Acute Respiratory Distress Syndrome (ARDS)-Part 3


Treatment

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

Treatment of Fever (see Fever)

Rationale

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

Clinical Efficacy

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

Bronchodilators

Agents

Clinical Efficacy

  • Beta-Agonist Lung Injury Trial (BALTI) and Beta-Agonist Lung Injury Trial-2 (BALTI-2) Trials in Acute Respiratory Distress Syndrome (ARDS) (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 Acute Respiratory Distress Syndrome (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 Respiratory Distress Syndrome (ARDS)
      • Therefore, the Routine Use of β2-Agonist Therapy in Mechanically Ventilated Patients with Acute Respiratory Distress Syndrome (ARDS) is Not Recommended

Recommendations for Patients with Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (ARDS) (Strong Recommendation, Moderate Quality of Evidence)

Supplemental Oxygen Therapy (see Oxygen)

Clinical Efficacy

  • Randomized Trial of Conservative Oxygen Strategy in Mechanically-Ventilated Patients (Am J Respir Crit Care Med, 2016) [MEDLINE]
    • Conservative Oxygen Strategy (SpO 88-92%) Did Not Impact the ICU or 90-Day Mortality Rate or Risk of Organ Dysfunction, as Compared to Liberal Oxygen Strategy (SpO2 ≥96%)
  • Italian Oxygen-ICU Trial of Conventional Oxygen Strategy (pO2 Up to 150 mm Hg or SaO2 97-100%) vs Conservative Oxygen Strategy (pO2 70-100 or SaO2 94-98%) in a General ICU Population (Stay of ≥72 hrs) (JAMA, 2016) [MEDLINE]
    • Trial Had Unplanned, Early Termination
    • Conservative Oxygen Strategy Decreased the Mortality Rate, as Compared to Conventional Oxygen Strategy
  • French HYPERS2S Trial of Hyperoxia and Hypertonic Saline in Septic Shock (Lancet Respir Med, 2017) [MEDLINE]
    • Trial Stopped Prematurely for Safety Reasons
    • Setting FiO2 to 100% to Induce Arterial Hyperoxia Might Increase the Mortality Rate in Septic Shock
    • Hypertonic (3%) Saline Resuscitation Did Not Decrease the Mortality Rate in Septic Shock
  • Improving Oxygen Therapy in Acute-illness (IOTA) Systematic Review and Meta-Analysis of Conservative vs Liberal Oxygen Strategy in Critically Ill Patients (Lancet, 2018) [MEDLINE]: n = 25 trials (in patients with sepsis, critical illness, stroke, trauma, myocardial infarction, cardiac arrest, and emergency surgery)
    • In Acutely Ill Adults, Liberal Oxygen Therapy Strategy (Median SaO2 96%, Range 94-99%) Increases the 30-Day (and Longest Follow-Up) Mortality Rate, as Compared to a Conservative Oxygen Therapy Strategy (Relative Risk at 30 Days was 1.21, 95% CI 1.03-1.43)
      • Supplemental Oxygen Might Become Unfavorable with SaO2 >94-96%
  • Post Hoc Analysis of HYPERS2S Trial Data (Ann Intensive Care, 2018) [MEDLINE]
    • Hyperoxia May Be Associated with a Increased Mortality Rate in Patients with Septic Shock Using the Sepsis-3 Criteria (with Serum Lactate > 2 mmol/L), But Not in Patients with Hypotension Alone
    • In Patients with Serum Lactate ≤2 mmol/L, Hyperoxia Had No Effect on the Mortality Rate, Nor on Other Outcomes
  • Observational Study of Hyperoxia in the Emergency Department in Patients with Acute Respiratory Failure (Crit Care, 2018) [MEDLINE]: n = 688
    • Emergency Department Exposure to Hyperoxia is Common and Associated with Increased Mortality in Mechanically Ventilated Patients Achieving Normoxia After Admission
    • This Suggests that Hyperoxia in the Immediate Post-Intubation Period Could Be Particularly Injurious and Targeting Normoxia from Initiation of Mechanical Ventilation May Improve Outcome
  • Australian/New Zealand ICU-ROX Trial of Conservative Oxygen Strategy in Mechanically-Ventilated Patients in the Intensive Care Unit (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 Acute Respiratory Distress Syndrome (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 Intensive Care Unit (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

Recommendations (European Society of Intensive Care Medicine/ESCIM Taskforce on Acute Respiratory Distress Syndrome/ARDS Guidelines, 2023) (Intensive Care Med, 2023)[MEDLINE]

