early Acute Respiratory Distress Syndrome
  • Administration
    • Glucocorticoids Should be Weaned and Not Stopped Abruptly
    • Reinstitution of Glucocorticoids Should Be Considered with Recurrence of Signs of Sepsis, Hypotension, or Worsening Oxygenation
  • Glucocorticoids in the Management of Patients with Community-Acquired Pneumonia, Liver Failure, Pancreatitis, Those Undergoing Cardiac Surgery, and Other Groups of Critically Ill Patients Requires Further Investigation

Fluid Management

Rationale

  • Decreased Lung Water Results in Improved Oxygenation

Exclusion Criteria for Diuresis of the ARDS Patient

  • Hypotension (see Hypotension)
  • Recent Vasopressor Use (Within 12 hrs)
  • Central Venous Pressure (CVP) <4 mm Hg (see Hemodynamics)
  • Oliguria + Central Venous Pressure (CVP) 4-8 mm Hg (see Hemodynamics)

Clinical Efficacy-Swan-Ganz Catheter (see Swan-Ganz Catheter)

  • Study of Pulmonary Capillary Wedge Pressure in Acute Respiratory Distress Syndrome (Intensive Care Med, 2002) [MEDLINE]
    • Median PCWP was 16.6 mm Hg in ARDS Patients
    • Patients Who Met Standard Criteria for ARDS Were More Likely to Have a High PCWP
    • PCWP >18 mm Hg was a Strong Predictor of Mortality in ARDS Patients (After Correction of Baseline Differences)
  • Study of Swan-Ganz Catheter to Guide Treatment of Acute Respiratory Distress Syndrome (N Engl J Med, 2006) [MEDLINE]
    • Swan-Ganz Catheter-Guided Therapy Did Not Improve Mortality Rate or Organ Function, But was Associated with More Complications than Central Venous Catheter-Guided Therapy
  • Study of Swan-Ganz Catheter in Shock and ARDS (JAMA, 2003) [MEDLINE]
    • Early Use of Swan-Ganz Catheter Did Not Improve Morbidity or Mortality in Patients with Shock and/or ARDS

Clinical Efficacy-Fluid Management Strategy

  • Study of Albumin + Lasix for Fluid Removal in ALI (Crit Care Med, 2002) [MEDLINE]
    • Albumin and Furosemide Therapy Improved Fluid Balance, Oxygenation, and Hemodynamics in Hypoproteinemic Patients with ALI
  • Study of Albumin + Lasix for Fluid Removal in ALI/ARDS (Crit Care Med, 2005) [MEDLINE]
    • The addition of albumin to furosemide therapy in hypoproteinemic patients with ALI/ARDS significantly improves oxygenation, with greater net negative fluid balance and better maintenance of hemodynamic stability
  • Fluid and Catheter Treatment Trial (FACTT): Comparison of Two Fluid Management Strategies in Acte Lung Injury (NEJM, 2006) [MEDLINE]: randomized trial (n = 1000) in patients with acute lung injury, comparing aconservative (CVP <4, PCWP <8) and liberal (CVP 10-14, PCWP 14-18) strategies of fluid management
    • Conservative Fluid Management Strategy Did Not Impact 60-Day Mortality
    • Conservative Fluid Management Strategy Improved Oxygenation, Increased Ventilator-Free Days, and Decreased ICU Stay
    • Conservative Fluid Management Strategy Had No Impact on Shock, Non-Pulmonary Organ Failure, or Need for Hemodialysis
  • The Adult Respiratory Distress Syndrome Cognitive Outcomes Study (Am J Resp Crit Care Med, 2012) [MEDLINE]
    • Fluid Management Strategy is a Potential Risk Factor for Long-Term Cognitive Impairment
  • Systematic Review and Meta-Analysis of Albumin in ARDS (Crit Care, 2014) [MEDLINE]
    • Albumin Improved Oxygenation, But Did Not Impact the Mortality Rate: randomized controlled trials are needed
  • Study of Simplified Conservative Fluid Management Strategy in ARDS (“FACTT Lite”) (Crit Care Med, 2015) [MEDLINE]: trial used simpified prootcol based on CVP (or PCWP, if available) and urine output
    • FACTT Lite Protocol
      • CVP >8 (or PCWP >12) + Urine Output <0.5 mL/kg/hr -> furosemide, reassess in 1 hr
      • CVP >8 (or PCWP >12) + Urine Output ≥0.5 mL/kg/hr -> furosemide, reassess in 4 hrs
      • CVP 4-8 (or PCWP 8-12) + Urine Output <0.5 mL/kg/hr -> give fluid bolus, reassess in 1 hr
      • CVP 4-8 (or PCWP 8-12) + Urine Output ≥0.5 mL/kg/hr -> furosemide, reassess in 4 hrs
      • CVP <4 (or PCWP <8) + Urine Output <0.5 mL/kg/hr -> give fluid bolus, reassess in 1 hr
      • CVP <4 (or PCWP <8) + Urine Output ≥0.5 mL/kg/hr -> no intervention, reassess in 4 hrs
    • FACTT Lite Had a Greater Cumulative Fluid Balance than FACTT Conservative, But Had Equivalent Clinical and Safety Outcomes in ARDS
  • Study of the Association Between Fluid Balance and Survival in Critical Illness (J Intern Med, 2015) [MEDLINE]
    • Positive Fluid Balance at the Time of ICU Discharge is Associated with Increased 90-Day Mortality, Especially in Patients with Underlying Heart/Kidney Disease
  • Secondary Analysis of FACTT Trial Data (Ann Am Thorac Soc, 2017) [MEDLINE]
    • Conservative Fluid Management Improved 1-Year Mortality in Non-Hispanic Black ARDS Patients, with No Benefit Observed in White Subjects

Recommendations for Patients with ARDS Associated with Sepsis (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]

  • Conservative Fluid Management Strategy is Recommended in Established Sepsis-Associated ARDS without Evidence of Tissue Hypoperfusion (Strong Recommendation, Moderate Quality of Evidence)
  • Swan-Ganz Catheter is Not Routinely Recommended in the Management of Sepsis-Associated ARDS (Strong Recommendation, High Quality of Evidence)

Supplemental Oxygen Therapy (see Oxygen)

Clinical Efficacy

  • Randomized Trial of Conservative Oxygen Strategy in Mechanically-Ventilated Patients (Am J Respir Crit Care Med, 2016) [MEDLINE]
    • Conservative Oxygen Strategy (SpO 88-92%) Did Not Impact the ICU or 90-Day Mortality Rate or Risk of Organ Dysfunction, as Compared to Liberal Oxygen Strategy (SpO2 ≥96%)
  • Italian Oxygen-ICU Trial of Conventional Oxygen Strategy (pO2 Up to 150 mm Hg or SaO2 97-100%) vs Conservative Oxygen Strategy (pO2 70-100 or SaO2 94-98%) in a General ICU Population (Stay of ≥72 hrs) (JAMA, 2016) [MEDLINE]
    • Trial Had Unplanned, Early Termination
    • Conservative Oxygen Strategy Decreased the Mortality Rate, as Compared to Conventional Oxygen Strategy
  • French HYPERS2S Trial of Hyperoxia and Hypertonic Saline in Septic Shock (Lancet Respir Med, 2017) [MEDLINE]
    • Trial Stopped Prematurely for Safety Reasons
    • Setting FiO2 to 100% to Induce Arterial Hyperoxia Might Increase the Mortality Rate in Septic Shock
    • Hypertonic (3%) Saline Resuscitation Did Not Decrease the Mortality Rate in Septic Shock
  • Improving Oxygen Therapy in Acute-illness (IOTA) Systematic Review and Meta-Analysis of Conservative vs Liberal Oxygen Strategy in Critically Ill Patients (Lancet, 2018) [MEDLINE]: n = 25 trials (in patients with sepsis, critical illness, stroke, trauma, myocardial infarction, cardiac arrest, and emergency surgery)
    • In Acutely Ill Adults, Liberal Oxygen Therapy Strategy (Median SaO2 96%, Range 94-99%) Increases the 30-Day (and Longest Follow-Up) Mortality Rate, as Compared to a Conservative Oxygen Therapy Strategy (Relative Risk at 30 Days was 1.21, 95% CI 1.03-1.43)
      • Supplemental Oxygen Might Become Unfavorable with SaO2 >94-96%
  • Post Hoc Analysis of HYPERS2S Trial Data (Ann Intensive Care, 2018) [MEDLINE]
    • Hyperoxia May Be Associated with a Increased Mortality Rate in Patients with Septic Shock Using the Sepsis-3 Criteria (with Serum Lactate > 2 mmol/L), But Not in Patients with Hypotension Alone
    • In Patients with Serum Lactate ≤2 mmol/L, Hyperoxia Had No Effect on the Mortality Rate, Nor on Other Outcomes
  • Observational Study of Hyperoxia in the Emergency Department in Patients with Acute Respiratory Failure (Crit Care, 2018) [MEDLINE]: n = 688
    • Emergency Department Exposure to Hyperoxia is Common and Associated with Increased Mortality in Mechanically Ventilated Patients Achieving Normoxia After Admission
    • This Suggests that Hyperoxia in the Immediate Post-Intubation Period Could Be Particularly Injurious and Targeting Normoxia from Initiation of Mechanical Ventilation May Improve Outcome
  • Australian/New Zealand ICU-ROX Trial of Conservative Oxygen Strategy in Mechanically-Ventilated Patients in the ICU (NEJM, 2020) [MEDLINE]: n = 1000
    • RCT of Conservative Oxygen Therapy Using SpO2 <97%
    • There was No Difference Between Conservative Oxygen Group (Median Duration: 21.3 Days; Interquartile Range: 0-26.3) and Usual Care Oxygen Group (Median Duration: 22.1 days; Interquartile Range: 0-26.2), in Terms of Number of Ventilator-Free Days
    • The Conservative Oxygen Group Spent More Time in the ICU (Median Duration: 29 hrs; Interquartile Range: 5-78) ) with an FiO2 of 21% than the Usual Care Oxygen Group (Median Duration: 1 hr; Interquartile Range: 0-17)
    • The Conservative Oxygen Group Spent Less Time with an SpO2 >96% (Median Duration: 27 hrs; Interquartile Range: 11-63.5) than the Usual Care Oxygen Group (Median Duration: 49 hrs; Interquartile Range: 22-112)
    • At 180 days, Mortality was 35.7% in the Conservative Oxygen Group and 34.5% in the Usual Care Oxygen Group, for an Unadjusted Odds Ratio of 1.05 (95% CI: 0.81-1.37)
  • French Multicenter, Randomized, Liberal or Conservative Oxygen 2 (LOCO2) Trial in ARDS (NEJM, 2020) [MEDLINE]: n= 205
    • In ARDS, Early Conservative Oxygen Strategy (Target pO2 55-70 mm Hg or SpO2 88-92%) Did Not Improve 28-Day Survival, as Compared to Liberal Oxygen Strategy (Target pO2 90-105 mm Hg or SpO2 ≥96%) When Used for 7 Days
    • Same Mechanical Ventilation Strategy was Used in Both Groups

Recommendations (British Thoracic Society Emergency Oxygen Guidelines, 2017) (Thorax, 2017) [MEDLINE]

  • SpO2 Target
    • Oxygen Should Be Prescribed to Achieve a Target Saturation of 94–98% for Most Acutely Ill Patients or 88–92% or Patient-Specific Target Range for Those at Risk of Hypercapnic Respiratory Failure
    • Best Practice is to Prescribe a Target Range for All Hospitalized Patients at the Time of Hospital Admission So that Appropriate Oxygen Therapy Can Be Started in the Event of Unexpected Clinical Deterioration with Hypoxemia and Also to Ensure that the Oximetry Section of the Early Warning Score Can Be Scored Appropriately

Recommendations (British Medical Journal-Oxygen Therapy for Acutely Ill Medical Patients: Clinical Practice Guideline, 2018) (BMJ, 2018) [MEDLINE]

  • Supplemental Oxygen Therapy Should Be Titrated to SpO2 ≤96% (Strong Recommendation)
    • SpO2 >96% likely is Associated with a Small, But Important, Increased Risk of Death without Plausible Clinical Benefit

Sedation (see Sedation)

Recommendations for Patients with ARDS Associated with Sepsis (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]

  • Continuous or Intermittent Sedation Should Be Minimized (with Specific Sedation Endpoints) in Sepsis-Associated Mechanically-Ventilated Respiratory Failure (Best Practice Statement)

Paralysis (Neuromuscular Junction Blockade) (see Neuromuscular Junction Antagonists)

Epidemiology

  • Prevalence of Use of Neuromuscular Junction Antagonists: approximately 25-55% of ARDS patients enrolled in multicenter, randomized controlled trials receive neuromuscular blockers as part of their therapy
  • Most Common Reasons for Paralytic Administration
    • Improvement in Oxygenation: paralytics decrease oxygen consumption
    • Improvement in Patient-Ventilator Synchrony

Administration

  • Always Provide Adequate Sedation Prior to Paralysis (see Sedation)
  • Monitor “Train of Four” During Neuromuscular Blockade
  • Use Neuromuscular Junction Blockers for the Shortest Period of Time Possible to Minimize the Risk of Prolonged Paralysis
    • Aminosteroid Neuromuscular Junction Blockers Have the Highest Risk of Prolonged Paralysis: although all neuromuscular junction blockers increase this risk
    • Avoid the Concomitant Use of Corticosteroids (see Corticosteroids): which increase the risk of prolonged paralysis

Clinical Efficacy

  • French RCT Studying Effect of Neuromuscular Junction Blockade on Oxygenation in ARDS (Crit Care Med, 2004) [MEDLINE]
    • Neuromuscular Junction Blockade for the First 48 hrs Resulted in Sustained Improvement in Oxygenation Over the Entire 120 hrs Studied
  • French RCT Studying Effect of Neuromuscular Junction Blockade on the Inflammatory Response in ARDS (Crit Care Med, 2006) [MEDLINE]
    • Early Use of Neuromuscular Junction Blockade Decreased the Proinflammatory Response (Mediated by Various Cytokines) Associated with ARDS and Mechanical Ventilation
  • French ARDS et Curarisation Systematique (ACURASYS) Study (NEJM, 2010) [MEDLINE]: multicenter, double-blind trial (n = 340) of ICU patients with ARDS onset within the previous 48 hrs
    • Early Paralysis (for a Period of 48 hrs) Improved the 90-Day Mortality Rate and Increased the Time Off of the Ventilator Without Increasing Muscular Weakness
    • Subsequent to the ACURASYS Study, Deep Sedation was Demonstrated to Increase the Incidence of a Specific Type of Ventilator Dyssynchrony Called “Reverse Triggering Dyssynchrony” (During Which a Ventilator-Delivered Breath Paradoxically Triggered a Diaphragmatic Contraction, Which Initiated a Spontaneous Breath, Resulting in Breath Stacking) (Chest, 2013) [MEDLINE]
      • Reverse Triggering Dyssynchrony May Occur in Up to 30% of Patients with ARDS (Intensive Care Med, 2019) [MEDLINE]
      • Reverse Triggering Dyssynchrony is Difficult to Detect without an Esophageal Balloon or Diaphragmatic Electromyogram
      • Reverse Triggering Dyssynchrony Causes Overdistention, Increases the Work of Breathing, and May Cause Diaphragmatic Muscle Damage
      • Deep Sedation without Paralysis Might Have Inadvertently Increased Reverse Triggering Dyssynchrony with an Increased Risk of Lung Injury in the ACURASYS Trial (An Effect Which Would Not Have Occurred in the Group Which Received Deep Sedation and Paralysis) (NEJM, 2019)) [MEDLINE]
  • Reevaluation of Systemic Early Neuromuscular Blockade (ROSE) Trial of Early Continuous (48 hrs) Cisatracurium Paralysis in ARDS (NEJM, 2019) [MEDLINE]: n= 1,006
    • Trial was Stopped Prematurely for Lack of Efficacy
    • In Moderate-Severe ARDS Treated with High PEEP, Early Continuous (48 hrs) Cisatracurium Paralysis Did Not Decrease the 90-Day Mortality Rate (42.5%), as Compared to Usual Care with a Lighter Sedation Target (42.8%)

Recommendations for Patients with ARDS Associated with Sepsis (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]

  • Neuromuscular Junction Blockade (for ≤48 hrs) is Suggested for Adult Patients with Sepsis-Associated ARDS and pO2/FIO2 Ratio <150 (Weak Recommendation, Moderate Quality of Evidence)

Respiratory Rate (RR)

Clinical Efficacy

  • Small Study of Respiratory Rate Management in Patients with Acute Respiratory Failure (Crit Care Med, 2002) [MEDLINE]: n = 14
    • High Respiratory Rates in Patients Mechanically-Ventilated for Acute Respiratory Failure Can Produce Dynamic Hyperinflation (with Development of Auto-PEEP), Increase the Dead Space/Tidal Volume Ratio, and Impair Right Ventricular Ejection with a Decrease in the Cardiac Output
  • Study of pCO2 Management During ARDS (Data from LUNG SAFE Study) (Chest, 2020) [MEDLINE]: n = 2,813 (19.6% were hypocapnic, 36.2% were normocapnic, 43.2% were hypercapnic)
    • Hypocapnia was More Frequent and Severe in Patients on Noninvasive Positive-Pressure Ventilation
    • There was No Association Between Arterial CO2 and Outcome
    • Hospital Mortality was 36% in Both Sustained Normocapnic and Hypercapnic Patients
    • In Patients with Mild-Moderate ARDS, the ICU Mortality Rate was Higher in Patients with Receiving Sustained Hypocapnia (38.1%), as Compared to Normocapnia (27.1%)

General Recommendations

  • In General, the Respiratory Rate Should Be Adjusted to Maintain Normal pH and Normocapnia
    • In Terms of Setting a Minimum Respiratory Rate, Rate Should Be Set to Allow an Adequate Minute Ventilation, Should the Patient Become Apneic
    • In Terms of Setting a Maximal Respiratory Rate in ARDS, the Maximum Respiratory Rate Should Be Set ≤35 Breaths/min
  • Use Permissive Hypercapnia (When Required) and Avoid the Development of Auto-PEEP
    • When Increasing the Respiratory Rate, the Patient Should Be Monitored for the Development of Auto-PEEP In a Patient Who Develops Auto-PEEP on a Respiratory Rate Which Achieves a Normal pH, Respiratory Rate Can Be Decreased and “Permissive Hypercapnia” Utilized
    • When Increasing the Respiratory Rate in Some Modes of Ventilation, Inspiratory Flow Rate Can Be Increased to Maintain the I/E Ratio: to prevent the development of auto-PEEP
  • Avoid Hypocapnia
    • Avoid Unnecessary Hyperventilation Which May Increase the Risk of Ventilator-Induced Lung Injury in ARDS

Lung Protective (Low Tidal Volume and Minimization of Plateau Pressure) Ventilation Strategy

Rationale

  • Plateau Pressure is Believed to Be the Best Surrogate for Alveolar Pressure (Which Predicts Risk of Barotrauma)
    • Driving Pressure = Plateau Pressure – PEEP

Technique

  • Predicted Body Weight (PBW) [ARDSNet]
    • Male: PBW = 50 + 2.3 (ht in inches – 60)
    • Female: PBW = 45.5 + 2.3 (ht in inches – 60)
  • How to Titrate Tidal Volume Using Plateau Pressure (Pplat) as a Guide [ARDSNet]
    • If Plateau Pressure >30 cm H2O: decrease tidal volume by 1 mL/kg PBW steps (to minimum 4 mL/kg PBW)
    • If Plateau Pressure (Pplat) <25 cm H2O and Tidal Volume <6 mL/kg PBW: increase tidal volume (VT) by 1 mL/kg PBW steps until plateau pressure >25 cm H2O or tidal volume = 6 mL/kg PBW)
    • If Plateau Pressure <30 cm H2O and Breath Stacking or Dyssynchrony Occurs: increase tidal volume by 1 mL/kg PBW (to maximum 7-8 mL/kg PBW) If plateau pressure remains ≤30 cm H2O)
  • pH Management [ARDSNet]
    • If pH <7.15: increase respiratory rate (to maximum 35 breaths/min)
    • If pH 7.15-7.30: increase respiratory rate until pH >7.30 or pCO2 <25 mm Hg (maximum: 35 breaths/min)
    • If pH >7.45: Decrease Respiratory rate
  • I:E Ratio Management
    • Maintain Inspiratory Time < Expiratory Time (I:E Ratio <0.5-1.0)
  • If Possible, Minimize Instrumental Dead Space When Using Low Tidal Volume (Lung Protective) Ventilation
    • Instrumental Dead Space Can Be Minimized by Replacing a Heat and Moisture Exchanger with a Heated Humidifier, Removing Catheter Mounts, etc (Chest, 2020 [MEDLINE]
      • The Net Effect of Decreasing the Instrumental Dead Space is to Increase Alveolar Ventilation, Enhancing Carbon Dioxide Elimination

