MD Nexus

Acute Respiratory Distress Syndrome (ARDS)-Part 2

Treatment

General Comments

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

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

Treatment of Fever (see Fever)

Rationale

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

Clinical Efficacy

  • Rabbit Study of Treatment of Fever in Lung Injury (Crit Care Med, 2004) [MEDLINE]
    • Hyperthermia Augmented the Development of Lung Injury in a Rabbit Model, as Compared to Hypothermia
    • Effects were Not Due to Cardiovascular Factors or Consequences of Heating Non-Pulmonary Organs

Bronchodilators

Agents

Clinical Efficacy

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

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

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

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

Management of Patient-Ventilator Dyssynchrony

Corticosteroids (see Corticosteroids)

Clinical Efficacy

  • National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network Corticosteroids in Persistent ARDS Study (NEJM, 2006) [MEDLINE]: RCT (n = 180) ARDS patients of at least 7 days duration
    • Corticosteroid Use in ALI/ARDS Did Not Alter the Mortality Rate, Sepsis Rate, Renal Dysfunction Rate, or Hepatic Dysfunction Rate
    • Starting Methylprednisolone Therapy >2 wks After the Onset of ARDS May Increase the Risk of Death
    • Corticosteroids Facilitated Ventilator Withdrawal in ARDS, But Increased Reintubation Rates
  • Meta-Analysis of Corticosteroids in ARDS (Respirology, 2007) [MEDLINE]
    • Corticosteroids Had No Benefit in Either Early or Late ARDS
  • Meta-Analysis of Corticosteroids in ARDS (BMJ, 2008) [MEDLINE]
    • Corticosteroids Had Unclear Benefit in ARDS
    • Preventative Corticosteroids Possibly Increased the Risk of ARDS in Critically Ill Patients
  • Meta-Analysis of Glucocorticoids in ARDS (Intensive Care Med, 2008) [MEDLINE]
    • Prolonged Glucocorticoids Improved Patient-Centered Outcome Variables and Had a Survival Benefit When Initiated Before Day 14 of ARDS
  • Consensus Statement from the American College of Critical Care Medicine (Crit Care Med, 2008) [MEDLINE]
    • Moderate-Dose Glucocorticoids Should Be Considered in the Management Strategy of Patients with Early Severe ARDS and Before Day 14 for Patients with Unresolving ARDS (Weak 2b Recommendation, Moderate Quality Evidence)
  • Systematic Review and Meta-Analysis of Corticosteroids in ALI/ARDS (Crit Care Med, 2009) [MEDLINE]
    • Low-Dose Corticosteroids Were Associated with Improved Mortality and Morbidity Outcomes Without Increased Adverse Reactions in ALI/ARDS: however, the mortality benefits in early ARDS should be confirmed by an adequately powered randomized trial
  • Effect of Corticosteroids on the Development of Delirium in ALI/ARDS (Crit Care Med, 2014) [MEDLINE]: prospective cohort study
    • After Adjusting for Other Risk Factors, Systemic Corticosteroids Were Significantly Associated with the Development of Delirium in ALI/ARDS
  • Study of the Role of Open Lung Biopsy in Unresolving ARDS (Intensive Care Med, 2015) [MEDLINE]
    • Diffuse Alveolar Damage is Present in Most Patients with Unresolving ARDS and its Frequency is the Same Regardless of the Stage of ARDS (Mild, Moderate, Severe): on this basis, authors concluded that corticosteroid therapy is not recommended
  • Meta-Analysis of Corticosteroids in ARDS (Intensive Care Med, 2016) [MEDLINE]
    • Prolonged Methylprednisolone Accelerated the Resolution of ARDS, Decreased Hospital Mortality (20% vs 33%), and Increased ICU-Free Days: analysis of the data suggests that any benefit is likely limited to patients in whom corticosteroid treatment is initiated prior to day 14
    • Methylprednisolone Did Not Increase the Risk for Infection
  • Spanish Multicenter, Randomized Controlled Trial of Dexamethasone in Acute Respiratory Distress Syndrome (ARDS) (Lancet Respir Med, 2020) [MEDLINE]: n = 277
    • Trial Stopped Due to Low Enrollment After Enrolling >88% (277/314) of the Planned Sample Size
    • Mean Number of Ventilator-Free Days was Higher in the Dexamethasone Group, as Compared to the Control Group (Between Group Difference was 4.8 Days; CI: 2.57-7.03; p<0.0001
    • At 60 Days, 21% of the Patients in Dexamethasone Group and 36% of the Patients in Control Group Had Died (Between Group Difference -15.3%; CI: -25.9 tp -4.9; p=0.0047)
    • Adverse Events Did Not Differ Significantly Between the Dexamethasone and Control Group
      • The Most Common Adverse Events Hyperglycemia (76% in the Dexamethasone Group vs 70% in the Control Group), New Infections (24% in the Dexamethasone Group vs 25% in the Control Group), and Barotrauma (10% in the Dexamethasone Group vs 7% in the Control Group)
  • CoDEX Trial of Dexamethasone in Moderate-Severe Acute Respiratory Distress Syndrome (ARDS) and COVID-19 (JAMA, 2020) [MEDLINE]: n = 299
    • In Patients with COVID-19 and Moderate-Severe ARDS, Intravenous Dexamethasone Resulted in a Significant Increase in the Number of Ventilator-Free Days (Days Alive and Free of Mechanical Ventilation Over 28 Days), as Compared to Standard Care Alone
    • At 7 Days, Patients in the Dexamethasone Group had a Mean SOFA Score of 6.1 (95% CI: 5.5-6.7) vs 7.5 (95% CI: 6.9-8.1) in the Standard Care Group (Difference -1.16; 95% CI: -1.94 to -0.38; P = 0.004)
    • No Significant Difference in 28-Day All-Cause Mortality Rate, ICU-Free Days During the First 28 Days, Mechanical Ventilation at 28 Days
    • Adverse Events
      • Approximately 31.1% of Patients in the Dexamethasone Group Required Insulin for Glycemic Control, as Compared to 28.3% in the Standard Care Group
      • Approximately 21.9% of Patients in the Dexamethasone Group Experienced Secondary Infections, as Compared to 29.1% in the Standard Care Group
      • Approximately 3.3% of Patients in the Dexamethasone Group Experienced Other Serious Adverse Events, as Compared to 6.1% in the Standard Care Group