  • Non‐Mechanically Ventilated Patients with Acute Hypoxemic Respiratory Failure (Not Due to Cardiogenic Pulmonary Edema or Acute Chronic Obstructive Pulmonary Disease (COPD) Exacerbation) Should Receive Receive High-Flow Nasal Cannula Oxygen vs Conventional Oxygen Therapy to Reduce the Risk of Intubation (Strong Recommendation; Moderate Level of Evidence in Favor)
    • No Recommendation Regarding Use of High-Flow Nasal Cannula Oxygen Over Conventional Oxygen Therapy to Reduce the Mortality Rate (No Recommendation; High Level of Evidence of No Effect)
    • Recommendation Also Applies to Acute Hypoxemic Respiratory Failure from COVID‐19 (Strong Recommendation; Low Level of Evidence in Favor for Intubation and No Recommendation; Moderate Level of Evidence of No Effect for Mortality, for Indirectness)
  • No Recommendation Regarding the Use of High-Flow Nasal Cannula Oxygen vs Noninvasive Positive-Pressure Ventilation (NIPPV) to Reduce Intubation Rate or Mortality Rate in the Treatment of Unselected Patients with Acute Hypoxemic Respiratory Failure (Not Due Cardiogenic Pulmonary Edema or Acute Chronic Obstructive Pulmonary Disease (COPD) Exacerbation) (No Recommendation; Moderate Level of Evidence for Mortality, Low Level of Evidence for Intubation, Not in Favor Nor Against)
  • Noninvasive Positive-Pressure Ventilation (NIPPV) Can Be Considered Instead of High-Flow Nasal Cannula Oxygen for the Treatment of Acute Hypoxemic Respiratory Failure Due to COVID‐19 to Reduce the Risk of Intubation (Weak Recommendation, High Level of Evidence), But No Recommendation Can Be Made for Whether Noninvasive Positive-Pressure Ventilation (NIPPV) Can Decrease Mortality, as Compared to High-Flow Nasal Cannula Oxygen in Patients with COVID‐19 (No Recommendation; High Level of Evidence of No Effect)

Noninvasive Positive-Pressure Ventilation (NIPPV) (see Noninvasive Positive-Pressure Ventilation)

Clinical Efficacy-General

  • Systematic Review and Meta-Analysis of Trials Using NIPPV for Prevention or Treatment of Acute Respiratory Failure or as a Tool to Facilitate Early Extubation (Crit Care Med, 2015) [MEDLINE]: n = 78 trials
    • Overall (in All Populations), NIPPV Decreased the Mortality Rate (at Longest F/U) with Relative Risk 0.73 (95% CI: 0.66–0.81) (p<0.001): number needed to treat = 19
    • Acute Respiratory Failure (Mixed Etiologies)
      • NIPPV Decreased Mortality Rate (at Longest F/U) with Relative Risk 0.66 (95% CI: 0.54–0.80) (p<0.001)
  • Study of Tidal Volume on NIPPV in De Novo Acute Hypoxemic Respiratory Failure (Crit Care Med, 2016) [MEDLINE]: n = 62 (82% of cases were due to pneumonia)
    • Rationale: a low-moderate expired tidal volume can be difficult to achieve during NIPPV for de novo acute hypoxemic respiratory failure (i.e. respiratory failure not due to chronic lung disease or heart failure)
    • A Low Exhaled Tidal Volume is Almost Impossible to Achieve in Patients Receiving NIPPV for De Novo Acute Hypoxemic Respiratory Failure
    • High Exhaled Tidal Volume is Independently Associated with NIPPV Failure
      • In Patients with Moderate-Severe Hypoxemia, Exhaled Tidal Volume >9.5 mL/kg Predicted Body Weight Accurately Predicted NIPPV Failure
  • Trial Comparing Helmet vs Face Mask NIPPV in ARDS (JAMA, 2016) [MEDLINE]: single-center randomized, controlled trial
    • Helmet NIPPV Decreased the Intubation Rate and 90-Day Mortality in ARDS, as Compared to Face Mask NIPPV
    • Helmet NIPPV Increased Ventilator-Free Days, as Compared to Face Mask NIPPV
  • NIPPV is Used Commonly in the Treatment of Patients with Respiratory Failure Due to ARDS
    • Analysis of NIPPV Use in Patients with ARDS with Data from the LUNG SAFE Study (Am J Respir Crit Care Med, 2017) [MEDLINE]
      • NIPPV was Used in 15% of ARDS Cases
      • NIPPV was Associated with a Higher ICU Mortality Rate in ARDS Patients with a pO2/FiO2 Ratio <150 mm Hg
  • Systematic Review and Meta-Analysis Comparing High-Flow Nasal Cannula vs Standard Oxygen vs NIPPV in Acute Respiratory Failure (Chest, 2017) [MEDLINE]
    • High-Flow Nasal Cannula and NIPPV Comparably Decreased the Intubation Rate in Acute Respiratory Failure, as Compared to Standard Oxygen Therapy in Acute Respiratory Failure
  • Systematic Review and Meta-Analysis of NIPPV in Acute Hypoxemic (Non-Hypercapnic) Respiratory Failure (Crit Care Med, 2017) [MEDLINE]: analysis excluded chronic obstructive pulmonary disease exacerbation and cardiogenic pulmonary edema patients
    • NIPPV Decreased Intubation Rate and Mortality Rate in Acute Hypoxemia (Non-Hypercapnic) Respiratory Failure
    • There was InSufficient Evidence to Recommend Bilevel Positive Airway Pressure or Helmet Due to the Limited Number of Trials Available
  • Meta-Analysis Examining High-Flow Nasal Cannula in Acute Hypoxemic Respiratory Failure (CMAJ, 2017) [MEDLINE]
    • The Intubation Rate with High-Flow Nasal Cannula Oxygen was Lower than the Rate with Conventional Oxygen Therapy and Similar to the Rate with NIPPV in Patients with Acute Hypoxemic Respiratory Failure
  • Systematic Review and Meta-Analysis of NIPPV in the Treatment of Hypoxemic Respiratory Failure (J Crit Care, 2019) [MEDLINE]: n = 9 studies
    • NIPPV Decreased Intubation Rate in Immunocompromised Patients (Cancer/Transplant) with Hypoxemic Respiratory Failure
    • NIPPV Decreased Intubation Rate in Acute Pulmonary Edema with Hypoxemic Respiratory Failure
    • NIPPV Decreased Intubation Rate in Community-Acquired Pneumonia (CAP) with Hypoxemic Respiratory Failure
    • Effect of NIPPV in Hypoxemic Respiratory Failure Due to Other Etiologies was Unclear
  • National Cohort Study of Noninvasive Positive-Pressure Ventilation in Acute Respiratory Distress Syndrome (ARDS) (Crit Care Res Pract, 2019) [MEDLINE]
    • NIPPV Success Group Had the Lowest Mortality Rate (4.9% [3.8-6.4]) and the Shortest Length of Stay (7 Days [6.6-7.5])
    • NIPPV Failure Rate was 21%
    • Sepsis, Pneumonia, and Chronic Liver Disease were Associated with Higher Odds of NIPPV Failure (Adjusted Odds Ratio: 4.47, 2.65, and 2.23, Respectively)