Clinical Efficacy

  • The Acute Respiratory Distress Syndrome Network (ARDSNet) Multicenter Randomized Trial Comparing High Tidal Volume (12 mL/kg PBW and Plateau Pressure <50 cm H2O) with Low Tidal Volume (6 mL/kg PBW and Plateau Pressure <30 cm H2O) Ventilation (NEJM, 2000) [MEDLINE]: n = 861
    • Trial was Stopped Prematurely Due to Mortality Benefit and Increased Ventilator-Free Days in Low Tidal Volume Ventilation Group
    • Low Tidal Volume Group Had Decreased Mortality Rate (31%), as Compared to High Tidal Volume Group (39.8%)
      • However, Tidal Volumes Between 6 and 12 mL/g PBW were Not Studied
    • Low Tidal Volume Group Had Increased Ventilator-Free Days During the First 28 Days (12 +/- 11), as Compared to the High Tidal Volume Group (10 +/- 11)
    • Mean Tidal Volumes Achieved on Days 1-3 in Low Tidal Volume Group were Lower (6.2 +/- 0.8 mL/kg PBW), as Compared to High Tidal Volume Group (11.8 +/- 0.8 mL/kg PBW)
    • Mean Plateau Pressures Achieved in Low Tidal Volume Group were Lower (25 +/- 6 cm H2O), as Compared to High Tidal Volume Group (33 +/- 8 cm H2O)
    • Arterial pCO2 was 4-7 mm Hg Higher in Low Tidal Volume Group, But pCO2 Never Exceeded 44 mm Hg: this is likely not clinically significant
    • FIO2 was Higher in the Low Tidal Volume Group on Days 1 and 3, Becoming Equivalent by Day 7: this suggests that the institution of low tidal volumes resulted in a transient worsening of oxygenation
    • Auto-PEEP was Higher in the Low Tidal Volume Group (Who Had Higher Respiratory Rates), Although the Difference in Median Auto-PEEP was <1 cm H2O: this is likely not clinically significant (Crit Care Med, 2005) [MEDLINE]
  • Review of Animal/Human Data from ARDS Clinical Trials Network (and Original Data) Examining if There is a Safe Upper Limit of Plateau Pressure in ARDS (Am J Respir Crit Care Med, 2005)
    • Authors Could Not Identify a Safe Upper Limit for Plateau Pressure in ARDS
  • Study of Sedative Use During Low Tidal Volume Ventilation (Crit Care Med, 2005) [MEDLINE]
    • Low Tidal Volume Ventilation Does Not Result in Increased Use of Sedatives, Opiates, or Paralytics
  • Meta-Analysis of Low Tidal Volume and Limited Airway Pressure or Higher PEEP in ALI/ARDS (Ann Intern Med, 2009) [MEDLINE]
    • Decreased Mortality with Routine Use of Low Tidal Volume, But Not High PEEP Ventilation, in Unselected Patients with ARDS or Acute Lung Injury
    • High PEEP May Help to Prevent Life-Threatening Hypoxemia in Selected Patients
  • Systematic Review of Pressure/Volume-Limited Strategies (PLoS One, 2011) [MEDLINE]: the ARDS Network trial [MEDLINE] contributed 21.4% of the weight toward the summary estimate of effect in this analysis
    • Pressure/Volume-Limited Strategies Decrease Mortality Rate and are Associated with Increased Use of Paralytics
  • Cochrane Database Review of Lung Protective Ventilation Strategies in ARDS (Cochrane Database Syst Rev, 2013) [MEDLINE]
    • Lung Protective Strategies (Low Tidal Volume or Plateau Pressure <30 cm H2O) Decrease Mortality
  • Trial Examining Predictors of Ventilator-Induced Lung Injury in ARDS (Anesthesiology, 2013) [MEDLINE]
    • Rationale: stress index describes the shape of the airway pressure-time curve profile and may indicate tidal recruitment or tidal overdistension (convex downward pressure curve indicates initial low compliance with better compliance later in the breath due to recruitment, while convex upward curve indicates overdistention -> optimal curve is straight diagonal initial pressure waveform)
    • Plateau Pressure Partitioned to the Respiratory System (Pplat,Rs) >25 cm H20 and Stress Index Partitioned to the Respiratory System (SI,Rs) >1.05 were Most Associated with Injurious Ventilation
  • Systematic Review/Meta-Analysis of Morbidity/Mortality in Post-Operative Acute Lung Injury (Lancet Respir Med, 2014) [MEDLINE]
    • Lung Protective Mechanical Ventilation Strategies (Applied During Surgery) Decrease the Incidence of Post-Operative Acute Lung Injury, But Do Not Decrease the Mortality Rate
  • Study of Contribution of Driving Pressure to Mortality in ARDS (NEJM, 2015) [MEDLINE]: study used data from 9 prior randomized trials
    • Rationale: lower tidal volume, lower plateau pressure, and higher PEEP are all believed to decrease mechanical stresses on the lung in ARDS (which can induce ventilator-associated lung injury)
      • However, There is an Uncertainty When Optimizing One Component Adversely Affects Another (Example: Increasing PEEP May Undesirably Increase the Plateau Pressure), Which this Study Attempted to Address
      • Authors Theorized in Their Study that Optimizing the Tidal Volume/Respiratory System Compliance Ratio (Known as the Driving Pressure = Delta P) Would Provide a Better Predictor of Outcome in ARDS
    • Driving Pressure (Plateau Pressure – PEEP or Delta P) was the Best Predictor of Survival
      • Decreases in Tidal Volume or Increases in PEEP Were Beneficial Only if They Resulted in a Decrease in Delta P (In Other Words, PEEP Increments are Protective Only When They are Associated with an Improvement in Respiratory System Compliance, So that the Same Tidal Volume Can Be Delivered with a Lower Delta P)
      • Further Trials Using Specific Manipulation of Delta P are Required Before Recommending this Strategy as a Standard
    • Caveat: Delta P Can Only Be Accurately Assessed in Non-Breathing Patients

Clinical Efficacy-Personalized Ventilation

  • French Randomized, Multicenter LIVE Trial of Personalized Mechanical Ventilation According to Lung Morphology in Moderate-Severe ARDS (Lancet Respir Med, 2019) [MEDLINE]: n = 420 (from 2014-2017)
    • Control Group Received Standard 6 mL/kg PBW Tidal Volumes, PEEP was Used Per a PEEP/FIO2 Table, and Early Prone Ventilation was Encouraged
    • In the Personalized Group, Treatment was Based on Lung Morphology
      • Patients with Focal ARDS Received 8 mL/kg PBW Tidal Volumes, Low PEEP, and Prone Ventilation
      • Patients with Non-Focal ARDS Received 6 mL/kg PBW Tidal Volumes, Recruitment Maneuvers, and High PEEP
    • Primary Outcome was 90-Day Mortality Rate (with Intention-to-Treat Analysis)
    • Personalized Mechanical Ventilation Did Not Decrease the 90-Day Mortality Rate in ARDS (Possibly Related to Misclassification of 21% of the Patients)

Recommendations for Patients with ARDS (American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine Clinical Practice Guidelines for Mechanical Ventilation in ARDS) (Am J Respir Crit Care Med, 2017) [MEDLINE]

  • Ventilation Strategy Targeting Low Tidal Volume Ventilation (4-8 mL/kg PBW) and Low Plateau Pressure (<30 cm H2O) is Recommended (Strong Recommendation, Moderate Confidence)

Recommendations for Patients with ARDS Associated with Sepsis (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]

  • Low Tidal Volume (6 mL/kg PBW) is Recommended Over High Tidal Volume (12 mL/kg PBW) in Sepsis-Associated ARDS (Strong Recommendation, High Quality of Evidence)
  • Low Tidal Volume (6 mL/kg PBW) is Recommended Over High Tidal Volume (12 mL/kg PBW) in Sepsis-Associated Respiratory Failure without ARDS (Weak Recommendation, Low Quality of Evidence)
  • Plateau Pressure Upper Limit of 30 cm H2O is Recommended in Sepsis-Associated Severe ARDS (Strong Recommendation, Moderate Quality of Evidence)
  • Respiratory Rate Max Should Be 35 Breaths/min (Recognizing that Some Patients May Experience Hypercapnia
    • Hypercapnia is Generally Well-Tolerated in the Absence of Contraindications (Such as Increased Intracranial Pressure, Sickle Cell Crisis, etc)

Positive End-Expiratory Pressure (PEEP)

Physiology of PEEP, Beneficial Effects of PEEP, and Adverse Effects of PEEP

Techniques/Strategies to Set the Optimum Amount of PEEP

Clinical Efficacy

  • ARDSNet ALVEOLI Study (NEJM, 2004) [MEDLINE]
    • In Patients with ALI/ARDS Who Receive Low Tidal Volume Ventilation (6 ml/kg PBW) and Plateau Pressure Limit of 30 cm H2O, Lower or Higher PEEP Levels Had No Impact on Mortality Rate, ICU Length of Stay, Weaning from the Ventilator, Ventilator-Free Days, or Organ Failure-Free Days
  • Expiratory Pressure (EXPRESS) Study (JAMA, 2008) [MEDLINE]: French multicenter RCT (n = 767)
    • Setting PEEP Aimed at Increasing Alveolar Recruitment While Limiting Hyperinflation Had No Impact on Mortality Rate
    • However, it Improved Lung Function, Increased Ventilator-Free Days, and Decreased Non-Pulmonary Organ Failure-Free Days
  • Lung Open Ventilation (LOV) Study (JAMA, 2008) [MEDLINE]
    • Open Lung Ventilation Had No Impact on Mortality Rate
    • However, There was Decreased Need for Salvage Therapies and Lower Incidence of Refractory Hypoxemia
  • Systematic Review and Meta-Analysis of PEEP Levels in ARDS (JAMA, 2010) [MEDLINE]
    • Higher PEEP was Not Associated with Improved Hospital Survival, as Compared to Lower PEEP
    • However, in the Subset of ARDS Patients with pO2/FiO2 Ratio <200 mm Hg, PEEP Improved Survival
  • Trial Examining Predictors of Ventilator-Induced Lung Injury in ARDS (Anesthesiology, 2013) [MEDLINE]
    • Rationale: stress index describes the shape of the airway pressure-time curve profile and may indicate tidal recruitment or tidal overdistension (convex downward pressure curve indicates initial low compliance with better compliance later in the breath due to recruitment, while convex upward curve indicates overdistention -> optimal curve is straight diagonal initial pressure waveform)
    • Plateau Pressure Partitioned to the Respiratory System (Pplat,Rs) >25 cm H20 and Stress Index Partitioned to the Respiratory System (SI,Rs) >1.05 were Most Associated with Injurious Ventilation
  • Study of Contribution of Driving Pressure to Mortality in ARDS (NEJM, 2015) [MEDLINE]: study used data from 9 prior randomized trials
    • Rationale: lower tidal volume, lower plateau pressure, and higher PEEP are all believed to decrease mechanical stresses on the lung in ARDS (which can induce ventilator-associated lung injury)
      • However, There is an Uncertainty When Optimizing One Component Adversely Affects Another (Example: Increasing PEEP May Undesirably Increase the Plateau Pressure), Which this Study Attempted to Address
      • Authors Theorized in Their Study that Optimizing the Tidal Volume/Respiratory System Compliance Ratio (Known as the Driving Pressure = Delta P) Would Provide a Better Predictor of Outcome in ARDS
    • Driving Pressure (Plateau Pressure – PEEP or Delta P) was the Best Predictor of Survival
      • Decreases in Tidal Volume or Increases in PEEP Were Beneficial Only if They Resulted in a Decrease in Delta P (In Other Words, PEEP Increments are Protective Only When They are Associated with an Improvement in Respiratory System Compliance, So that the Same Tidal Volume Can Be Delivered with a Lower Delta P)
      • Further Trials Using Specific Manipulation of Delta P are Required Before Recommending this Strategy as a Standard
    • Caveat: Delta P Can Only Be Accurately Assessed in Non-Breathing Patients
  • Randomized Trial of Open Lung Approach in ARDS (Crit Care Med, 2016) [MEDLINE]: n = 200
    • Open Lung Approach Improved Oxygenation and Driving Pressure, without Detrimental Effects on Mortality, Ventilator-Free Days, or Barotrauma
  • Study of Driving Pressure and Lung Stress in ARDS (Crit Care, 2016) [MEDLINE]
    • The Applied Tidal Volume (mL/kg of Ideal Body Weight) was Not Related to Lung Gas Volume (r2 = 0.0005; p = 0.772)
    • At Both PEEP Levels, the higher Airway Driving Pressure Group Had a Significantly Higher Lung Stress, Respiratory System and Lung Elastance, as Compared to the Lower Airway Driving Pressure Group
    • Airway Driving Pressure was Significantly Related to Lung Stress (at PEEP +5, r2 = 0.581; p < 0.0001/at PEEP +15, r2 = 0.353; p < 0.0001)
    • For a Lung Stress of 24 and 26 cmH2O, the Optimal Cutoff Values for the Airway Driving Pressure were 15.0 cm H2O (ROC AUC 0.85, 95 % CI: 0.782-0.922) and 16.7 (ROC AUC 0.84, 95 % CI: 0.742-0.936)
  • Systematic Review and Meta-Analysis of Driving Pressure and Mortality Rate in ARDS (Crit Care Med, 2018) [MEDLINE]: n = 6,062 (7 studies)
    • Median (Interquartile Range) Driving Pressure Between Higher and Lower Driving Pressure Groups was 15 cm H2O (14-16 cm H2O)
    • Higher Driving pressure was Associated with a Significantly Higher Mortality Rate (Pooled Risk Ratio 1.44; 95% CI: 1.11-1.88; I = 85%)
    • Sensitivity Analysis Restricted to the Three Studies with Similar Driving Pressure Cutoffs (13-15 cm H2O) Demonstrated Similar Results (Pooled Risk Ratio, 1.28; 95% CI: 1.14-1.43; I = 0%)
  • Trial of PEEP in ARDS (Crit Care, 2018) [MEDLINE]
    • Optimal PEEP (as Determined by Stress Index on the Ventilator) Depended on Tidal Volume
  • Phase 2 Randomized EPVent-2 Trial Evaluating Esophageal Pressure-Guided Positive End-Expiratory Pressure (PEEP) Titration Strategy in ARDS (JAMA, 2019) [MEDLINE]: n = 200 (14 hospitals in North America)
    • In Moderate-Severe ARDS (with Standard Low Tidal Volume Ventilation), Esophageal Pressure-Guided PEEP Titration Strategy Did Not Improve Mortality Rate or Ventilator-Free Days, as Compared to a Standard Empirical FIO2/PEEP Strategy

General Recommendations

  • PEEP of 0 cm H2O is Generally is Accepted to Be Harmful in ARDS
  • PEEP of 8-15 cm H2O is Appropriate in Most Patients with ARDS: although higher PEEP levels might be used in patients for whom a greater potential for recruitment can be demonstrated
  • Although Further Trials are Required Before This Strategy Can Be Recommended, Increasing PEEP May Only Be Beneficial if it Results in a Decrease in the Delta P (Plateau Pressure – PEEP)

Recommendations for Patients with ARDS (American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine Clinical Practice Guidelines for Mechanical Ventilation in ARDS) (Am J Respir Crit Care Med, 2017) [MEDLINE]

  • Higher PEEP (Rather Than Lower PEEP) is Recommended in Adults with Moderate-Severe ARDS (Conditional Recommendation, Moderate Confidence)

Recommendations for Patients with ARDS Associated with Sepsis (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]

  • Higher PEEP is Recommended Over Lower PEEP in Adults with Sepsis-Associated Moderate-Severe ARDS (Weak Recommendation, Moderate Quality of Evidence)
    • The Optimal Method for Selecting PEEP is Unclear (Common Methods Include Titrating PEEP Upward on Tidal Volume of 6 mL/kg Until Plateau Pressure is 28 cm H20, Titrating PEEP to Optimize Thoracoabdominal Compliance with the Lowest Driving Pressure, Titrating PEEP Based on Decreasing the FIO2 to Maintain Oxygenation, etc)

Esophageal Pressure-Guided Mechanical Ventilation

Rationale

  • Pressures
    • Esophageal Pressure is a Surrogate for Pleural Pressure
    • Transpulmonary Pressure = Alveolar Pressure – Pleural Pressure
      • Alternative, Transpulmonary Pressure = Airway Pressure – Esophageal Pressure
  • Optimal Level of PEEP Maintains Oxygenation, While Preventing Lung Injury Due to Repeated Alveolar Collapse and Overdistention
    • In Patients with Low Pleural Pressure, PEEP Can Be Maintained Low to Keep Transpulmonary Pressure Low
    • In Patients with High Pleural Pressure (Where Underinflation May Cause Hypoxemia), PEEP Can Be Increased to Maintain a Positive Transpulmonary Pressure Which Might Improve Aeration and Oxygenation without Causing Overdistention
  • Stress Index
    • Rationale: stress index calculation allows determination of the optimal PEEP
    • Technique
      • Software-Derived Dimensionless Value Obtained During a Constant Flow Breath Reflecting the Shape of the Airway Pressure vs Time Curve
      • Requires Absence of Patient Effort
    • Optimal Stress Index is a Straight Diagonal (i.e. 1.0): reflecting unchanging compliance throughout the breath
      • Alternatively, if recruitment/derecruitment is occurring during the breath, the stress index curve is concave bowing upward (low compliance early, followed by high compliance later in the breath) -> stress index <1
      • Alternatively, if overdistention is occurring during the breath, the stress index curve is concave bowing downward (high compliance early, followed by low compliance later in the breath) -> stress index >1

Clinical Efficacy

  • EPVent Pilot Study Using Transpulmonary Pressure (NEJM, 2008) [MEDLINE]
    • Esophageal Pressure was Used as a Surrogate for Pleural Pressure
    • PEEP Levels were Set to Maintain End-Expiratory Transpulmonary Pressure Between 0-10 cm H2O and End-Inspiratory Transpulmonary Pressure to <25 cm H2O, Based on a Sliding Scale Using the Patient’s pO2 and FIO2
      • Transpulmonary Pressure was Used to Determine the Optimal Level of PEEP Based on Lung and Chest Wall Mechanics
      • pH was Maintained Between 7.30-7.45
      • pO2 was Maintained Between 55-120 mm Hg
    • As Compared to Standard Care, a Ventilator Strategy Using Esophageal Pressures to Estimate Transpulmonary Pressure Improved Oxygenation and Respiratory System Compliance and Had a Trend Toward a Decreased Mortality Rate
  • Study of Stress Index (Using Airway Pressure vs Time) to Decrease Injurious Ventilation (as Assessed by CT Scanning Measures of Ventilator-Induced Lung Injury) in ARDS (Anesthesiology, 2013) [MEDLINE]
    • Injurious Ventilation was Most Associated with Pplat,rs >25 cm H2O and Stress Index >1.05
      • Pplat,rs = plateau pressure for the respiratory system (inspiratory)
      • Stress Index = dimensionless number obtained during a constant flow breath which describes the shape of airway pressure vs time curve and the shape of the transpulmonary pressure (PL) vs time curve

Recruitment Maneuvers

Rationale and Technique

  • Brief Application of High Level of Continuous Positive-Airway Pressure (Usually 35-40 cm H2O for 30-40 sec) Which Transiently Increases the Transpulmonary Pressure and is Intended to Open Collapsed Alveoli in ARDS
    • There is a Large-Scale Loss of Aerated Lung and Once the End-Inspiratory Pressure Surpasses the Regional Critical Opening Pressure of the Lung Units, those Lung Units are Likely to Reopen
    • The pO2 Typically Increases After a Recruitment Maneuver (Am J Respir Crit Care Med, 2008) [MEDLINE]
      • Degree of Increase in pO2 is Greatest When the Patient is Placed on High PEEP (16 cm H20, etc) After the Recruitment Manuever (Intensive Care Med, 2000) [MEDLINE]
    • Most of the Clinical Benefit of Recruitment Manuever Occurs within the First 10 sec of the Manuever (Intensive Care Med, 2011) [MEDLINE]
      • Hypotension Typically Follows the Maneuver, with Recovery within 30 sec
  • Clinical Utility of Recruitment Maneuvers
    • Recruitment Maneuvers are Believed to Be Especially Beneficial After a Patient Has Been Disconnected from the Ventilator or the Ciruit Has Been Opened (During Bronchoscopy, Ventilator Tubing Change, Change to a Transport Ventilator, etc), Since Even Brief Disconnections without Positive End-Expiratory Pressure (PEEP) Can Result in Alveolar Collapse
    • Recruitment Maneuvers May Also Be Considered in an Attempt to Improve Oxygenation in a Patient with Refractory Hypoxemia, Despite the Use of a Lung Protective (Low Tidal Volume, Low Plateau Pressure) Ventilation Strategy
  • Adverse Effects (Am J Respir Crit Care Med, 2008) [MEDLINE]
    • Barotrauma: typically only when a recruitment maneuver is prolonged
    • Cardiac Arrest (see Cardiac Arrest): typically only when a recruitment maneuver is prolonged
    • Hypotension (see Hypotension)
    • Hypoxemia (see Hypoxemia)