General Recommendations

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

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

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

British Thoracic Society 2019 Guidelines for the Management of Acute Respiratory Distress Syndrome (ARDS) (BMJ Open Respir Res, 2019) [MEDLINE]

  • The Use of Corticosteroids in Established Acute Respiratory Distress Syndrome Should Be the Subject of a Suitably Powered, Multicenter Randomized Controlled Trial with Long-Term Follow-Up (Grade Recommendation: Research Recommendation)

Fluid Management

Rationale

  • Decreased Lung Water Results in Improved Oxygenation

Exclusion Criteria for Diuresis of the ARDS Patient

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

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

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

Clinical Efficacy-Fluid Management Strategy

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

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

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

British Thoracic Society 2019 Guidelines for the Management of Acute Respiratory Distress Syndrome (ARDS) (BMJ Open Respir Res, 2019) [MEDLINE]

  • Use of a Conservative Fluid Strategy is Recommended in Patients with Acute Respiratory Distress Syndrome (ARDS) (Grade Recommendation: Weakly in Favor)

Supplemental Oxygen Therapy (see Oxygen)

Clinical Efficacy

  • Randomized Trial of Conservative Oxygen Strategy in Mechanically-Ventilated Patients (Am J Respir Crit Care Med, 2016) [MEDLINE]
    • Conservative Oxygen Strategy (SpO 88-92%) Did Not Impact the ICU or 90-Day Mortality Rate or Risk of Organ Dysfunction, as Compared to Liberal Oxygen Strategy (SpO2 ≥96%)
  • Italian Oxygen-ICU Trial of Conventional Oxygen Strategy (pO2 Up to 150 mm Hg or SaO2 97-100%) vs Conservative Oxygen Strategy (pO2 70-100 or SaO2 94-98%) in a General ICU Population (Stay of ≥72 hrs) (JAMA, 2016) [MEDLINE]
    • Trial Had Unplanned, Early Termination
    • Conservative Oxygen Strategy Decreased the Mortality Rate, as Compared to Conventional Oxygen Strategy
  • French HYPERS2S Trial of Hyperoxia and Hypertonic Saline in Septic Shock (Lancet Respir Med, 2017) [MEDLINE]
    • Trial Stopped Prematurely for Safety Reasons
    • Setting FiO2 to 100% to Induce Arterial Hyperoxia Might Increase the Mortality Rate in Septic Shock
    • Hypertonic (3%) Saline Resuscitation Did Not Decrease the Mortality Rate in Septic Shock
  • Improving Oxygen Therapy in Acute-illness (IOTA) Systematic Review and Meta-Analysis of Conservative vs Liberal Oxygen Strategy in Critically Ill Patients (Lancet, 2018) [MEDLINE]: n = 25 trials (in patients with sepsis, critical illness, stroke, trauma, myocardial infarction, cardiac arrest, and emergency surgery)
    • In Acutely Ill Adults, Liberal Oxygen Therapy Strategy (Median SaO2 96%, Range 94-99%) Increases the 30-Day (and Longest Follow-Up) Mortality Rate, as Compared to a Conservative Oxygen Therapy Strategy (Relative Risk at 30 Days was 1.21, 95% CI 1.03-1.43)
      • Supplemental Oxygen Might Become Unfavorable with SaO2 >94-96%
  • Post Hoc Analysis of HYPERS2S Trial Data (Ann Intensive Care, 2018) [MEDLINE]
    • Hyperoxia May Be Associated with a Increased Mortality Rate in Patients with Septic Shock Using the Sepsis-3 Criteria (with Serum Lactate > 2 mmol/L), But Not in Patients with Hypotension Alone
    • In Patients with Serum Lactate ≤2 mmol/L, Hyperoxia Had No Effect on the Mortality Rate, Nor on Other Outcomes
  • Observational Study of Hyperoxia in the Emergency Department in Patients with Acute Respiratory Failure (Crit Care, 2018) [MEDLINE]: n = 688
    • Emergency Department Exposure to Hyperoxia is Common and Associated with Increased Mortality in Mechanically Ventilated Patients Achieving Normoxia After Admission
    • This Suggests that Hyperoxia in the Immediate Post-Intubation Period Could Be Particularly Injurious and Targeting Normoxia from Initiation of Mechanical Ventilation May Improve Outcome
  • Australian/New Zealand ICU-ROX Trial of Conservative Oxygen Strategy in Mechanically-Ventilated Patients in the ICU (NEJM, 2020) [MEDLINE]: n = 1000
    • RCT of Conservative Oxygen Therapy Using SpO2 <97%
    • There was No Difference Between Conservative Oxygen Group (Median Duration: 21.3 Days; Interquartile Range: 0-26.3) and Usual Care Oxygen Group (Median Duration: 22.1 days; Interquartile Range: 0-26.2), in Terms of Number of Ventilator-Free Days
    • The Conservative Oxygen Group Spent More Time in the ICU (Median Duration: 29 hrs; Interquartile Range: 5-78) ) with an FiO2 of 21% than the Usual Care Oxygen Group (Median Duration: 1 hr; Interquartile Range: 0-17)
    • The Conservative Oxygen Group Spent Less Time with an SpO2 >96% (Median Duration: 27 hrs; Interquartile Range: 11-63.5) than the Usual Care Oxygen Group (Median Duration: 49 hrs; Interquartile Range: 22-112)
    • At 180 days, Mortality was 35.7% in the Conservative Oxygen Group and 34.5% in the Usual Care Oxygen Group, for an Unadjusted Odds Ratio of 1.05 (95% CI: 0.81-1.37)
  • French Multicenter, Randomized, Liberal or Conservative Oxygen 2 (LOCO2) Trial in ARDS (NEJM, 2020) [MEDLINE]: n= 205
    • In ARDS, Early Conservative Oxygen Strategy (Target pO2 55-70 mm Hg or SpO2 88-92%) Did Not Improve 28-Day Survival, as Compared to Liberal Oxygen Strategy (Target pO2 90-105 mm Hg or SpO2 ≥96%) When Used for 7 Days
    • Same Mechanical Ventilation Strategy was Used in Both Groups
  • Multicenter, Randomized HOT-ICU Trial of Lower or Higher Oxygenation Targets for Acute Hypoxemic Respiratory Failure (NEJM, 2021) [MEDLINE]: n = 2928
    • Enrolled Patients Who Had Recently Been Admitted to the ICU (≤12 hrs Before Randomization) and Who were Receiving ≥10 Liters of Oxygen Per Minute in an Open System or Had a Fraction of Inspired Oxygen ≥50% in a Closed System to Receive Oxygen Therapy Targeting a pO2 of Either 60 mm Hg (Lower Oxygenation Group) or 90 mm Hg (Higher Oxygenation Group) for a Maximum of 90 Days
    • At 90 Days, There was No Difference in Mortality Rate Between the Low Oxygenation (42.9%) and High Oxygenation (42.4%) Groups
    • At 90 Days, There were No Significant Between-Group Difference in the Percentage of Days that Patients were Alive without Life Support or in the Percentage of Days They were Alive After Hospital Discharge
    • The Percentage of Patients Who Had New Episodes of Shock, Myocardial Ischemia, Ischemic Stroke, or Intestinal Ischemia were Similar in the Two Groups
  • Dutch Randomized, Multicenter O2-ICU Trial of Low (60-90 mm Hg) vs High (105-135 mm Hg) Oxygenation Targets in Critically Ill Patients (with ≥2 SIRS Criteria and Expected ICU Stay >48 hrs) (JAMA, 2021) [MEDLINE]: n = 574
    • Comparing Low-Normal to High-Normal pO2 Groups, There was No Significant Difference in the Median Duration of Mechanical Ventilation (3.4 vs 3.1 Days; Median Difference, -0.15 [95% CI, -0.88 to 0.47]; p = 0.59)
    • Comparing Low-Normal to High-Normal pO2 Groups, There was No Significant Difference in the In-Hospital Mortality Rate (32% vs 31%; Odds Ratio, 1.04 [95% CI, 0.67 to 1.63]; p = 0.91)
    • Comparing Low-Normal to High-Normal pO2 Groups, There was No Significant Difference in the Risk of Acute Kidney Failure (10% vs 11%)
    • Comparing Low-Normal to High-Normal pO2 Groups, There was No Significant Difference in the Risk of Acute Myocardial Infarction (2.9% vs 3.6%)