Recommendations (European Society of Intensive Care Medicine/ESCIM Taskforce on Acute Respiratory Distress Syndrome/ARDS Guidelines, 2023) (Intensive Care Med, 2023)[MEDLINE]

  • No Recommendation Regarding the Use of High-Flow Nasal Cannula Oxygen vs Continuous Positive-Pressure (CPAP)/Noninvasive Positive-Pressure Ventilation (NIPPV) to Reduce Intubation Rate or Mortality Rate in the Treatment of Unselected Patients with Acute Hypoxemic Respiratory Failure (Not Due Cardiogenic Pulmonary Edema or Acute Chronic Obstructive Pulmonary Disease (COPD) Exacerbation) (No Recommendation; Moderate Level of Evidence for Mortality, Low Level of Evidence for Intubation, Not in Favor Nor Against)
  • Continuous Positive-Pressure (CPAP)/Noninvasive Positive-Pressure Ventilation (NIPPV) Can Be Considered Instead of High-Flow Nasal Cannula Oxygen for the Treatment of Acute Hypoxemic Respiratory Failure Due to COVID‐19 to Reduce the Risk of Intubation (Weak Recommendation, High Level of Evidence), But No Recommendation Can Be Made for Whether Noninvasive Positive-Pressure Ventilation (NIPPV) Can Decrease Mortality, as Compared to High-Flow Nasal Cannula Oxygen in Patients with COVID‐19 (No Recommendation; High Level of Evidence of No Effect)
  • No Recommendation Regarding the Use Continuous Positive-Pressure (CPAP)/Noninvasive Positive-Pressure Ventilation (NIPPV) vs Conventional Oxygen Therapy, for the Treatment of Acute Hypoxemic Respiratory Failure (Not Related to Cardiogenic Pulmonary Edema or Acute Chronic Obstructive Pulmonary Disease (COPD) Exacerbation) to Reduce Mortality or to Prevent Intubation (No Recommendation; High Level of Evidence for Mortality, Moderate Level of Evidence for Intubation)
  • Continuous Positive-Pressure (CPAP) Should Be Considered Over Conventional Oxygen Therapy to Reduce the Risk of Intubation in Patients with Acute Hypoxemic Respiratory Failure Due to COVID‐19 (Weak Recommendation; Low Level of Evidence in Favor)
    • In this Population, No Recommendation Regarding the Use of Noninvasive Positive-Pressure Ventilation (NIPPV) Over Conventional Oxygen Therapy to Reduce the Mortality Rate (No Recommendation; Moderate Level of Evidence of No Effect)
  • No Recommendation Regarding the Use of Helmet Interface for Continuous Positive-Pressure (CPAP)/Noninvasive Positive-Pressure Ventilation (NIPPV) vs Face Mask to Prevent Intubation or Reduce the Mortality Rate in Patients with Acute Hypoxemic Respiratory Failure (No Recommendation; Very Low Level of Evidence in Favor)
  • No Recommendation Regarding the Use of Noninvasive Positive-Pressure Ventilation (NIPPV) vs Continuous Positive-Pressure (CPAP) for the Treatment of Acute Hypoxemic Respiratory Failure (No Recommendation; No Evidence)

