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
Muscarinic Receptor Antagonists
Ipratropium Bromide (see Ipratropium Bromide): high local anticholinergic activity
Tiotropium (Spiriva) (see Tiotropium): high local anticholinergic activity
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
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
Fluid Management
Rationale
Decreased Lung Water Results in Improved Oxygenation
Exclusion Criteria for Diuresis of the ARDS Patient
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 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
CVP <4 (or PCWP <8) + Urine Output <0.5 mL/kg/hr -> give fluid bolus, reassess in 1 hr
CVP <4 (or PCWP <8) + Urine Output ≥0.5 mL/kg/hr -> no intervention, reassess in 4 hrs
FACTT Lite Had a Greater Cumulative Fluid Balance than FACTT Conservative, But Had Equivalent Clinical and Safety Outcomes in ARDS
Study of the Association Between Fluid Balance and Survival in Critical Illness (J Intern Med, 2015) [MEDLINE]
Positive Fluid Balance at the Time of ICU Discharge is Associated with Increased 90-Day Mortality, Especially in Patients with Underlying Heart/Kidney Disease
Secondary Analysis of FACTT Trial Data (Ann Am Thorac Soc, 2017) [MEDLINE]
Conservative Fluid Management Improved 1-Year Mortality in Non-Hispanic Black ARDS Patients, with No Benefit Observed in White Subjects
Recommendations for Patients with ARDS Associated with Sepsis (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]
Conservative Fluid Management Strategy is Recommended in Established Sepsis-Associated ARDS without Evidence of Tissue Hypoperfusion (Strong Recommendation, Moderate Quality of Evidence)
Swan-Ganz Catheter is Not Routinely Recommended in the Management of Sepsis-Associated ARDS (Strong Recommendation, High Quality of Evidence)
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%)
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 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)
Prevalence of Use of Neuromuscular Junction Antagonists: approximately 25-55% of ARDS patients enrolled in multicenter, randomized controlled trials receive neuromuscular blockers as part of their therapy
Most Common Reasons for Paralytic Administration
Improvement in Oxygenation: paralytics decrease oxygen consumption
Improvement in Patient-Ventilator Synchrony
Administration
Always Provide Adequate Sedation Prior to Paralysis (see Sedation)
Monitor “Train of Four” During Neuromuscular Blockade
Use Neuromuscular Junction Blockers for the Shortest Period of Time Possible to Minimize the Risk of Prolonged Paralysis
Aminosteroid Neuromuscular Junction Blockers Have the Highest Risk of Prolonged Paralysis: although all neuromuscular junction blockers increase this risk
Avoid the Concomitant Use of Corticosteroids (see Corticosteroids): which increase the risk of prolonged paralysis
Clinical Efficacy
French RCT Studying Effect of Neuromuscular Junction Blockade on Oxygenation in ARDS (Crit Care Med, 2004) [MEDLINE]
Neuromuscular Junction Blockade for the First 48 hrs Resulted in Sustained Improvement in Oxygenation Over the Entire 120 hrs Studied
French RCT Studying Effect of Neuromuscular Junction Blockade on the Inflammatory Response in ARDS (Crit Care Med, 2006) [MEDLINE]
Early Use of Neuromuscular Junction Blockade Decreased the Proinflammatory Response (Mediated by Various Cytokines) Associated with ARDS and Mechanical Ventilation
French ARDS et Curarisation Systematique (ACURASYS) Study (NEJM, 2010) [MEDLINE]: multicenter, double-blind trial (n = 340) of ICU patients with ARDS onset within the previous 48 hrs
Early Paralysis (for a Period of 48 hrs) Improved the 90-Day Mortality Rate and Increased the Time Off of the Ventilator Without Increasing Muscular Weakness
Subsequent to the ACURASYS Study, Deep Sedation was Demonstrated to Increase the Incidence of a Specific Type of Ventilator Dyssynchrony Called “Reverse Triggering Dyssynchrony” (During Which a Ventilator-Delivered Breath Paradoxically Triggered a Diaphragmatic Contraction, Which Initiated a Spontaneous Breath, Resulting in Breath Stacking) (Chest, 2013) [MEDLINE]
Reverse Triggering Dyssynchrony May Occur in Up to 30% of Patients with ARDS (Intensive Care Med, 2019) [MEDLINE]
Reverse Triggering Dyssynchrony is Difficult to Detect without an Esophageal Balloon or Diaphragmatic Electromyogram
Reverse Triggering Dyssynchrony Causes Overdistention, Increases the Work of Breathing, and May Cause Diaphragmatic Muscle Damage
Deep Sedation without Paralysis Might Have Inadvertently Increased Reverse Triggering Dyssynchrony with an Increased Risk of Lung Injury in the ACURASYS Trial (An Effect Which Would Not Have Occurred in the Group Which Received Deep Sedation and Paralysis) (NEJM, 2019)) [MEDLINE]
Reevaluation of Systemic Early Neuromuscular Blockade (ROSE) Trial of Early Continuous (48 hrs) Cisatracurium Paralysis in ARDS (NEJM, 2019) [MEDLINE]: n= 1,006
Trial was Stopped Prematurely for Lack of Efficacy
In Moderate-Severe ARDS Treated with High PEEP, Early Continuous (48 hrs) Cisatracurium Paralysis Did Not Decrease the 90-Day Mortality Rate (42.5%), as Compared to Usual Care with a Lighter Sedation Target (42.8%)
Recommendations for Patients with ARDS Associated with Sepsis (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]
Neuromuscular Junction Blockade (for ≤48 hrs) is Suggested for Adult Patients with Sepsis-Associated ARDS and pO2/FIO2 Ratio <150 (Weak Recommendation, Moderate Quality of Evidence)
Respiratory Rate (RR)
Clinical Efficacy
Small Study of Respiratory Rate Management in Patients with Acute Respiratory Failure (Crit Care Med, 2002) [MEDLINE]: n = 14
High Respiratory Rates in Patients Mechanically-Ventilated for Acute Respiratory Failure Can Produce Dynamic Hyperinflation (with Development of Auto-PEEP), Increase the Dead Space/Tidal Volume Ratio, and Impair Right Ventricular Ejection with a Decrease in the Cardiac Output
Study of pCO2 Management During ARDS (Data from LUNG SAFE Study) (Chest, 2020) [MEDLINE]: n = 2,813 (19.6% were hypocapnic, 36.2% were normocapnic, 43.2% were hypercapnic)
Hypocapnia was More Frequent and Severe in Patients on Noninvasive Positive-Pressure Ventilation
There was No Association Between Arterial CO2 and Outcome
Hospital Mortality was 36% in Both Sustained Normocapnic and Hypercapnic Patients
In Patients with Mild-Moderate ARDS, the ICU Mortality Rate was Higher in Patients with Receiving Sustained Hypocapnia (38.1%), as Compared to Normocapnia (27.1%)
General Recommendations
In General, the Respiratory Rate Should Be Adjusted to Maintain Normal pH and Normocapnia
In Terms of Setting a Minimum Respiratory Rate, Rate Should Be Set to Allow an Adequate Minute Ventilation, Should the Patient Become Apneic
In Terms of Setting a Maximal Respiratory Rate in ARDS, the Maximum Respiratory Rate Should Be Set ≤35 Breaths/min
Use Permissive Hypercapnia (When Required) and Avoid the Development of Auto-PEEP
When Increasing the Respiratory Rate, the Patient Should Be Monitored for the Development of Auto-PEEP
In a Patient Who Develops Auto-PEEP on a Respiratory Rate Which Achieves a Normal pH, Respiratory Rate Can Be Decreased and “Permissive Hypercapnia” Utilized
When Increasing the Respiratory Rate in Some Modes of Ventilation, Inspiratory Flow Rate Can Be Increased to Maintain the I/E Ratio: to prevent the development of auto-PEEP
Avoid Hypocapnia
Avoid Unnecessary Hyperventilation Which May Increase the Risk of Ventilator-Induced Lung Injury in ARDS
Lung Protective (Low Tidal Volume and Minimization of Plateau Pressure) Ventilation Strategy
Rationale
Plateau Pressure is Believed to Be the Best Surrogate for Alveolar Pressure (Which Predicts Risk of Barotrauma)
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)
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
The Acute Respiratory Distress Syndrome Network (ARDSNet) Multicenter Randomized Trial Comparing High Tidal Volume (12 mL/kg PBW and Plateau Pressure <50 cm H2O) with Low Tidal Volume (6 mL/kg PBW and Plateau Pressure <30 cm H2O) Ventilation (NEJM, 2000) [MEDLINE]: n = 861
Trial was Stopped Prematurely Due to Mortality Benefit and Increased Ventilator-Free Days in Low Tidal Volume Ventilation Group
Low Tidal Volume Group Had Decreased Mortality Rate (31%), as Compared to High Tidal Volume Group (39.8%)
However, Tidal Volumes Between 6 and 12 mL/g PBW were Not Studied
Low Tidal Volume Group Had Increased Ventilator-Free Days During the First 28 Days (12 +/- 11), as Compared to the High Tidal Volume Group (10 +/- 11)
Mean Tidal Volumes Achieved on Days 1-3 in Low Tidal Volume Group were Lower (6.2 +/- 0.8 mL/kg PBW), as Compared to High Tidal Volume Group (11.8 +/- 0.8 mL/kg PBW)
Mean Plateau Pressures Achieved in Low Tidal Volume Group were Lower (25 +/- 6 cm H2O), as Compared to High Tidal Volume Group (33 +/- 8 cm H2O)
