Acute Respiratory Distress Syndrome (ARDS)

Epidemiology

History

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

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 Only Used in 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 improvement

Risk 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
      • High-Risk Surgery
        • Aortic/Vascular: LIPS points +3.5
        • Cardiac: LIPS points +2.5
        • Acute Abdomen: LIPS points +2
        • Orthopedic Spine: LIPS points +1
      • High-Risk Trauma
        • Traumatic Brain Injury: LIPS points +2
        • Smoke Inhalation: LIPS points +2
        • Near Drowning LIPS points +2
        • Lung Contusion: LIPS points +1.5
        • Multiple Fractures: LIPS points +1.5
      • Pneumonia: LIPS points +1.5
      • Shock: LIPS points +2
      • Sepsis: LIPS points +1
      • Negative Risk Modifiers (Decrease the Risk of Acute Lung Injury)
        • Diabetes Mellitus: LIPS points -1 (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%: LIPS points +2
        • pH <7.35: LIPS points +1.5
        • Tachypnea with RR >30: LIPS points +1.5
        • Alcohol Abuse: LIPS points +1
        • Obesity with BMI >30: LIPS points +1
        • Hypoalbuminemia: LIPS points +1
        • Chemotherapy: LIPS points +1
        • SpO2 <95%: LIPS points +1
  • 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

Etiology

Infection

General

Viral Pneumonia

Bacterial Pneumonia

Fungal Pneumonia

Parasitic Pneumonia

Aspiration

Trauma/Surgery

  • Burns (see Burns, Burns)
  • Blast Injury
    • Explosion
    • Lightning
  • Fat Embolism (see Fat Embolism, Fat Embolism)
  • Pulmonary Contusion (see Pulmonary Contusion, 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
  • Trauma

Mechanical Pulmonary Edema

Hemodynamic Disturbance

Hematologic Disorder

Neurogenic Pulmonary Edema (see Neurogenic Pulmonary Edema, Neurogenic Pulmonary Edema)

Rheumatologic Disease

Lung Transplant Rejection/Dysfunction (see Lung Transplant Rejection, Lung Transplant Rejection)

Drug

Toxin

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

Pathology

Diffuse Alveolar Damage (DAD)


Diagnosis

Blood Culture (see Blood Culture, Blood Culture)

  • Useful to Rule Out an Infectious Etiology of ARDS

Sputum Culture (see Sputum Culture, Sputum Culture)

  • Useful to Rule Out an Infectious Etiology of ARDS

Bronchoscopy (see Bronchoscopy, Bronchoscopy)

  • Useful to Rule Out an Infectious Etiology of ARDS

Echocardiogram (see Echocardiogram, Echocardiogram)

  • Useful to Rule Out Cardiac Etiology (of Cardiogenic Pulmonary Edema)

Swan-Ganz Catheter (see Swan-Ganz Catheter, Swan-Ganz Catheter)

  • May Be Useful in Select Cases to Rule Out Cardiac Etiology (of Cardiogenic Pulmonary Edema)

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 Hantavirus Cardiopulmonary Syndrome, Hantavirus Cardiopulmonary Syndrome and Hemorrhagic Fever with Renal Syndrome, Hemorrhagic Fever with Renal Syndrome)
  • Leptospirosis Serology (see Leptospirosis, Leptospirosis)
  • Other Etiologies
    • Antinuclear Antibody (ANA) (see xxxxx, xxxx)

  • 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 (not fully explained by effusions, lobar/lung collapse, or 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)
      • 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

    Pulmonary Manifestations

    Barotrauma

    Bilateral Infiltrates

    • Physiology

    Hypoxemia (see Hypoxemia, Hypoxemia)

    • Physiology

    Bronchospasm (see Obstructive Lung Disease, Obstructive Lung Disease)

    • Physiology

    Decreased Lung Compliance (see xxxx, xxxx)

    • Physiology

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

    • Physiology

    Pulmonary Hypertension (see Pulmonary Hypertension, Pulmonary Hypertension)

    • Physiology
      • Hypercapnia-Induced Pulmonary Vasoconstriction (see Hypercapnia, 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, Hypoxemia)
        • Hypoxic Vasoconstriction is Enhanced by Acidosis