Corticosteroids (see Corticosteroids)

Corticosteroid Dosing Regimens Used in Pre-COVID Trials (Am J Respir Crit Care Med, 2023) [MEDLINE]

  • Methylprednisolone (see Methylprednisolone)
    • Methylprednisolone 2 mg/kg/Day x 14 Days, Then 1 mg/kg x 7 Days, then 0.25 mg/kg x 3 Days, then 0.125 mg/kg x 2 Days
      • Duration Up to 32 Days
    • Methylprednisolone 2 mg/kg Predicted Body Weight x 1, Then 0.5 mg/kg Predicted Body Weight q6hrs x 14 Days, then 0.5 mg/kg PBW Q12H x 7 Days
      • Duration Up to 21 Days
    • Methylprednisolone 1 mg/kg/Day x 1 Loading Dose, Then 1 mg/kg x 14 Days, Then 0.5 mg/kg x 7 Days, Then 0.25 mg/kg x 3 Days, Then 0.125 mg/kg x 3 Days
      • Duration Up to 14 Days
    • 1 mg/kg/Day x 1 Loading Dose, Then 1 mg/kg x 14 Days, Then 0.5 mg/kg x 7 Days, Then 0.25 mg/kg x 3 Days, Then 0.125 mg/kg x 3 Days
      • Duration Up to 14 Days
    • Methylprednisolone 120 mg/Day
      • Duration Up to 7 Days
    • Methylprednisolone 1-2 mg/Day
      • Duration Up to 3-14 Days
  • Hydrocortisone (see Hydrocortisone)
    • Hydrocortisone 100 mg TID
      • Duration Up to 7 Days
    • Hydrocortisone 50 mg q6hrs
      • Duration Up to 7 Days
    • Hydrocortisone 50 mg q6hrs and Fludrocortisone 50 mcg/Day
      • Duration Up to 7 Days
  • Dexamethasone (see Dexamethasone)
    • Dexamethasone 20 mg/day x 5 Days, then 10 mg/Day x 5 Days
      • Duration Up to 10 Days

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 Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (ARDS) May Increase the Risk of Death
    • Corticosteroids Facilitated Ventilator Withdrawal in Acute Respiratory Distress Syndrome (ARDS), But Increased Reintubation Rates
  • Meta-Analysis of Corticosteroids in Acute Respiratory Distress Syndrome (ARDS) (Respirology, 2007) [MEDLINE]
    • Corticosteroids Had No Benefit in Either Early or Late Acute Respiratory Distress Syndrome (ARDS)
  • Meta-Analysis of Corticosteroids in Acute Respiratory Distress Syndrome (ARDS) (BMJ, 2008) [MEDLINE]
    • Corticosteroids Had Unclear Benefit in Acute Respiratory Distress Syndrome (ARDS)
    • Preventative Corticosteroids Possibly Increased the Risk of Acute Respiratory Distress Syndrome (ARDS) in Critically Ill Patients
  • Meta-Analysis of Glucocorticoids in Acute Respiratory Distress Syndrome (ARDS) (Intensive Care Med, 2008) [MEDLINE]
    • Prolonged Glucocorticoids Improved Patient-Centered Outcome Variables and Had a Survival Benefit When Initiated Before Day 14 of Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (ARDS) and Before Day 14 for Patients with Unresolving ARDS (Weak 2b Recommendation, Moderate Quality Evidence)
  • Systematic Review and Meta-Analysis of Corticosteroids in Acute Respiratory Distress Syndrome (ARDS) (Crit Care Med, 2009) [MEDLINE]
    • Low-Dose Corticosteroids Were Associated with Improved Mortality and Morbidity Outcomes Without Increased Adverse Reactions in Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (ARDS)
  • Study of the Role of Open Lung Biopsy in Unresolving Acute Respiratory Distress Syndrome (ARDS) (Intensive Care Med, 2015) [MEDLINE]
    • Diffuse Alveolar Damage is Present in Most Patients with Unresolving Acute Respiratory Distress Syndrome (ARDS) and its Frequency is the Same Regardless of the Stage of Acute Respiratory Distress Syndrome (ARDS) (Mild, Moderate, Severe): on this basis, authors concluded that corticosteroid therapy is not recommended
  • Meta-Analysis of Corticosteroids in Acute Respiratory Distress Syndrome (ARDS) (Intensive Care Med, 2016) [MEDLINE]
    • Prolonged Methylprednisolone Accelerated the Resolution of Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (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
  • Pooled Analysis of the Effect of Corticosteroids in Acute Respiratory Distress Syndrome (ARDS) (Am J Respir Crit Care Med, 2023) [MEDLINE]: n = 2,790 (19 randomized controlled trials)
    • Corticosteroids Probably Decrease Mortality Rate (n = 17 Studies; Relative Risk 0.84; 95% CI: 0.73–0.96; Moderate Certainty)
    • Corticosteroids May Decrease Duration of Mechanical Ventilation (n = 9 Studies; Mean Difference 4 Days Less; 95% CI: 25.5 to 22.5; Low Certainty)
    • Corticosteroids May Decrease Hospital Length of Stay (n = 4 Studies; Mean Difference 8 Days Shorter; 95% CI: 213 to 23; Low Certainty)
    • Effect of Corticosteroids on the Intensive Care Unit (ICU) Length of Length is Uncertain (n = 4 Studies; Mean Difference 0.8 Days Shorter; 95% CI: 24.1 to 15.7; Very Low Certainty)
    • Safety Outcomes
      • Corticosteroids Probably increase the Risk of Serious Hyperglycemia (n = 6 Studies; Relative Risk 1.11; 95% CI: 1.01–1.23; Moderate Certainty)
      • Corticosteroids May Increase the Risk of Gastrointestinal Bleeding (n = 5 Studies; Relative Risk 1.20; 95% CI: 0.43–3.34; Low Certainty)
      • Corticosteroids Have an Uncertain Effect on Neuromuscular Weakness (n = 2 Studies; Relative Risk 0.85; 95% CI: 0.62–1.18; Very Low Certainty)