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

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

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

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

Sedation (see Sedation)

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

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

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

Epidemiology

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

Administration

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

Clinical Efficacy

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

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

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

British Thoracic Society 2019 Guidelines for the Management of Acute Respiratory Distress Syndrome (ARDS) (BMJ Open Respir Res, 2019) [MEDLINE]

  • Neuromuscular Junction Blockade is Not Recommended for All Patients with Acute Respiratory Distress Syndrome (ARDS) (Grade Recommendation: Weakly Against)
    • Use of Cisatracurium Besylate by Continuous 48 hours Infusion is Recommended in Patients Suffering Early Moderate/Severe Acute Respiratory Distress Syndrome (ARDS) (P/F Ratio <20 kPa) (Grade Recommendation: Weakly in Favor)

Respiratory Rate (RR)

Clinical Efficacy

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

General Recommendations

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

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

Rationale

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

Technique

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

Clinical Efficacy-General

  • Randomized Trial of Lung Protective Ventilation in Acute Respiratory Distress Syndrome (ARDS) (NEJM, 1998) [MEDLINE]: n = 53
    • As Compared to Standard Tidal Volume of 12 mL/kg PBW (with Normal pCO2 35-38 mm Hg), Protective Ventilation Involved End-Expiratory Pressures Above the Lower Inflection Point on the Static Pressure-Volume Curve, Tidal Volume <6 mL/kg PBW, Driving Pressures <20 cm of Water Above the PEEP Value, Permissive Hypercapnia, and Preferential Use of Pressure-Limited Ventilatory Modes
    • Lung Protective Ventilation (38%) Improved the 28-Day Mortality Rate vs Standard Ventilation (71%) (P<0.001), Improved Weaning from Mechanical Ventilation, and Decreased Rate of Barotrauma
    • Protective Ventilation Did Not Increase Survival to Hospital Discharge
  • The Acute Respiratory Distress Syndrome Network (ARDSNet) Multicenter Randomized Trial Comparing High Tidal Volume (12 mL/kg PBW and Plateau Pressure <50 cm H2O) with Low Tidal Volume (6 mL/kg PBW and Plateau Pressure <30 cm H2O) Ventilation (NEJM, 2000) [MEDLINE]: n = 861
    • Trial was Stopped Prematurely Due to Mortality Benefit and Increased Ventilator-Free Days in Low Tidal Volume Ventilation Group
    • Low Tidal Volume Group Had Decreased Mortality Rate (31%), as Compared to High Tidal Volume Group (39.8%)
      • However, Tidal Volumes Between 6 and 12 mL/g PBW were Not Studied
    • Low Tidal Volume Group Had Increased Ventilator-Free Days During the First 28 Days (12 +/- 11), as Compared to the High Tidal Volume Group (10 +/- 11)
    • Mean Tidal Volumes Achieved on Days 1-3 in Low Tidal Volume Group were Lower (6.2 +/- 0.8 mL/kg PBW), as Compared to High Tidal Volume Group (11.8 +/- 0.8 mL/kg PBW)
    • Mean Plateau Pressures Achieved in Low Tidal Volume Group were Lower (25 +/- 6 cm H2O), as Compared to High Tidal Volume Group (33 +/- 8 cm H2O)
    • Arterial pCO2 was 4-7 mm Hg Higher in Low Tidal Volume Group, But pCO2 Never Exceeded 44 mm Hg: this is likely not clinically significant
    • FIO2 was Higher in the Low Tidal Volume Group on Days 1 and 3, Becoming Equivalent by Day 7: this suggests that the institution of low tidal volumes resulted in a transient worsening of oxygenation
    • Auto-PEEP was Higher in the Low Tidal Volume Group (Who Had Higher Respiratory Rates), Although the Difference in Median Auto-PEEP was <1 cm H2O: this is likely not clinically significant (Crit Care Med, 2005) [MEDLINE]
    • Critiques of This Trial (and the NEJM 1998 Protective Ventilation Trial Above)
      • Bedside Clinicians Had Already Stopped Using High Tidal Volumes (Such as 12 mL/kg) Before Publication of Both of These Trials (Crit Care, 2022) [MEDLINE]
      • Tidal Volume of 6 mL/kg Has Never Been Demonstrated to Be Superior to Tidal Volume of 11 mL/kg or Anything in Between, Raising Questions About How the Trial Design (of 12 mL/kg vs 6 mL/kg) Has Impacted Modern Ventilatory Practice in Acute Respiratory Distress Syndrome (ARDS) (Crit Care, 2022) [MEDLINE]