Clinical Efficacy

  • Study of Lung Recruitment Using CT Scanning with Breath Holding at Various Airway Pressures in ARDS (NEJM, 2006) [MEDLINE]
    • The Percentage of Recruitable Lung was Extremely Variable in ARDS: on average, 24% of lung could not be recruited
    • The Percentage of Recruitable Lung was Associated with the Response to PEEP
  • Cochrane Database Review of Recruitment Maneuvers in Patients with ARDS (Cochrane Database Syst Rev, 2009) [MEDLINE]
    • No Clinical Benefit of Recruitment Maneuvers in Either Mortality or Length of Mechanical Ventilation
  • Randomized Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) of Recruitment in Moderate-Severe ARDS (JAMA, 2017) [MEDLINE]: n = 1,010
    • In Moderate-Severe ARDS, Lung Recruitment and Titrated PEEP Strategy Increased 28-Day All-Cause Mortality, as Compared to Low PEEP Strategy
    • Lung Recruitment and Titrated PEEP Strategy Decreased the Number of Ventilator-Free Days, Increased the Risk of Pneumothorax Requiring Chest Tube Drainage), and Increased the Risk of Barotrauma, as Compared to Low PEEP Strategy
    • Lung Recruitment and Titrated PEEP Strategy Had No Impact on ICU Length of Stay, Hospital Length of Stay, or In-Hospital Mortality Rate, as Compared to Low PEEP Strategy

Recommendations for Patients with ARDS (American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine Clinical Practice Guidelines for Mechanical Ventilation in ARDS) (Am J Respir Crit Care Med, 2017) [MEDLINE]

  • Recruitment Maneuvers are Recommended in Adults with ARDS (Conditional Recommendation, Low-Moderate Confidence)
    • Recruitment Maneuvers Should Be Used with Caution in Patients with Pre-Existing Hypovolemia/Shock Due to Concern About Causing Hemodynamic Compromise

Recommendations for Patients with ARDS Associated with Sepsis (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]

  • Recruitment Maneuvers are Recommended in Sepsis-Associated ARDS (Weak Recommendation, Moderate Quality of Evidence)
    • Selected Patients with Severe Hypoxemia May Benefit from Recruitment Maneuvers in Conjunction with Higher Levels of PEEP

High-Frequency Ventilation (HFV) (see High-Frequency Ventilation)

Concept

  • Ventilation Mode Employing the Use of High Respiratory Rates

Techniques

  • General Comments: all techniques utilize respiratory rates >100 breaths/min
  • Conventional Mechanical Ventilation with Small Tidal Volumes and Rapid Respiratory Rates
  • Chest Wall Oscillation
  • High-Frequency Percussive Ventilation (HFPV): flow-regulated, pressure-limited, and time-cycled ventilator that delivers a series of high-frequency small volumes (at 200-900 cycles/min) in a successive stepwise stacking pattern
  • High-Frequency Jet Ventilation
  • High-Frequency Oscillation Ventilation (HFOV): most widely used type of high-frequency ventilation used in adult critical care -> delivers a small tidal volume by oscillating a bias gas flow in the airway

Clinical Efficacy

  • Randomized, Controlled Multicenter Oscillatory Ventilation For Acute Respiratory Distress Syndrome Trial) MOAT Trial of High-Frequency Oscillation Ventilation (Am J Respir Crit Care Med, 2002) [MEDLINE]
    • While the Study was Not Powered to Evaluate Mortality Differences, But an Insignificant Trend Toward Improved Overall 30-Day Mortality Rate in the High-Frequency Oscillation Ventilation Group, as Compared with the Conventional Ventilation Group (37% vs 52% 30-Day Mortality, p=0.098)
    • There Were No Significant Difference Between Groups in New or Worsening Barotrauma, Endotracheal Tube Obstruction, or Adverse Hemodynamic Effects
  • Retrospective Chart Review of High-Frequency Oscillation Ventilation for Rescue Therapy in Medical-Surgical ICU Patients (Chest, 2004) [MEDLINE]: n = 156
    • High-Frequency Oscillation Ventilation Had Beneficial Effects on pO2/FIO2 Ratios and Oxygenation Index
    • 30-Day Mortality Rate was 61.7%
    • Pneumothorax Rate was 21.8%
  • Canadian Clinical Trials Group OSCILLATE High-Frequency Oscillation Study in ARDS (NEJM, 2013) [MEDLINE]
    • In Adults with Moderate-to-Severe ARDS, Early Application of High-Frequency Oscillation Ventilation (as Compared with a Ventilation Strategy of Low Tidal Volume and High PEEP) Did Not Decrease and May Increase, the In-Hospital Mortality Rate

Recommendations for Patients with ARDS (American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine Clinical Practice Guidelines for Mechanical Ventilation in ARDS) (Am J Respir Crit Care Med, 2017) [MEDLINE]

  • High Frequency Ventilation is Not Routinely Recommended in Moderate-Severe ARDS (Strong Recommendation, Moderate-High Confidence)

Recommendations for Patients with ARDS Associated with Sepsis (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]

  • Ventilation Mode
    • No Ventilator Mode is Recommended Over Another
    • However, High-Frequency Oscillation Ventilation is Not Recommended in Adult Patients with Sepsis-Associated ARDS (Strong Recommendation, Moderate Quality of Evidence) (see High-Frequency Ventilation)

Pressure Assist Control Ventilation (PCV)

Concept

  • Pressure-Targeted, Time-Cycled Mode
    • Patient Can Trigger Additional Breaths Above the Set Respiratory Rate (with Each Breath Consisting of a Full Pressure Breath)
  • Types of Breaths
    • Pressure Control Breaths: machine triggered
    • Pressure Assist Breaths: patient triggered
  • Work of Breathing
    • Very Low: most of the patient’s work of breathing in this mode (which is generally minimal) involves triggering ventilator-delivered breaths (if the patient is nor triggering any breaths, their work of breathing is effectively zero)

Settings

  • Respiratory Rate (RR)
  • Delta P (Driving Pressure): since driving pressure is manually set, tidal volume that occurs will depend on lung/chest wall compliance
  • PEEP: typically initially set to +5
  • FIO2: typically initially set to 100% FIO2

Monitor

  • Tidal Volume (VT)

Advantages

  • Assuming No Change in Lung/Chest Wall Compliance, Provides Guaranteed Delivery of the Desired Minute Ventilation (Due to a Set Driving Pressure and Set Respiratory Rate): this is useful if the patient is heavily sedated/paralyzed or apneic for other reasons

Disadvantages

  • If Lung/Chest Wall Compliance Decreases During the Course of Ventilation (Due to Hemothorax, Pneumothorax, Pulmonary Edema), Tidal Volume Will Decrease: for this reason, tidal volumes need to be monitored closely in this mode (with ventilator alarms set accordingly)

Recommendations for Patients with ARDS Associated with Sepsis (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]

  • No Ventilator Mode is Recommended Over Another for Mechanical Ventilation in Patients with Sepsis

Rationale

  • Peak Inspiratory Pressure is Generally Lower Than with Volume-Cycled Ventilation: this is due to the flow pattern used with pressure control ventilation
    • However, GIven the Same Tidal Volume, the Plateau Pressure is the same for Pressure Control Ventilation as it is for Volume-Cycled Ventilation
  • Improved Patient-Ventilatory Synchrony with PCV: although this is controversial
  • Improved Gas Exchange with PCV
    • Increased Mean Airway Pressure
    • Lower End-Inspiratory Flow Rates
    • PC has High Initial Flow Rate, Allowing Recruitment of Alveoli with Longer Time Constants
      • Time Constant of Alveolus (Product of the Resistance x Compliance) Determines How Rapidly the Alveolus Will Fill and Empty

Clinical Efficacy

  • No Mortality Benefit Has Been Demonstrated for Pressure Control Ventilation
    • Note: pressure control ventilation was not used in the ARDSnet trial
    • Note: the differences between PCV and modern volume-cycled modes are probably negligible (as mnay modern ventilators can be configured using a descending ramp flow waveform)

Pressure Control-Inverse Ratio Ventilation (PC-IRV) (see Pressure Control Ventilation)

Rationale

  • PC-IRV Increases Mean Airway Pressure and Decreases PIP
  • PC-IRV Creates Auto-PEEP, resulting in Decreased intrapulmonary Shunt (Like Extrinsic PEEP): improves oxygenation
  • PC-IRV Does Not Appear to Significantly Improve V/Q Matching

Potential Adverse Effects

  • Elevated Mean Airway Pressure and Auto-PEEP Can Adversely Impact Hemodynamics

Administration

  • Useful for Refractory Hypoxemia, Despite Adequate PEEP
  • Typically Requires Sedation and Paralysis, as Most Patients Will Tolerate iInversion of I/E Ratio

Clinical Efficacy

  • No Mortality Benefit

Recommendations for Patients with ARDS Associated with Sepsis (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]

  • No Ventilator Mode is Recommended Over Another

Airway Pressure Release Ventilation (APRV) (see Airway Pressure Release Ventilation)

Clinical Efficacy

  • Trial of APRV vs Pressure Control Ventilation in Trauma Patients with ARDS (Am J Respir Crit Care Med, 2001) [MEDLINE]: n = 30
    • APRV was Associated with Increased Respiratory System Compliance, Increased Arterial pO2, Increased Cardiac Index, Increased Oxygen Delivery, Decreased Venous Admixture (QVA/QT), and Decreased Oxygen Extraction
    • Pressure Control Ventilation was Associated with Decreased Respiratory System Compliance, Decreased Arterial pO2, Decreased Cardiac Index, Decreased Oxygen Delivery, Increased Venous Admixture (QVA/QT), Increased Need for Sufentanil/Midazolam/Norepinephrine/Dobutamine
    • APRV was Associated with a Shorter Duration of Ventilatory Support and ICU Length of Stay
    • No Difference in Mortality Rates
  • Large Randomized Controlled Trial of APRV (Acta Anaesthesiol Scand, 2004) [MEDLINE]: RCT (n = 58) comparing APRV with SIMV with PS (study was terminated early for futility)
    • No 28-Day or 1-Year Mortality Benefit
    • No Difference in Ventilator-Free Days at 28 Days
    • However, Proning was Used in Both Arms and its Effects May Have Overshadowed the Potential Effects of APRV in this Study
  • Randomized Trial of APRV in Adult Trauma Patients with Respiratory Failure (J Trauma, 2010) [MEDLINE]: n= 63
    • For Adult Trauma Patients Requiring Mechanical Ventilation >72 hrs, APRV Had a Similar Safety Profile as Low Tidal Volume Ventilation
    • Trends for APRV Patients to Have Increased Ventilator Days, ICU Length of Stay, and Ventilator-Associated Pneumonia May Be Explained by Initial Higher Acute Physiology and Chronic Health Evaluation II Scores
  • Retrospective Review of APRV in Trauma Patients (J Trauma Acute Care Surg, 2012) [MEDLINE]
    • After Controlling for Confounding Factors, APRV Mode Increased the Number of Ventilator Days in Trauma Patients
  • Animal Study of APRV in Traumatized Pigs with Combined Brain and Lung Trauma (J Trauma Acute Care Surg, 2015) [MEDLINE]
    • Microdialysis Data Suggested a Trend Toward Increased Cerebral Ischemia Associated with APRV Over Time
  • Trial of APRV vs Standard Low Tidal Volume Ventilation in ARDS (Intensive Care Med, 2017) [MEDLINE]: n = 148
    • Early Application of APRV in ARDS Improved Oxygenation, Improved Respiratory System Compliance, Decreased Pplat, Decreased Duration of Mechanical Ventilation, and Decreased the ICU Length of Stay
  • Prospective Randomized Intermountain Trial of Low Tidal vs Traditional APRV and Volume Control Ventilation Protocols (Crit Care Med, 2018) [MEDLINE]: n = 246 planned (study stopped early because of low enrollment and inability to consistently achieve tidal volumes <6.5 mL/kg in the low tidal volume-airway pressure release ventilation arm)
    • APRV Often Resulted in Release Volumes >12 mL/kg Despite a Protocol Targeting Low Tidal Volume Ventilation
    • Current APRV Protocols are Unable to Achieve Consistent and Reproducible Delivery of Low Tidal Volume Ventilation Goals
  • Systematic Review and Meta-Analysis of APRV in Acute Hypoxemic Respiratory Failure (Ann Intensive Care, 2019) [MEDLINE]: n = 330 (5 RCT’s)
    • Evidence was Low Quality with Moderate Heterogeneity
    • APRV was Associated with a Higher Number of Ventilator-Free Days at Day 28
    • APRV was Associated with a Lower Hospital Mortality Rate
    • APRV was Not Associated with Any Negative Hemodynamic Impact or Increased Risk of Barotrauma

Recommendations for Patients with ARDS Associated with Sepsis (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]

  • No Ventilator Mode is Recommended Over Another

Body Position -> Proning

History

  • 1974: proning was first proposed (Am Rev Respir Dis, 1974) [MEDLINE]

Physiologic Mechanisms

  • Recruitment of Previously Underventilated Areas (with Minimal Changes in Perfusion), Resulting in Improved V/Q Matching: main mechanism
  • Decreased Cardiac Compression of Lung Tissue: less lung lies inferior to the heart with patient in the prone position
  • Decreased Shunt Fraction: due to decreased dependent pleural pressure and decreased pleural pressure gradient
    • Suggests that Greater Proportion of the Dependent Lung Volume is Above the Closing Volume in the Prone Position
  • Increased Mobilization of Secretions Toward the Mouth
  • Recruitment and Stabilization of Dorsal Lung Units
  • Redistribution of Trans-Lung Forces
  • Reduction of Supine Gradient of Trans-Lung Pressure

Unknown Aspects of Proning

  • When to Start Proning
  • How Long to Continue Proning
  • Optimal Daily Duration of Proning
  • Effect on Ventilator-Induced Lung Injury

Technique

  • Rotoprone Bed
  • Vollman Proning Device

Practical Application

  • If Not Using Rotoprone Bed: recommended to execute proning in 2 steps (side first, then prone) to avoid hemodynamic deterioration, dislodgement of lines, etc
  • Onset of Effect: most of improvement occurs quickly (usually within min)
  • Timing: can be performed successfully at any time during the course of disease
  • Duration of Proning: although not entirely clear, periods pf proning >12 hrs are probably necessary to achieve benefit
  • Repeat Attempts at Proning: proning may improve oxygenation after an initial failure of prior proning
  • Effect on Gas Exchange: significant improvement in pO2 occurs in 66-75% of patients
  • Duration of Effect: improvement in oxygenation can persist in some patients when returned to the supine position
  • Degree of Improvement: not related to the degree of gas exchange impairment
  • Monitoring of Gas Exchange Efficiency During Proning
    • pCO2 Better Tracks Gas Exchange Efficiency (Than pO2) and is Probably a Better Reflection of Proning-Induced Recruitment (Crit Care Med, 2003) [MEDLINE]
    • ALI/ARDS Patients Who Respond to Prone Positioning with Reduction of Their pCO2 Have Improved 28-Day Survival

Absolute Contraindications to Proning

Relative Contraindications to Proning

  • Advanced Osteoarthritis or Rheumatoid Arthritis (RA) (see Rheumatoid Arthritis)
  • Asymmetric/Unilateral Lung Disease
  • Body Weight >135 kg
  • Cardiac Pacemaker Insertion within Prior 2 Days (see Cardiac Pacemaker)
  • Continuous Venovenous Hemodialysis (CVVHD) (see Hemodialysis)
  • Deep Venous Thrombosis (DVT) Treated for <2 Days (see Deep Venous Thrombosis)
  • Difficult Airway Management
  • Elevated Intracranial Pressure (ICP) (see Increased Intracranial Pressure)
  • Femur/Pelvic Fractures and/or External Pelvic Fixation
  • Hemodynamic Instability/Recent Cardiopulmonary Arrest (see Cardiac Arrest)
  • Increased Intraocular Pressure
  • Intra-Aortic Balloon Pump (see Intra-Aortic Balloon Pump)
  • Kyphoscoliosis (see Kyphoscoliosis)
  • Open Thoracic or Abdominal Wounds
  • Massive Hemoptysis Requiring an Immediate Surgical or Interventional Radiology Procedure
  • Multiple Trauma with Unstabilized Fractures
  • Pregnancy (see Pregnancy)
  • Recent Abdominal Surgery/Stoma Formation
  • Recent Cardiothoracic Surgery/Unstable Mediastinum or Open Chest
  • Serious Facial Trauma/Surgery within Prior 15 Days
  • Severe Chest Wall Lesions and/or Rib Fractures
  • Single Anterior Chest Tube with Air Leak
  • Tracheal Surgery or Sternotomy During the Prior 15 Days
  • Tracheostomy within Prior 24 hrs
  • Unstable Injuries
  • Ventricular Assist Device (VAD) (see Ventricular Assist Device)

Adverse Effects/Complications of Proning

Clinical Efficacy

  • Study of the Effect of Proning in ARDS (NEJM, 2001) [MEDLINE]
    • Proning Improved Oxygenation, But Not Improve the Mortality Rate
    • Importantly, This Trial Did Not Use a Lung-Protective Ventilation Protocol
  • Study of the Effects of Proning on pCO2 in ARDS (Crit Care Med, 2003) [MEDLINE]
    • Decrease in pCO2 with Proning is Predictive of Improved Outcome in ARDS
  • Trial of Proning (JAMA, 2004) [MEDLINE]
    • Proning Did Not Improve Mortality
    • Proning May Have Lowered the Incidence of Ventilator-Associated Pneumonia
  • Systematic Review and Meta-Analysis (CMAJ, 2008) [MEDLINE]
    • Proning Improves Oxygenation and Decreases Risk of Pneumonia
    • No Mortality Benefit or Impact on Duration of Mechanical Ventilation
  • Systematic Review and Meta-Analysis (Intensive Care Med, 2010) [MEDLINE]
    • Proning Improves Mortality Only in Subset of Patients with pO2/FIO2 <100
    • Proning Increases Risks of Pressure Ulcers, Endotracheal Tube Obstruction, and Chest Tube Dislodgement
  • French PROSEVA Proning Trial in Severe ARDS (NEJM, 2013) [MEDLINE]: multi-center, randomized, prospective, controlled trial (n = 237 in prone group, n = 229 in supine group) in severe ARDS (defined as pO2/FIO2 ratio <150 with FIO2 ≥60% + PEEP ≥5 cm H20 + VT close to 6 ml/kg PBW)
    • Proning Decreased 28-Day Mortality Rate (16%), as Compared to Supine Group (32.8%)
    • Proning Decreased 90-Day Mortality Rate (23.6%), as Compared to Supine Group (41%)
    • No Difference in Complication Rates Between the Groups (Except for Incidence of Cardiac Arrests was Higher in Supine Group)
  • Systematic Review of Proning in ARDS in Adults (Cochrane Database Syst Rev, 2015) [MEDLINE]
    • Proning Had No Benefit or Harm
      • However, the Subgroups with Early Implementation of Proning, Prolonged Proning, and Severe Hypoxemia at Study Entry Demonstrated Mortality Benefit with Proning
    • Complication of Tracheal Obstruction was Increased with Proning

Recommendations for Patients with ARDS Associated with Sepsis (2012 Surviving Sepsis Guidelines; Crit Care Med, 2013) [MEDLINE]

  • Proning is Recommended in Patients with pO2/FiO2 Ratio ≤100 in Sepsis-Associated ARDS (Grade 2B Recommendation)

Recommendations for Patients with ARDS (American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine Clinical Practice Guidelines for Mechanical Ventilation in ARDS) (Am J Respir Crit Care Med, 2017) [MEDLINE]

  • Proning (for >12 hrs Per Day) is Recommended in Adult Patients with Severe ARDS (Strong Recommendation, Moderate-High Confidence)

Recommendations for Patients with ARDS Associated with Sepsis (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]

  • Prone Position is Recommended Over Supine Position in Sepsis-Associated ARDS and pO2/FIO2 Ratio <150 (Strong Recommendation, Moderate Quality of Evidence)

Body Position -> Head of Bed at ≥30°

Rationale

  • Head of Bed at ≥30° Decreases the Frequency and Severity of Gastric Aspiration in Mechanically Ventilated Patients (Ann Intern Med, 1992) [MEDLINE]
    • The Longer the Patient is in Supine Position, the More Likely They are to Aspirate

Recommendations for Patients with ARDS Associated with Sepsis (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]

  • Elevation of the Head of the Bed to 30-45 Degrees is Recommended to Limit the Aspiration Risk and to Prevent the Development of Ventilator-Associated Pneumonia (VAP) During Mechanical Ventilation in Sepsis-Associated Respiratory Failure (Strong Recommendation, Low Quality of Evidence)