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 Multidisciplinary, Multispecialty 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 (ARDS)
  • 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)

American Thoracic Society (ATS) 2023 Clinical Practice Guideline for Acute Respiratory Distress Syndrome (ARDS) (Am J Respir Crit Care Med, 2023) [MEDLINE]

  • Corticosteroids are Suggested for Patients with Acute Respiratory Distress Syndrome (ARDS) (Conditional Recommendation, Moderate Certainty of Evidence)
    • Corticosteroids May Be Associated with Increased Risk of Harm When Initiated After >14 days of Mechanical Ventilation
    • Optimal Type and Regimen of Corticosteroid is Unknown
    • Consider Discontinuation of Corticosteroid at Time of Extubation

Society of Critical Care Medicine (SCCM) Recommendations (2024 Focused Update: Guidelines on Use of Corticosteroids in Sepsis, Acute Respiratory Distress Syndrome (ARDS), and Community-Acquired Pneumonia) (Crit Care Med, 2024) [MEDLINE]

  • Administration of Corticosteroids is Suggested for Adult Hospitalized Patients with Acute Respiratory Distress Syndrome (ARDS) (Conditional Recommendation, Moderate Certainty Evidence)
    • In Prior 2017 Recommendations
      • Administration of Corticosteroids is Suggested for Patients with Early Moderate-Severe Acute Respiratory Distress Syndrome (ARDS) (pO2/FIO2 of <200 and within 14 Days of Onset) (Conditional Recommendation, Moderate Quality of Evidence)

Fluid Management

Rationale

  • Decreased Lung Water Results in Improved Oxygenation

Contraindications to Diuresis of the Acute Respiratory Distress Syndrome (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 (ARDS) (Intensive Care Med, 2002) [MEDLINE]
    • Median PCWP was 16.6 mm Hg in Acute Respiratory Distress Syndrome (ARDS) Patients
    • Patients Who Met Standard Criteria for Acute Respiratory Distress Syndrome (ARDS) were More Likely to Have a High PCWP
    • PCWP >18 mm Hg was a Strong Predictor of Mortality in Acute Respiratory Distress Syndrome (ARDS) Patients (After Correction for Baseline Differences)
  • Study of Swan-Ganz Catheter to Guide Treatment of Acute Respiratory Distress Syndrome (ARDS) (NEJM, 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 Acute Respiratory Distress Syndrome (ARDS) (JAMA, 2003) [MEDLINE]
    • Early Use of Swan-Ganz Catheter Did Not Improve Morbidity or Mortality in Patients with Shock and/or Acute Respiratory Distress Syndrome (ARDS)

Clinical Efficacy-Fluid Management Strategy

  • Study of Albumin and Lasix for Fluid Removal in Acute Respiratory Distress Syndrome (ARDS) (Crit Care Med, 2002) [MEDLINE]
    • Albumin and Furosemide Therapy Improved Fluid Balance, Oxygenation, and Hemodynamics in Hypoproteinemic Patients with Acute Respiratory Distress Syndrome (ARDS)
  • Study of Albumin and Lasix for Fluid Removal in Acute Respiratory Distress Syndrome (ARDS) (Crit Care Med, 2005) [MEDLINE]
    • The Addition of Albumin to Furosemide Therapy in Hypoproteinemic Patients with Acute Respiratory Distress Syndrome (ARDS) Significantly Improved 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 Acute Respiratory Distress Syndrome (ARDS) (NEJM, 2006) [MEDLINE]: randomized trial (n = 1000) in patients with acute lung injury, comparing conservative (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 (ARDS) 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 Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (ARDS) (Strong Recommendation, High Quality of Evidence)