    Other Manifestations

    • xxx
    • xxx

    Neurologic Manifestations

    • Delirium (see Delirium, Delirium)
      • 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

    Prevention

    Aspirin (see Acetylsalicylic Acid, 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

    Corticosteroids (see Corticosteroids, 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

    Treatment

    Bronchodilators

    Agents

    Clinical Efficacy

    • BALTI (Am J Respir Crit Care Med, 2006) and BALTI-2 (Health Technol Assess, 2013) Trials [MEDLINE] [MEDLINE]
      • While BALTI Trial Suggested 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 (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)

    Corticosteroids (see Corticosteroids, 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
    • 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 (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 Treatment 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

    Clinical Efficacy

    • 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 (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)

    Oxygen (see Oxygen, Oxygen)

    Clinical Efficacy

    • 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

    Sedation (see Sedation, Sedation)

    Recommendations (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, Neuromuscular Junction Antagonists)

    Epidemiology

    • Prevalence of Use of Neuromuscular Junction Antagonists: approximately 25-55% of ALI/ARDS patients enrolled in multi-center, 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, 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, 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 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

    Recommendations (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)

    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)

    Administration

    • Predicted Body Weight (PBW)
      • Male: PBW = 50 + 2.3 (ht in inches – 60)
      • Female: PBW = 45.5 + 2.3 (ht in inches – 60)

    Clinical Efficacy

    • The Acute Respiratory Distress Syndrome Network (ARDSNet) Trial (NEJM, 2000) [MEDLINE]
      • Study: multi-center, randomized, controlled trial (n = 861) comparing high tidal volume (12 ml/kg PBW) + plateau pressure of <50 cm H2O against low tidal volume (6 ml/kg PBW) + a plateau pressure of <30 cm H2O
        • Trial stopped prematurely due to mortality benefit andf ventilator-free dats benefit in low tidal volume ventilation group
      • Main Findings: supports low tidal volume ventilation (although tidal volumes between 6 and 12 ml/kg PBW have not been studied)
        • Low tidal volume group: lower 31% mortality (vs 39.8% in high tidal volume group)
        • Low tial volume group: during first 28 days, increased ventilator-free days at 12 +/-11 (vs. 10 +/-11 in high tidal volume group)
        • Mean tidal volumes achieved during study (on days 1-3): 6.2 +/-0.8 ml/kg PBW in low tidal volume group (vs 11.8 +/-0.8 ml/kg PBW in high tidal volume group)
        • Mean plateau pressures achieved during study: 25 +/-6 cm H2O in low tidal volume group (vs 33+ +/-8 cm H2O in high tidal volume group)
        • Arterial pCO2 levels was 4-7 mm Hg higher in low tidal volume group, but pCO2 never exceeded 44 mmHg -> likely clinically unimportant
        • Auto-PEEP was statistically higher in the low tidal volume group (who had higher respiratory rates), although difference in median auto-PEEP was <1 cm H20 -> likely clinically unimportant [MEDLINE]
    • 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

    Recommendations (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 (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) (see PEEP + Auto-PEEP, PEEP + Auto-PEEP)

    Rationale

    • PEEP Decreases Intrapulmonary Shunting
    • PEEP Prevents Alveolar De-Recruitment (Collapse) at End-Expiration: rather than increasing alveolar recruitment
    • PEEP May Potentially Increase Physiologic Dead Space in Some Lung Regions: by increasing V/Q ratio in those areas
    • PEEP Decreases Dynamic Airway Compression

    Administration

    • Use ARDSNet FIO2/PEEP Table [ARDSNet]

    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
      • Hoever, 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

    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 (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 (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 (titrating PEEP upward on a 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

    Recruitment Maneuvers

    Rationale

    • Ventilatory Strategy that Transiently Increases the Transpulmonary Pressure to Reopen the Recruitable Lung Units 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

    Clinical Efficacy

    • Cochrane Database Review of Recruitment Maneuvers (Cochrane Database Syst Rev, 2009) [MEDLINE]
      • No Clinical Benefit of Recruitment Maneuvers in Either Mortality or Length of Mechanical Ventilation