  • Review of Animal/Human Data from ARDS Clinical Trials Network (and Original Data) Examining if There is a Safe Upper Limit of Plateau Pressure in ARDS (Am J Respir Crit Care Med, 2005)
    • Authors Could Not Identify a Safe Upper Limit for Plateau Pressure in ARDS
  • Study of Sedative Use During Low Tidal Volume Ventilation (Crit Care Med, 2005) [MEDLINE]
    • Low Tidal Volume Ventilation Does Not Result in Increased Use of Sedatives, Opiates, or Paralytics
  • Meta-Analysis of Low Tidal Volume and Limited Airway Pressure or Higher PEEP in ALI/ARDS (Ann Intern Med, 2009) [MEDLINE]
    • Decreased Mortality with Routine Use of Low Tidal Volume, But Not High PEEP Ventilation, in Unselected Patients with ARDS or Acute Lung Injury
    • High PEEP May Help to Prevent Life-Threatening Hypoxemia in Selected Patients
  • Systematic Review of Pressure/Volume-Limited Strategies (PLoS One, 2011) [MEDLINE]: the ARDS Network trial [MEDLINE] contributed 21.4% of the weight toward the summary estimate of effect in this analysis
    • Pressure/Volume-Limited Strategies Decrease Mortality Rate and are Associated with Increased Use of Paralytics
  • Cochrane Database Review of Lung Protective Ventilation Strategies in ARDS (Cochrane Database Syst Rev, 2013) [MEDLINE]
    • Lung Protective Strategies (Low Tidal Volume or Plateau Pressure <30 cm H2O) Decrease Mortality
  • Trial Examining Predictors of Ventilator-Induced Lung Injury in ARDS (Anesthesiology, 2013) [MEDLINE]
    • Rationale: stress index describes the shape of the airway pressure-time curve profile and may indicate tidal recruitment or tidal overdistension (convex downward pressure curve indicates initial low compliance with better compliance later in the breath due to recruitment, while convex upward curve indicates overdistention -> optimal curve is straight diagonal initial pressure waveform)
    • Plateau Pressure Partitioned to the Respiratory System (Pplat,Rs) >25 cm H20 and Stress Index Partitioned to the Respiratory System (SI,Rs) >1.05 were Most Associated with Injurious Ventilation
  • Systematic Review/Meta-Analysis of Morbidity/Mortality in Post-Operative Acute Lung Injury (Lancet Respir Med, 2014) [MEDLINE]
    • Lung Protective Mechanical Ventilation Strategies (Applied During Surgery) Decrease the Incidence of Post-Operative Acute Lung Injury, But Do Not Decrease the Mortality Rate
  • Study of Contribution of Driving Pressure to Mortality in ARDS (NEJM, 2015) [MEDLINE]: study used data from 9 prior randomized trials
    • Rationale: lower tidal volume, lower plateau pressure, and higher PEEP are all believed to decrease mechanical stresses on the lung in ARDS (which can induce ventilator-associated lung injury)
      • However, There is an Uncertainty When Optimizing One Component Adversely Affects Another (Example: Increasing PEEP May Undesirably Increase the Plateau Pressure), Which this Study Attempted to Address
      • Authors Theorized in Their Study that Optimizing the Tidal Volume/Respiratory System Compliance Ratio (Known as the Driving Pressure = Delta P) Would Provide a Better Predictor of Outcome in ARDS
    • Driving Pressure (Plateau Pressure – PEEP or Delta P) was the Best Predictor of Survival
      • Decreases in Tidal Volume or Increases in PEEP Were Beneficial Only if They Resulted in a Decrease in Delta P (In Other Words, PEEP Increments are Protective Only When They are Associated with an Improvement in Respiratory System Compliance, So that the Same Tidal Volume Can Be Delivered with a Lower Delta P)
      • Further Trials Using Specific Manipulation of Delta P are Required Before Recommending this Strategy as a Standard
    • Caveat: Delta P Can Only Be Accurately Assessed in Non-Breathing Patients
  • Database Study of the Impact of Mechanical Power on ARDS Mortality (Am J Respir Crit Care Med, 2021) [MEDLINE]: n = 4,549
    • Among the Ventilator Variables Used in the Computation of Mechanical Power, Only Driving Pressure and Respiratory Rate were Independently Associated with Mortality Rate
      • The Effect of Driving Pressure was Not Modified by Respiratory Rate
    • Mechanical Power was Independently Associated with Mortality, But Mainly Due to its Dynamic-Elastic Component
      • Mechanical Power is a Composite of Risk Factors Associated with Disease Severity and Modifiable Factors Which Cause Lung Injury (Tidal Volume, Respiratory Rate)
    • If Confirmed in a Randomized Clinical Trial, the Potential Implications on Clinical Decision Making are that Low Driving Pressure and Low Respiratory Rate Should Both Be Targets