British Thoracic Society (BTS) 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)

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)

Rationale

  • Mechanism of Benefit is Unclear, But Likely Involves the Following
    • Decreases Ventilator-Induced Lung Injury Via a Reduction in Patient–Ventilator Dyssynchrony
    • Decreases Oxygen Consumption
    • Decreases Pulmonary Inflammation
    • Decreases Alveolar Fluid

Epidemiology

  • Prevalence of Use of Neuromuscular Junction Antagonists
    • Approximately 25-55% of Acute Respiratory Distress Syndrome (ARDS) Patients Enrolled in Multicenter, Randomized Controlled Trials Receive Neuromuscular Blockers as Part of Their Therapy

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)
      • Concomitant Corticosteroids Increase the Risk of Prolonged Paralysis

Clinical Efficacy

  • French RCT Studying Effect of Neuromuscular Junction Blockade on Oxygenation in Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (ARDS) (Crit Care Med, 2006) [MEDLINE]
    • Early Use of Neuromuscular Junction Blockade Decreased the Proinflammatory Response (Mediated by Various Cytokines) Associated with Acute Respiratory Distress Syndrome (ARDS) and Mechanical Ventilation
  • French Acute Respiratory Distress Syndrome (ARDS) et Curarisation Systematique (ACURASYS) Study (NEJM, 2010) [MEDLINE]: multicenter, double-blind trial (n = 340) of ICU patients with acute respiratory Distress syndrome (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 Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (ARDS) (NEJM, 2019) [MEDLINE]: n= 1,006
    • Trial was Stopped Prematurely for Lack of Efficacy
    • In Moderate-Severe Acute Respiratory Distress Syndrome (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%)
  • Pooled Analysis of Neuromuscular Junction Antagonists in Acute Respiratory Distress Syndrome (ARDS) (Am J Respir Crit Care Med, 2023) [MEDLINE]
    • Cisatracurium was Used in the Two Largest Randomized Controlled Trials and May Be Associated with Pleiotropic Effects (Decrease in Inflammatory Cytokines), Suggesting that it May Be a Preferable Neuromuscular Junction Antagonist for Patients with Acute Respiratory Distress Syndrome (ARDS)
    • Neuromuscular Junction Antagonists Decreased the Mortality Rate for Patients with Moderate-Severe Acute Respiratory Distress Syndrome (ARDS), as Compared to Those Who Did Not Receive Neuromuscular Junction Antagonists (Relative Risk 0.74; 95% CI: 0.56–0.98; Low Certainty)
      • However, Concerns Related to Inconsistency and Individual Study Risk of Bias Led to a Low Certainty of Evidence
    • Subgroup Analyses Demonstrated a Decrease in the Mortality Rate for Patients Receiving Neuromuscular Junction Antagonists, as Compared with Deep Sedation (n = 3 Studies, 431 Patients; Relative Risk 0.72; 95% CI: 0.58–0.91), an Effect Not Observed in the Single Randomized Controlled Trial Which Compared Neuromuscular Junction Antagonists vs Light Sedation (Relative Risk 0.99; 95% CI: 0.86–1.15)
    • Neuromuscular Junction Antagonists Decreased the Incidence of Barotrauma (n = 4 Studies, 1,437 Patients; Relative Risk 0.55; 95% CI: 0.35–0.85; Moderate Certainty)
    • Neuromuscular Junction Antagonists Increased in Ventilator-Free Days (n = 5 Studies; Mean Difference 0.89 Days More; 95% CI: 0.38 Fewer to 2.18 More; Low Certainty)
    • Neuromuscular Junction Antagonists Increased the Rates of ICU-Acquired Weakness (n = 4 Studies, 885 Patients; Relative Risk 1.16; 95% CI: 0.98–1.37; Moderate Certainty)

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 Acute Respiratory Distress Syndrome (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)

American Thoracic Society (ATS) 2023 Clinical Practice Guideline for Acute Respiratory Distress Syndrome (ARDS) (Am J Respir Crit Care Med, 2023) [MEDLINE]

  • Neuromuscular Blockade is Suggested in Patients with Early Severe Acute Respiratory Distress Syndrome (ARDS) (<48 hrs Since ARDS Onset and pO2/FIO2 Ratio <100 mm Hg) (Conditional Recommendation, Low Certainty)
    • There is an Unknown and Potentially Increased Risk of Neuromuscular Weakness with Use for >48 hrs
    • Use with Caution in Patients with Preexisting Neuromuscular Disease

Recommendations (European Society of Intensive Care Medicine/ESCIM Taskforce on Acute Respiratory Distress Syndrome/ARDS Guidelines, 2023) (Intensive Care Med, 2023)[MEDLINE]