    Recommendations (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 (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, High-Frequency Ventilation)

    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
    • 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

    • Canadian Clinical Trials Group High-Frequency Oscillation Study (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
    • xxxxx

    Recommendations (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 (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, High-Frequency Ventilation)

    Pressure Control Ventilation (PCV) (see Pressure Control Ventilation, Pressure Control Ventilation)

    Rationale

    • Peak Inspiratory Pressure is Generally Lower Than with Volume-Cycled Ventilation: this is due to the flow pattern used with PCV
      • However, given the same tidal volume, the plateau pressure is the same for PCV 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-inspiratry flow rates
      • PC has high initial flow rate: may allow 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
      • Note: PCV 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)

    Recommendations (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]

    • No Ventilator Mode is Recommended Over Another

    Pressure Control-Inverse Ratio Ventilation (PC-IRV) (see Pressure Control Ventilation, 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 (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, Airway Pressure Release Ventilation)

    Clinical Efficacy

    • 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 Mortality Benefit at 28 Days and 1 Year
      • 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

    Recommendations (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

    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 (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 (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 (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]

    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 (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

    • Studies: in trauma, CVA, ARDS, brain/spinal cord injury, nontraumatic critical illness, liver transplant, pulmonary contusion, and intubated newborns
      • Large-scale, randomized, controlled trials are needed to determine if this form of therapy is cost effective and to determine which patients will benefit most
    • Findings: as compared to conventional manual q2hr turning by nurse
      • Decreased ICU Length of Stay
      • Decreased Incidence of Hospital-Acquired Pneumonia
      • Improved Oxygenation/Gas Exchange
      • Decreased Pulmonary Shunt
      • No Impact on Mortality

    Inhaled Nitric Oxide (iNO) (see Nitric Oxide, Nitric Oxide)

    Rationale

    • Selective Vasodilation of Better Ventilated Lung Regions: improves V/Q matching
    • Decreased PA Pressure: modest effect occurs in the majority of pts
    • Improved CO2 Elimination: only at high NO concentrations + only with baseline pCO2 >50 mm Hg
      • Due to improved perfusion -> decreased alveolar dead space
    • 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, Methemoglobinemia)
    • 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)

    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)
      • Impairement of Hypoxic Vasoconstriction: due to drug itself or due to higher mized venous pO2
      • Changes in Intracardiac Pressure or Pulmonary Artery Pressure Leading to Redistriction 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, Venovenous Extracorporeal Membrane Oxygenation and Venoarterial Extracorporeal Membrane Oxygenation, 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
    • SUPERNOVA Trial of ECCO2R + Low Tidal Ventilation: trial underway
    • REST Trial of ECCO2R + Low Tidal Ventilation: trial underway
    • EOLIA Trial of VV-ECMO in ARDS: trial underway

    Recommendations (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

    Tracheostomy (see Tracheostomy, Tracheostomy)

    Clinical Efficacy

    • Study of Impact of Early Tracheostomy on VAP Rate (BMJ, 2005) [MEDLINE]
      • Early Tracheostomy Decreases the Duration of Mechanical Ventilation and ICU Stay, But Does Not Impact Mortality or VAP Rate
    • Systematic Review and Meta-Analysis of Effect of Early Tracheostomy on VAP Rates (Chest, 2011) [MEDLINE]
      • Early Tracheostomy Did Not Impact VAP Rates, Duration of Mechanical Ventilation, or Mortality Rate
    • Study of Early Tracheostomy in Cardiothoracic Surgery Population (Ann Intern Med 2011) [MEDLINE]
      • Early Tracheostomy Did Not Decrease Length of Hospital Stay, Mortality Rate, Infectious Complication Rate, Long-Term Health-Related Quality of Life in Patients Who Required Long-Term Mechanical Ventilation After Cardiothoracic Surgery
      • Early Tracheostomy was Well-Tolerated and Associated with Decreased Sedation Use, Better Comfort, and Earlier Resumption of Autonomy
    • TracMan Trial of Early vs Late Tracheostomy in the UK (JAMA, 2013) [MEDLINE]
      • Early Tracheostomy (Within 4 Days of Intubation) Did Not Improve 30-Day All-Cause Mortality, 2-Year Mortality, or Length of ICU Stay
      • The Ability of Clinicians to Predict Which Patients Would Require Extended Mechanical Ventilation Support was Limited