    Clinical Efficacy-Personalized Ventilation

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

    Clinical Efficacy-Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV2, COVID-19) (see Severe Acute Respiratory Syndrome Coronavirus-2)

    • ProVENT-COVID Secondary Analysis Study of Low Tidal Volume Ventilation in COVID-19-Associated ARDS During the First Wave of the Pandemic (J Crit Care, 2022)[MEDLINE]: n = 903
      • Low Tidal Volume Ventilation Demonstrated a Decreased 28-Day Mortality Rate (23.1%), as Compared to Group Which Did Not Receive Low Tidal Ventilation (31.7%)(P < 0.001)

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

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

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

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

    British Thoracic Society 2019 Guidelines for the Management of Acute Respiratory Distress Syndrome (ARDS) (BMJ Open Respir Res, 2019) [MEDLINE]

    • The Routine Use of Lower Tidal Volumes are Recommended for the Management of Patients with Acute Respiratory Distress Syndrome (ARDS) (Grade Recommendation: Strongly in Favor)

    Positive End-Expiratory Pressure (PEEP)

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

    Techniques/Strategies to Set the Optimum Amount of PEEP

    Clinical Efficacy

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

    General Recommendations

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

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

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

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

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

    British Thoracic Society 2019 Guidelines for the Management of Acute Respiratory Distress Syndrome (ARDS) (BMJ Open Respir Res, 2019) [MEDLINE]

    • Use of High PEEP Strategies is Recommended for Patients with Moderate/Severe Acute Respiratory Distress Syndrome (ARDS) (P/F Ratio <27 kPa) (Grade Recommendation: Weakly in Favor)

    Esophageal Pressure-Guided Mechanical Ventilation

    Rationale

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

    Clinical Efficacy

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

    Recruitment Maneuvers

    Rationale and Technique

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

    Clinical Efficacy

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

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

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

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

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

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

    Concept

    • Ventilation Mode Employing the Use of High Respiratory Rates

    Techniques

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

    Clinical Efficacy

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

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

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

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

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

    British Thoracic Society 2019 Guidelines for the Management of Acute Respiratory Distress Syndrome (ARDS) (BMJ Open Respir Res, 2019) [MEDLINE]

    • Use of High-Frequency Oscillation Ventilation is Not Recommended in the Management of Patients with Acute Respiratory Distress Syndrome (ARDS) (Grade Recommendation: Strongly Against)

    Pressure Assist Control Ventilation (PCV)

    Concept

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

    Settings

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

    Monitor

    • Tidal Volume (VT)

    Advantages

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

    Disadvantages

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

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

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

    Rationale

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

    Clinical Efficacy

    • No Mortality Benefit Has Been Demonstrated for Pressure Control Ventilation
      • Note that Pressure Control Ventilation was Not Used in the ARDSnet Trial
      • Note that the Differences Between Pressure Control Ventilation and Modern Volume-Cycled Modes are Probably Negligible (as Many Modern Ventilators Can Be Configured Using a Descending Ramp Flow Waveform
    • Cochrane Database Systematic Review of Pressure-Controlled vs Volume-Controlled Ventilation in Acute Respiratory Distress Syndrome (ARDS) (Cochrane Database Syst Rev, 2015) [MEDLINE]: n = 1089 (from 3 randomized controlled trials, recruited from 43 intensive care units in Australia, Canada, Saudi Arabia, Spain, and the USA)
      • For In-Hospital Mortality, Relative Risk with Pressure-Controlled Ventilation was 0.83 (95% CI: 0.67-1.02; Three Trials, 1089 Subjects; Moderate-Quality Evidence), as Compared to Volume-Controlled Ventilation
      • For 28-Day Mortality, One Study Provided No Evidence of Benefit with the Ventilatory Mode (Relative Risk 0.88 (95% CI: 0.73-1.06; 983 Subjects; Moderate-Quality Evidence)
      • Currently Available Data were Insufficient to Determine if There was Any Difference Between Pressure-Controlled and Volume-Controlled Ventilation in ARDS

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

    Rationale

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

    Potential Adverse Effects

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

    Administration

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

    Clinical Efficacy

    • No Mortality Benefit

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

    • No Ventilator Mode is Recommended Over Another

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

    Clinical Efficacy

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

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

    • No Ventilator Mode is Recommended Over Another

    Body Position -> Proning

    History

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

    Physiologic Mechanisms

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

    Unknown Aspects of Proning

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

    Technique

    • Rotoprone Bed
    • Vollman Proning Device

    Practical Application

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

    Absolute Contraindications to Proning

    Relative Contraindications to Proning

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

    Adverse Effects/Complications of Proning

    Clinical Efficacy-General

    • 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
    • Small Study of the Effect of Proning on Respiratory Effort in Acute Respiratory Distress Syndrome (Am J Respir Crit Care Med, 2021) [MEDLINE]: n = 12
      • Proning Improved Oxygenation, Decreased Dynamic Lung Stress, and Decreased Spontaneous Inspiratory Effort (Despite Matched Levels of Sedation)
        • Improved Oxygenation in Prone Position May Have Decreased Respiratory Drive
        • Proning is Known to Increase End-Expiratory Lung Volume (and the Force Generated by Diaphragmatic Contraction is Linearly Decreased as Lung Volume is Increased)
    • Study of the Ability of Chest CT Findings to Predict Proning Response in Moderate-Severe ARDS (BMC Pulm Med, 2022) [MEDLINE]: n = 96
      • A Greater Difference in the Extent of Consolidation Along the Dependent-Independent Axis (i.e. Median Dorsal-Ventral Difference) on Chest CT Scan was Associated with Subsequent Prone Positioning Oxygenation Response, But Not with the 60-Day Mortality Rate
      • High Total Ground Glass Opacity Scores (≥15) were Associated with an Increased 60-Day Mortality Rate (Odds Ratio 4.07; 95% Confidence Interval: 1.39-11.89; p = 0.010)