Arterial pCO2 was 4-7 mm Hg Higher in Low Tidal Volume Group, But pCO2 Never Exceeded 44 mm Hg: this is likely not clinically significant
FIO2 was Higher in the Low Tidal Volume Group on Days 1 and 3, Becoming Equivalent by Day 7: this suggests that the institution of low tidal volumes resulted in a transient worsening of oxygenation
Auto-PEEP was Higher in the Low Tidal Volume Group (Who Had Higher Respiratory Rates), Although the Difference in Median Auto-PEEP was <1 cm H2O: this is likely not clinically significant (Crit Care Med, 2005) [MEDLINE]
Review of Animal/Human Data from ARDS Clinical Trials Network (and Original Data) Examining if There is a Safe Upper Limit of Plateau Pressure in ARDS (Am J Respir Crit Care Med, 2005)
Authors Could Not Identify a Safe Upper Limit for Plateau Pressure in ARDS
Study of Sedative Use During Low Tidal Volume Ventilation (Crit Care Med, 2005) [MEDLINE]
Low Tidal Volume Ventilation Does Not Result in Increased Use of Sedatives, Opiates, or Paralytics
Meta-Analysis of Low Tidal Volume and Limited Airway Pressure or Higher PEEP in ALI/ARDS (Ann Intern Med, 2009) [MEDLINE]
Decreased Mortality with Routine Use of Low Tidal Volume, But Not High PEEP Ventilation, in Unselected Patients with ARDS or Acute Lung Injury
High PEEP May Help to Prevent Life-Threatening Hypoxemia in Selected Patients
Systematic Review of Pressure/Volume-Limited Strategies (PLoS One, 2011) [MEDLINE]: the ARDS Network trial [MEDLINE] contributed 21.4% of the weight toward the summary estimate of effect in this analysis
Pressure/Volume-Limited Strategies Decrease Mortality Rate and are Associated with Increased Use of Paralytics
Cochrane Database Review of Lung Protective Ventilation Strategies in ARDS (Cochrane Database Syst Rev, 2013) [MEDLINE]
Lung Protective Strategies (Low Tidal Volume or Plateau Pressure <30 cm H2O) Decrease Mortality
Trial Examining Predictors of Ventilator-Induced Lung Injury in ARDS (Anesthesiology, 2013) [MEDLINE]
Rationale: stress index describes the shape of the airway pressure-time curve profile and may indicate tidal recruitment or tidal overdistension (convex downward pressure curve indicates initial low compliance with better compliance later in the breath due to recruitment, while convex upward curve indicates overdistention -> optimal curve is straight diagonal initial pressure waveform)
Plateau Pressure Partitioned to the Respiratory System (Pplat,Rs) >25 cm H20 and Stress Index Partitioned to the Respiratory System (SI,Rs) >1.05 were Most Associated with Injurious Ventilation
Systematic Review/Meta-Analysis of Morbidity/Mortality in Post-Operative Acute Lung Injury (Lancet Respir Med, 2014) [MEDLINE]
Lung Protective Mechanical Ventilation Strategies (Applied During Surgery) Decrease the Incidence of Post-Operative Acute Lung Injury, But Do Not Decrease the Mortality Rate
Study of Contribution of Driving Pressure to Mortality in ARDS (NEJM, 2015) [MEDLINE]: study used data from 9 prior randomized trials
Rationale: lower tidal volume, lower plateau pressure, and higher PEEP are all believed to decrease mechanical stresses on the lung in ARDS (which can induce ventilator-associated lung injury)
However, There is an Uncertainty When Optimizing One Component Adversely Affects Another (Example: Increasing PEEP May Undesirably Increase the Plateau Pressure), Which this Study Attempted to Address
Authors Theorized in Their Study that Optimizing the Tidal Volume/Respiratory System Compliance Ratio (Known as the Driving Pressure = Delta P) Would Provide a Better Predictor of Outcome in ARDS
Driving Pressure (Plateau Pressure – PEEP or Delta P) was the Best Predictor of Survival
Decreases in Tidal Volume or Increases in PEEP Were Beneficial Only if They Resulted in a Decrease in Delta P (In Other Words, PEEP Increments are Protective Only When They are Associated with an Improvement in Respiratory System Compliance, So that the Same Tidal Volume Can Be Delivered with a Lower Delta P)
Further Trials Using Specific Manipulation of Delta P are Required Before Recommending this Strategy as a Standard
Caveat: Delta P Can Only Be Accurately Assessed in Non-Breathing Patients
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)
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 ARDS (American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine Clinical Practice Guidelines for Mechanical Ventilation in ARDS) (Am J Respir Crit Care Med, 2017) [MEDLINE]
Ventilation Strategy Targeting Low Tidal Volume Ventilation (4-8 mL/kg PBW) and Low Plateau Pressure (<30 cm H2O) is Recommended (Strong Recommendation, Moderate Confidence)
Recommendations for Patients with ARDS Associated with Sepsis (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]
Low Tidal Volume (6 mL/kg PBW) is Recommended Over High Tidal Volume (12 mL/kg PBW) in Sepsis-Associated ARDS (Strong Recommendation, High Quality of Evidence)
Low Tidal Volume (6 mL/kg PBW) is Recommended Over High Tidal Volume (12 mL/kg PBW) in Sepsis-Associated Respiratory Failure without ARDS (Weak Recommendation, Low Quality of Evidence)
Plateau Pressure Upper Limit of 30 cm H2O is Recommended in Sepsis-Associated Severe ARDS (Strong Recommendation, Moderate Quality of Evidence)
Respiratory Rate Max Should Be 35 Breaths/min (Recognizing that Some Patients May Experience Hypercapnia
Hypercapnia is Generally Well-Tolerated in the Absence of Contraindications (Such as Increased Intracranial Pressure, Sickle Cell Crisis, etc)
Positive End-Expiratory Pressure (PEEP)
Physiology of PEEP, Beneficial Effects of PEEP, and Adverse Effects of PEEP
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%)
Optimal PEEP (as Determined by Stress Index on the Ventilator) Depended on Tidal Volume
Phase 2 Randomized EPVent-2 Trial Evaluating Esophageal Pressure-Guided Positive End-Expiratory Pressure (PEEP) Titration Strategy in ARDS (JAMA, 2019) [MEDLINE]: n = 200 (14 hospitals in North America)
In Moderate-Severe ARDS (with Standard Low Tidal Volume Ventilation), Esophageal Pressure-Guided PEEP Titration Strategy Did Not Improve Mortality Rate or Ventilator-Free Days, as Compared to a Standard Empirical FIO2/PEEP Strategy
General Recommendations
PEEP of 0 cm H2O is Generally is Accepted to Be Harmful in ARDS
PEEP of 8-15 cm H2O is Appropriate in Most Patients with ARDS: although higher PEEP levels might be used in patients for whom a greater potential for recruitment can be demonstrated
Although Further Trials are Required Before This Strategy Can Be Recommended, Increasing PEEP May Only Be Beneficial if it Results in a Decrease in the Delta P (Plateau Pressure – PEEP)
Recommendations for Patients with ARDS (American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine Clinical Practice Guidelines for Mechanical Ventilation in ARDS) (Am J Respir Crit Care Med, 2017) [MEDLINE]
Higher PEEP (Rather Than Lower PEEP) is Recommended in Adults with Moderate-Severe ARDS (Conditional Recommendation, Moderate Confidence)
Recommendations for Patients with ARDS Associated with Sepsis (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]
Higher PEEP is Recommended Over Lower PEEP in Adults with Sepsis-Associated Moderate-Severe ARDS (Weak Recommendation, Moderate Quality of Evidence)
The Optimal Method for Selecting PEEP is Unclear (Common Methods Include Titrating PEEP Upward on Tidal Volume of 6 mL/kg Until Plateau Pressure is 28 cm H20, Titrating PEEP to Optimize Thoracoabdominal Compliance with the Lowest Driving Pressure, Titrating PEEP Based on Decreasing the FIO2 to Maintain Oxygenation, etc)
Esophageal Pressure-Guided Mechanical Ventilation
Rationale
Pressures
Esophageal Pressure is a Surrogate for Pleural Pressure
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
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
Ventilation Mode Employing the Use of High Respiratory Rates
Techniques
General Comments: all techniques utilize respiratory rates >100 breaths/min
Conventional Mechanical Ventilation with Small Tidal Volumes and Rapid Respiratory Rates
Chest Wall Oscillation
High-Frequency Percussive Ventilation (HFPV): flow-regulated, pressure-limited, and time-cycled ventilator that delivers a series of high-frequency small volumes (at 200-900 cycles/min) in a successive stepwise stacking pattern
High-Frequency Jet Ventilation
High-Frequency Oscillation Ventilation (HFOV): most widely used type of high-frequency ventilation used in adult critical care -> delivers a small tidal volume by oscillating a bias gas flow in the airway
Clinical Efficacy
Randomized, Controlled Multicenter Oscillatory Ventilation For Acute Respiratory Distress Syndrome Trial) MOAT Trial of High-Frequency Oscillation Ventilation (Am J Respir Crit Care Med, 2002) [MEDLINE]
While the Study was Not Powered to Evaluate Mortality Differences, But an Insignificant Trend Toward Improved Overall 30-Day Mortality Rate in the High-Frequency Oscillation Ventilation Group, as Compared with the Conventional Ventilation Group (37% vs 52% 30-Day Mortality, p=0.098)