  • Routine Use of Continuous Infusions of Neuromuscular Junction Antagonists is Not Recommended to Reduce the Mortality Rate in Patients with Moderate‐to‐Severe Acute Respiratory Distress Syndrome (ARDS) Not Due to COVID‐19 (Strong Recommendation, Moderate Level of Evidence)
    • No Recommendation Regarding the Routine Use of Continuous Infusions of Neuromuscular Junction Antagonists to Reduce the Mortality in Rate in Patients with Moderate-Severe Acute Respiratory Distress Syndrome (ARDS) Due to COVID‐19 (No Recommendation; No Evidence)

Respiratory Rate (RR)

Clinical Efficacy

  • Small Study of Respiratory Rate Management in Patients with Acute Respiratory Failure (Crit Care Med, 2002) [MEDLINE]: n = 14
    • High Respiratory Rates in Patients Mechanically-Ventilated for Acute Respiratory Failure Can Produce Dynamic Hyperinflation (with Development of Auto-PEEP), Increase the Dead Space/Tidal Volume Ratio, and Impair Right Ventricular Ejection with a Decrease in the Cardiac Output
  • Study of pCO2 Management During Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (ARDS) Received 8 mL/kg PBW Tidal Volumes, Low PEEP, and Prone Ventilation
      • Patients with Non-Focal Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome) (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 Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (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)

Recommendations (European Society of Intensive Care Medicine/ESCIM Taskforce on Acute Respiratory Distress Syndrome/ARDS Guidelines, 2023) (Intensive Care Med, 2023)[MEDLINE]

  • Use of Low Tidal Volume Ventilation Strategies (i.e. 4–8 mL/kg Predicted Body Weight) is Recommended vs Larger Tidal Volume to Reduce Mortality in Patients with Acute Respiratory Distress Syndrome (ARDS) Not Due to COVID‐19 (Strong Recommendation Based on Expert Opinion Despite Lack of Statistical Significance; High Level of Evidence)
    • Recommendation Applies Also to Acute Respiratory Distress Syndrome (ARDS) from COVID‐19 (Strong Recommendation; Moderate Level of Evidence for Indirectness)

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 Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (ARDS) (JAMA, 2010) [MEDLINE]
    • Higher PEEP was Not Associated with Improved Hospital Survival, as Compared to Lower PEEP
    • However, in the Subset of Acute Respiratory Distress Syndrome (ARDS) Patients with pO2/FiO2 Ratio <200 mm Hg, PEEP Improved Survival
  • Trial Examining Predictors of Ventilator-Induced Lung Injury in Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (ARDS) (JAMA, 2019) [MEDLINE]: n = 200 (14 hospitals in North America)
    • In Moderate-Severe Acute Respiratory Distress Syndrome (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
  • Study of Lung Response to Higher PEEP Levels in COVID-Associated ARDS (Ventilated in Supine Position, Studied within 3 Days of Intubation) (Chest, 2022) [MEDLINE]: n = 40
    • Definitions (Using Whole Lung Static CT)
      • Recruitment was Defined as a Decrease in Volume of Non-Aerated Lung (Density Above -100 Hounsfield Units)
      • Hyperinflation was Defined as an Increase in Volume of Over-Aerated Lung (Density Below -900 Hounsfield Units)
    • From PEEP 5-15 cm H2O, Oxygenation Improved in 90% of Patients
      • Compliance Improved Only in 28% of Patients
      • pCO2 Improved in Only in 35% of Patients
    • From PEEP 5-45 cm H2O, Recruitment was 351 mL (Range: 161-462 mL) and Hyperinflation was 465 mL (Range: 220-681 mL)
    • From PEEP 5-15 cm H2O, Recruitment was 168 mL (Range: 110-202 mL) and Hyperinflation was 121 mL (Range: 63-270 mL)
    • Hyperinflation Variably Developed in All Patients and Exceeded Recruitment in More than Half of the Patients
  • Systematic Review and Network Meta-Analysis of PEEP in Acute Respiratory Distress Syndrome (ARDS) (Am J Respir Crit Care Med, 2022) [MEDLINE]: n = 2,299 (3 randomized controlled trials)
    • Higher PEEP Improved Survival, as Compared to Lower PEEP in Patients with Moderate-Severe Acute Respiratory Distress Syndrome (ARDS) (Relative Risk 0.90; 05% CI: 0.81–1.00; P = 0.049)
    • Higher PEEP Possibly Increased the Mortality Rate in Patients with Mild Acute Respiratory Distress Syndrome (ARDS) (Adjusted Relative Risk 1.29; 95% CI: 0.91–1.83; P = 0.02)

General Recommendations

  • PEEP of 0 cm H2O is Generally is Accepted to Be Harmful in Acute Respiratory Distress Syndrome (ARDS)
  • PEEP of 8-15 cm H2O is Appropriate in Most Patients with Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (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)

American Thoracic Society (ATS) 2023 Clinical Practice Guideline for Acute Respiratory Distress Syndrome (ARDS) (Am J Respir Crit Care Med, 2023) [MEDLINE]