Body Position -> Continuous Lateral Rotational/Kinetic Bed Therapy

History

  • 1967: first implemented

Rationale

  • Continuous Lateral Rotational/Kinetic Bed Therapy Was Developed in Effort to Decrease Complications of Prolonged Immobilization (Pneumonia, Venous Stasis, Skin Breakdown) and Mobilize Secretions

Administration

  • Utilize Rotational Arc >80° (40° in Either Direction): arcs of less than this amount have unknown benefit
  • Beds are Not Available for Purchase: can only be rented at $175-$275/day

Clinical Efficacy

  • Study of Continuous Oscillation Therapy in ARDS (J Crit Care, 1995) [MEDLINE]
    • In Selected Critically Ill Patients, Oscillating Therapy May Improve Survival and Improve Airway Clearance: however, the frequency and degree of turning needed to prevent complications is unclear
  • Study of Rotational Therapy in ARDS (Intensive Care Med, 1998) [MEDLINE]
    • Continuous Axial Rotation Might Acutely Decrease V/Q Mismatch in Mild-Moderate Acute Lung Injury, But it is Not Effective in Progressive-Late ARDS
    • Further Studies re Required
  • Review and Meta-Analysis of Rotational Bed Therapy in ARDS (Am J Crit Care, 2007) [MEDLINE]: n = 15 nonrandomized, uncontrolled, or retrospective studies (1987-2004)
    • As Compared to Nurse Turning q2hrs, Meta-Analysis Suggested that Rotational Bed Therapy Decreased the Incidence of Pneumonia, But Had No Effect on Duration of Mechanical Ventilation, ICU Length of Stay, or Hospital Mortality Rate
  • Case Series of Rotational Percussion Bed Therapy in ARDS Patients Supported on EMCO Therapy (ASAIO J, 2016) [MEDLINE]
    • Use of Chest Physiotherapy, Frequent Body Repositioning, and Bronchoscopy May Be Helpful in the Management of Pulmonary Secretions in ARDS Patients Supported with ECMO

Inhaled Nitric Oxide (iNO) (see Nitric Oxide)

Rationale

  • Improved Carbon Dioxide Elimination: occurs only at high NO concentrations and only with baseline pCO2 >50 mm Hg
    • Due to Improved Perfusion, Resulting in Decreased Alveolar Dead Space
  • Pulmonary Artery Vasodilation: modestly decreased pulmonary artery pressure occurs in the majority of patients
  • Selective Pulmonary Artery Vasodilation of Better Ventilated Lung Regions, Resulting in Improved V/Q Matching
  • Anti-Inflammatory/Anti-Platelet Effects: both theoretical

Administration

  • Half-Life: several milliseconds
  • FDA Approval: only for treatment of term/near-term (34 wk) neonates with hypoxic respiratory failure and pulmonary hypertension
  • Dosing and Response: 60-80% respond to <10 ppm with >20% increase in pO2 (lower response rate in sepsis-related ARDS, due to higher background inducible NO levels)
  • Improved Oxygenation Lasts <4 Days

Adverse Effects

  • Increases NO2
  • Methemoglobinemia (see Methemoglobinemia): likely occurs predominantly in patients with methemoglobin reductase deficiency
  • Generation of O2 Radicals: however, clinically significant toxicity has not been reported in trials)

Clinical Efficacy

  • Systematic Review and Meta-Analysis (BMJ, 2007) [MEDLINE]
    • Inhaled Nitric Oxide Results in Limited Improvement in Oxygenation in Patients with ALI/ARDS, But Confers No Mortality Benefit (and May Cause Harm)
  • Cochrane Database Systematic Review of iNO in ARDS (Cochrane Database Syst Rev, 2016) [MEDLINE]
    • Evidence is Insufficient to Support iNO in Any Category of Critically Ill Patients with Acute Hypoxemic Respiratory Failure
    • Inhaled Nitric Oxide Results in a Transient Improvement in Oxygenation, But Does Not Decrease the Mortality Rate and May Be Harmful, as it Seems to Increase Renal Impairment

Inhaled Prostacyclin (see Prostacyclin)

Rationale

  • Inhaled Pulmonary Vasodilator Which Selectively Dilates Pulmonary Arteries Which Perfuse Well-Ventilated Lung Zones, Resulting in Improved V/Q Matching and Improved Oxygenation
    • Pulmonary Vasodilation Also Decreases Pulmonary Artery Pressures

Clinical Efficacy

  • Systematic Review and Meta-Analysis of Inhaled Prostaglandins in ARDS (Chest, 2015) [MEDLINE]
    • Inhaled prostaglandins improve oxygenation and decrease pulmonary artery pressures and may be associated with harm
    • Data are limited both in terms of methodologic quality and demonstration of clinical benefit
    • The Use of inhaled prostaglandins in ARDS needs further study

Inhaled Iloprost (see Iloprost)

Rationale

  • Inhaled Pulmonary Vasodilator Which Selectively Dilates Pulmonary Arteries Which Perfuse Well-Ventilated Lung Zones, Resulting in Improved V/Q Matching and Improved Oxygenation
    • Pulmonary Vasodilation Also Decreases Pulmonary Artery Pressures

Clinical Efficacy

  • Study of Inhaled Iloprost in ARDS with Pulmonary Hypertension (Chest, 2013) [MEDLINE]
    • Inhaled (Nebulized) Iloprost Improved Gas Exchange without Adverse Effects on Pulmonary Mechanics or Systemic Hemodynamics

Avoidance of Systemically-Active Vasodilators

  • Pharmacology
    • However, Pulmonary Vasodilation by Itself Does Not Uniformly Cause Hypoxemia
  • Mechanisms by Which Systemic Vasodilators Can Exacerbate/Induce Hypoxemia
    • Increased Cardiac Output (CO)
    • Impairment of Hypoxic Vasoconstriction: due to drug itself or due to higher mixed venous pO2
    • Changes in Intracardiac Pressure or Pulmonary Artery Pressure Leading to Redistribution of Pulmonary Blood Flow
    • Direct Action on Pulmonary Vascular Tone: this can be seen with nitroprusside, hydralazine, nitroglycerin, nifedipine, dopamine, and dobutamine
    • Suppression of Hypercapnic Response: this can be seen with dopamine

Venovenous Extracorporeal Membrane Oxygenation (VV-ECMO), Venoarterial Extracorporeal Membrane Oxygenation (VA-ECMO), and ECCO2R (see Venovenous Extracorporeal Membrane Oxygenation and Venoarterial Extracorporeal Membrane Oxygenation)

Indications from NEJM, 2011 Review of ECMO in ARDS [MEDLINE]

  • Severe Hypoxemia: pO2/FiO2 Ratio <80 Despite High PEEP (15–20 cm of H2O for at Least 6 hrs in Patients with Potentially Reversible Respiratory Failure
  • Uncompensated Hypercapnia with Acidemia (pH <7.15) Despite the Optimized Ventilator Management
  • Excessively High Plateau Pressure (>35–45 cm of H2O, According to the Patient’s Body Size) Despite Optimized Ventilator Management

Absolute Contraindications

  • Contraindication to Anticoagulation: although in patients with severe bleeding, anticoagulation can be held for limited periods of time

Relative Contraindications (NEJM, 2011) [MEDLINE]

  • Any Condition or Organ Dysfunction that Would Limit the Likelihood of Overall Benefit from ECMO, Such as Severe, Irreversible Brain Injury or Untreatable Metastatic Cancer
  • High FiO2 Requirement >80% for >7 Days
  • High-Pressure Ventilation (Plateau Pressure >30 cm of H2O) for >7 Days
  • Limited Vascular Access

Technique

  • Requires Local Expertise and Invasive Vascular Access: venovenous access is most commonly used (although venoarterial access can be used, as well)

Clinical Efficacy

  • Early JAMA ECMO Trial (JAMA, 1979) [MEDLINE]
    • ECMO Had No Mortality Benefit
  • ECCO2R Trial (Am J Respir Crit Care Med, 1994) [MEDLINE]
    • ECCO2R Had No Mortality Benefit
  • ANZ ECMO Influenza Trial (JAMA, 2009) [MEDLINE]
    • ECMO Had No Mortality Benefit in Treatment of ARDS Associated with Influenza
  • CESAR Trial of ECMO in the UK (Lancet, 2009) [MEDLINE]
    • ECMO Decreased Mortality Rate/Severe Disability at 6 mo
    • However, the Study was Flawed by Not Defining the Usual Care Group and ECMO Patients Were Concentrated in One Center in the Trial
  • Systematic Review and Meta-Analysis of ECMO in Adult Patients with ARDS (J Crit Care, 2013) [MEDLINE]
    • ECMO Had an Unclear Hospital Mortality Benefit: further studies were recommended
  • Cochrane Review of VV-ECMO and VA-ECMO in Critically Ill Adults (Cochrane Database Syst Rev, 2015) [MEDLINE]
    • ECMO Had No 6-Month (or Prior to 6 Month) All-Cause Mortality Benefit: low-moderate quality of evidence from trials
  • Study of the Long-Term Survival and Quality of Life Following ECMO (Eur J Cardiothorac Surg, 2017) [MEDLINE]
    • Survival to Discharge was Higher in the Non-ECMO Group, as Compared to the ECMO Group: however, this difference was not statistically significant after propensity score matching
    • One Year Survival was 67% in the Non-ECMO Group vs 60% in the ECMO Group
    • Two Year Survival was 50% in the Non-ECMO Group vs 45% in the ECMO Group
  • Single-Center Swedish Retrospective Study of Outcomes After ECMO for ARDS Associated with Sepsis (Crit Care Med, 2017) [MEDLINE]
    • Approximately 64% of ECMO Patients Survived to Discharge
    • High Mortality Rate Within the First Few Months After Discharge
  • Systematic Review and Meta-Analysis of Mortality and Complications with the Use of Venovenous ECMO in ARDS (Ann Intensive Care, 2017) [MEDLINE]
    • Mortality Rate at Hospital Discharge was 37.7%
    • Factors Associated with Increased Hospital Mortality
      • Age
      • Year of Study
      • Mechanical Ventilation and Prone Positioning Days Prior to ECMO
  • Systematic Review of Venovenous ECMO for ARDS (J Crit Care, 2017) [MEDLINE]: n = 27 studies
    • Mortality Benefit of ECMO is Unclear
  • French EOLIA Trial of VV-ECMO in ARDS (NEJM, 2018) [MEDLINE]
    • In Very Severe ARDS, VV-ECMO Did Not Decrease the 60-Day Mortality Rate, as Compared to a Conventional Mechanical Ventilation Strategy Which Included VV-ECMO as a Rescue Therapy
  • Systematic Review and Meta-Analysis of ECMO in Adults with ARDS (Lancet Respir Med, 2019) [MEDLINE]: n = 773 (2 randomized controlled trials and 3 observational studies with matching techniques)
    • Compared with Conventional Mechanical Ventilation, the Use of Venovenous ECMO in Adults with Severe Acute Respiratory Distress Syndrome was Associated with a Decreased 60-Day Mortality Rate (73 [34%] of 214 vs 101 [47%] of 215; RR 0.73 [95% CI 0.58-0.92]; p=0.008; I2 0%; Moderate Grade Evidence)
    • However, Venovenous ECMO was Also Associated with a Moderate Risk of Major Hemorrhage (Occurred in 19% of Cases)
  • SUPERNOVA Trial of ECCO2R + Low Tidal Ventilation: trial underway
  • pRotective vEntilation with veno-venouS lung assisT (REST) Trial of ECCO2R + Low Tidal Ventilation: trial underway

Clinical Efficacy-Mechanical Ventilation Settings During VV-EMCO

  • Based Only on Expert Opinion, Protective Mechanical Ventilation Strategies Should Be Used During VV-ECMO (Minerva Anestesiol, 2015) [MEDLINE]
    • Extracorporeal Life Support Organization (ELSO) Suggests Using Mechanical Ventilation “at Low Settings to Allow Lung Rest”
      • ELSO Also Suggests that “For Patients with Respiratory Failure, a Common Mistake is to Try to Recruit Lung Volume During the Acute Inflammatory Stage Early in ECMO”
    • French Consensus Conference on Extracorporeal Life Support for Patients with ARDS Recommends “Adjust Mechanical Ventilation to Minimize Plateau Pressure While Administering a Minimum PEEP” without Citing Specific Values

Recommendations for Patients with ARDS Associated with Sepsis (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]

Recommendations for Patients with ARDS (American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine Clinical Practice Guidelines for Mechanical Ventilation in ARDS) (Am J Respir Crit Care Med, 2017) [MEDLINE]

  • No Recommendation was Made with Regard to the Use of ECMO in ARDS: further study is required

Allogeneic Mesenchymal Stromal Cells

Clinical Efficacy

  • START (Phase a Safety) Trial of Allogeneic Mesenchymal Stromal Cells in ARDS (Lancet Respir Med, 2019) [MEDLINE]
    • One Dose of Intravenous Mesenchymal Stromal Cells was Safe in Patients with Moderate-Severe ARDS

Tracheostomy (see Tracheostomy)

  • See Tracheostomy

Early Mobilization/Rehabilitation

Clinical Efficacy

  • Trial of Early Mobilization with Physical/Occupational Therapy in Critically Ill Patients (Lancet, 2009) [MEDLINE]
    • Early Mobilization (with Interruption of Sedation and Physical/Occupational Therapy) in the Earliest Days of Critical Illness was Safe and Well-Tolerated
    • Early Mobilization (with Interruption of Sedation and Physical/Occupational Therapy) in the Earliest Days of Critical Illness Improved Functional Outcomes at Hospital Discharge, Decreased Duration of Delirium, and Increased Ventilator-Free Days, as Compared to Standard Care
  • Multi-Center German/Austrian/US Trial of Early Mobilization in Surgical ICU Patients (Lancet, 2016) [MEDLINE]: n = 200
    • Early Mobilization Increased Mobilization, Decreased ICU Length of Stay, and Improved Functional Mobility at Hospital Discharge
    • Early Mobilization Group Had Higher Incidence of Adverse Events (2.8% vs 0.8%), as Compared to Control Group: however, no serious adverse events were observed
    • Early Mobilization Group Had Higher In-Hospital Mortality Rate (16% vs 8%), as Compared to Control Group
    • Early Mobilization Group Had Higher 3-Month Mortality Rate (22% vs 17%), as Compared to Control Group
  • Trial of Standardized Rehabilitation (Daily Physical Therapy) in Acute Respiratory Failure (Requiring Mechanical Ventilation) in the ICU (JAMA, 2016) [MEDLINE]: single-center randomized trial (n = 300)
    • Standardized Rehabilitation Therapy Did Not Decrease Hospital Length of Stay, ICU Length of Stay, or Ventilator Days in Patients with Acute Respiratory Failure
  • Systematic Review of Early Mobilization in the ICU (Intensive Care Med, 2017) [MEDLINE]
    • Active Mobilisation and Rehabilitation in the ICU has No Impact on Short and Long-Term Mortality, But May Improve Mobility Status, Muscle Strength and Days Alive and Out of Hospital at 180 Days
  • Trial of Chest Physiotherapy with Earlu Mobilization in Critically Ill ICU Patients (Clin Respir J, 2018) [MEDLINE]: n = 439
    • Intensive Chest Physiotherapy Decreased the Extubation Failure Rate in Mechanically Ventilated Patients
    • Chest Physiotherapy Improved the Rapid Shallow Breathing Index (RSBI) Score
  • Single-Center Randomized Trial of In-Bed Cycling and Electrical Stimulation of the Quadriceps in Critically Ill ICU Patients (JAMA, 2018) [MEDLINE]
    • No Clinical Efficacy in Terms of Global Muscle Strength

Nutritional Support

Clinical Efficacy (General)

  • OMEGA Trial Examining the Effect of Supplementation with Omega-3 (n-3) Fatty Acids (Docosahexaenoic Acid = DHA, Eicosapentaenoic Acid = EPA), γ-Linolenic Acid, and Antioxidants in Acute Lung Injury (JAMA, 2011) [MEDLINE]
    • Enteral Omega-3 Fatty Acids, Gamma-Linolenic Acid, and Antioxidants Did Not Improve the Primary Endpoint of Ventilator-Free Days or Other Clinical Outcomes in Patients with Acute Lung Injury and May Be Harmful
  • EDEN Trial of Enteral Nutrition in Acute Lung Injury (JAMA, 2012) [MEDLINE]
    • Initial Trophic Feeding (For Up to 6 Days) Did Not Improve Ventilator Days, 60-Day Mortality, or Infectious Complications, as Compared to Full Feeding
    • Full Feeding Group Had More Gastrointestinal Intolerance (Vomiting, Constipation, and Elevated Gastric Residual Volumes): they received more pro-kinetic agents
  • Trial of Glutamine and Antioxidants in Critically Ill Patients with Mutiorgan Failure on Mechanical Ventilation (NEJM, 2013) [MEDLINE]
    • Early Provision of Glutamine or Antioxidants Did Not Improve Clinical Outcomes, and Glutamine was Associated with an Increase in Mortality Among Critically IIl Patients with Multiorgan Failure
  • Australia/New Zealand TARGET Trial of Energy-Dense Enteral Nutrition in Patients on Mechanical Ventilation (NEJM, 2018) [MEDLINE]
    • In Patients on Mechanical Ventilation, the Energy-Dense Enteral Nutrition Had No Impact on the 90-Day Mortality Rate, as Compared to Routine Enteral Nutrition

Clinical Efficacy (During Prone Ventilation)

  • Study of Early Enteral Nutrition in Association with Prone Ventilation (Crit Care Med, 2004) [MEDLINE]
    • Early Enteral Nutrition is Poorly-Tolerated in Patients Who are Prone-Ventilated
    • Prokinetic Agents, Transpyloric Feeding, and Semirecumbency Should Be Considered to Enhance Gastric Emptying and to Prevent Vomiting in This Population
  • Study of Head of Bed Elevation in Enteral Nutrition in Association with Prone Ventilation (Clin Nutr, 2010) [MEDLINE]:
    • Elevation (25 Degrees) Increased Acceleration of Tube Feedings to Target Rate
    • Erythromycin Improved Delivery of Enteral Nutrition
  • Study of Enteral Nutrition in Association with Prone Ventilation (J Parenter Enteral Nutr, 2016) [MEDLINE]
    • Enteral Nutrition in Association with Prone Ventilation is Feasible, Safe, and Not Associated with an Increased Risk of Gastrointestinal Complications

Recommendations (Society of Critical Care Medicine, SCCM, and American Society for Parenteral and Enteral Nutrition, ASPEN, 2016 Guidelines) [MEDLINE]

  • High Fat/Low Carbohydrate Tube Feedings are Not Recommended in Patients with Acute Respiratory Failure (Quality of Evidence: Very Low)
  • Either Trophic or Full Feedings are Acceptable in ARDS with an Expected Duration of Mechanical Ventilation ≥72 hrs (Quality of Evidence: High)
    • Both Trophic and Full Feeding Strategies Have Similar Outcomes for the First Week of Hospitalization
  • In Acute Respiratory Failure, Fluid-Restricted, Energy-Dense Enteral Formulations Should Be Considered, Especially in the State of Volume Overload (Quality of Evidence: Expert Consensus)
  • Supplemental Antioxidant Vitamins (Vitamins E and C) and Trace Minerals (Selenium, Zinc, Copper) May Be Beneficial in Burns, Trauma, Critical Illness Requiring Mechanical Ventilation (Quality of Evidence: Low)
  • Supplemental Omega-3 (n-3) Fatty Acids (Docosahexaenoic Acid = DHA, Eicosapentaenoic Acid = EPA) Are Not Recommended in ARDS

Weaning

Recommendations for Patients with ARDS Associated with Sepsis (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]

  • Spontaneous Breathing Trials (When Specific Criteria are Met) are Recommended in Sepsis-Associated Respiratory Failure (Strong Recommendation, High Quality of Evidence)
  • Weaning Protocol is Recommended for Appropriate Patients During Mechanical Ventilation in Sepsis-Associated Respiratory Failure (Strong Recommendation)

Therapies with Unclear or No Clinical Benefit in ARDS

  • Activated Protein C (see Drotrecogin Alfa)
    • Clinical Efficacy
      • Dutch Randomized Trial of Intravenous Recombinant Human Activated Protein C in ARDS (PLoS One, 2014) [MEDLINE]
        • Intravenous Recombinant Human Activated Protein C (x 4 Days) Did Not Impact the Mortality Rate in ARDS
        • Trial was Prematurely Discontinued as Drotrecogin Alfa was Withdrawn from the Market
  • Antioxidants
  • Ibuprofen (see Ibuprofen)
  • Ketoconazole (see Ketoconazole)
  • Macrolides (see Macrolides)
    • Rationale: macrolides have potential anti-inflammatory effects
    • Clinical Efficacy
      • Secondary Analysis of Randomized Controlled Acute Respiratory Distress Syndrome Network Lisofylline and Respiratory Management of Acute Lung Injury (LARMA) Trial Examining Macrolide Use in ARDS (Chest, 2012) [MEDLINE]
        • Receipt of Macrolide Antibiotics (Erythromycin, Azithromycin) was Associated with Decreased 180-Day Mortality Rate and Shorter Time to Successful Discontinuation of Mechanical Ventilation in ARDS, as Compared to Fluoroquinolones and Cephalosporins
        • Importantly, Patients Receiving Macrolides Were More Likely to Have Pneumonia as Their ARDS Risk Factor, Were Less Likely to Have Non-Pulmonary Sepsis or Be Randomized to Low Tidal Volume Ventilation, and Had Shorter Length of Stay Prior to Trial Enrollment
  • N-Acetylcysteine (see N-Acetylcysteine)
  • Neutrophil Elastase Inhibitors
  • Partial Liquid Ventilation
    • Clinical Efficacy
      • Cochrane Database Review of Partial Liquid Ventilation in ALI/ARDS (Cochrane Database Syst Rev, 2013) [MEDLINE]
        • Partial Liquid Ventilation Had No Mortality Benefit in ARDS: some evidence suggests an increased risk of adverse events
  • Prostaglandin E1 (see Prostaglandin E1)
  • Statins (see HMG-CoA Reductase Inhibitors)
  • Surfactant