There Were No Significant Difference Between Groups in New or Worsening Barotrauma, Endotracheal Tube Obstruction, or Adverse Hemodynamic Effects
Retrospective Chart Review of High-Frequency Oscillation Ventilation for Rescue Therapy in Medical-Surgical ICU Patients (Chest, 2004) [MEDLINE]: n = 156
High-Frequency Oscillation Ventilation Had Beneficial Effects on pO2/FIO2 Ratios and Oxygenation Index
30-Day Mortality Rate was 61.7%
Pneumothorax Rate was 21.8%
Canadian Clinical Trials Group OSCILLATE High-Frequency Oscillation Study in ARDS (NEJM, 2013) [MEDLINE]
In Adults with Moderate-to-Severe ARDS, Early Application of High-Frequency Oscillation Ventilation (as Compared with a Ventilation Strategy of Low Tidal Volume and High PEEP) Did Not Decrease and May Increase, the In-Hospital Mortality Rate
Recommendations for Patients with ARDS (American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine Clinical Practice Guidelines for Mechanical Ventilation in ARDS) (Am J Respir Crit Care Med, 2017) [MEDLINE]
High Frequency Ventilation is Not Routinely Recommended in Moderate-Severe ARDS (Strong Recommendation, Moderate-High Confidence)
Recommendations for Patients with ARDS Associated with Sepsis (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]
Ventilation Mode
No Ventilator Mode is Recommended Over Another
However, High-Frequency Oscillation Ventilation is Not Recommended in Adult Patients with Sepsis-Associated ARDS (Strong Recommendation, Moderate Quality of Evidence) (see High-Frequency Ventilation)
Pressure Assist Control Ventilation (PCV)
Concept
Pressure-Targeted, Time-Cycled Mode
Patient Can Trigger Additional Breaths Above the Set Respiratory Rate (with Each Breath Consisting of a Full Pressure Breath)
Types of Breaths
Pressure Control Breaths: machine triggered
Pressure Assist Breaths: patient triggered
Work of Breathing
Very Low: most of the patient’s work of breathing in this mode (which is generally minimal) involves triggering ventilator-delivered breaths (if the patient is nor triggering any breaths, their work of breathing is effectively zero)
Settings
Respiratory Rate (RR)
Delta P (Driving Pressure): since driving pressure is manually set, tidal volume that occurs will depend on lung/chest wall compliance
PEEP: typically initially set to +5
FIO2: typically initially set to 100% FIO2
Monitor
Tidal Volume (VT)
Advantages
Assuming No Change in Lung/Chest Wall Compliance, Provides Guaranteed Delivery of the Desired Minute Ventilation (Due to a Set Driving Pressure and Set Respiratory Rate): this is useful if the patient is heavily sedated/paralyzed or apneic for other reasons
Disadvantages
If Lung/Chest Wall Compliance Decreases During the Course of Ventilation (Due to Hemothorax, Pneumothorax, Pulmonary Edema), Tidal Volume Will Decrease: for this reason, tidal volumes need to be monitored closely in this mode (with ventilator alarms set accordingly)
Recommendations for Patients with ARDS Associated with Sepsis (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]
No Ventilator Mode is Recommended Over Another for Mechanical Ventilation in Patients with Sepsis
Rationale
Peak Inspiratory Pressure is Generally Lower Than with Volume-Cycled Ventilation: this is due to the flow pattern used with pressure control ventilation
However, GIven the Same Tidal Volume, the Plateau Pressure is the same for Pressure Control Ventilation as it is for Volume-Cycled Ventilation
Improved Patient-Ventilatory Synchrony with PCV: although this is controversial
Improved Gas Exchange with PCV
Increased Mean Airway Pressure
Lower End-Inspiratory Flow Rates
PC has High Initial Flow Rate, Allowing Recruitment of Alveoli with Longer Time Constants
Time Constant of Alveolus (Product of the Resistance x Compliance) Determines How Rapidly the Alveolus Will Fill and Empty
Clinical Efficacy
No Mortality Benefit Has Been Demonstrated for Pressure Control Ventilation
Note 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
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
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 ARDS Associated with Sepsis (2012 Surviving Sepsis Guidelines; Crit Care Med, 2013) [MEDLINE]
Proning is Recommended in Patients with pO2/FiO2 Ratio ≤100 in Sepsis-Associated ARDS (Grade 2B Recommendation)
Recommendations for Patients with ARDS (American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine Clinical Practice Guidelines for Mechanical Ventilation in ARDS) (Am J Respir Crit Care Med, 2017) [MEDLINE]
Proning (for >12 hrs Per Day) is Recommended in Adult Patients with Severe ARDS (Strong Recommendation, Moderate-High Confidence)
Recommendations for Patients with ARDS Associated with Sepsis (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]
Prone Position is Recommended Over Supine Position in Sepsis-Associated ARDS and pO2/FIO2 Ratio <150 (Strong Recommendation, Moderate Quality of Evidence)
Body Position -> Head of Bed at ≥30°
Rationale
Head of Bed at ≥30° Decreases the Frequency and Severity of Gastric Aspiration in Mechanically Ventilated Patients (Ann Intern Med, 1992) [MEDLINE]
The Longer the Patient is in Supine Position, the More Likely They are to Aspirate
Recommendations for Patients with ARDS Associated with Sepsis (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]
Elevation of the Head of the Bed to 30-45 Degrees is Recommended to Limit the Aspiration Risk and to Prevent the Development of Ventilator-Associated Pneumonia (VAP) During Mechanical Ventilation in Sepsis-Associated Respiratory Failure (Strong Recommendation, Low Quality of Evidence)
Body Position -> Continuous Lateral Rotational/Kinetic Bed Therapy
History
1967: first implemented
Rationale
Continuous Lateral Rotational/Kinetic Bed Therapy Was Developed in Effort to Decrease Complications of Prolonged Immobilization (Pneumonia, Venous Stasis, Skin Breakdown) and Mobilize Secretions
Administration
Utilize Rotational Arc >80° (40° in Either Direction): arcs of less than this amount have unknown benefit
Beds are Not Available for Purchase: can only be rented at $175-$275/day
Clinical Efficacy
Study of Continuous Oscillation Therapy in ARDS (J Crit Care, 1995) [MEDLINE]
In Selected Critically Ill Patients, Oscillating Therapy May Improve Survival and Improve Airway Clearance: however, the frequency and degree of turning needed to prevent complications is unclear
Study of Rotational Therapy in ARDS (Intensive Care Med, 1998) [MEDLINE]
Continuous Axial Rotation Might Acutely Decrease V/Q Mismatch in Mild-Moderate Acute Lung Injury, But it is Not Effective in Progressive-Late ARDS
Further Studies re Required
Review and Meta-Analysis of Rotational Bed Therapy in ARDS (Am J Crit Care, 2007) [MEDLINE]: n = 15 nonrandomized, uncontrolled, or retrospective studies (1987-2004)
As Compared to Nurse Turning q2hrs, Meta-Analysis Suggested that Rotational Bed Therapy Decreased the Incidence of Pneumonia, But Had No Effect on Duration of Mechanical Ventilation, ICU Length of Stay, or Hospital Mortality Rate
Case Series of Rotational Percussion Bed Therapy in ARDS Patients Supported on EMCO Therapy (ASAIO J, 2016) [MEDLINE]
Use of Chest Physiotherapy, Frequent Body Repositioning, and Bronchoscopy May Be Helpful in the Management of Pulmonary Secretions in ARDS Patients Supported with ECMO
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
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)
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 VV-EMCO
Based Only on Expert Opinion, Protective Mechanical Ventilation Strategies Should Be Used During VV-ECMO (Minerva Anestesiol, 2015) [MEDLINE]
Extracorporeal Life Support Organization (ELSO) Suggests Using Mechanical Ventilation “at Low Settings to Allow Lung Rest”
ELSO Also Suggests that “For Patients with Respiratory Failure, a Common Mistake is to Try to Recruit Lung Volume During the Acute Inflammatory Stage Early in ECMO”
French Consensus Conference on Extracorporeal Life Support for Patients with ARDS Recommends “Adjust Mechanical Ventilation to Minimize Plateau Pressure While Administering a Minimum PEEP” without Citing Specific Values
Recommendations for Patients with ARDS Associated with Sepsis (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]
VV-EMCO May Be Considered in Centers with Local Expertise
Recommendations for Patients with ARDS (American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine Clinical Practice Guidelines for Mechanical Ventilation in ARDS) (Am J Respir Crit Care Med, 2017) [MEDLINE]
No Recommendation was Made with Regard to the Use of ECMO in ARDS: further study is required
Allogeneic Mesenchymal Stromal Cells
Clinical Efficacy
START (Phase a Safety) Trial of Allogeneic Mesenchymal Stromal Cells in ARDS (Lancet Respir Med, 2019) [MEDLINE]
One Dose of Intravenous Mesenchymal Stromal Cells was Safe in Patients with Moderate-Severe ARDS
Trial of Early Mobilization with Physical/Occupational Therapy in Critically Ill Patients (Lancet, 2009) [MEDLINE]