      Clinical Efficacy-Implementation of Proning

      • Qualitative Study of the Implementation of Proning in the Intensive Care Unit During the COVID-19 Pandemic (Ann Am Thorac Soc, 2022) [MEDLINE]
        • ICU Clinicians Reported that During the COVID-19 Pandemic, Proning is Viewed as Standard Early Therapy for COVID-Associated ARDS, Rather than as a Salvage Therapy for Refractory Hypoxemia
        • With Experience with Proning, Clinicians Gained Increased Comfort with Proning and Now View Proning as a Low-Risk High-Benefit Intervention
        • Within the ICU, Adequate Trained Staffing, Increased Team Agreement Around Proning, and the Availability of Specific Equipment (to Limit Pressure Injuries, etc Facilitated Greater Proning Use
        • Hospital Level Supports Included Proning Teams, Centralized Educational Resources Specific to the Management of COVID-19 (Including Proning Recommendations), and an Electronic Medical Record Proning Order
        • Important Proning Implementation Processes Included Informal Dissemination of Best Practices Through On-the-Job Education and Team Interactions During Routine Bedside Care

      Clinical Efficacy-Patient Directed Proning

      • Non-Blinded Pragmatic Randomized Controlled Trial of Patient-Directed Proning in Non-Intubated Acute Respiratory Distress Syndrome (ARDS) Due to COVID-19 (Ann Am Thorac Soc, 2021) [MEDLINE]: n = 30
        • Adherence to Patient-Directed Proning was Very Low
        • Unexpectedly, Patient-Directed Proning Did Not Improve Oxygenation
          • There was No Change in pO2/FIO2 Ratio at 72 hrs (Prone -80.1; 95% CI: -138.8 to -21.4 vs Usual Care -18.2; 95% CI: -63.0 to 26.5, p = 0.077)

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

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

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

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

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

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

      British Thoracic Society 2019 Guidelines for the Management of Acute Respiratory Distress Syndrome (ARDS) (BMJ Open Respir Res, 2019) [MEDLINE]

      • The Routine Use of Prone Positioning is Not Recommended for All Patients with Acute Respiratory Distress Syndrome (ARDS)
        • The Use of Prone Positioning is Recommended for ≥12 hrs Per Day in Patients with Moderate/Severe Acute Respiratory Distress Syndrome (ARDS) (P/F Ratio <20 kPa) (Grade Recommendation: Strongly in Favor)

      Body Position -> Head of Bed at ≥30°

      Rationale

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

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

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

      Body Position -> Continuous Lateral Rotational/Kinetic Bed Therapy

      History

      • 1967: first implemented

      Rationale

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

      Administration

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

      Clinical Efficacy

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

      Inhaled Nitric Oxide (iNO) (see Nitric Oxide)

      Rationale

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

      Administration

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

      Adverse Effects

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

      Clinical Efficacy

      • Systematic Review and Meta-Analysis (BMJ, 2007) [MEDLINE]
        • Inhaled Nitric Oxide Results in Limited Improvement in Oxygenation in Patients with ALI/ARDS, But Confers No Mortality Benefit (and May Cause Harm)
      • Cochrane Database Systematic Review of iNO in ARDS (Cochrane Database Syst Rev, 2016) [MEDLINE]
        • Evidence is Insufficient to Support iNO in Any Category of Critically Ill Patients with Acute Hypoxemic Respiratory Failure
        • Inhaled Nitric Oxide Results in a Transient Improvement in Oxygenation, But Does Not Decrease the Mortality Rate and May Be Harmful, as it Seems to Increase Renal Impairment
      • US Database Study of Inhaled Nitric Oxide Use in the Treatment of Acute Respiratory Distress Syndrome (Chest, 2022) [MEDLINE]: n = 11,200 (303 hospitals from Premier Healthcare Database)
        • 56.8% of Patients Received Inhaled Nitric Oxide First, 42.1% of Patients Received Inhaled Epoprostenol First, and 1% of Patients Received Both Therapies on the Same Day
        • 34.3% of Hospitals Exclusively Used Inhaled Nitric Oxide and 38.9% of Hospitals Exclusively Used Inhaled Epoprostenol
        • No Differences were Found in the Likelihood of Successful Extubation Between Patients Admitted to Inhaled Nitric Oxide-Only Hospitals vs Those Admitted to Inhaled Epoprostenol-Only Hospitals (Subdistribution Hazard Ratio 0.97; 95% CI, 0.80-1.18)
        • Also, No Differences were Found in Total Hospital Costs or Death

      British Thoracic Society 2019 Guidelines for the Management of Acute Respiratory Distress Syndrome (ARDS) (BMJ Open Respir Res, 2019) [MEDLINE]

      • Use of Inhaled Nitric Oxide is Not Recommended in Patients with Acute Respiratory Distress Syndrome (ARDS) (Grade Recommendation: Weakly Against)

      Inhaled Prostacyclin (see Prostacyclin)

      Rationale

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

      Clinical Efficacy

      • Systematic Review and Meta-Analysis of Inhaled Prostaglandins in ARDS (Chest, 2015) [MEDLINE]
        • Inhaled Prostaglandins Improve Oxygenation and Decrease Pulmonary Artery Pressures and May Be Associated with Harm
        • Data are Limited Both in Terms of Methodologic Quality and Demonstration of Clinical Benefit
        • Use of Inhaled Prostaglandins in ARDS Needs Further Study
      • US Database Study of Inhaled Nitric Oxide Use in the Treatment of Acute Respiratory Distress Syndrome (Chest, 2022) [MEDLINE]: n = 11,200 (303 hospitals from Premier Healthcare Database)
        • 56.8% of Patients Received Inhaled Nitric Oxide First, 42.1% of Patients Received Inhaled Epoprostenol First, and 1% of Patients Received Both Therapies on the Same Day
        • 34.3% of Hospitals Exclusively Used Inhaled Nitric Oxide and 38.9% of Hospitals Exclusively Used Inhaled Epoprostenol
        • No Differences were Found in the Likelihood of Successful Extubation Between Patients Admitted to Inhaled Nitric Oxide-Only Hospitals vs Those Admitted to Inhaled Epoprostenol-Only Hospitals (Subdistribution Hazard Ratio 0.97; 95% CI, 0.80-1.18)
        • Also, No Differences were Found in Total Hospital Costs or Death