Prognosis

Reported Acute Respiratory Distress Syndrome (ARDS) Mortality Rates

  • Historical ARDS Mortality Rates (Studies Published in 2000): 30-40% (NEJM, 2000) [MEDLINE] [MEDLINE]
  • ARDS Mortality Rate on Current Lung Protective Ventilation Strategies (Studies Published in 1999 and 2004): 13-23% (Intensive Care Med, 1999) [MEDLINE] (Intensive Care Med, 2004) [MEDLINE]
  • ALIEN Study of ARDS Mortality Rates in the Current Era of Lung Protective Ventilation Strategies (Intensive Care Med, 2011) [MEDLINE]
    • ICU Mortality Rate: 42.7%
    • Hospital Mortality Rate: 47.8%
  • ARDS Mortality Rate in Patients Without Clinical Improvement in pO2/FIO2 Ratio in First 24 hrs After Initiating Mechanical Ventilation: 53-68% (Intensive Care Med, 1999) [MEDLINE] (Intensive Care Med, 2004) [MEDLINE]
  • Mortality Rate by Berlin Definition Class (JAMA, 2012) [MEDLINE]
    • Mild ARDS: 27% mortality rate (95% CI: 24%-30%)
    • Moderate ARDS: 32% mortality rate (95% CI: 29%-34%)
    • Severe ARDS: 45% mortality rate (95% CI: 42%-48%)

Predicted Duration of Mechanical Ventilation in Acute Respiratory Distress Syndrome (ARDS) Survivors by Berlin Definition Class (JAMA, 2012) [MEDLINE]

  • Mild ARDS: 5 days (2-11 days)
  • Moderate ARDS: 7 days (4-14 days)
  • Severe ARDS: 9 days (5-17 days)

Predictors of Acute Respiratory Distress Syndrome (ARDS) Mortality

  • Cirrhosis/End-Stage Liver Disease (see Cirrhosis)
  • Failure of Pulmonary Function to Improve After 1 Week of Therapy
  • Increased Physiologic Dead Space Fraction (VD/VT) in Early ARDS (Respir Care, 2014) [MEDLINE]
  • Nonpulmonary Organ Dysfunction
  • Sepsis (see Sepsis)
  • Note: initial pO2/FIO2 ratio and initial indexes of ventilation do not predict mortality -> patients with the worse pO2/FIO2 ratios had the best survival

Post-Operative Acute Respiratory Distress Syndrome (ARDS) Mortality

  • Systematic Review/Meta-Analysis of Morbidity/Mortality in Post-Operative Acute Lung Injury (Lancet Respir Med, 2014) [MEDLINE]
    • Postoperative Acute Lung Injury is Associated with Increased In-Hospital Mortality Rate (Overall 19% Mortality Rate), Increased ICU Length of Stay, and Increased Hospital Length of Stay
    • Mortality Due to Acute Lung Injury Associated with Thoracic Surgery is Higher (26.5% mortality) than Acute Lung Injury Associated with Abdominal Surgery (12.2% Mortality) Rate
    • Lung Protective Mechanical Ventilation Strategies Decrease the Incidence of Postoperative Acute Lung Injury, But Do Not Impact the Mortality Rate

Sequelae of Acute Respiratory Distress Syndrome (ARDS)

Exercise Limitation/Physical Dysfunction

  • Canadian Clinical Trials Group 5-Year Study of ARDS Sequelae (NEJM, 2011) [MEDLINE]: ARDS survivors (n = 109) studied at at 3, 6, and 12 months and at 2, 3, 4, and 5 years after discharge from the intensive care unit
    • Exercise Limitation (Decreased 6-Minute Walk Test) and Physical Dysfunction May Persist for Up to 5 yrs After ARDS
    • Pulmonary Function was Near Normal-Normal
  • NHLBI ARDS Network Prospective Longitudinal (1 Year) Multicenter Study of Physical Impairment in ARDS Survivors (Am J Respir Crit Care Med, 2014) [MEDLINE]
    • ARDS Survivors Demonstrated Impairment in 6-Minute Walk Test Distance (Distance was 64% Predicted at 6 Months, 67% Predicted at 1 Year) and Short Form-36 (SF-36) Physical Function Outcome Measures
    • Impairment Appeared to Be Correlated with Mean Daily Corticosteroid Dose and ICU Length of Stay
  • Prospective Longitudinal (2 Year) Multicenter Study of Physical Impairment in ARDS Survivors (Crit Care Med, 2014) [MEDLINE]
    • Muscle Weakness is Common at Hospital Discharge Following ARDS, Usually Recovering Within 1 Year
    • Muscle Weakness is Associated with Substantial Impairment in Physical Function and Health-Related QOL, Which Continue Beyond 12 Months
    • Corticosteroid Dose and Use of Neuromuscular Blockade Were Not Associated with the Development of Weakness

Decreased Quality of Life (QOL)

  • Canadian Clinical Trials Group 5-Year Study of ARDS Sequelae (NEJM, 2011) [MEDLINE]: ARDS survivors (n = 109) studied at at 3, 6, and 12 months and at 2, 3, 4, and 5 years after discharge from the intensive care unit
    • Decreased QOL May Persist for Up to 5 yrs After ARDS
  • Prospective Longitudinal (2 Year) Multicenter Study of Physical Impairment in ARDS Survivors (Crit Care Med, 2014) [MEDLINE]
    • Muscle Weakness is Common at Hospital Discharge Following ARDS, Usually Recovering Within 1 Year
    • Muscle Weakness is Associated with Substantial Impairment in Physical Function and Health-Related QOL, Which Continue Beyond 12 Months
    • Corticosteroid Dose and Use of Neuromuscular Blockade Were Not Associated with the Development of Weakness

Increased Costs and Use of Health Care Services

  • Canadian Clinical Trials Group 5-Year Study of ARDS Sequelae (NEJM, 2011) [MEDLINE]: ARDS survivors (n = 109) studied at at 3, 6, and 12 months and at 2, 3, 4, and 5 years after discharge from the intensive care unit
    • Increased Health Care Costs and Increased Use of Health Care Services May Persist for Up to 5 yrs After ARDS
    • Patients with More Coexisting Illnesses Incurred Greater 5-Year Costs

Neuropsychologic Dysfunction

  • Canadian Clinical Trials Group 5-Year Study of ARDS Sequelae (NEJM, 2011) [MEDLINE]: ARDS survivors (n = 109) studied at at 3, 6, and 12 months and at 2, 3, 4, and 5 years after discharge from the intensive care unit
    • Psychological Problems May Persist for Up to 5 years after ARDS
  • Adult Respiratory Distress Syndrome Cognitive Outcomes Study (Am J Respir Crit Care Med) [MEDLINE]: study of ARDS survivors (n = 213)
    • Long-term cognitive impairment was present in 55% of subjects
    • Depression was present in 36% of subjects
    • Post-traumatic stress disorder (PTSD) was present in 39% of subjects
    • Anxiety was present in 62% of subjects
    • Impact of Hypoxemia: presence of hypoxemia is a risk factor for long-term cognitive and psychiatric impairment
    • Impact of Fluid Management Strategy: conservative fluid management strategy is a potential risk factor for long-term cognitive impairment (however, this finding requires further studies for confirmation)
  • BRAIN-ICU Study of Patients with Respiratory Failure or Shock in the Medical/Surgical ICU (NEJM, 2013) [MEDLINE]: n = 821)
    • Delirium Developed in 74% of Cases During Hospital Stay
    • Outcomes At 3 Months
      • 40% of Patients Had Impaired Global Cognition Scores that Were 1.5 SD Below the Population Mean, Similar to Scores for Patients with Moderate Traumatic Brain Injury
      • 26% of Patients Had Scores 2 SD Below the Population Mean (similar to scores for patients with Mild Alzheimer’s Disease
    • Outcomes At 12 Months
      • Similar Persistent Cognitive Dysfunction Occurs as in Those with Moderate Traumatic Brain Injury
      • Similar Persistent Cognitive Dysfunction Occurs as in Those with Mild Alzheimer’s Disease
    • Impact of Duration of Delirium
      • Longer Duration of Delirium was Significantly Associated with Worse Global Cognition at 3 and 12 Months and Worse Executive Function at 3 and 12 Months
    • Impact of Sedative Use
      • Use of Sedatives or Analgesics was Not Associated with Cognitive Impairment at 3 and 12 Months
    • Cognitive Dysfunction was Also Independent of Age, Pre-Existing Cognitive Impairment, Presence or Severity of Coexisting Conditions, and Organ Failure During ICU Care

References

General

  • The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination.  Am J Respir Crit Care Med   1994;149:818–824 [MEDLINE]
  • The acute respiratory distress syndrome. N Engl J Med 1995; 332:27-37
  • Clinical risk factors for pulmonary barotrauma: a multivariate analysis. Am J Respir Crit Care Med 1995; 152:1235-1240
  • Pathogenesis and treatment of the adult respiratory distress syndrome. Arch Intern Med 1996; 156:29-38
  • The relation of pneumothorax and other air leaks to mortality in the acute respiratory distress syndrome. N Engl J Med 1998; 338:341-346
  • The acute respiratory distress syndrome. N Engl J Med. 2000 May 4;342(18):1334-49 [MEDLINE]
  • What has computed tomography taught us about the acute respiratory distress syndrome? Am J Respir Crit Care Med. 2001 Nov 1;164(9):1701-11 [MEDLINE]
  • Hypocapnia. NEJM 2002: 347:43-53 [MEDLINE]
  • Pressure-volume curves and compliance in acute lung injury: evidence of recruitment above the lower inflection point. Am J Respir Crit Care Med 1999; 159:1172-1178
  • Consensus conference on mechanical ventilation. Intensive Care Med 1994; 20:64-79, 150-162
  • The American-European consensus conference on ARDS. Am J Respir Crit Care Med 1994;149:818-824
  • Patient-ventilator interactions. Clin Chest Med 1996; 17:423-438.
  • Patient-ventilator interaction. Br J Anaesthes 2003; 19:106-119.
  • Patient ventilator interaction. Am J Respir Crit Care Med 2001; 163:1059-1063.
  • Influence of cardiac output on intrapulmonary shunt. J Appl Physiol 1979; 46:315-321
  • Respiratory system mechanics in ventilated patients: techniques and indications. Mayo Clin Proc 1987; 62:358-368
  • Physiologic approach to mechanical ventilation Crit Care Med 1990; 18:103-113
  • Current definitions of acute lung injury and the acute respiratory distress syndrome do not reflect their true severity and outcome. Intensive Care Med. 1999;25(9):930-935 [MEDLINE]
  • Screening of ARDS patients using standardized ventilator settings: influence on enrollment in a clinical trial. Intensive Care Med. 2004;30(6):1111-1116 [MEDLINE]
  • Severe Hypoxemic Respiratory Failure, Part 1—Ventilatory Strategies. Chest 2010; 137(5):1203–1216 [MEDLINE]
  • Severe hypoxemic respiratory failure: part 2-Nonventilatory strategies. Chest. 2010 Jun;137(6):1437-48 [MEDLINE]
  • Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012 Jun 20;307(23):2526-33 [MEDLINE]
  • The acute respiratory distress syndrome: what’s in a name?  JAMA  2012;307:2542–2544 [MEDLINE]
  • Update in acute respiratory distress syndrome and mechanical ventilation.  Am J Respir Crit Care Med  2012;188:285–292 [MEDLINE]
  • The new definition for acute lung injury and acute respiratory distress syndrome: is there room for improvement? Curr Opin Crit Care. 2013 Feb;19(1):16-23 [MEDLINE]
  • Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013 Feb;41(2):580-637. doi: 10.1097/CCM.0b013e31827e83af [MEDLINE]
  • Incidence of mortality and morbidity related to postoperative lung injury in patients who have undergone abdominal or thoracic surgery: a systematic review and meta-analysis. Lancet Respir Med. 2014 Dec;2(12):1007-15. doi: 10.1016/S2213-2600(14)70228-0. Epub 2014 Nov 13 [MEDLINE]
  • The association between physiologic dead-space fraction and mortality in subjects with ARDS enrolled in a prospective multi-center clinical trial. Respir Care. 2014;59:1611–1618 [MEDLINE]
  • Driving pressure and survival in the acute respiratory distress syndrome. N Engl J Med 2015;372:747-755 [MEDLINE]
  • Driving pressure and respiratory mechanics in ARDS. N Engl J Med 2015;372:776-777 [MEDLINE]
  • LUNG SAFE Study. Epidemiology, Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries. JAMA. 2016 Feb 23;315(8):788-800. doi: 10.1001/jama.2016.0291 [MEDLINE]
  • Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017 Jan 18. doi: 10.1007/s00134-017-4683-6 [MEDLINE]

Epidemiology

  • Epidemiology of acute lung injury. Curr Opin Crit Care. 2005;11(1):43 [MEDLINE]
  • Incidence and outcomes of acute lung injury. N Engl J Med. 2005;353(16):1685 [MEDLINE]
  • LUNG SAFE Study. Epidemiology, Patterns of Care, and Mortality for Patients With Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries. JAMA. 2016 Feb 23;315(8):788-800. doi: 10.1001/jama.2016.0291 [MEDLINE]
  • Preadmission Oral Corticosteroids Are Associated With Reduced Risk of Acute Respiratory Distress Syndrome in Critically Ill Adults With Sepsis. Crit Care Med. 2017 May;45(5):774-780. doi: 10.1097/CCM.0000000000002286 [MEDLINE]
  • Older Adult Patients Are at Lower Risk of ARDS Compared to Younger Patients at Risk: Secondary Analysis of a Multicenter Cohort Study. J Intensive Care Med. 2019 May 8:885066619848357. doi: 10.1177/0885066619848357 [MEDLINE]

Etiology

Infection

  • Chronic alcohol abuse is associated with an increased incidence of acute respiratory distress syndrome and severity of multiple organ dysfunction in patients with septic shock. Crit Care Med. 2003;31(3):869 [MEDLINE]
  • Risk factors for the development of acute lung injury in patients with septic shock: an observational cohort study. Crit Care Med. 2008;36(5):1518 [MEDLINE]
  • Early risk factors and the role of fluid administration in developing acute respiratory distress syndrome in septic patients. Ann Intensive Care. 2017;7(1):11. Epub 2017 Jan 23 [MEDLINE]

Hematologic Disorder

  • Adult haemophagocytic syndrome. Lancet. 2014;383(9927):1503 [MEDLINE]

Physiology

  • Ventilator-related causes of lung injury: the mechanical power. Intensive Care Med. 2016;42 (10):1567-1575 [MEDLINE]
  • Early Intravascular Events Are Associated with Development of Acute Respiratory Distress Syndrome. A Substudy of the LIPS-A Clinical Trial. Am J Respir Crit Care Med. 2018 Jun 15;197(12):1575-1585. doi: 10.1164/rccm.201712-2530OC [MEDLINE]

Diagnosis

General

  • Diagnosis of nosocomial bacterial pneumonia in acute, diffuse lung injury. Chest. 1981;80(3):254 [MEDLINE]
  • The Randomized Educational Acute Respiratory Distress Syndrome Diagnosis Study: A Trial to Improve the Radiographic Diagnosis of Acute Respiratory Distress Syndrome. Crit Care Med. 2018 May;46(5):743-748. doi: 10.1097/CCM.0000000000003000 [MEDLINE]

Chest X-Ray (see Chest X-Ray)

  • Interobserver variability in applying a radiographic definition for ARDS. Chest. 1999 Nov;116(5):1347-53 [MEDLINE]
  • Accuracy of the chest radiograph to identify bilateral pulmonary infiltrates consistent with the diagnosis of acute respiratory distress syndrome using computed tomography as reference standard. J Crit Care. 2013 Aug;28(4):352-7. doi: 10.1016/j.jcrc.2012.12.002 [MEDLINE]
  • Imaging of Acute Lung Injury. Radiol Clin North Am. 2016 Nov;54(6):1119-1132. doi: 10.1016/j.rcl.2016.05.006 [MEDLINE]

Chest Computed Tomography (CT) (see Chest Computed Tomography)

  • Adult respiratory distress syndrome profiles by computed tomography. J Thorac Imaging. 1986;1(3):25 [MEDLINE]
  • Congestive heart failure and adult respiratory distress syndrome. New insights using computed tomography. Radiol Clin North Am. 1996;34(1):33 [MEDLINE]
  • Computed tomography in adult respiratory distress syndrome: what has it taught us? Eur Respir J. 1996;9(5):1055 [MEDLINE]
  • Accuracy of the chest radiograph to identify bilateral pulmonary infiltrates consistent with the diagnosis of acute respiratory distress syndrome using computed tomography as reference standard. J Crit Care. 2013 Aug;28(4):352-7. doi: 10.1016/j.jcrc.2012.12.002 [MEDLINE]
  • Value of Computed Tomography of the Chest in Subjects With ARDS: A Retrospective Observational Study. Respir Care. 2016 Mar;61(3):316-23. doi: 10.4187/respcare.04308 [MEDLINE]

Echocardiogram (see Echocardiogram)

  • Acute left ventricular dilatation and shock-induced myocardial dysfunction. Crit Care Med. 2009 Feb;37(2):441-7 [MEDLINE]
  • Diastolic dysfunction and mortality in severe sepsis and septic shock. Eur Heart J. 2012 Apr;33(7):895-903 [MEDLINE]

Swan-Ganz (Pulmonary Artery) Catheter (see Swan-Ganz Catheter)

  • High values of the pulmonary artery wedge pressure in patients with acute lung injury and acute respiratory distress syndrome. Intensive Care Med. 2002;28(8):1073 [MEDLINE]
  • Early use of the pulmonary artery catheter and outcomes in patients with shock and acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2003;290(20):2713 [MEDLINE]
  • Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury. N Engl J Med. 2006;354(21):2213 [MEDLINE]

Serum Brain Natriuretic Peptide (BNP) (see Serum Brain Natriuretic Peptide)

  • Comparable increase of B-type natriuretic peptide and amino-terminal pro-B-type natriuretic peptide levels in patients with severe sepsis, septic shock, and acute heart failure. Crit Care Med. 2006;34(8):2140 [MEDLINE]
  • Diagnostic utility of B-type natriuretic peptide in critically ill patients with pulmonary edema: a prospective cohort study. Crit Care. 2008;12(1):R3 [MEDLINE]

Bronchoscopy (see Bronchoscopy)

  • Acute eosinophilic pneumonia with respiratory failure: a new syndrome? Am Rev Respir Dis. 1992;145(3):716 [MEDLINE]
  • Acute eosinophilic pneumonia. A summary of 15 cases and review of the literature. Medicine (Baltimore). 1996;75(6):334 [MEDLINE]
  • Diagnosis of nosocomial bacterial pneumonia in acute, diffuse lung injury. Chest. 1981;80(3):254 [MEDLINE]
  • Idiopathic acute eosinophilic pneumonia: a study of 22 patients. Am J Respir Crit Care Med. 2002;166(9):1235 [MEDLINE]

Lung Biopsy

  • Open-lung biopsy in patients with acute respiratory distress syndrome. Anesthesiology. 1998;88(4):935 [MEDLINE]
  • Combined bronchoalveolar lavage and transbronchial lung biopsy: safety and yield in ventilated patients. Eur Respir J. 2003;21(3):489 [MEDLINE]
  • The role of open-lung biopsy in ARDS. Chest. 2004;125(1):197 [MEDLINE]
  • Yield and safety of bedside open lung biopsy in mechanically ventilated patients with acute lung injury or acute respiratory distress syndrome. Surgery. 2008 Mar;143(3):426-33 [MEDLINE]
  • Open lung biopsy in nonresolving ARDS frequently identifies diffuse alveolar damage regardless of the severity stage and may have implications for patient management. Intensive Care Med. 2015 Feb;41(2):222-30 [MEDLINE]
  • Open Lung Biopsy Among Critically Ill, Mechanically Ventilated Patients. A Metaanalysis. Ann Am Thorac Soc. 2015;12(8):1226 [MEDLINE]
  • The Role of Open Lung Biopsy in Critically Ill Patients with Hypoxic Respiratory Failure: A Retrospective Cohort Study. Can Respir J. 2016;2016:8715024 [MEDLINE]
  • Utility of surgical lung biopsy in critically ill patients with diffuse pulmonary infiltrates: a retrospective review. Intern Med J. 2016;46(11):1306 [MEDLINE]