Early Mobilization (with Interruption of Sedation and Physical/Occupational Therapy) in the Earliest Days of Critical Illness was Safe and Well-Tolerated
Early Mobilization (with Interruption of Sedation and Physical/Occupational Therapy) in the Earliest Days of Critical Illness Improved Functional Outcomes at Hospital Discharge, Decreased Duration of Delirium, and Increased Ventilator-Free Days, as Compared to Standard Care
Multi-Center German/Austrian/US Trial of Early Mobilization in Surgical ICU Patients (Lancet, 2016) [MEDLINE]: n = 200
Early Mobilization Increased Mobilization, Decreased ICU Length of Stay, and Improved Functional Mobility at Hospital Discharge
Early Mobilization Group Had Higher Incidence of Adverse Events (2.8% vs 0.8%), as Compared to Control Group: however, no serious adverse events were observed
Early Mobilization Group Had Higher In-Hospital Mortality Rate (16% vs 8%), as Compared to Control Group
Early Mobilization Group Had Higher 3-Month Mortality Rate (22% vs 17%), as Compared to Control Group
Trial of Standardized Rehabilitation (Daily Physical Therapy) in Acute Respiratory Failure (Requiring Mechanical Ventilation) in the ICU (JAMA, 2016) [MEDLINE]: single-center randomized trial (n = 300)
Standardized Rehabilitation Therapy Did Not Decrease Hospital Length of Stay, ICU Length of Stay, or Ventilator Days in Patients with Acute Respiratory Failure
Systematic Review of Early Mobilization in the ICU (Intensive Care Med, 2017) [MEDLINE]
Active Mobilisation and Rehabilitation in the ICU has No Impact on Short and Long-Term Mortality, But May Improve Mobility Status, Muscle Strength and Days Alive and Out of Hospital at 180 Days
Trial of Chest Physiotherapy with Earlu Mobilization in Critically Ill ICU Patients (Clin Respir J, 2018) [MEDLINE]: n = 439
Intensive Chest Physiotherapy Decreased the Extubation Failure Rate in Mechanically Ventilated Patients
Chest Physiotherapy Improved the Rapid Shallow Breathing Index (RSBI) Score
Single-Center Randomized Trial of In-Bed Cycling and Electrical Stimulation of the Quadriceps in Critically Ill ICU Patients (JAMA, 2018) [MEDLINE]
No Clinical Efficacy in Terms of Global Muscle Strength
Nutritional Support
Clinical Efficacy (General)
OMEGA Trial Examining the Effect of Supplementation with Omega-3 (n-3) Fatty Acids (Docosahexaenoic Acid = DHA, Eicosapentaenoic Acid = EPA), γ-Linolenic Acid, and Antioxidants in Acute Lung Injury (JAMA, 2011) [MEDLINE]
Enteral Omega-3 Fatty Acids, Gamma-Linolenic Acid, and Antioxidants Did Not Improve the Primary Endpoint of Ventilator-Free Days or Other Clinical Outcomes in Patients with Acute Lung Injury and May Be Harmful
EDEN Trial of Enteral Nutrition in Acute Lung Injury (JAMA, 2012) [MEDLINE]
Initial Trophic Feeding (For Up to 6 Days) Did Not Improve Ventilator Days, 60-Day Mortality, or Infectious Complications, as Compared to Full Feeding
Full Feeding Group Had More Gastrointestinal Intolerance (Vomiting, Constipation, and Elevated Gastric Residual Volumes): they received more pro-kinetic agents
Trial of Glutamine and Antioxidants in Critically Ill Patients with Mutiorgan Failure on Mechanical Ventilation (NEJM, 2013) [MEDLINE]
Early Provision of Glutamine or Antioxidants Did Not Improve Clinical Outcomes, and Glutamine was Associated with an Increase in Mortality Among Critically IIl Patients with Multiorgan Failure
Australia/New Zealand TARGET Trial of Energy-Dense Enteral Nutrition in Patients on Mechanical Ventilation (NEJM, 2018) [MEDLINE]
In Patients on Mechanical Ventilation, the Energy-Dense Enteral Nutrition Had No Impact on the 90-Day Mortality Rate, as Compared to Routine Enteral Nutrition
Clinical Efficacy (During Prone Ventilation)
Study of Early Enteral Nutrition in Association with Prone Ventilation (Crit Care Med, 2004) [MEDLINE]
Early Enteral Nutrition is Poorly-Tolerated in Patients Who are Prone-Ventilated
Prokinetic Agents, Transpyloric Feeding, and Semirecumbency Should Be Considered to Enhance Gastric Emptying and to Prevent Vomiting in This Population
Study of Head of Bed Elevation in Enteral Nutrition in Association with Prone Ventilation (Clin Nutr, 2010) [MEDLINE]:
Elevation (25 Degrees) Increased Acceleration of Tube Feedings to Target Rate
Erythromycin Improved Delivery of Enteral Nutrition
Study of Enteral Nutrition in Association with Prone Ventilation (J Parenter Enteral Nutr, 2016) [MEDLINE]
Enteral Nutrition in Association with Prone Ventilation is Feasible, Safe, and Not Associated with an Increased Risk of Gastrointestinal Complications
Recommendations (Society of Critical Care Medicine, SCCM, and American Society for Parenteral and Enteral Nutrition, ASPEN, 2016 Guidelines) [MEDLINE]
High Fat/Low Carbohydrate Tube Feedings are Not Recommended in Patients with Acute Respiratory Failure (Quality of Evidence: Very Low)
Either Trophic or Full Feedings are Acceptable in ARDS with an Expected Duration of Mechanical Ventilation ≥72 hrs (Quality of Evidence: High)
Both Trophic and Full Feeding Strategies Have Similar Outcomes for the First Week of Hospitalization
In Acute Respiratory Failure, Fluid-Restricted, Energy-Dense Enteral Formulations Should Be Considered, Especially in the State of Volume Overload (Quality of Evidence: Expert Consensus)
Supplemental Antioxidant Vitamins (Vitamins E and C) and Trace Minerals (Selenium, Zinc, Copper) May Be Beneficial in Burns, Trauma, Critical Illness Requiring Mechanical Ventilation (Quality of Evidence: Low)
Supplemental Omega-3 (n-3) Fatty Acids (Docosahexaenoic Acid = DHA, Eicosapentaenoic Acid = EPA) Are Not Recommended in ARDS
Weaning
Recommendations for Patients with ARDS Associated with Sepsis (2016 Surviving Sepsis Guidelines; Intensive Care Med, 2017) [MEDLINE]
Spontaneous Breathing Trials (When Specific Criteria are Met) are Recommended in Sepsis-Associated Respiratory Failure (Strong Recommendation, High Quality of Evidence)
Weaning Protocol is Recommended for Appropriate Patients During Mechanical Ventilation in Sepsis-Associated Respiratory Failure (Strong Recommendation)
Therapies with Unclear or No Clinical Benefit in ARDS
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
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]
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
Systematic Review/Meta-Analysis of Morbidity/Mortality in Post-Operative Acute Lung Injury (Lancet Respir Med, 2014) [MEDLINE]
Postoperative Acute Lung Injury is Associated with Increased In-Hospital Mortality Rate (Overall 19% Mortality Rate), Increased ICU Length of Stay, and Increased Hospital Length of Stay
Mortality Due to Acute Lung Injury Associated with Thoracic Surgery is Higher (26.5% mortality) than Acute Lung Injury Associated with Abdominal Surgery (12.2% Mortality) Rate
Lung Protective Mechanical Ventilation Strategies Decrease the Incidence of Postoperative Acute Lung Injury, But Do Not Impact the Mortality Rate
Sequelae of Acute Respiratory Distress Syndrome (ARDS)
Exercise Limitation/Physical Dysfunction
Canadian Clinical Trials Group 5-Year Study of ARDS Sequelae (NEJM, 2011) [MEDLINE]: ARDS survivors (n = 109) studied at at 3, 6, and 12 months and at 2, 3, 4, and 5 years after discharge from the intensive care unit
Exercise Limitation (Decreased 6-Minute Walk Test) and Physical Dysfunction May Persist for Up to 5 yrs After ARDS
Pulmonary Function was Near Normal-Normal
NHLBI ARDS Network Prospective Longitudinal (1 Year) Multicenter Study of Physical Impairment in ARDS Survivors (Am J Respir Crit Care Med, 2014) [MEDLINE]
ARDS Survivors Demonstrated Impairment in 6-Minute Walk Test Distance (Distance was 64% Predicted at 6 Months, 67% Predicted at 1 Year) and Short Form-36 (SF-36) Physical Function Outcome Measures
Impairment Appeared to Be Correlated with Mean Daily Corticosteroid Dose and ICU Length of Stay
Prospective Longitudinal (2 Year) Multicenter Study of Physical Impairment in ARDS Survivors (Crit Care Med, 2014) [MEDLINE]
Muscle Weakness is Common at Hospital Discharge Following ARDS, Usually Recovering Within 1 Year
Muscle Weakness is Associated with Substantial Impairment in Physical Function and Health-Related QOL, Which Continue Beyond 12 Months
Corticosteroid Dose and Use of Neuromuscular Blockade Were Not Associated with the Development of Weakness
Decreased Quality of Life (QOL)
Canadian Clinical Trials Group 5-Year Study of ARDS Sequelae (NEJM, 2011) [MEDLINE]: ARDS survivors (n = 109) studied at at 3, 6, and 12 months and at 2, 3, 4, and 5 years after discharge from the intensive care unit
Decreased QOL May Persist for Up to 5 yrs After ARDS
Prospective Longitudinal (2 Year) Multicenter Study of Physical Impairment in ARDS Survivors (Crit Care Med, 2014) [MEDLINE]
Muscle Weakness is Common at Hospital Discharge Following ARDS, Usually Recovering Within 1 Year
Muscle Weakness is Associated with Substantial Impairment in Physical Function and Health-Related QOL, Which Continue Beyond 12 Months