    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 Hospitalized with Acute Respiratory Failure

    Nutritional Support

    Rationale

    • Nutritional Products Rich in Antioxidants and Supplemented with w-3 Fatty Acids (eEcosapentaenoic Acid, EPA, and Gamma-Linoleic Acid, GLA) Can Modulate Proinflammatory States in ARDS and Sepsis, Resulting in Improved Oxygenation and Improved Outcome
      • Further Studies are Needed Before Recommendations Can Be Made

    Clinical Efficacy

    • OMEGA Trial of Enteral Omega-3 Fatty Acids, Gamma-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
    • 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

    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 (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, 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, Ibuprofen)
    • Ketoconazole (see Ketoconazole, Ketoconazole)
    • Macrolides (see Macrolides, 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, 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, Prostaglandin E1)
    • Statins (see HMG-CoA Reductase Inhibitors, HMG-CoA Reductase Inhibitors)
    • Surfactant

    Prognosis

    Reported Acute Respiratory Distress Syndrome (ARDS) Mortality Rates

    • Historical ARDS Mortality Rates (Studies Published in 2000): 30-40% [MEDLINE] [MEDLINE]
    • ARDS Mortality Rate on Current Lung Protective Ventilation Strategies (Studies Published in 1999 and 2004): 13-23% [MEDLINE] [MEDLINE]
    • ALIEN Study of ARDS Mortality Rates on Current 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% [MEDLINE] [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 [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, 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, 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]
      • Post-operative acute lung injury is associated with increased in-hospital mortality (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)
      • Lung protective mechanical ventilation strategies decrease the incidence of post-operative 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
      • Pychological 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

    • Pulmonary barotrauma in mechanical ventilation: patterns and risk factors. Chest 1992; 102:568-572
    • Barotrauma: detection, recognition, and management. Chest 1993; 104:578-584
    • 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]
    • 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 [MEDLINE]
    • 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

    • 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]

    Etiology

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

    Clinical

    Pulmonary Hypertension (see Pulmonary Hypertension, 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]

    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]
    • 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]

    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]

    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]

    Corticosteroids (see Corticosteroids, 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]

    Oxygen (see Oxygen, Oxygen)

    • 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]

    Paralysis (Neuromuscular Junction Blockade) (see Neuromuscular Junction Antagonists, 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]
    • Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010 Sep 16;363(12):1107-16 [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]
    • 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]
    • 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]

    Positive End-Expiratory Pressure (PEEP) (see PEEP + Auto-PEEP, PEEP + Auto-PEEP)

    • 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]
    • Determination of auto-PEEP during spontaneous and controlled ventilation by monitoring changes in end-expiratory thoracic gas volume. Chest 1989; 96:613-616 [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]
    • Intrinsic (or auto-) positive end-expiratory pressure during spontaneous or assisted ventilation. Intensive Care Med 2002;28:1552 [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]
    • 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]
    • 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]
    • 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]
    • 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]
    • 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]

    Recruitment Maneuvers

    • Recruitment manoeuvres for adults with acute lung injury receiving mechanical ventilation. Cochrane Database Syst Rev. 2009 Apr 15;(2):CD006667 [MEDLINE]

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

    • 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, 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)

    • 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]
    • 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
    • Airway pressure release ventilation: what do we know? Respir Care. 2012 Feb;57(2):282-92 [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]

    Inhaled Nitric Oxide (iNO) (see Nitric Oxide, Nitric Oxide)

    • 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]

    Venovenous Extracorporeal Membrane Oxygenation (VV-ECMO) (see Venovenous Extracorporeal Membrane Oxygenation, 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. http://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 (http://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]
    • 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]

    Tracheostomy (see Tracheostomy, 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]
    • 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]

    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, 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]