  • Higher PEEP without Lung Recruitment Maneuvers is Suggested Rather than Lower PEEP in Patients with Moderate-Severe Acute Respiratory Distress Syndrome (ARDS) (Conditional Recommendation, Low-Moderate Certainty)
    • Conditional Recommendation is Given Because of the High Level of Heterogeneity Among Higher PEEP Strategies in the Included Randomized Controlled Trials
  • Prolonged (PEEP ≥35 cm H2O for >60 sec) Lung Recruitment Maneuvers are Not Recommended in Patients with Moderate-Severe Acute Respiratory Distress Syndrome (ARDS) (Strong Recommendation, Moderate Certainty)
    • High Potential for Harm is Presumably Due to Serious Adverse Hemodynamic Effects

Recommendations (European Society of Intensive Care Medicine/ESCIM Taskforce on Acute Respiratory Distress Syndrome/ARDS Guidelines, 2023) (Intensive Care Med, 2023)[MEDLINE]

  • No Recommendation Regarding Routine PEEP Titration with a Higher PEEP/FIO2 Strategy vs a Lower PEEP/FIO2 Strategy to Reduce Mortality in Patients with Acute Respiratory Distress Syndrome (ARDS) (No Recommendation; High Level of Evidence of No Effect)
    • Recommendation Also Applies to Acute Respiratory Distress Syndrome (ARDS) from COVID‐19 (No Recommendation; Moderate Level of Evidence of No Effect for Indirectness)
  • No Recommendation Regarding PEEP Titration Guided Principally by Respiratory Mechanics vs PEEP Titration Based Principally on PEEP/FIO2 Strategy to Reduce Mortality in Patients with Acute Respiratory Distress Syndrome (ARDS) (No Recommendation; High Level of Evidence of No Effect)
    • Recommendation Also Applies to Acute Respiratory Distress Syndrome (ARDS) from COVID‐19 (No Recommendation; Moderate Level of Evidence of No Effect for Indirectness)

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

Management of Patient-Ventilator Dyssynchrony

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 Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (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 Circuit 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]

Clinical Efficacy

  • Study of Lung Recruitment Using CT Scanning with Breath Holding at Various Airway Pressures in Acute Respiratory Distress Syndrome (ARDS) (NEJM, 2006) [MEDLINE]
    • The Percentage of Recruitable Lung was Extremely Variable in Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (ARDS) (JAMA, 2017) [MEDLINE]: n = 1,010
    • In Moderate-Severe Acute Respiratory Distress Syndrome (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 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]

  • Recruitment Maneuvers are Recommended in Adults with Acute Respiratory Distress Syndrome (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 Acute Respiratory Distress Syndrome (ARDS) Associated with Sepsis (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]

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

American Thoracic Society (ATS) 2023 Clinical Practice Guideline for Acute Respiratory Distress Syndrome (ARDS) (Am J Respir Crit Care Med, 2023) [MEDLINE]

  • Higher PEEP without Lung Recruitment Maneuvers is Suggested Rather than Lower PEEP in Patients with Moderate-Severe Acute Respiratory Distress Syndrome (ARDS) (Conditional Recommendation, Low-Moderate Certainty)
    • Conditional Recommendation is Given Because of the High Level of Heterogeneity Among Higher PEEP Strategies in the Included Randomized Controlled Trials
  • Prolonged (PEEP ≥35 cm H2O for >60 sec) Lung Recruitment Maneuvers are Not Recommended in Patients with Moderate-Severe Acute Respiratory Distress Syndrome (ARDS) (Strong Recommendation, Moderate Certainty)
    • High Potential for Harm is Presumably Due to Serious Adverse Hemodynamic Effects

Recommendations (European Society of Intensive Care Medicine/ESCIM Taskforce on Acute Respiratory Distress Syndrome/ARDS Guidelines, 2023) (Intensive Care Med, 2023)[MEDLINE]

  • Prolonged High‐Pressure Recruitment Maneuvers (Defined as Airway Pressure Maintained ≥35 cm H2O for ≥1 min) are Not Recommended to Reduce the Mortality Rate of Patients with Acute Respiratory Distress Syndrome (ARDS) (Strong Recommendation; Moderate Level of Evidence Against)
    • Recommendation Also Applies to Acute Respiratory Distress Syndrome (ARDS) from COVID‐19 (Strong Recommendation; Low Level of Evidence Against for Indirectness)
  • Brief High‐Pressure Recruitment Maneuvers (Defined as Airway Pressure Maintained ≥35 cmH2O for <1 min) are Not Recommended to Reduce the Mortality Rate in Patients with Acute Respiratory Distress Syndrome (ARDS) (Weak Recommendation; High Level of Evidence of No Effect)
    • Recommendation Also Applies to Acute Respiratory Distress Syndrome (ARDS) from COVID‐19 (Weak Recommendation; Moderate Level of Evidence of No Effect for Indirectness)


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