Corticosteroid Dose and Use of Neuromuscular Blockade Were Not Associated with the Development of Weakness
Increased Costs and Use of Health Care Services
Canadian Clinical Trials Group 5-Year Study of ARDS Sequelae (NEJM, 2011) [MEDLINE]: ARDS survivors (n = 109) studied at at 3, 6, and 12 months and at 2, 3, 4, and 5 years after discharge from the intensive care unit
Increased Health Care Costs and Increased Use of Health Care Services May Persist for Up to 5 yrs After ARDS
Patients with More Coexisting Illnesses Incurred Greater 5-Year Costs
Neuropsychologic Dysfunction
Canadian Clinical Trials Group 5-Year Study of ARDS Sequelae (NEJM, 2011) [MEDLINE]: ARDS survivors (n = 109) studied at at 3, 6, and 12 months and at 2, 3, 4, and 5 years after discharge from the intensive care unit
Psychological Problems May Persist for Up to 5 years after ARDS
Adult Respiratory Distress Syndrome Cognitive Outcomes Study (Am J Respir Crit Care Med) [MEDLINE]: study of ARDS survivors (n = 213)
Long-term cognitive impairment was present in 55% of subjects
Depression was present in 36% of subjects
Post-traumatic stress disorder (PTSD) was present in 39% of subjects
Anxiety was present in 62% of subjects
Impact of Hypoxemia: presence of hypoxemia is a risk factor for long-term cognitive and psychiatric impairment
Impact of Fluid Management Strategy: conservative fluid management strategy is a potential risk factor for long-term cognitive impairment (however, this finding requires further studies for confirmation)
BRAIN-ICU Study of Patients with Respiratory Failure or Shock in the Medical/Surgical ICU (NEJM, 2013) [MEDLINE]: n = 821)
Delirium Developed in 74% of Cases During Hospital Stay
Outcomes At 3 Months
40% of Patients Had Impaired Global Cognition Scores that Were 1.5 SD Below the Population Mean, Similar to Scores for Patients with Moderate Traumatic Brain Injury
26% of Patients Had Scores 2 SD Below the Population Mean (similar to scores for patients with Mild Alzheimer’s Disease
Outcomes At 12 Months
Similar Persistent Cognitive Dysfunction Occurs as in Those with Moderate Traumatic Brain Injury
Similar Persistent Cognitive Dysfunction Occurs as in Those with Mild Alzheimer’s Disease
Impact of Duration of Delirium
Longer Duration of Delirium was Significantly Associated with Worse Global Cognition at 3 and 12 Months and Worse Executive Function at 3 and 12 Months
Impact of Sedative Use
Use of Sedatives or Analgesics was Not Associated with Cognitive Impairment at 3 and 12 Months
Cognitive Dysfunction was Also Independent of Age, Pre-Existing Cognitive Impairment, Presence or Severity of Coexisting Conditions, and Organ Failure During ICU Care
References
Treatment
General
An Official American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine Clinical Practice Guideline: Mechanical Ventilation in Adult Patients with Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med. 2017 May 1;195(9):1253-1263. doi: 10.1164/rccm.201703-0548ST [MEDLINE]
Effect of core body temperature on ventilator-induced lung injury. Crit Care Med. 2004;32(1):144 [MEDLINE]
Bronchodilators
The beta-agonist lung injury trial (BALTI): a randomized placebo-controlled clinical trial. Am J Respir Crit Care Med. 2006 Feb 1;173(3):281-7 [MEDLINE]
Randomized, placebo-controlled clinical trial of an aerosolized β₂-agonist for treatment of acute lung injury. Am J Respir Crit Care Med. 2011 Sep 1;184(5):561-8 [MEDLINE]
Beta-Agonist Lung injury TrIal-2 (BALTI-2): a multicentre, randomised, double-blind, placebo-controlled trial and economic evaluation of intravenous infusion of salbutamol versus placebo in patients with acute respiratory distress syndrome. Health Technol Assess. 2013 Sep;17(38):1-88 [MEDLINE]
Management of Ventilator-Induced Lung Injury (VILI)/Barotrauma
International consensus conferences in intensive care medicine: Ventilator-associated Lung Injury in ARDS. This official conference report was cosponsored by the American Thoracic Society, The European Society of Intensive Care Medicine, and The Societéde Réanimation de Langue Française, and was approved by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med. 1999;160(6):2118 [MEDLINE]
Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med. 2006 Apr 20;354(16):1671-84 [MEDLINE]
American College of Critical Care Medicine. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med. 2008;36(6):1937-1949 [MEDLINE]
Do glucocorticoids decrease mortality in acute respiratory distress syndrome? A meta-analysis. Respirology. 2007;12(4):585 [MEDLINE]
Corticosteroids in the prevention and treatment of acute respiratory distress syndrome (ARDS) in adults: meta-analysis. BMJ. 2008;336(7651):1006. Epub 2008 Apr 23 [MEDLINE]
Steroid treatment in ARDS: a critical appraisal of the ARDS network trial and the recent literature. Intensive Care Med. 2008;34(1):61. Epub 2007 Nov 14 [MEDLINE]
Use of corticosteroids in acute lung injury and acute respiratory distress syndrome: a systematic review and meta-analysis. Crit Care Med. 2009;37(5):1594-1603 [MEDLINE]
Corticosteroids and transition to delirium in patients with acute lung injury. Crit Care Med. 2014 Jun;42(6):1480-6. doi: 10.1097/CCM.0000000000000247 [MEDLINE]
Prolonged glucocorticoid treatment is associated with improved ARDS outcomes: analysis of individual patients’ data from four randomized trials and trial-level meta-analysis of the updated literature. Intensive Care Med. 2016 May;42(5):829-40. Epub 2015 Oct 27 [MEDLINE]
Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med. 2020 Mar;8(3):267-276. doi: 10.1016/S2213-2600(19)30417-5 [MEDLINE]
Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19: The CoDEX Randomized Clinical Trial. JAMA. 2020 Oct 6;324(13):1307-1316. doi: 10.1001/jama.2020.17021 [MEDLINE]
The standard of care of patients with ARDS: ventilatory settings and rescue therapies for refractory hypoxemia. Intensive Care Med 2016;42:699-711 [MEDLINE]
Oxygen in the ICU: too much of a good thing? JAMA 2016;316: 1553-4 [MEDLINE]
Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in50countries.JAMA2016;315:788-800 [MEDLINE]
Effectiveness and clinical outcomes of a two-step implementation of conservative oxygenation targets in critically ill patients: a before and after trial. Crit Care Med 2016;44:554-63 [MEDLINE]
Effect of Conservative vs Conventional Oxygen Therapy on Mortality Among Patients in an Intensive Care Unit: The Oxygen-ICU Randomized Clinical Trial. JAMA. 2016;316(15):1583 [MEDLINE]
Conservative versus Liberal Oxygenation Targets for Mechanically Ventilated Patients. A Pilot Multicenter Randomized Controlled Trial. Am J Respir Crit Care Med. 2016 Jan;193(1):43-51 [MEDLINE]
Effect of Conservative vs Conventional Oxygen Therapy on Mortality Among Patients in an Intensive Care Unit: The Oxygen-ICU Randomized Clinical Trial. JAMA. 2016 Oct 18;316(15):1583-1589. doi: 10.1001/jama.2016.11993 [MEDLINE]
British Thoracic Society Emergency Oxygen Guideline Group BTS Emergency Oxygen Guideline Development Group. BTS guideline for oxygen use in adults in healthcare and emergency settings. Thorax 2017;72(Suppl 1):ii1-90. 10.1136/ thoraxjnl-2016-209729 pmid:28507176 [MEDLINE]
Hyperoxia and hypertonic saline in patients with septic shock (HYPERS2S): a two-by-two factorial, multicentre, randomised, clinical trial. Lancet Respir Med. 2017 Mar;5(3):180-190. doi: 10.1016/S2213-2600(17)30046-2 [MEDLINE]
Oxygen therapy for acutely ill medical patients: a clinical practice guideline. BMJ. 2018 Oct 24;363:k4169. doi: 10.1136/bmj.k4169 [MEDLINE]
Mortality and morbidity in acutely ill adults treated with liberal versus conservative oxygen therapy (IOTA): a systematic review and meta-analysis. Lancet. 2018 Apr 28;391(10131):1693-1705. doi: 10.1016/S0140-6736(18)30479-3 [MEDLINE]
Emergency department hyperoxia is associated with increased mortality in mechanically ventilated patients: a cohort study. Crit Care. 2018 Jan 18;22(1):9. doi: 10.1186/s13054-017-1926-4 [MEDLINE]
ICU-ROX Trial. Conservative Oxygen Therapy during Mechanical Ventilation in the ICU. N Engl J Med. 2020 Mar 12;382(11):989-998. doi: 10.1056/NEJMoa1903297 [MEDLINE]
LOCO2 Trial. Liberal or Conservative Oxygen Therapy for Acute Respiratory Distress Syndrome. N Engl J Med. 2020 Mar 12;382(11):999-1008. doi: 10.1056/NEJMoa1916431 [MEDLINE]
HOT-ICU Trial. Lower or Higher Oxygenation Targets for Acute Hypoxemic Respiratory Failure. N Engl J Med. 2021 Jan 20. doi: 10.1056/NEJMoa2032510 [MEDLINE]
O2-ICU Trial. Effect of Low-Normal vs High-Normal Oxygenation Targets on Organ Dysfunction in Critically Ill Patients: A Randomized Clinical Trial. JAMA. 2021 Aug 31. doi: 10.1001/jama.2021.13011 [MEDLINE]
Effect of neuromuscular blocking agents on gas exchange in patients presenting with acute respiratory distress syndrome. Crit Care Med. 2004;32(1):113-119 [MEDLINE]