      Inhaled Iloprost (see Iloprost)

      Rationale

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

      Clinical Efficacy

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

      Avoidance of Systemically-Active Vasodilators

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

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

      Indications from NEJM, 2011 Review of ECMO in Acute Respiratory Distress Syndrome (ARDS) [MEDLINE]

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

      Absolute Contraindications

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

      Relative Contraindications (NEJM, 2011) [MEDLINE]

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

      Technique

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

      Clinical Efficacy

      • Early JAMA ECMO Trial (JAMA, 1979) [MEDLINE]
        • ECMO Had No Mortality Benefit
      • ECCO2R Trial (Am J Respir Crit Care Med, 1994) [MEDLINE]
        • ECCO2R Had No Mortality Benefit
      • ANZ ECMO Influenza Trial (JAMA, 2009) [MEDLINE]
        • ECMO Had No Mortality Benefit in Treatment of ARDS Associated with Influenza
      • CESAR Trial of ECMO in the UK (Lancet, 2009) [MEDLINE]
        • ECMO Decreased Mortality Rate/Severe Disability at 6 mo
        • However, the Study was Flawed by Not Defining the Usual Care Group and ECMO Patients Were Concentrated in One Center in the Trial
      • Systematic Review and Meta-Analysis of ECMO in Adult Patients with ARDS (J Crit Care, 2013) [MEDLINE]
        • ECMO Had an Unclear Hospital Mortality Benefit: further studies were recommended
      • Cochrane Review of VV-ECMO and VA-ECMO in Critically Ill Adults (Cochrane Database Syst Rev, 2015) [MEDLINE]
        • ECMO Had No 6-Month (or Prior to 6 Month) All-Cause Mortality Benefit: low-moderate quality of evidence from trials
      • Study of the Long-Term Survival and Quality of Life Following ECMO (Eur J Cardiothorac Surg, 2017) [MEDLINE]
        • Survival to Discharge was Higher in the Non-ECMO Group, as Compared to the ECMO Group: however, this difference was not statistically significant after propensity score matching
        • One Year Survival was 67% in the Non-ECMO Group vs 60% in the ECMO Group
        • Two Year Survival was 50% in the Non-ECMO Group vs 45% in the ECMO Group
      • Single-Center Swedish Retrospective Study of Outcomes After ECMO for ARDS Associated with Sepsis (Crit Care Med, 2017) [MEDLINE]
        • Approximately 64% of ECMO Patients Survived to Discharge
        • High Mortality Rate Within the First Few Months After Discharge
      • Systematic Review and Meta-Analysis of Mortality and Complications with the Use of Venovenous ECMO in ARDS (Ann Intensive Care, 2017) [MEDLINE]
        • Mortality Rate at Hospital Discharge was 37.7%
        • Factors Associated with Increased Hospital Mortality
          • Age
          • Year of Study
          • Mechanical Ventilation and Prone Positioning Days Prior to ECMO
      • Systematic Review of Venovenous ECMO for ARDS (J Crit Care, 2017) [MEDLINE]: n = 27 studies
        • Mortality Benefit of ECMO is Unclear
      • French EOLIA Trial of VV-ECMO in ARDS (NEJM, 2018) [MEDLINE]
        • In Very Severe ARDS, VV-ECMO Did Not Decrease the 60-Day Mortality Rate, as Compared to a Conventional Mechanical Ventilation Strategy Which Included VV-ECMO as a Rescue Therapy
      • Systematic Review and Meta-Analysis of ECMO in Adults with ARDS (Lancet Respir Med, 2019) [MEDLINE]: n = 773 (2 randomized controlled trials and 3 observational studies with matching techniques)
        • Compared with Conventional Mechanical Ventilation, the Use of Venovenous ECMO in Adults with Severe Acute Respiratory Distress Syndrome was Associated with a Decreased 60-Day Mortality Rate (73 [34%] of 214 vs 101 [47%] of 215; RR 0.73 [95% CI 0.58-0.92]; p=0.008; I2 0%; Moderate Grade Evidence)
        • However, Venovenous ECMO was Also Associated with a Moderate Risk of Major Hemorrhage (Occurred in 19% of Cases)
      • Randomized, Multicenter pRotective vEntilation with veno-venouS lung assisT (REST) Trial of ECCO2R and Low Tidal Ventilation in Acute Hypoxemic Respiratory Failure (JAMA, 2021) [MEDLINE]: n = 412
        • Study was Terminated Early (Due to Futility)
        • Extracorporeal Carbon Dioxide Removal (ECCO2R) to Facilitate Lower Tidal Volume Ventilation Did Not Impact the 90-Day Mortality Rate, as Compared to Conventional Low Tidal Volume Ventilation
      • SUPERNOVA Trial of ECCO2R and Low Tidal Ventilation: trial underway

      Clinical Efficacy-Mechanical Ventilation Settings During Venovenous Extracorporeal Membrane Oxygenation (VV-ECMO)