Clinical Manifestations

General

  • Incidence, site, and outcome of infections in patients with the adult respiratory distress syndrome. Am Rev Respir Dis. 1986;134(1):12 [MEDLINE]
  • Nosocomial pneumonia in ventilated patients: a cohort study evaluating attributable mortality and hospital stay. Am J Med. 1993;94(3):281 [MEDLINE]
  • The effect of late-onset ventilator-associated pneumonia in determining patient mortality. Chest. 1995;108(6):1655 [MEDLINE]
  • Nosocomial pneumonia and mortality among patients in intensive care units. JAMA. 1996;275(11):866 [MEDLINE]
  • “Imitators” of the ARDS: implications for diagnosis and treatment. Chest. 2004;125(4):1530 [MEDLINE]
  • Comparison of the SpO2/FIO2 ratio and the PaO2/FIO2 ratio in patients with acute lung injury or ARDS. Chest. 2007;132(2):410 [MEDLINE]
  • Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012 Jun 20;307(23):2526-33 [MEDLINE]
  • The acute respiratory distress syndrome: what’s in a name?  JAMA  2012;307:2542–2544 [MEDLINE]
  • Berlin definition of ARDS: an expanded rationale, justification, and supplementary material. Intensive Care Med. 2012 Oct;38(10):1573-82 [MEDLINE]
  • Comparison of the Berlin definition for acute respiratory distress syndrome with autopsy. Am J Respir Crit Care Med. 2013;187(7):761 [MEDLINE]
  • Nonlinear Imputation of PaO2/FIO2 From SpO2/FIO2 Among Mechanically Ventilated Patients in the ICU: A Prospective, Observational Study. Crit Care Med. 2017;45(8):1317 [MEDLINE]

Intensive Care Unit (ICU)-Acquired Weakness

  • Impact of Vasoactive Medications on ICU-Acquired Weakness in Mechanically Ventilated Patients Chest. 2018 Oct;154(4):781-787. doi: 10.1016/j.chest.2018.07.016 [MEDLINE]

Ventilator-Induced Lung Injury (VILI)/Barotrauma

  • Incidence of pulmonary barotrauma in a medical ICU. Crit Care Med. 1983;11(2):67 [MEDLINE]
  • Persistent bronchopleural air leak during mechanical ventilation. A review of 39 cases. Chest. 1986;90(3):321 [MEDLINE]
  • The effects of ventilatory pattern on hyperinflation, airway pressures, and circulation in mechanical ventilation of patients with severe air-flow obstruction. Am Rev Respir Dis. 1987 Oct;136(4):872-9 [MEDLINE]
  • Closure of a bronchopleural fistula with bronchoscopic instillation of tetracycline. Chest. 1991;99(4):1040 [MEDLINE]
  • Mean airway pressure: physiologic determinants and clinical importance–Part 2: Clinical implications. Crit Care Med. 1992;20(11):1604 [MEDLINE]
  • Risk factors for morbidity in mechanically ventilated patients with acute severe asthma. Am Rev Respir Dis. 1992;146(3):60 [MEDLINE]
  • Pulmonary barotrauma in mechanical ventilation: patterns and risk factors. Chest 1992; 102:568-572
  • Barotrauma: detection, recognition, and management. Chest 1993; 104:578-584
  • Continuous venous air embolism in patients receiving positive end-expiratory pressure. Am Rev Respir Dis. 1993;147(4):1034 [MEDLINE]
  • Mechanisms of ventilator-induced lung injury. Crit Care Med. 1993;21(1):131 [MEDLINE]
  • Lung structure and function in different stages of severe adult respiratory distress syndrome. JAMA. 1994;271(22):1772 [MEDLINE]
  • Peak airway pressure: why the fuss? Chest. 1994;105(1):242 [MEDLINE]
  • Frequency and importance of barotrauma in 100 patients with acute lung injury. Crit Care Med. 1995;23(2):272 [MEDLINE]
  • Independent lung ventilation with a single ventilator using a variable resistance valve. Chest. 1995;107(1):256 [MEDLINE]
  • Frequency and importance of barotrauma in 100 patients with acute lung injury. Crit Care Med. 1995;23(2):272 [MEDLINE]
  • Clinical risk factors for pulmonary barotrauma: a multivariate analysis. Am J Respir Crit Care Med. 1995;152(4 Pt 1):1235 [MEDLINE]
  • Closure of a bronchopleural fistula using decalcified human spongiosa and a fibrin sealant. Ann Thorac Surg. 1997;64(1):230 [MEDLINE]
  • The relation of pneumothorax and other air leaks to mortality in the acute respiratory distress syndrome. N Engl J Med. 1998;338(6):341 [MEDLINE]
  • International consensus conferences in intensive care medicine: Ventilator-associated Lung Injury in ARDS. This official conference report was cosponsored by the American Thoracic Society, The European Society of Intensive Care Medicine, and The Societéde Réanimation de Langue Française, and was approved by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med. 1999;160(6):2118 [MEDLINE]
  • Nitric oxide and high frequency jet ventilation in a patient with bilateral bronchopleural fistulae and ARDS. Can J Anaesth. 2000;47(1):53 [MEDLINE]
  • The Macklin effect: a frequent etiology for pneumomediastinum in severe blunt chest trauma. Chest. 2001 Aug;120(2):543-7 [MEDLINE]
  • Relationship between ventilatory settings and barotrauma in the acute respiratory distress syndrome. Intensive Care Med. 2002;28(4):406 [MEDLINE]
  • Airway pressures and early barotrauma in patients with acute lung injury and acute respiratory distress syndrome. Am J Respir Crit Care Med. 2002;165(7):978 [MEDLINE]
  • Management of a bronchopleural fistula using differential lung airway pressure release ventilation. J Cardiothorac Vasc Anesth. 2003;17(6):744 [MEDLINE]
  • Pneumothorax associated with long-term non-invasive positive pressure ventilation in Duchenne muscular dystrophy. Neuromuscul Disord. 2004 Jun;14(6):353-5 [MEDLINE]
  • Incidence, risk factors and outcome of barotrauma in mechanically ventilated patients. Intensive Care Med. 2004;30(4):612 [MEDLINE]
  • Management of advanced ARDS complicated by bilateral pneumothoraces with high-frequency oscillatory ventilation in an adult. Br J Anaesth. 2004;93(3):454 [MEDLINE]
  • High frequency oscillatory ventilation in the management of a high output bronchopleural fistula: a case report. Can J Anaesth. 2004;51(1):78 [MEDLINE]
  • Pneumothorax: an important complication of non-invasive ventilation in neuromuscular disease. Neuromuscul Disord. 2004 Jun;14(6):351-2 [MEDLINE]
  • Use of a modified endobronchial tube for mechanical ventilation of patients with bronchopleural fistula. Eur J Cardiothorac Surg. 2005;28(1):169 [MEDLINE]
  • Independent lung ventilation in the management of traumatic bronchopleural fistula. Am Surg. 2006;72(6):530 [MEDLINE]
  • Occurrence of pneumothorax during noninvasive positive pressure ventilation through a helmet. J Clin Anesth. 2007 Dec;19(8):632-5 [MEDLINE]
  • Extracorporeal membrane oxygenator as a bridge to successful surgical repair of bronchopleural fistula following bilateral sequential lung transplantation: a case report and review of literature. J Cardiothorac Surg. 2007;2:28 [MEDLINE]
  • [Evaluation of the incidence of pneumothorax and background of patients with pneumothorax during noninvasive positive pressure ventilation]. Nihon Kokyuki Gakkai Zasshi. 2008 Nov;46(11):870-4 [MEDLINE]
  • Benefits and complications of noninvasive mechanical ventilation for acute exacerbation of chronic obstructive pulmonary disease. Rev Bras Ter Intensiva. 2008 Jun;20(2):184-9 [MEDLINE]
  • Independent lung ventilation in the postoperative management of large bronchopleural fistula. J Thorac Cardiovasc Surg. 2010;139(2):e21 [MEDLINE]
  • Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010;363(12):1107 [MEDLINE]
  • Pressure and volume limited ventilation for the ventilatory management of patients with acute lung injury: a systematic review and meta-analysis. PLoS One. 2011;6(1):e14623 [MEDLINE]
  • Intrabronchial valves: a case series describing a minimally invasive approach to bronchopleural fistulas in medical intensive care unit patients. J Bronchology Interv Pulmonol. 2012 Apr;19(2):137-41 [MEDLINE]
  • Neuromuscular blocking agents in acute respiratory distress syndrome: a systematic review and meta-analysis of randomized controlled trials. Crit Care. 2013 Mar;17(2):R43 [MEDLINE]
  • Differential lung ventilation and venovenous extracorporeal membrane oxygenation for traumatic bronchopleural fistula. Ann Thorac Surg. 2013;96(5):1859 [MEDLINE]
  • Pulmonary interstitial emphysema in adults: a clinicopathologic study of 53 lung explants. Am J Surg Pathol. 2014 Mar;38(3):339-45 [MEDLINE]
  • Pressure-controlled versus volume-controlled ventilation for acute respiratory failure due to acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Cochrane Database Syst Rev. 2015;1:CD008807 [MEDLINE]
  • Independent lung ventilation in the management of ARDS and bronchopleural fistula. Heart Lung. 2016;45(3):258 [MEDLINE]
  • High-Frequency Oscillatory Ventilation (HFOV) as Primary Ventilator Strategy in the Management of Severe Acute Respiratory Distress Syndrome (ARDS) with Pneumothorax in the Setting of Trauma. Am Surg. 2017;83(5):525 [MEDLINE]
  • Positive pressure ventilation in a patient with a right upper lobar bronchocutaneous fistula: right upper bronchus occlusion using the cuff of a left-sided double lumen endobronchial tube. J Anesth. 2017;31(4):627 [MEDLINE]
  • Bronchopleural Fistula Resolution with Endobronchial Valve Placement and Liberation from Mechanical Ventilation in Acute Respiratory Distress Syndrome: A Case Series. Case Rep Crit Care. 2017;2017:3092457 [MEDLINE]

Pulmonary Hypertension (see Pulmonary Hypertension)

  • Human pulmonary vascular response to 4 h of hypercapnia and hypocapnia measured using Doppler echocardiography. J Appl Physiol 2003, 94:1543-1551 [MEDLINE]
  • Impact of acute hypercapnia and augmented positive end-expiratory pressure on right ventricle function in severe acute respiratory distress syndrome. Intensive Care Med 2009, 35:1850-1858 [MEDLINE]
  • Pulmonary vascular and right ventricular dysfunction in adult critical care: current and emerging options for management: a systematic literature review. Crit Care. 2010;14(5):R169 [MEDLINE]

Other

  • Fever is associated with delayed ventilator liberation in acute lung injury. Ann Am Thorac Soc. 2013 Dec;10(6):608-15. doi: 10.1513/AnnalsATS.201303-052OC [MEDLINE]

Complications

  • Factors associated with acute kidney injury in acute respiratory distress syndrome. Ann Intensive Care 2019 Jul 1;9(1):74. doi: 10.1186/s13613-019-0552-5 [MEDLINE]

Prevention

  • Early identification of patients at risk of acute lung injury.  Am J Respir Crit Care Med  2011;183:462–470 [MEDLINE]
  • Lung injury prediction score for the emergency department:  first step towards prevention in patients at risk.  Int J Emerg Med  2012;5:33–43 [MEDLINE]
  • IMPROVE Trial. A trial of intraoperative low-tidal-volume ventilation in abdominal surgery. N Engl J Med. 2013 Aug 1;369(5):428-37. doi: 10.1056/NEJMoa1301082 [MEDLINE]
  • Intraoperative low-tidal-volume ventilation. N Engl J Med. 2013;369(19):1861 [MEDLINE]
  • Association between tidal volume size, duration of ventilation,and sedation needs in patients without acute respiratory distress syndrome: an individual patient data meta-analysis. Intensive Care Med. 2014;40(7):950-957 [MEDLINE]
  • LIPS-A Trial. Effect of Aspirin on Development of ARDS in At-Risk Patients Presenting to the Emergency Department: The LIPS-A Randomized Clinical Trial. JAMA. 2016;315(22):2406 [MEDLINE]
  • A Meta-analysis of Intraoperative Ventilation Strategies to Prevent Pulmonary Complications: Is Low Tidal Volume Alone Sufficient to Protect Healthy Lungs? Ann Surg. 2016 May;263(5):881-7. doi: 10.1097/SLA.0000000000001443 [MEDLINE]
  • PReVENT Trial. Effect of a Low vs Intermediate Tidal Volume Strategy on Ventilator-Free Days in Intensive Care Unit Patients Without ARDS: A Randomized Clinical Trial. JAMA. 2018 Oct 24. doi: 10.1001/jama.2018.14280 [MEDLINE]

Treatment

General

  • An Official American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine Clinical Practice Guideline: Mechanical Ventilation in Adult Patients with Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med. 2017 May 1;195(9):1253-1263. doi: 10.1164/rccm.201703-0548ST [MEDLINE]

Treatment of Fever (see Fever)

  • Effect of core body temperature on ventilator-induced lung injury. Crit Care Med. 2004;32(1):144 [MEDLINE]

Bronchodilators

  • The beta-agonist lung injury trial (BALTI): a randomized placebo-controlled clinical trial. Am J Respir Crit Care Med. 2006 Feb 1;173(3):281-7 [MEDLINE]
  • Randomized, placebo-controlled clinical trial of an aerosolized β₂-agonist for treatment of acute lung injury. Am J Respir Crit Care Med. 2011 Sep 1;184(5):561-8 [MEDLINE]
  • Beta-Agonist Lung injury TrIal-2 (BALTI-2): a multicentre, randomised, double-blind, placebo-controlled trial and economic evaluation of intravenous infusion of salbutamol versus placebo in patients with acute respiratory distress syndrome. Health Technol Assess. 2013 Sep;17(38):1-88 [MEDLINE]

Management of Ventilator-Induced Lung Injury (VILI)/Barotrauma

  • International consensus conferences in intensive care medicine: Ventilator-associated Lung Injury in ARDS. This official conference report was cosponsored by the American Thoracic Society, The European Society of Intensive Care Medicine, and The Societéde Réanimation de Langue Française, and was approved by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med. 1999;160(6):2118 [MEDLINE]

Corticosteroids (see Corticosteroids)

  • Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med. 2006 Apr 20;354(16):1671-84 [MEDLINE]
  • American College of Critical Care Medicine. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med. 2008;36(6):1937-1949 [MEDLINE]
  • Do glucocorticoids decrease mortality in acute respiratory distress syndrome? A meta-analysis. Respirology. 2007;12(4):585 [MEDLINE]
  • Corticosteroids in the prevention and treatment of acute respiratory distress syndrome (ARDS) in adults: meta-analysis. BMJ. 2008;336(7651):1006. Epub 2008 Apr 23 [MEDLINE]
  • Steroid treatment in ARDS: a critical appraisal of the ARDS network trial and the recent literature. Intensive Care Med. 2008;34(1):61. Epub 2007 Nov 14 [MEDLINE]
  • Use of corticosteroids in acute lung injury and acute respiratory distress syndrome: a systematic review and meta-analysis. Crit Care Med. 2009;37(5):1594-1603 [MEDLINE]
  • Corticosteroids and transition to delirium in patients with acute lung injury. Crit Care Med. 2014 Jun;42(6):1480-6. doi: 10.1097/CCM.0000000000000247 [MEDLINE]
  • Prolonged glucocorticoid treatment is associated with improved ARDS outcomes: analysis of individual patients’ data from four randomized trials and trial-level meta-analysis of the updated literature. Intensive Care Med. 2016 May;42(5):829-40. Epub 2015 Oct 27 [MEDLINE]

Supplemental Oxygen Therapy (see Oxygen)

  • The standard of care of patients with ARDS: ventilatory settings and rescue therapies for refractory hypoxemia. Intensive Care Med 2016;42:699-711 [MEDLINE]
  • Oxygen in the ICU: too much of a good thing? JAMA 2016;316: 1553-4 [MEDLINE]
  • Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in50countries.JAMA2016;315:788-800 [MEDLINE]
  • Effectiveness and clinical outcomes of a two-step implementation of conservative oxygenation targets in critically ill patients: a before and after trial. Crit Care Med 2016;44:554-63 [MEDLINE]
  • Effect of Conservative vs Conventional Oxygen Therapy on Mortality Among Patients in an Intensive Care Unit: The Oxygen-ICU Randomized Clinical Trial. JAMA. 2016;316(15):1583 [MEDLINE]
  • Conservative versus Liberal Oxygenation Targets for Mechanically Ventilated Patients. A Pilot Multicenter Randomized Controlled Trial. Am J Respir Crit Care Med. 2016 Jan;193(1):43-51 [MEDLINE]
  • Effect of Conservative vs Conventional Oxygen Therapy on Mortality Among Patients in an Intensive Care Unit: The Oxygen-ICU Randomized Clinical Trial. JAMA. 2016 Oct 18;316(15):1583-1589. doi: 10.1001/jama.2016.11993 [MEDLINE]
  • British Thoracic Society Emergency Oxygen Guideline Group BTS Emergency Oxygen Guideline Development Group. BTS guideline for oxygen use in adults in healthcare and emergency settings. Thorax 2017;72(Suppl 1):ii1-90. 10.1136/ thoraxjnl-2016-209729 pmid:28507176 [MEDLINE]
  • Hyperoxia and hypertonic saline in patients with septic shock (HYPERS2S): a two-by-two factorial, multicentre, randomised, clinical trial. Lancet Respir Med. 2017 Mar;5(3):180-190. doi: 10.1016/S2213-2600(17)30046-2 [MEDLINE]
  • Oxygen therapy for acutely ill medical patients: a clinical practice guideline. BMJ. 2018 Oct 24;363:k4169. doi: 10.1136/bmj.k4169 [MEDLINE]
  • Mortality and morbidity in acutely ill adults treated with liberal versus conservative oxygen therapy (IOTA): a systematic review and meta-analysis. Lancet. 2018 Apr 28;391(10131):1693-1705. doi: 10.1016/S0140-6736(18)30479-3 [MEDLINE]
  • Emergency department hyperoxia is associated with increased mortality in mechanically ventilated patients: a cohort study. Crit Care. 2018 Jan 18;22(1):9. doi: 10.1186/s13054-017-1926-4 [MEDLINE]
  • ICU-ROX Trial. Conservative Oxygen Therapy during Mechanical Ventilation in the ICU. N Engl J Med. 2020 Mar 12;382(11):989-998. doi: 10.1056/NEJMoa1903297 [MEDLINE]
  • LOCO2 Trial. Liberal or Conservative Oxygen Therapy for Acute Respiratory Distress Syndrome. N Engl J Med. 2020 Mar 12;382(11):999-1008. doi: 10.1056/NEJMoa1916431 [MEDLINE]

Paralysis (Neuromuscular Junction Blockade) (see Neuromuscular Junction Antagonists)

  • Effect of neuromuscular blocking agents on gas exchange in patients presenting with acute respiratory distress syndrome. Crit Care Med. 2004;32(1):113-119 [MEDLINE]
  • Neuromuscular blocking agents decrease inflammatory response in patients presenting with acute respiratory distress syndrome. Crit Care Med. 2006;34(11):2749-2757 [MEDLINE]
  • ARDS et Curarisation Systematique (ACURASYS) Trial. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010 Sep 16;363(12):1107-16 [MEDLINE]
  • Mechanical ventilation-induced reverse-triggered breaths: a frequently unrecognized form of neuromechanical coupling. Chest. 2013 Apr;143(4):927-938. doi: 10.1378/chest.12-1817 [MEDLINE]
  • Reevaluation of Systemic Early Neuromuscular Blockade (ROSE) Trial. Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome. N Engl J Med. 2019 May 19. doi: 10.1056/NEJMoa1901686 [MEDLINE]
  • Early Paralytic Agents for ARDS? Yes, No, and Sometimes. NEJM, 2019 DOI: 10.1056/NEJMe1905627 [MEDLINE]
  • Variability of reverse triggering in deeply sedated ARDS patients. Intensive Care Med. 2019 May;45(5):725-726. doi: 10.1007/s00134-018-5500-6 [MEDLINE]