Neuromuscular blocking agents decrease inflammatory response in patients presenting with acute respiratory distress syndrome. Crit Care Med. 2006;34(11):2749-2757 [MEDLINE]
ARDS et Curarisation Systematique (ACURASYS) Trial. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010 Sep 16;363(12):1107-16 [MEDLINE]
Mechanical ventilation-induced reverse-triggered breaths: a frequently unrecognized form of neuromechanical coupling. Chest. 2013 Apr;143(4):927-938. doi: 10.1378/chest.12-1817 [MEDLINE]
Reevaluation of Systemic Early Neuromuscular Blockade (ROSE) Trial. Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome. N Engl J Med. 2019 May 19. doi: 10.1056/NEJMoa1901686 [MEDLINE]
Early Paralytic Agents for ARDS? Yes, No, and Sometimes. NEJM, 2019 DOI: 10.1056/NEJMe1905627 [MEDLINE]
Variability of reverse triggering in deeply sedated ARDS patients. Intensive Care Med. 2019 May;45(5):725-726. doi: 10.1007/s00134-018-5500-6 [MEDLINE]
Fluid Management
Albumin and furosemide therapy in hypoproteinemic patients with acute lung injury. Crit Care Med. 2002;30(10):2175-2182 [MEDLINE]
SAFE Study Investigators. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med. 2004;350(22):2247-2256 [MEDLINE]
A randomized, controlled trial of furosemide with or without albumin in hypoproteinemic patients with acute lung injury. Crit Care Med. 2005;33(8):1681-1687 [MEDLINE]
FACTT Trial: Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006 Jun 15;354(24):2564-75 [MEDLINE]
The adult respiratory distress syndrome cognitive outcomes study: long-term neuropsychological function in survivors of acute lung injury. Am J Respir Crit Care Med. 2012;185:1307–1315 [MEDLINE]
The Adult Respiratory Distress Syndrome Cognitive Outcomes Study: long-term neuropsychological function in survivors of acute lung injury. Crit Care. 2013 May 24;17(3):317. doi: 10.1186/cc12709 [MEDLINE]
Fluids in ARDS: from onset through recovery. Curr Opin Crit Care. 2014;20:373–377 [MEDLINE]
Albumin versus crystalloid solutions in patients with the acute respiratory distress syndrome: a systematic review and meta-analysis. Crit Care 2014 [MEDLINE]
Association between fluid balance and survival in critically ill patients. J Intern Med. 2015;277:468–477 [MEDLINE]
Fluid management with a simplified conservative protocol for the acute respiratory distress syndrome. Crit Care Med. 2015;43:288–295 [MEDLINE]
Relationship between Race and the Effect of Fluids on Long-term Mortality after Acute Respiratory Distress Syndrome: Secondary Analysis of the NHLBI Fluid and Catheter Treatment Trial. Ann Am Thorac Soc. 2017 Jul 14. doi: 10.1513/AnnalsATS.201611-906OC [MEDLINE]
Respiratory Rate
Patterns and impact of arterial CO 2 management in patients with Acute Respiratory Distress Syndrome: Insights from the LUNG SAFE study. Chest 2020 Jun 23;S0012-3692(20)31731-1 [MEDLINE]
Low Tidal Volume Ventilation
Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 1998; 338:347-354 [MEDLINE]
Evaluation of a ventilation strategy to prevent barotrauma in patients at high risk for acute respiratory distress syndrome. N Engl J Med 1998; 338:355-361 [MEDLINE]
Evaluation of a ventilation strategy to prevent barotrauma in patients at high risk for acute respiratory distress syndrome. N Engl J Med 1998; 338:355-361 [MEDLINE]
Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med. 2000 May 4;342(18):1301-8 [MEDLINE]
ARDSNet lower tidal volume ventilatory strategy may generate intrinsic positive end-expiratory pressure in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 2002;165:1271 [MEDLINE]
Tidal volume reduction in patients with acute lung injury when plateau pressures are not high. Am J Respir Crit Care Med. 2005 Nov 15;172(10):1241-5. Epub 2005 Aug 4 [MEDLINE]
Intrinsic positive end-expiratory pressure in Acute Respiratory Distress Syndrome (ARDS) Network subjects. Crit Care Med. 2005 Mar;33(3):527-32 [MEDLINE]
Low tidal volume ventilation does not increase sedation use in patients with acute lung injury. Crit Care Med. 2005 Apr;33(4):766-71 [MEDLINE]
Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2008;299:637 [MEDLINE]
Lung stress and strain during mechanical ventilation for acute respiratory distress syndrome. Am J Respir Crit Care Med. 2008 Aug 15;178(4):346-55. doi: 10.1164/rccm.200710-1589OC. Epub 2008 May 1 [MEDLINE]
Meta-analysis: ventilation strategies and outcomes of the acute respiratory distress syndrome and acute lung injury. Ann Intern Med. 2009 Oct 20;151(8):566-76 [MEDLINE]
Pressure and volume limited ventilation for the ventilatory management of patients with acute lung injury: a systematic review and meta-analysis. PLoS One. 2011 Jan 28;6(1):e14623 [MEDLINE]
Lung protective ventilation strategy for the acute respiratory distress syndrome. Cochrane Database Syst Rev. 2013 Feb 28;2:CD003844 [MEDLINE]
Ventilator-induced lung injury. N Engl J Med. 2013 Nov 28;369(22):2126-36. doi: 10.1056/NEJMra1208707 [MEDLINE]
Personalised mechanical ventilation tailored to lung morphology versus low positive end-expiratory pressure for patients with acute respiratory distress syndrome in France (the LIVE study): a multicentre, single-blind, randomised controlled trial. Lancet Respir Med. 2019 Oct;7(10):870-880. doi: 10.1016/S2213-2600(19)30138-9 [MEDLINE]
Impact of Respiratory Rate and Dead Space in the Current Era of Lung Protective Mechanical Ventilation. Chest 2020 Jul;158(1):45-47. doi: 10.1016/j.chest.2020.02.033 [MEDLINE]
Ventilatory Variables and Mechanical Power in Patients with Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med. 2021 Mar 30. doi: 10.1164/rccm.202009-3467OC [MEDLINE]
Low tidal volume ventilation is associated with mortality in COVID-19 patients-Insights from the PRoVENT-COVID study. J Crit Care. 2022 Aug;70:154047. doi: 10.1016/j.jcrc.2022.154047 [MEDLINE]
Positive End-Expiratory Pressure (PEEP)
Optimum end-expiratory airway pressure in patients with acute pulmonary failure. N Engl J Med 1975;292:284–289 [MEDLINE]
Occult positive end-expiratory pressure in mechanically ventilated patients with airflow obstruction: The auto-PEEP effect. Am Rev Respir Dis 1982; 126:166-170 [MEDLINE]
Effect of positive end-expiratory pressure and body position in unilateral lung injury. J Appl Physiol Respir Environ Exerc Physiol. 1982;52(1):147 [MEDLINE]
Physiologic PEEP. Respir Care. 1988; 33:620
Determination of auto-PEEP during spontaneous and controlled ventilation by monitoring changes in end-expiratory thoracic gas volume. Chest 1989; 96:613-616 [MEDLINE]
Should PEEP be used in airflow obstruction? Am Rev Respir Dis 1989; 140:1-3 [MEDLINE]
PEEP, auto-PEEP, and waterfalls. Chest. 1989 Sep;96(3):449-51 [MEDLINE]
Auto-PEEP during CPR: an “occult” cause of electromechanical dissociation? Chest 1991;99:492–493 [MEDLINE]
Physiologic effects of positive end-expiratory pressure in chronic obstructive pulmonary disease during acute ventilatory failure and controlled mechanical ventilation. Am Rev Respir Dis. 1993;147:5–13 [MEDLINE]
Effects of Extrinsic Positive End-Expiratory Pressure on Mechanically Ventilated Patients With Chronic Obstructive Pulmonary Disease and Dynamic Hyperinflation. Intensive Care Med. 1993;19(4):197-203. doi: 10.1007/BF01694770 [MEDLINE]
Positive end-expiratory pressure increases the right to-left shunt in mechanically ventilated patients with patent foramen ovale. Ann Intern Med 1993; 119:887-894 [MEDLINE]
Interaction between intrinsic positive end-expiratory pressure and externally applied positive end-expiratory pressure during controlled mechanical ventilation. Crit Care Med 1993; 21:348-356 [MEDLINE]
The effects of applied vs auto-PEEP on local lung unit pressure and volume in a four-unit lung model. Chest. 1995 Oct;108(4):1073-9 [MEDLINE]
Auto-PEEP and electromechanical dissociation. N Engl J Med 1996;335:674–675 [MEDLINE]
Does positive end-expiratory pressure ventilation improve left ventricular function? A comparative study by transesophageal echocardiography in cardiac and noncardiac patients. Chest. 1998;114(2):556 [MEDLINE]
Pressure-volume curves and compliance in acute lung injury: evidence of recruitment above the lower inflection point. Am J Respir Crit Care Med. 1999 Apr;159(4 Pt 1):1172-8 [MEDLINE]
Use of pulse oximetry to recognize severity of airflow obstruction in obstructive airway disease: correlation with pulsus paradoxus. Chest 1999;115:475–481 [MEDLINE]
Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med. 2000 May 4;342(18):1301-8 [MEDLINE]
Influence of positive end-expiratory pressure on intracranial pressure and cerebral perfusion pressure in patients with acute stroke. Stroke. 2001;32(9):2088 [MEDLINE]
Intrinsic (or auto-) positive end-expiratory pressure during spontaneous or assisted ventilation. Intensive Care Med 2002;28:1552 [MEDLINE]
Positive end-expiratory pressure alters intracranial and cerebral perfusion pressure in severe traumatic brain injury. J Trauma. 2002;53(3):488 [MEDLINE]
ALVEOLI Study: The National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 2004;351:327-36 [MEDLINE]