      • Based Only on Expert Opinion, Protective Mechanical Ventilation Strategies Should Be Used During VV-ECMO (Minerva Anestesiol, 2015) [MEDLINE]
        • Extracorporeal Life Support Organization (ELSO) Suggests Using Mechanical Ventilation “at Low Settings to Allow Lung Rest”
          • ELSO Also Suggests that “For Patients with Respiratory Failure, a Common Mistake is to Try to Recruit Lung Volume During the Acute Inflammatory Stage Early in ECMO”
        • French Consensus Conference on Extracorporeal Life Support for Patients with ARDS Recommends “Adjust Mechanical Ventilation to Minimize Plateau Pressure While Administering a Minimum PEEP” without Citing Specific Values
      • Prospective, Randomized Trial of Ultra-Protective Ventilation in Acute Respiratory Distress Syndrome (ARDS) Patients on Venovenous Extracorporeal Membrane Oxygenation (VV-ECMO) (Crit Care, 2022) [MEDLINE]: n = 39
        • Despite a Decrease in Mechanical Power with Ultra-Protective Ventilation (VT 1-2 mL/kg PBW, RR 5-10 breaths/min, Positive Expiratory Transpulmonary Pressure, and Proning x 16 hrs), This Strategy for 48 hrs Did Not Reduce Biotrauma (as Assessed by Alveolar Concentrations of Interleukin-1β, Interleukin-6/Interleukin-8/Surfactant Protein D and Blood Concentrations of Serum Advanced Glycation End Products/Angiopoietin), as Compared to Control

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

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

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

        British Thoracic Society 2019 Guidelines for the Management of Acute Respiratory Distress Syndrome (ARDS) (BMJ Open Respir Res, 2019) [MEDLINE]

        • The Routine Use of Venovenous Extracorporeal Membrane Oxygenation (VV-ECMO) is Not Recommended for All Patients with Acute Respiratory Distress Syndrome (ARDS) (Grade Recommendation: Weakly Against)
          • The Use of Venovenous Extracorporeal Membrane Oxygenation (VV-ECMO) with Lung Protective Mechanical Ventilation is Recommended in Selected Patients with Severe Acute Respiratory Distress Syndrome (ARDS) (Grade Recommendation: Weakly in Favor)
        • Use of ECCO2R in Established Acute Respiratory Distress Syndrome (ARDS) Should Be the Subject of a Suitably Powered Multicenter Randomized Controlled Trial with Long-Term Follow-Up and Economic Analysis (Grade Recommendation: Research Recommendation)

        Allogeneic Mesenchymal Stromal Cells

        Clinical Efficacy

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

        Tracheostomy (see Tracheostomy)

        • See Tracheostomy

        Early Mobilization/Rehabilitation

        Clinical Efficacy

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

        Nutritional Support

        Clinical Efficacy (General)

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

        Clinical Efficacy (During Prone Ventilation)

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

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

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

        Weaning

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

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

        Therapies with Unclear or No Clinical Benefit in Acute Respiratory Distress Syndrome (ARDS)

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

        Prognosis

        Reported Acute Respiratory Distress Syndrome (ARDS) Mortality Rates

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

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

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

        Predictors of Acute Respiratory Distress Syndrome (ARDS) Mortality

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

        Postoperative Acute Respiratory Distress Syndrome (ARDS) Mortality

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

        Sequelae of Acute Respiratory Distress Syndrome (ARDS)

        Exercise Limitation/Physical Dysfunction

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

        Decreased Quality of Life (QOL)

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

        Increased Costs and Use of Health Care Services

        • Canadian Clinical Trials Group 5-Year Study of ARDS Sequelae (NEJM, 2011) [MEDLINE]: ARDS survivors (n = 109) studied at at 3, 6, and 12 months and at 2, 3, 4, and 5 years after discharge from the intensive care unit
          • Increased Health Care Costs and Increased Use of Health Care Services May Persist for Up to 5 yrs After ARDS
          • Patients with More Coexisting Illnesses Incurred Greater 5-Year Costs
        • French Cluster Analysis Study of Patient Disposition and Outcome After Critical Illness (Chest, 2022) [MEDLINE]: n = 77,132 ICU ICU survivors who spent ≥2 nights in a French ICU during 2018 and were treated with invasive mechanical ventilation or vasopressors or inotropes (trauma, burn, organ transplant, stroke, and neurosurgical patients were excluded)
          • 89% of All Patients were Able to Return to Home
            • In the Year After Discharge, These Patients Spent a Median of 330 (Interquartile Range [IQR]: 283-349) Days at Home
          • At 1 Year
            • 77% of Patients were Still at Home
            • 17% Had Died
            • 51% Had Been Re-Hospitalized
            • 10% Required Further ICU Admission
          • 48% of Patients Required Rehabilitation Facilities and 5.7% Required Hospital at Home
          • Three Clusters of Patients with Distinct Post-ICU Trajectories were Identified
            • Patients in Cluster 1 (68% of Total) Survived and Spent Most of the Year at Home (338 [323-354] Days)
            • Patients in Cluster 2 (18%) Had More Complex Trajectories, But Most Could Return Home (91%), Spending 242 (174-277) Days at Home
            • Patients in Cluster 3 (14%) Died with Only 37% Returning Home for 45 (15-90) Days

        Neuropsychologic Dysfunction

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

        References

        Treatment

        General

        Treatment of Fever (see Fever)

        Bronchodilators

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

        Corticosteroids (see Corticosteroids)

        Supplemental Oxygen Therapy (see Oxygen)

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

        Fluid Management

        Respiratory Rate

        Low Tidal Volume Ventilation

        Positive End-Expiratory Pressure (PEEP)

        Esophageal Pressure-Guided Mechanical Ventilation

        Recruitment Maneuvers

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

        Pressure Control Ventilation

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

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

        Partial Liquid Ventilation

        Body Position -> Proning

        Body Position -> Head of Bed at 30°

        Body Position -> Continuous Lateral Rotational/Kinetic Bed Therapy

        Inhaled Nitric Oxide (iNO) (see Nitric Oxide)

        Inhaled Prostacyclin (see Prostacyclin)

        Inhaled Iloprost (see Iloprost)

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

        Allogeneic Mesenchymal Stromal Cells

        Tracheostomy (see Tracheostomy)

        Early Mobilization/Rehabilitation

        Nutritional Support

        Activated Protein C

        Macrolides (see Macrolides)

        Prognosis/Sequelae