Fluid Management

  • Albumin and furosemide therapy in hypoproteinemic patients with acute lung injury. Crit Care Med. 2002;30(10):2175-2182 [MEDLINE]
  • SAFE Study Investigators. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004;350(22):2247-2256 [MEDLINE]
  • A randomized, controlled trial of furosemide with or without albumin in hypoproteinemic patients with acute lung injury. Crit Care Med. 2005;33(8):1681-1687 [MEDLINE]
  • FACTT Trial: Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006 Jun 15;354(24):2564-75 [MEDLINE]
  • The adult respiratory distress syndrome cognitive outcomes study: long-term neuropsychological function in survivors of acute lung injury.  Am J Respir Crit Care Med.  2012;185:1307–1315 [MEDLINE]
  • The Adult Respiratory Distress Syndrome Cognitive Outcomes Study: long-term neuropsychological function in survivors of acute lung injury. Crit Care. 2013 May 24;17(3):317. doi: 10.1186/cc12709 [MEDLINE]
  • Fluids in ARDS: from onset through recovery.  Curr Opin Crit Care.  2014;20:373–377 [MEDLINE]
  • Albumin versus crystalloid solutions in patients with the acute respiratory distress syndrome: a systematic review and meta-analysis. Crit Care 2014 [MEDLINE]
  • Association between fluid balance and survival in critically ill patients. J Intern Med.  2015;277:468–477 [MEDLINE]
  • Fluid management with a simplified conservative protocol for the acute respiratory distress syndrome.  Crit Care Med.  2015;43:288–295 [MEDLINE]
  • Relationship between Race and the Effect of Fluids on Long-term Mortality after Acute Respiratory Distress Syndrome: Secondary Analysis of the NHLBI Fluid and Catheter Treatment Trial. Ann Am Thorac Soc. 2017 Jul 14. doi: 10.1513/AnnalsATS.201611-906OC [MEDLINE]

Low Tidal Volume Ventilation

  • Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 1998; 338:347-354 [MEDLINE]
  • Evaluation of a ventilation strategy to prevent barotrauma in patients at high risk for acute respiratory distress syndrome. N Engl J Med 1998; 338:355-361 [MEDLINE]
  • Evaluation of a ventilation strategy to prevent barotrauma in patients at high risk for acute respiratory distress syndrome. N Engl J Med 1998; 338:355-361 [MEDLINE]
  • Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med. 2000 May 4;342(18):1301-8 [MEDLINE]
  • ARDSNet lower tidal volume ventilatory strategy may generate intrinsic positive end-expiratory pressure in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 2002;165:1271 [MEDLINE]
  • Tidal volume reduction in patients with acute lung injury when plateau pressures are not high. Am J Respir Crit Care Med. 2005 Nov 15;172(10):1241-5. Epub 2005 Aug 4 [MEDLINE]
  • Intrinsic positive end-expiratory pressure in Acute Respiratory Distress Syndrome (ARDS) Network subjects. Crit Care Med. 2005 Mar;33(3):527-32 [MEDLINE]
  • Low tidal volume ventilation does not increase sedation use in patients with acute lung injury. Crit Care Med. 2005 Apr;33(4):766-71 [MEDLINE]
  • Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2008;299:637 [MEDLINE]
  • Lung stress and strain during mechanical ventilation for acute respiratory distress syndrome. Am J Respir Crit Care Med. 2008 Aug 15;178(4):346-55. doi: 10.1164/rccm.200710-1589OC. Epub 2008 May 1 [MEDLINE]
  • Meta-analysis: ventilation strategies and outcomes of the acute respiratory distress syndrome and acute lung injury. Ann Intern Med. 2009 Oct 20;151(8):566-76 [MEDLINE]
  • Pressure and volume limited ventilation for the ventilatory management of patients with acute lung injury: a systematic review and meta-analysis. PLoS One. 2011 Jan 28;6(1):e14623 [MEDLINE]
  • Lung protective ventilation strategy for the acute respiratory distress syndrome. Cochrane Database Syst Rev. 2013 Feb 28;2:CD003844 [MEDLINE]
  • Ventilator-induced lung injury. N Engl J Med. 2013 Nov 28;369(22):2126-36. doi: 10.1056/NEJMra1208707 [MEDLINE]
  • Personalised mechanical ventilation tailored to lung morphology versus low positive end-expiratory pressure for patients with acute respiratory distress syndrome in France (the LIVE study): a multicentre, single-blind, randomised controlled trial. Lancet Respir Med. 2019 Oct;7(10):870-880. doi: 10.1016/S2213-2600(19)30138-9 [MEDLINE]

Positive End-Expiratory Pressure (PEEP)

  • Optimum end-expiratory airway pressure in patients with acute pulmonary failure. N Engl J Med 1975;292:284–289 [MEDLINE]
  • Occult positive end-expiratory pressure in mechanically ventilated patients with airflow obstruction: The auto-PEEP effect. Am Rev Respir Dis 1982; 126:166-170 [MEDLINE]
  • Effect of positive end-expiratory pressure and body position in unilateral lung injury. J Appl Physiol Respir Environ Exerc Physiol. 1982;52(1):147 [MEDLINE]
  • Physiologic PEEP. Respir Care. 1988; 33:620
  • Determination of auto-PEEP during spontaneous and controlled ventilation by monitoring changes in end-expiratory thoracic gas volume. Chest 1989; 96:613-616 [MEDLINE]
  • Should PEEP be used in airflow obstruction? Am Rev Respir Dis 1989; 140:1-3 [MEDLINE]
  • PEEP, auto-PEEP, and waterfalls. Chest. 1989 Sep;96(3):449-51 [MEDLINE]
  • Auto-PEEP during CPR: an “occult” cause of electromechanical dissociation? Chest 1991;99:492–493 [MEDLINE]
  • Physiologic effects of positive end-expiratory pressure in chronic obstructive pulmonary disease during acute ventilatory failure and controlled mechanical ventilation. Am Rev Respir Dis. 1993;147:5–13 [MEDLINE]
  • Effects of Extrinsic Positive End-Expiratory Pressure on Mechanically Ventilated Patients With Chronic Obstructive Pulmonary Disease and Dynamic Hyperinflation. Intensive Care Med. 1993;19(4):197-203. doi: 10.1007/BF01694770 [MEDLINE]
  • Positive end-expiratory pressure increases the right to-left shunt in mechanically ventilated patients with patent foramen ovale. Ann Intern Med 1993; 119:887-894 [MEDLINE]
  • Interaction between intrinsic positive end-expiratory pressure and externally applied positive end-expiratory pressure during controlled mechanical ventilation. Crit Care Med 1993; 21:348-356 [MEDLINE]
  • The effects of applied vs auto-PEEP on local lung unit pressure and volume in a four-unit lung model. Chest. 1995 Oct;108(4):1073-9 [MEDLINE]
  • Auto-PEEP and electromechanical dissociation. N Engl J Med 1996;335:674–675 [MEDLINE]
  • Does positive end-expiratory pressure ventilation improve left ventricular function? A comparative study by transesophageal echocardiography in cardiac and noncardiac patients. Chest. 1998;114(2):556 [MEDLINE]
  • Pressure-volume curves and compliance in acute lung injury: evidence of recruitment above the lower inflection point. Am J Respir Crit Care Med. 1999 Apr;159(4 Pt 1):1172-8 [MEDLINE]
  • Use of pulse oximetry to recognize severity of airflow obstruction in obstructive airway disease: correlation with pulsus paradoxus. Chest 1999;115:475–481 [MEDLINE]
  • Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med. 2000 May 4;342(18):1301-8 [MEDLINE]
  • Influence of positive end-expiratory pressure on intracranial pressure and cerebral perfusion pressure in patients with acute stroke. Stroke. 2001;32(9):2088 [MEDLINE]
  • Intrinsic (or auto-) positive end-expiratory pressure during spontaneous or assisted ventilation. Intensive Care Med 2002;28:1552 [MEDLINE]
  • Positive end-expiratory pressure alters intracranial and cerebral perfusion pressure in severe traumatic brain injury. J Trauma. 2002;53(3):488 [MEDLINE]
  • ALVEOLI Study: The National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 2004;351:327-36 [MEDLINE]
  • Effects of positive end-expiratory pressure on gastric mucosal perfusion in acute respiratory distress syndrome. Crit Care. 2004;8(5):R306 [MEDLINE]
  • Airway pressure-time curve profile (stress index) detects tidal recruitment/hyperinflation in experimental acute lung injury. Crit Care Med. 2004 Apr;32(4):1018-27 [MEDLINE]
  • Effects of positive end-expiratory pressure on regional cerebral blood flow, intracranial pressure, and brain tissue oxygenation. Crit Care Med. 2005;33(10):2367 [MEDLINE]
  • Cardiovascular issues in respiratory care. Chest. 2005;128(5 Suppl 2):592S [MEDLINE]
  • Lung recruitment in patients with the acute respiratory distress syndrome. N Engl J Med. 2006 Apr 27;354(17):1775-86 [MEDLINE]
  • Review of ventilatory techniques to optimize mechanical ventilation in acute exacerbation of chronic obstructive pulmonary disease.  Int J Chron Obstruct Pulmon Dis  2007 Dec;2(4):441–452 [MEDLINE]
  • Positive-end expiratory pressure reduces incidence of ventilator-associated pneumonia in nonhypoxemic patients. Crit Care Med. 2008;36(8):2225 [MEDLINE]
  • Positive-end expiratory pressure setting in adult acute lung injury and acute respiratory distress syndrome: a randomized, controlled trial. JAMA 2008;299:646 [MEDLINE]
  • Effect of positive expiratory pressure and type of tracheal cuff on the incidence of aspiration in mechanically ventilated patients in an intensive care unit. Crit Care Med. 2008;36(2):409 [MEDLINE]
  • Clinical concise review: Mechanical ventilation of patients with chronic obstructive pulmonary disease. Crit Care Med. 2008 May;36(5):1614-9. doi: 10.1097/CCM.0b013e318170f0f3 [MEDLINE]
  • LOV Study: Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2008;299:637 [MEDLINE]
  • EXPRESS Study: Positive-end expiratory pressure setting in adult acute lung injury and acute respiratory distress syndrome: a randomized, controlled trial. JAMA 2008;299:646 [MEDLINE]
  • Effect of positive expiratory pressure and type of tracheal cuff on the incidence of aspiration in mechanically ventilated patients in an intensive care unit. Crit Care Med. 2008;36(2):409 [MEDLINE]
  • Clinical concise review: Mechanical ventilation of patients with chronic obstructive pulmonary disease. Crit Care Med. 2008 May;36(5):1614-9. doi: 10.1097/CCM.0b013e318170f0f3 [MEDLINE]
  • Positive end-expiratory pressure redistributes regional blood flow and ventilation differently in supine and prone humans. Anesthesiology. 2010;113(6):1361 [MEDLINE]
  • Cardiac output estimation using pulmonary mechanics in mechanically ventilated patients. Biomed Eng Online. 2010;9:80 [MEDLINE]
  • Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis. JAMA 2010; 303:865-873 [MEDLINE]
  • Hemodynamic impact of a positive end-expiratory pressure setting in acute respiratory distress syndrome: importance of the volume status. Crit Care Med 2010;38:802–807 [MEDLINE]
  • Dynamic hyperinflation and auto-positive end-expiratory pressure: lessons learned over 30 years. Am J Respir Crit Care Med. 2011;184:756–762 [MEDLINE]
  • Patient-ventilator interactions. Implications for clinical management. Am J Respir Crit Care Med. 2013;188:1058–1068 [MEDLINE]
  • Accuracy of plateau pressure and stress index to identify injurious ventilation in patients with acute respiratory distress syndrome. Anesthesiology. 2013 Oct;119(4):880-9. doi: 10.1097/ALN.0b013e3182a05bb8 [MEDLINE]
  • High versus low positive end-expiratory pressure during general anaesthesia for open abdominal surgery (PROVHILO trial): a multicentre randomised controlled trial. Lancet. 2014 Aug 9;384(9942):495-503. doi: 10.1016/S0140-6736(14)60416-5. Epub 2014 Jun 2 [MEDLINE]
  • Oxygenation response to positive end-expiratory pressure predicts mortality in acute respiratory distress syndrome. A secondary analysis of the LOVS and ExPress trials. Am J Respir Crit Care Med 2014;190:70–76 [MEDLINE]
  • Bedside selection of positive end-expiratory pressure in mild, moderate, and severe acute respiratory distress syndrome. Crit Care Med 2014;42:252–264 [MEDLINE]
  • Asynchronies during mechanical ventilation are associated with mortality. Intensive Care Med. 2015;41(4): 633–641; published online Feb 2015 [MEDLINE]
  • Driving pressure and survival in the acute respiratory distress syndrome.  N Engl J Med.  2015;372:747–755 [MEDLINE]
  • Driving pressure and respiratory mechanics in ARDS.  N Engl J Med.  2015;372:776–777 [MEDLINE]
  • Novel approaches to minimize ventilator-induced lung injury. Curr Opin Crit Care. 2015 Feb;21(1):20-5. doi: 10.1097/MCC.0000000000000172 [MEDLINE]
  • Airway driving pressure and lung stress in ARDS patients. Crit Care. 2016; 20: 276 [MEDLINE]
  • Open Lung Approach for the Acute Respiratory Distress Syndrome: A Pilot, Randomized Controlled Trial. Crit Care Med. 2016 Jan;44(1):32-42. doi: 10.1097/CCM.0000000000001383 [MEDLINE]
  • High PEEP in Acute Respiratory Distress Syndrome: Quantitative Evaluation Between Improved Arterial Oxygenation and Decreased Oxygen Delivery. Br J Anaesth. 2016 Nov;117(5):650-658. doi: 10.1093/bja/aew314 [MEDLINE]
  • How ARDS should be treated. Crit Care. 2016 Apr 6;20:86. doi: 10.1186/s13054-016-1268-7 [MEDLINE]
  • Effect of Intensive vs Moderate Alveolar Recruitment Strategies Added to Lung-Protective Ventilation on Postoperative Pulmonary Complications: A Randomized Clinical Trial. JAMA. 2017;317(14):1422 [MEDLINE]
  • ART Trial. Effect of Lung Recruitment and Titrated Positive End-Expiratory Pressure (PEEP) vs Low PEEP on Mortality in Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial. JAMA. 2017 Oct 10;318(14):1335-1345. doi: 10.1001/jama.2017.14171 [MEDLINE]
  • Fifty Years of Research in ARDS. Setting Positive End-Expiratory Pressure in Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med. 2017 Jun 1;195(11):1429-1438. doi: 10.1164/rccm.201610-2035CI [MEDLINE]
  • Association of Driving Pressure With Mortality Among Ventilated Patients With Acute Respiratory Distress Syndrome: A Systematic Review and Meta-Analysis. Crit Care Med. 2018 Feb;46(2):300–6 [MEDLINE]
  • Stress Index Can Be Accurately and Reliably Assessed by Visually Inspecting Ventilator Waveforms. Respir Care. 2018 Sep;63(9):1094-1101. doi: 10.4187/respcare.06151 [MEDLINE]
  • Best PEEP trials are dependent on tidal volume. Crit Care. 2018;22(1):115 [MEDLINE]
  • Individualised perioperative open-lung approach versus standard protective ventilation in abdominal surgery (iPROVE): a randomised controlled trial. Lancet Respir Med. 2018;6(3):193 [MEDLINE]
  • The future of driving pressure: a primary goal for mechanical ventilation? J Intensive Care. 2018 Oct 4;6:64. doi: 10.1186/s40560-018-0334-4. eCollection 2018 [MEDLINE]
  • EPVent-2 Trial. Effect of Titrating Positive End-Expiratory Pressure (PEEP) With an Esophageal Pressure-Guided Strategy vs an Empirical High PEEP-Fio2 Strategy on Death and Days Free From Mechanical Ventilation Among Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial. JAMA. 2019 Feb 18. doi: 10.1001/jama.2019.0555 [MEDLINE]
  • Optimal Ventilator Strategies in Acute Respiratory Distress Syndrome. Semin Respir Crit Care Med. 2019 Feb;40(1):81-93. doi: 10.1055/s-0039-1683896 [MEDLINE]

Esophageal Pressure-Guided Mechanical Ventilation

  • Airway pressure-time curve profile (stress index) detects tidal recruitment/hyperinflation in experimental acute lung injury. Crit Care Med. 2004 Apr;32(4):1018-27 [MEDLINE]
  • EPVent Study. Mechanical ventilation guided by esophageal pressure in acute lung injury. N Engl J Med 2008; 359:2095– 2104 [MEDLINE]
  • Accuracy of plateau pressure and stress index to identify injurious ventilation in patients with acute respiratory distress syndrome. Anesthesiology. 2013 Oct;119(4):880-9. doi: 10.1097/ALN.0b013e3182a05bb8 [MEDLINE]
  • The application of esophageal pressure measurement in patients with respiratory failure. Am J Respir Crit Care Med 2014; 189:520–531 [MEDLINE]
  • The assessment of transpulmonary pressure in mechanically ventilated ARDS patients. Intensive Care Med 2014; 40:1670–1678 [MEDLINE]
  • Novel approaches to minimize ventilator-induced lung injury. Curr Opin Crit Care. 2015 Feb;21(1):20-5. doi: 10.1097/MCC.0000000000000172 [MEDLINE]

Recruitment Maneuvers

  • Effects of periodic lung recruitment maneuvers on gas exchange and respiratory mechanics in mechanically ventilated acute respiratory distress syndrome (ARDS) patients. Intensive Care Med. 2000;26(5):501 [MEDLINE]
  • Recruitment maneuvers for acute lung injury: a systematic review. Am J Respir Crit Care Med. 2008;178(11):1156 [MEDLINE]
  • Recruitment manoeuvres for adults with acute lung injury receiving mechanical ventilation. Cochrane Database Syst Rev. 2009 Apr 15;(2):CD006667 [MEDLINE]
  • Optimal duration of a sustained inflation recruitment maneuver in ARDS patients. Intensive Care Med. 2011;37(10):1588 [MEDLINE]
  • ART Trial. Effect of Lung Recruitment and Titrated Positive End-Expiratory Pressure (PEEP) vs Low PEEP on Mortality in Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial. JAMA. 2017 Oct 10;318(14):1335-1345. doi: 10.1001/jama.2017.14171 [MEDLINE]

High-Frequency Ventilation (HFV) (see High-Frequency Ventilation)

  • OSCILLATE Trial. High-frequency oscillation in early acute respiratory distress syndrome. N Engl J Med. 2013 Feb 28;368(9):795-805 [MEDLINE]

Pressure Control-Inverse Ratio Ventilation (see Pressure Control Ventilation)

  • Randomized clinical trial of pressure controlled inverse ratio ventilation and extracorporeal CO2 removal for adult respiratory distress syndrome. Am J Respir Crit Care Med 1994; 149:295-305 [MEDLINE]
  • Should inverse ratio ventilation be used in adult respiratory distress syndrome? Am J Respir Crit Care Med 1994: 149:1354-1358

Airway Pressure Release Ventilation (APRV) (see Airway Pressure Release Ventilation)

  • Airway pressure release ventilation as a primary ventilatory mode in acute respiratory distress syndrome. Acta Anaesthesiol Scand. 2004 Jul;48(6):722-31 [MEDLINE]
  • Other approaches to open-lung ventilation: Airway pressure release ventilation. Crit Care Med. 2005 Mar;33(3 Suppl):S228-40 [MEDLINE]
  • Respiratory controversies in the critical care setting. Does airway pressure release ventilation offer important new advantages in mechanical ventilator support? Respir Care. 2007 Apr;52(4):452-8; discussion 458-60 [MEDLINE]
  • Airway pressure release ventilation and biphasic positive airway pressure: a systemic review of definitional criteria. Intensive Care Med 2008;34(10):1766-1773 [MEDLINE]
  • Comparison of APRV and BIPAP in a mechanical model of ARDS (abstract). Respir Care 2010;55(11): 1516
  • A randomized prospective trial of airway pressure release ventilation and low tidal volume ventilation in adult trauma patients with acute respiratory failure. J Trauma. 2010;69(3):501-510 [MEDLINE]
  • Airway pressure release ventilation in acute respiratory distress syndrome. Crit Care Clin. 2011 Jul;27(3):501-9. doi: 10.1016/j.ccc.2011.05.003 [MEDLINE]
  • Airway pressure release ventilation: what do we know? Respir Care. 2012 Feb;57(2):282-92 [MEDLINE]
  • Airway pressure release ventilation prevents ventilator-induced lung injury in normal lungs. JAMA Surg. 2013 Nov;148(11):1005-12. doi: 10.1001/jamasurg.2013.3746 [MEDLINE]
  • Early application of airway pressure release ventilation may reduce mortality in high-risk trauma patients: a systematic review of observational trauma ARDS literature. J Trauma Acute Care Surg. 2013 Oct;75(4):635-41 [MEDLINE]
  • Early airway pressure release ventilation prevents ARDS-a novel preventive approach to lung injury. Shock. 2013 Jan;39(1):28-38. doi: 10.1097/SHK.0b013e31827b47bb [MEDLINE]
  • Airway pressure release ventilation in morbidly obese surgical patients with acute lung injury and acute respiratory distress syndrome Am Surg. 2013 Mar;79(3):242-6 [MEDLINE]
  • Airway Pressure Release Ventilation and High-Frequency Oscillatory Ventilation: Potential Strategies to Treat Severe Hypoxemia and Prevent Ventilator-Induced Lung Injury. Respir Care. 2015 Oct;60(10):1509-21. doi: 10.4187/respcare.04255 [MEDLINE]
  • Airway Pressure Release Ventilation May Result in Occult Atelectrauma in Severe ARDS. Respir Care. 2016 Sep;61(9):1278-80. doi: 10.4187/respcare.05099 [MEDLINE]
  • Should Airway Pressure Release Ventilation Be the Primary Mode in ARDS? Respir Care. 2016 Jun;61(6):761-73. doi: 10.4187/respcare.04653 [MEDLINE]