Effects of positive end-expiratory pressure on gastric mucosal perfusion in acute respiratory distress syndrome. Crit Care. 2004;8(5):R306 [MEDLINE]
Airway pressure-time curve profile (stress index) detects tidal recruitment/hyperinflation in experimental acute lung injury. Crit Care Med. 2004 Apr;32(4):1018-27 [MEDLINE]
Effects of positive end-expiratory pressure on regional cerebral blood flow, intracranial pressure, and brain tissue oxygenation. Crit Care Med. 2005;33(10):2367 [MEDLINE]
Cardiovascular issues in respiratory care. Chest. 2005;128(5 Suppl 2):592S [MEDLINE]
Lung recruitment in patients with the acute respiratory distress syndrome. N Engl J Med. 2006 Apr 27;354(17):1775-86 [MEDLINE]
Review of ventilatory techniques to optimize mechanical ventilation in acute exacerbation of chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 2007 Dec;2(4):441–452 [MEDLINE]
Positive-end expiratory pressure reduces incidence of ventilator-associated pneumonia in nonhypoxemic patients. Crit Care Med. 2008;36(8):2225 [MEDLINE]
Positive-end expiratory pressure setting in adult acute lung injury and acute respiratory distress syndrome: a randomized, controlled trial. JAMA 2008;299:646 [MEDLINE]
Effect of positive expiratory pressure and type of tracheal cuff on the incidence of aspiration in mechanically ventilated patients in an intensive care unit. Crit Care Med. 2008;36(2):409 [MEDLINE]
Clinical concise review: Mechanical ventilation of patients with chronic obstructive pulmonary disease. Crit Care Med. 2008 May;36(5):1614-9. doi: 10.1097/CCM.0b013e318170f0f3 [MEDLINE]
LOV Study: Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2008;299:637 [MEDLINE]
EXPRESS Study: Positive-end expiratory pressure setting in adult acute lung injury and acute respiratory distress syndrome: a randomized, controlled trial. JAMA 2008;299:646 [MEDLINE]
Effect of positive expiratory pressure and type of tracheal cuff on the incidence of aspiration in mechanically ventilated patients in an intensive care unit. Crit Care Med. 2008;36(2):409 [MEDLINE]
Clinical concise review: Mechanical ventilation of patients with chronic obstructive pulmonary disease. Crit Care Med. 2008 May;36(5):1614-9. doi: 10.1097/CCM.0b013e318170f0f3 [MEDLINE]
Positive end-expiratory pressure redistributes regional blood flow and ventilation differently in supine and prone humans. Anesthesiology. 2010;113(6):1361 [MEDLINE]
Cardiac output estimation using pulmonary mechanics in mechanically ventilated patients. Biomed Eng Online. 2010;9:80 [MEDLINE]
Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis. JAMA 2010; 303:865-873 [MEDLINE]
Hemodynamic impact of a positive end-expiratory pressure setting in acute respiratory distress syndrome: importance of the volume status. Crit Care Med 2010;38:802–807 [MEDLINE]
Dynamic hyperinflation and auto-positive end-expiratory pressure: lessons learned over 30 years. Am J Respir Crit Care Med. 2011;184:756–762 [MEDLINE]
Patient-ventilator interactions. Implications for clinical management. Am J Respir Crit Care Med. 2013;188:1058–1068 [MEDLINE]
Accuracy of plateau pressure and stress index to identify injurious ventilation in patients with acute respiratory distress syndrome. Anesthesiology. 2013 Oct;119(4):880-9. doi: 10.1097/ALN.0b013e3182a05bb8 [MEDLINE]
High versus low positive end-expiratory pressure during general anaesthesia for open abdominal surgery (PROVHILO trial): a multicentre randomised controlled trial. Lancet. 2014 Aug 9;384(9942):495-503. doi: 10.1016/S0140-6736(14)60416-5. Epub 2014 Jun 2 [MEDLINE]
Oxygenation response to positive end-expiratory pressure predicts mortality in acute respiratory distress syndrome. A secondary analysis of the LOVS and ExPress trials. Am J Respir Crit Care Med 2014;190:70–76 [MEDLINE]
Bedside selection of positive end-expiratory pressure in mild, moderate, and severe acute respiratory distress syndrome. Crit Care Med 2014;42:252–264 [MEDLINE]
Asynchronies during mechanical ventilation are associated with mortality. Intensive Care Med. 2015;41(4): 633–641; published online Feb 2015 [MEDLINE]
Driving pressure and survival in the acute respiratory distress syndrome. N Engl J Med. 2015;372:747–755 [MEDLINE]
Driving pressure and respiratory mechanics in ARDS. N Engl J Med. 2015;372:776–777 [MEDLINE]
Airway driving pressure and lung stress in ARDS patients. Crit Care. 2016; 20: 276 [MEDLINE]
Open Lung Approach for the Acute Respiratory Distress Syndrome: A Pilot, Randomized Controlled Trial. Crit Care Med. 2016 Jan;44(1):32-42. doi: 10.1097/CCM.0000000000001383 [MEDLINE]
High PEEP in Acute Respiratory Distress Syndrome: Quantitative Evaluation Between Improved Arterial Oxygenation and Decreased Oxygen Delivery. Br J Anaesth. 2016 Nov;117(5):650-658. doi: 10.1093/bja/aew314 [MEDLINE]
How ARDS should be treated. Crit Care. 2016 Apr 6;20:86. doi: 10.1186/s13054-016-1268-7 [MEDLINE]
Effect of Intensive vs Moderate Alveolar Recruitment Strategies Added to Lung-Protective Ventilation on Postoperative Pulmonary Complications: A Randomized Clinical Trial. JAMA. 2017;317(14):1422 [MEDLINE]
ART Trial. Effect of Lung Recruitment and Titrated Positive End-Expiratory Pressure (PEEP) vs Low PEEP on Mortality in Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial. JAMA. 2017 Oct 10;318(14):1335-1345. doi: 10.1001/jama.2017.14171 [MEDLINE]
Fifty Years of Research in ARDS. Setting Positive End-Expiratory Pressure in Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med. 2017 Jun 1;195(11):1429-1438. doi: 10.1164/rccm.201610-2035CI [MEDLINE]
Association of Driving Pressure With Mortality Among Ventilated Patients With Acute Respiratory Distress Syndrome: A Systematic Review and Meta-Analysis. Crit Care Med. 2018 Feb;46(2):300–6 [MEDLINE]
Stress Index Can Be Accurately and Reliably Assessed by Visually Inspecting Ventilator Waveforms. Respir Care. 2018 Sep;63(9):1094-1101. doi: 10.4187/respcare.06151 [MEDLINE]
Best PEEP trials are dependent on tidal volume. Crit Care. 2018;22(1):115 [MEDLINE]
Individualised perioperative open-lung approach versus standard protective ventilation in abdominal surgery (iPROVE): a randomised controlled trial. Lancet Respir Med. 2018;6(3):193 [MEDLINE]
The future of driving pressure: a primary goal for mechanical ventilation? J Intensive Care. 2018 Oct 4;6:64. doi: 10.1186/s40560-018-0334-4. eCollection 2018 [MEDLINE]
EPVent-2 Trial. Effect of Titrating Positive End-Expiratory Pressure (PEEP) With an Esophageal Pressure-Guided Strategy vs an Empirical High PEEP-Fio2 Strategy on Death and Days Free From Mechanical Ventilation Among Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial. JAMA. 2019 Feb 18. doi: 10.1001/jama.2019.0555 [MEDLINE]
Optimal Ventilator Strategies in Acute Respiratory Distress Syndrome. Semin Respir Crit Care Med. 2019 Feb;40(1):81-93. doi: 10.1055/s-0039-1683896 [MEDLINE]
Esophageal Pressure-Guided Mechanical Ventilation
Airway pressure-time curve profile (stress index) detects tidal recruitment/hyperinflation in experimental acute lung injury. Crit Care Med. 2004 Apr;32(4):1018-27 [MEDLINE]
EPVent Study. Mechanical ventilation guided by esophageal pressure in acute lung injury. N Engl J Med 2008; 359:2095– 2104 [MEDLINE]
Accuracy of plateau pressure and stress index to identify injurious ventilation in patients with acute respiratory distress syndrome. Anesthesiology. 2013 Oct;119(4):880-9. doi: 10.1097/ALN.0b013e3182a05bb8 [MEDLINE]
The application of esophageal pressure measurement in patients with respiratory failure. Am J Respir Crit Care Med 2014; 189:520–531 [MEDLINE]
The assessment of transpulmonary pressure in mechanically ventilated ARDS patients. Intensive Care Med 2014; 40:1670–1678 [MEDLINE]
Effects of periodic lung recruitment maneuvers on gas exchange and respiratory mechanics in mechanically ventilated acute respiratory distress syndrome (ARDS) patients. Intensive Care Med. 2000;26(5):501 [MEDLINE]
Recruitment maneuvers for acute lung injury: a systematic review. Am J Respir Crit Care Med. 2008;178(11):1156 [MEDLINE]
Recruitment manoeuvres for adults with acute lung injury receiving mechanical ventilation. Cochrane Database Syst Rev. 2009 Apr 15;(2):CD006667 [MEDLINE]
Optimal duration of a sustained inflation recruitment maneuver in ARDS patients. Intensive Care Med. 2011;37(10):1588 [MEDLINE]
ART Trial. Effect of Lung Recruitment and Titrated Positive End-Expiratory Pressure (PEEP) vs Low PEEP on Mortality in Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial. JAMA. 2017 Oct 10;318(14):1335-1345. doi: 10.1001/jama.2017.14171 [MEDLINE]
OSCILLATE Trial. High-frequency oscillation in early acute respiratory distress syndrome. N Engl J Med. 2013 Feb 28;368(9):795-805 [MEDLINE]
Pressure Control Ventilation
Pressure-controlled versus volume-controlled ventilation for acute respiratory failure due to acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Cochrane Database Syst Rev. 2015 Jan 14;1(1):CD008807. doi: 10.1002/14651858.CD008807.pub2 [MEDLINE]