Partial Liquid Ventilation

  • Partial liquid ventilation for preventing death and morbidity in adults with acute lung injury and acute respiratory distress syndrome. Cochrane Database Syst Rev. 2013 Jul 23;7:CD003707 [MEDLINE]

Body Position -> Proning

  • Conference on the scientific basis of respiratory therapy. Pulmonary physiotherapy in the pediatric age group. Comments of a devil’s advocate. Am Rev Respir Dis 1974; 110: 143-144 [MEDLINE]
  • Effect of prone position on patients with hydrostatic pulmonary edema compared with patients with acute respiratory distress syndrome and pulmonary fibrosis. Am J Respir Crit Care Med 2000;151:360-368 [MEDLINE]
  • Effect of prone positioning on the survival of patients with acute respiratory failure. N Engl J Med 2001;345:568-573 [MEDLINE]
  • Decrease in PaCO2 with prone position is predictive of improved outcome in acute respiratory distress syndrome. Crit Care Med. 2003 Dec;31(12):2727-33 [MEDLINE]
  • Effect of systematic prone positioning in hypoxemic acute respiratory failure. JAMA 2004;292:2379-2387 [MEDLINE]
  • A multicenter trial of prolonged prone ventilation in severe acute respiratory distress syndrome. Am J Respir Crit Care Med 2006; 173: 1233-1239 [MEDLINE]
  • Effect of mechanical ventilation in the prone position on clinical outcomes in patients with acute hypoxemic respiratory failure: a systematic review and meta-analysis. CMAJ. 2008 Apr 22;178(9):1153-61 [MEDLINE]
  • The effect of prone positioning in acute respiratory distress syndrome or acute lung injury. Intensive Care Med 2008;34:1002-1011 [MEDLINE]
  • Prone ventilation reduces mortality in patients with acute respiratory failure and severe hypoxemia: systematic review and meta-analysis. Intensive Care Med. 2010 Apr;36(4):585-99 [MEDLINE]
  • PROSEVA: Prone positioning in severe acute respiratory distress syndrome. Engl J Med. 2013 Jun 6;368(23):2159-68. doi: 10.1056/NEJMoa1214103. Epub 2013 May 20 [MEDLINE]
  • In prone ventilation, one good turn deserves another. N Engl J Med 2013;368(23):2227-2228 [MEDLINE]
  • Effects of interventions on survival in acute respiratory distress syndrome: an umbrella review of 159 published randomized trials and 29 meta-analyses. Intensive Care Med 2014; 40: 769-787 [MEDLINE]
  • Prone positioning reduces mortality from acute respiratory distress syndrome in the low tidal volume era: a meta- analysis. Intensive Care Med 2014; 40: 332-341 [MEDLINE]
  • The efficacy and safety of prone positional ventilation in acute respiratory distress syndrome: updated study-level meta-analysis of 11 randomized controlled trials. Crit Care Med 2014; 42: 1252-1262 [MEDLINE]
  • Prone position for acute respiratory failure in adults. Cochrane Database Syst Rev 2015; 11: CD008095 [MEDLINE]
  • Efficacy of prone position in acute respiratory distress syndrome patients: A pathophysiology-based review. World J Crit Care Med. 2016 May 4;5(2):121-36. doi: 10.5492/wjccm.v5.i2.121. eCollection 2016 [MEDLINE]

Body Position -> Head of Bed at 30°

  • Pulmonary aspiration of gastric contents in patients receiving mechanical ventilation: the effect of body position. Ann Intern Med 1992; 116:540-543 [MEDLINE]

Body Position -> Continuous Lateral Rotational/Kinetic Bed Therapy

  • Continuous lateral rotation therapy and nosocomial pneumonia. Chest 1991; 99:1263-1267 [MEDLINE]
  • Effect of air-supported, continuous, postural oscillation on the risk of early ICU pneumonia in nontraumatic critical illness. Chest. 1993 May;103(5):1543-7 [MEDLINE]
  • Continuous oscillation: outcome in critically ill patients. J Crit Care. 1995 Sep;10(3):97-103 [MEDLINE]
  • Acute effects of continuous rotational therapy on ventilation-perfusion inequality in lung injury. Intensive Care Med. 1998 Feb;24(2):132-7 [MEDLINE]
  • Rotational bed therapy to prevent and treat respiratory complications: a review and meta-analysis. Am J Crit Care. 2007 Jan;16(1):50-61; quiz 62 [MEDLINE]
  • Automated Rotational Percussion Bed and Bronchoscopy Improves Respiratory Mechanics and Oxygenation in ARDS Patients Supported with Extracorporeal Membrane Oxygenation. ASAIO J. 2016 May-Jun;62(3):e27-9. doi: 10.1097/MAT.0000000000000341 [MEDLINE]

Inhaled Nitric Oxide (iNO) (see Nitric Oxide)

  • Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Inhaled Nitric Oxide in ARDS Study Group. Crit Care Med. 1998;26(1):15 [MEDLINE]
  • Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial. JAMA. 2004;291(13):1603 [MEDLINE]
  • Effect of nitric oxide on oxygenation and mortality in acute lung injury: systematic review and meta-analysis. BMJ. 2007 Apr 14;334(7597):779 [MEDLINE]
  • Therapies for refractory hypoxemia in acute respiratory distress syndrome. JAMA. 2010;304(22):2521 [MEDLINE]
  • Inhaled nitric oxide for acute respiratory distress syndrome and acute lung injury in adults and children: a systematic review with meta-analysis and trial sequential analysis. Anesth Analg. 2011;112(6):1411 [MEDLINE]
  • Inhaled nitric oxide does not reduce mortality in patients with acute respiratory distress syndrome regardless of severity: systematic review and meta-analysis. Crit Care Med. 2014;42(2):404 [MEDLINE]
  • Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) in children and adults. Cochrane Database Syst Rev. 2016 Jun 27;(6):CD002787. doi: 10.1002/14651858.CD002787.pub3 [MEDLINE]
  • The effect of inhaled nitric oxide in acute respiratory distress syndrome in children and adults: a Cochrane Systematic Review with trial sequential analysis. Anaesthesia. 2017 Jan;72(1):106-117 [MEDLINE]

Inhaled Prostacyclin (see Prostacyclin)

  • Inhalational agents for pulmonary hypertension. Lancet. 1993 Oct;342(8877):941-2 [MEDLINE]
  • Inhaled prostacyclin (PGI2) versus inhaled nitric oxide in adult respiratory distress syndrome. Am J Respir Crit Care Med. 1996;154(6 Pt 1):1671 [MEDLINE]
  • Direct comparison of inhaled nitric oxide and aerosolized prostacyclin in acute respiratory distress syndrome. Am J Respir Crit Care Med. 1996;153(3):991 [MEDLINE]
  • Is outcome from ARDS related to the severity of respiratory failure? Eur Respir J. 1997;10(6):1297 [MEDLINE]
  • Dose-response to inhaled aerosolized prostacyclin for hypoxemia due to ARDS. Chest. 2000 Mar;117(3):819-27 [MEDLINE]
  • Nebulized prostacyclin (PGI2) in acute respiratory distress syndrome: impact of primary (pulmonary injury) and secondary (extrapulmonary injury) disease on gas exchange response. Crit Care Med. 2001 Jan;29(1):57-62 [MEDLINE]
  • Aerosolized prostacyclin for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Cochrane Database Syst Rev. 2010 [MEDLINE]
  • The use of inhaled prostaglandins in patients with ARDS: a systematic review and meta-analysis. Chest. 2015;147(6):1510 [MEDLINE]

Inhaled Iloprost (see Iloprost)

  • Iloprost improves gas exchange in patients with pulmonary hypertension and ARDS. Chest. 2013;144(1):55 [MEDLINE]

Venovenous Extracorporeal Membrane Oxygenation (VV-ECMO) (see Venovenous Extracorporeal Membrane Oxygenation)

  • Extracorporeal membrane oxygenation in severe acute respiratory failure. A randomized prospective study. JAMA. 1979 Nov 16;242(20):2193-6 [MEDLINE]
  • Low-frequency positive-pressure ventilation with extracorporeal CO2 removal in severe acute respiratory failure. JAMA. 1986;256(7):881-886 [MEDLINE]
  • Randomized clinical trial of pressure-controlled inverse ratio ventilation and extracorporeal CO2 removal for adult respiratory distress syndrome. Am J Respir Crit Care Med. 1994 Feb;149(2 Pt 1):295-305 [MEDLINE]
  • Clinical predictors of and mortality in acute respiratory distress syndrome: potential role of red cell transfusion. Crit Care Med 33: 1191–1198, 2005 [MEDLINE]
  • Association of RBC transfusion with mortality in patients with acute lung injury. Chest 132: 1116–1123, 2007 [MEDLINE]
  • Venoarterial extracorporeal membrane oxygenation for treatment of cardiogenic shock: clinical experiences in 45 adult patients. J Thorac Cardiovasc Surg. 2008;135(2):382–388 [MEDLINE]
  • Outcomes and long-term quality-of-life of patients supported by extracorporeal membrane oxygenation for refractory cardiogenic shock. Crit Care Med. 2008;36:1404–1411 [MEDLINE]
  • Review of ECMO (extra corporeal membrane oxygenation) support in critically ill adult patients.  Heart Lung Circ  2008;17:S41–S47.  doi: 10.1016/j.hlc.2008.08.009. Epub 2008 Oct 29 [MEDLINE]
  • Extracorporeal Life Support Organization (ELSO). Patient Specific Supplements to the ELSO General Guidelines, 2009. https://square.umin.ac.jp/jrcm/pdf/ecmo/ecmotext12.pdf
  • Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet. 2009 Oct 17;374(9698):1351-63 [MEDLINE]
  • Extracorporeal Membrane Oxygenation for 2009 Influenza A (H1N1) Acute Respiratory Distress Syndrome. JAMA. 2009 Nov 4;302(17):1888-95 [MEDLINE]
  • Extracorporeal Life Support Organization. Patient specific guidelines: a supplement to the ELSO general guidelines. April 2009:15-19 (https://www.elso.med.umich .edu/WordForms/ELSO%20P+%20Specif ic %20Guidelines.pdf)
  • Early and intermediate results of rescue extracorporeal membrane oxygenation in adult cardiogenic shock. Ann Thorac Surg. 2009;88(6):1897–1903 [MEDLINE]
  • Extracorporeal membrane oxygenation in nonintubated patients as bridge to lung transplantation. Am J Transplant 2010;10:2173–2178 [MEDLINE]
  • A review of the fundamental principles and evidence base in the use of extracorporeal membrane oxygenation (ECMO) in critically ill adult patients. J Intensive Care Med. 2011;26:13– 26. doi: 10.1177/0885066610384061 [MEDLINE]
  • Extracorporeal membrane oxygenation for ARDS in adults.  N Engl J Med.  2011;365:1905–1914 [MEDLINE]
  • Extracorporeal membrane oxygenation for respiratory failure in adults.  Curr Opin Crit Care Med.  2012;18:99–104 [MEDLINE]
  • Venovenous extracorporeal membrane oxygenation in adults: Practical aspects of circuits, cannulae, and procedures.  J Cardiothorac Vasc Anesth 2012;26:893–909 [MEDLINE]
  • Venoarterial extracorporeal membrane oxygenation support for refractory cardiovascular dysfunction during severe bacterial septic shock. Crit Care Med. 2013 Jul;41(7):1616-26. doi: 10.1097/CCM.0b013e31828a2370 [MEDLINE]
  • Extracorporeal membrane oxygenation for severe respiratory failure in adult patients: a systematic review and meta-analysis of current evidence. J Crit Care. 2013 Dec;28(6):998-1005. doi: 10.1016/j.jcrc.2013.07.047. Epub 2013 Aug 16 [MEDLINE]
  • Extracorporeal Life Support Organization (ELSO) Guidelines for Adult Respiratory Failure v1.3 (2013) [LINK]
  • Extracorporeal life support devices and strategies for management of acute cardiorespiratory failure in adult patients: a comprehensive review. Crit Care. 2014;18(3):219–229 [MEDLINE]
  • Mechanical ventilation during extracorporeal membrane oxygenation. Crit Care. 2014 Jan 21;18(1):203. doi: 10.1186/cc13702 [MEDLINE]
  • Extracorporeal membrane oxygenation for critically ill adults. Cochrane Database Syst Rev. 2015 Jan 22;1:CD010381. doi: 10.1002/14651858.CD010381.pub2 [MEDLINE]
  • Roller and Centrifugal Pumps: A Retrospective Comparison of Bleeding Complications in Extracorporeal Membrane Oxygenation. ASAIO J. 2015 Sep-Oct;61(5):496-501. doi: 10.1097/MAT.0000000000000243 [MEDLINE]
  • Extracorporeal membrane oxygenation in adults with cardiogenic shock. Circulation. 2015;131(7): 676–680 [MEDLINE]
  • Setting mechanical ventilation in ARDS patients during VV-ECMO: where are we? Minerva Anestesiol. 2015 Dec;81(12):1369-76 [MEDLINE]
  • Contemporary extracorporeal membrane oxygenation therapy in adults: Fundamental principles and systematic review of the evidence. J Thorac Cardiovasc Surg. 2016 Jul;152(1):20-32. doi: 10.1016/j.jtcvs.2016.02.067. Epub 2016 Mar 12 [MEDLINE]
  • Management of refractory hypoxemia during venovenous extracorporeal membrane oxygenation for ARDS. ASAIO J. 2015 May-Jun;61(3):227-36. doi: 10.1097/MAT.0000000000000207 [MEDLINE]
  • Complications of Prone Positioning During Extracorporeal Membrane Oxygenation for Respiratory Failure: A Systematic Review. Respir Care. 2016 Feb;61(2):249-54. doi: 10.4187/respcare.03882. Epub 2015 Oct 13 [MEDLINE]
  • Long-term survival and quality of life after extracorporeal life support: a 10-year report. Eur J Cardiothorac Surg. 2017 May 18. doi: 10.1093/ejcts/ezx100 [MEDLINE]
  • Long-Term Survival in Adults Treated With Extracorporeal Membrane Oxygenation for Respiratory Failure and Sepsis. Crit Care Med, 2017 Feb;45(2):164-170. doi: 10.1097/CCM.0000000000002078 [MEDLINE]
  • Systematic review and meta-analysis of complications and mortality of venovenous extracorporeal membrane oxygenation for refractory acute respiratory distress syndrome. Ann Intensive Care. 2017 Dec;7(1):51. doi: 10.1186/s13613-017-0275-4. Epub 2017 May 12 [MEDLINE]
  • Extracorporeal membrane oxygenation (ECMO) as a treatment strategy for severe acute respiratory distress syndrome (ARDS) in the low tidal volume era: A systematic review. J Crit Care. 2017 Apr 27;41:64-71. doi: 10.1016/j.jcrc.2017.04.041 [MEDLINE]
  • Fifty Years of Research in ARDS. Is Extracorporeal Circulation the Future of Acute Respiratory Distress Syndrome Management? Am J Respir Crit Care Med. 2017 May 1;195(9):1161-1170. doi: 10.1164/rccm.201701-0217CP [MEDLINE]
  • EOLIA Trial. Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome. N Engl J Med. 2018;378(21):1965 [MEDLINE]
  • Venovenous extracorporeal membrane oxygenation for acute respiratory distress syndrome: a systematic review and meta-analysis. Lancet Respir Med. 2019 Feb;7(2):163-172. doi: 10.1016/S2213-2600(18)30452-1 [MEDLINE]

Allogeneic Mesenchymal Stromal Cells

  • Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial. Lancet Respir Med. 2019 Feb;7(2):154-162. doi: 10.1016/S2213-2600(18)30418-1 [MEDLINE]

Tracheostomy (see Tracheostomy)

  • The timing of tracheotomy in critically ill patients undergoing mechanical ventilation: a systematic review and meta-analysis of randomized controlled trials. Chest 2011;140(6):1456–1465 [MEDLINE]
  • Early percutaneous tracheotomy versus prolonged intubation of mechanically ventilated patients after cardiac surgery: a randomized trial. Ann Intern Med 2011;154:373–383 [MEDLINE]
  • Effect of early vs late tracheostomy placement on survival in patients receiving mechanical ventilation: the TracMan randomized trial.  JAMA.  2013;309:2121–2129 [MEDLINE]

Early Mobilization/Rehabilitation

  • Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial. Lancet 2009;373:1874–1882 [MEDLINE]
  • Muscle wasting and early mobilization in acute respiratory distress syndrome. Clin Chest Med. 2014 Dec;35(4):811-26. doi: 10.1016/j.ccm.2014.08.016 [MEDLINE]
  • Early, goal-directed mobilisation in the surgical intensive care unit: a randomised controlled trial. Lancet. 2016 Oct;388(10052):1377-1388 [MEDLINE]
  • Standardized Rehabilitation and Hospital Length of Stay Among Patients With Acute Respiratory Failure: A Randomized Clinical Trial. JAMA. 2016 Jun;315(24):2694-702 [MEDLINE]
  • The effects of active mobilisation and rehabilitation in ICU on mortality and function: a systematic review. Intensive Care Med. 2017 Feb;43(2):171-183. doi: 10.1007/s00134-016-4612-0 [MEDLINE]
  • Chest Physiotherapy with Early Mobilization may Improve Extubation Outcome in Critically Ill Patients in the Intensive Care Units. Clin Respir J. 2018 Sep 28. doi: 10.1111/crj.12965 [MEDLINE]
  • Early Mobilization in the Intensive Care Unit to Improve Long-Term Recovery. Crit Care Clin. 2018 Oct;34(4):557-571. doi: 10.1016/j.ccc.2018.06.005 [MEDLINE]
  • Effect of In-Bed Leg Cycling and Electrical Stimulation of the Quadriceps on Global Muscle Strength in Critically Ill Adults: A Randomized Clinical Trial. JAMA. 2018 Jul 24;320(4):368-378. doi: 10.1001/jama.2018.9592 [MEDLINE]
  • Early Mobilization of Patients in Intensive Care: Organization, Communication and Safety Factors that Influence Translation into Clinical Practice. Crit Care. 2018 Mar 20;22(1):77. doi: 10.1186/s13054-018-1998-9 [MEDLINE]

Nutritional Support

  • OMEGA Trial. Enteral omega-3 fatty acid, gamma-linolenic acid, and antioxidant supplementation in acute lung injury. JAMA. 2011;306:1574–1581 [MEDLINE]
  • A randomized trial of glutamine and antioxidants in critically ill patients. N Engl J Med. 2013;368:1489–1497 [MEDLINE]
  • Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr. 2016 Feb;40(2):159-211. doi: 10.1177/0148607115621863 [MEDLINE]

Activated Protein C

  • Recombinant human activated protein C in the treatment of acute respiratory distress syndrome: a randomized clinical trial. PLoS One. 2014 Mar 14;9(3):e90983. doi: 10.1371/journal.pone.0090983. eCollection 2014 [MEDLINE]

Macrolides (see Macrolides)

  • Macrolide antibiotics and survival in patients with acute lung injury. Chest. 2012;141(5):1153. Epub 2011 Nov 23 [MEDLINE]

Prognosis

  • Functional Disability 5 Years after Acute Respiratory Distress Syndrome NEJM 2011; 364:1293-1304 [MEDLINE]
  • The ALIEN study: incidence and outcome of acute respiratory distress syndrome in the era of lung protective ventilation. Intensive Care Med. 2011 Dec;37(12):1932-41 [MEDLINE]
  • The adult respiratory distress syndrome cognitive outcomes study: long-term neuropsychological function in survivors of acute lung injury. Am J Respir Crit Care Med. 2012 Jun 15;185(12):1307-15 [MEDLINE]
  • The Adult Respiratory Distress Syndrome Cognitive Outcomes Study: long-term neuropsychological function in survivors of acute lung injury. Crit Care. 2013 May 24;17(3):317 [MEDLINE]
  • BRAIN-ICU: Long-Term Cognitive Impairment after Critical Illness. N Engl J Med. 2013 Oct 3;369(14):1306-1316 [MEDLINE]
  • Risk factors for physical impairment after acute lung injury in a national, multicenter study.  Am J Respir Crit Care Med. 2014 May 15;189(10):1214-24. doi: 10.1164/rccm.201401-0158OC [MEDLINE]
  • Physical complications in acute lung injury survivors: a two-year longitudinal prospective study.  Crit Care Med.  2014;42:849–859 [MEDLINE]