Randomized clinical trial of pressure controlled inverse ratio ventilation and extracorporeal CO2 removal for adult respiratory distress syndrome. Am J Respir Crit Care Med 1994; 149:295-305 [MEDLINE]
Should inverse ratio ventilation be used in adult respiratory distress syndrome? Am J Respir Crit Care Med 1994: 149:1354-1358
Airway pressure release ventilation as a primary ventilatory mode in acute respiratory distress syndrome. Acta Anaesthesiol Scand. 2004 Jul;48(6):722-31 [MEDLINE]
Other approaches to open-lung ventilation: Airway pressure release ventilation. Crit Care Med. 2005 Mar;33(3 Suppl):S228-40 [MEDLINE]
Respiratory controversies in the critical care setting. Does airway pressure release ventilation offer important new advantages in mechanical ventilator support? Respir Care. 2007 Apr;52(4):452-8; discussion 458-60 [MEDLINE]
Airway pressure release ventilation and biphasic positive airway pressure: a systemic review of definitional criteria. Intensive Care Med 2008;34(10):1766-1773 [MEDLINE]
Comparison of APRV and BIPAP in a mechanical model of ARDS (abstract). Respir Care 2010;55(11): 1516
A randomized prospective trial of airway pressure release ventilation and low tidal volume ventilation in adult trauma patients with acute respiratory failure. J Trauma. 2010;69(3):501-510 [MEDLINE]
Airway pressure release ventilation in acute respiratory distress syndrome. Crit Care Clin. 2011 Jul;27(3):501-9. doi: 10.1016/j.ccc.2011.05.003 [MEDLINE]
Airway pressure release ventilation: what do we know? Respir Care. 2012 Feb;57(2):282-92 [MEDLINE]
Airway pressure release ventilation prevents ventilator-induced lung injury in normal lungs. JAMA Surg. 2013 Nov;148(11):1005-12. doi: 10.1001/jamasurg.2013.3746 [MEDLINE]
Early application of airway pressure release ventilation may reduce mortality in high-risk trauma patients: a systematic review of observational trauma ARDS literature. J Trauma Acute Care Surg. 2013 Oct;75(4):635-41 [MEDLINE]
Early airway pressure release ventilation prevents ARDS-a novel preventive approach to lung injury. Shock. 2013 Jan;39(1):28-38. doi: 10.1097/SHK.0b013e31827b47bb [MEDLINE]
Airway pressure release ventilation in morbidly obese surgical patients with acute lung injury and acute respiratory distress syndrome Am Surg. 2013 Mar;79(3):242-6 [MEDLINE]
Airway Pressure Release Ventilation and High-Frequency Oscillatory Ventilation: Potential Strategies to Treat Severe Hypoxemia and Prevent Ventilator-Induced Lung Injury. Respir Care. 2015 Oct;60(10):1509-21. doi: 10.4187/respcare.04255 [MEDLINE]
Airway Pressure Release Ventilation May Result in Occult Atelectrauma in Severe ARDS. Respir Care. 2016 Sep;61(9):1278-80. doi: 10.4187/respcare.05099 [MEDLINE]
Should Airway Pressure Release Ventilation Be the Primary Mode in ARDS? Respir Care. 2016 Jun;61(6):761-73. doi: 10.4187/respcare.04653 [MEDLINE]
Partial Liquid Ventilation
Partial liquid ventilation for preventing death and morbidity in adults with acute lung injury and acute respiratory distress syndrome. Cochrane Database Syst Rev. 2013 Jul 23;7:CD003707 [MEDLINE]
Body Position -> Proning
Conference on the scientific basis of respiratory therapy. Pulmonary physiotherapy in the pediatric age group. Comments of a devil’s advocate. Am Rev Respir Dis 1974; 110: 143-144 [MEDLINE]
Effect of prone position on patients with hydrostatic pulmonary edema compared with patients with acute respiratory distress syndrome and pulmonary fibrosis. Am J Respir Crit Care Med 2000;151:360-368 [MEDLINE]
Effect of prone positioning on the survival of patients with acute respiratory failure. N Engl J Med 2001;345:568-573 [MEDLINE]
Decrease in PaCO2 with prone position is predictive of improved outcome in acute respiratory distress syndrome. Crit Care Med. 2003 Dec;31(12):2727-33 [MEDLINE]
Effect of systematic prone positioning in hypoxemic acute respiratory failure. JAMA 2004;292:2379-2387 [MEDLINE]
A multicenter trial of prolonged prone ventilation in severe acute respiratory distress syndrome. Am J Respir Crit Care Med 2006; 173: 1233-1239 [MEDLINE]
Effect of mechanical ventilation in the prone position on clinical outcomes in patients with acute hypoxemic respiratory failure: a systematic review and meta-analysis. CMAJ. 2008 Apr 22;178(9):1153-61 [MEDLINE]
The effect of prone positioning in acute respiratory distress syndrome or acute lung injury. Intensive Care Med 2008;34:1002-1011 [MEDLINE]
Prone ventilation reduces mortality in patients with acute respiratory failure and severe hypoxemia: systematic review and meta-analysis. Intensive Care Med. 2010 Apr;36(4):585-99 [MEDLINE]
PROSEVA: Prone positioning in severe acute respiratory distress syndrome. Engl J Med. 2013 Jun 6;368(23):2159-68. doi: 10.1056/NEJMoa1214103. Epub 2013 May 20 [MEDLINE]
In prone ventilation, one good turn deserves another. N Engl J Med 2013;368(23):2227-2228 [MEDLINE]
Effects of interventions on survival in acute respiratory distress syndrome: an umbrella review of 159 published randomized trials and 29 meta-analyses. Intensive Care Med 2014; 40: 769-787 [MEDLINE]
Prone positioning reduces mortality from acute respiratory distress syndrome in the low tidal volume era: a meta- analysis. Intensive Care Med 2014; 40: 332-341 [MEDLINE]
The efficacy and safety of prone positional ventilation in acute respiratory distress syndrome: updated study-level meta-analysis of 11 randomized controlled trials. Crit Care Med 2014; 42: 1252-1262 [MEDLINE]
Prone position for acute respiratory failure in adults. Cochrane Database Syst Rev 2015; 11: CD008095 [MEDLINE]
Efficacy of prone position in acute respiratory distress syndrome patients: A pathophysiology-based review. World J Crit Care Med. 2016 May 4;5(2):121-36. doi: 10.5492/wjccm.v5.i2.121. eCollection 2016 [MEDLINE]
Prone Position Reduces Spontaneous Inspiratory Effort in Patients with Acute Respiratory Distress Syndrome: A Bi-Center Study. Am J Respir Crit Care Med. 2021 Feb 10. doi: 10.1164/rccm.202012-4509LE [MEDLINE]
Patient-Directed Prone Positioning in Awake Patients with COVID-19 Requiring Hospitalization (PAPR). Ann Am Thorac Soc. 2021 Feb 17. doi: 10.1513/AnnalsATS.202011-1466RL [MEDLINE]
Factors Influencing the Implementation of Prone Positioning During the COVID-19 Pandemic: A Qualitative Study. Ann Am Thorac Soc. 2022 Aug 10. doi: 10.1513/AnnalsATS.202204-349OC [MEDLINE]
Body Position -> Head of Bed at 30°
Pulmonary aspiration of gastric contents in patients receiving mechanical ventilation: the effect of body position. Ann Intern Med 1992; 116:540-543 [MEDLINE]
Body Position -> Continuous Lateral Rotational/Kinetic Bed Therapy
Effect of air-supported, continuous, postural oscillation on the risk of early ICU pneumonia in nontraumatic critical illness. Chest. 1993 May;103(5):1543-7 [MEDLINE]
Acute effects of continuous rotational therapy on ventilation-perfusion inequality in lung injury. Intensive Care Med. 1998 Feb;24(2):132-7 [MEDLINE]
Rotational bed therapy to prevent and treat respiratory complications: a review and meta-analysis. Am J Crit Care. 2007 Jan;16(1):50-61; quiz 62 [MEDLINE]
Automated Rotational Percussion Bed and Bronchoscopy Improves Respiratory Mechanics and Oxygenation in ARDS Patients Supported with Extracorporeal Membrane Oxygenation. ASAIO J. 2016 May-Jun;62(3):e27-9. doi: 10.1097/MAT.0000000000000341 [MEDLINE]
Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Inhaled Nitric Oxide in ARDS Study Group. Crit Care Med. 1998;26(1):15 [MEDLINE]
Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial. JAMA. 2004;291(13):1603 [MEDLINE]
Effect of nitric oxide on oxygenation and mortality in acute lung injury: systematic review and meta-analysis. BMJ. 2007 Apr 14;334(7597):779 [MEDLINE]
Therapies for refractory hypoxemia in acute respiratory distress syndrome. JAMA. 2010;304(22):2521 [MEDLINE]
Inhaled nitric oxide for acute respiratory distress syndrome and acute lung injury in adults and children: a systematic review with meta-analysis and trial sequential analysis. Anesth Analg. 2011;112(6):1411 [MEDLINE]
Inhaled nitric oxide does not reduce mortality in patients with acute respiratory distress syndrome regardless of severity: systematic review and meta-analysis. Crit Care Med. 2014;42(2):404 [MEDLINE]
Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) in children and adults. Cochrane Database Syst Rev. 2016 Jun 27;(6):CD002787. doi: 10.1002/14651858.CD002787.pub3 [MEDLINE]
The effect of inhaled nitric oxide in acute respiratory distress syndrome in children and adults: a Cochrane Systematic Review with trial sequential analysis. Anaesthesia. 2017 Jan;72(1):106-117 [MEDLINE]
Inhalational agents for pulmonary hypertension. Lancet. 1993 Oct;342(8877):941-2 [MEDLINE]
Inhaled prostacyclin (PGI2) versus inhaled nitric oxide in adult respiratory distress syndrome. Am J Respir Crit Care Med. 1996;154(6 Pt 1):1671 [MEDLINE]
Direct comparison of inhaled nitric oxide and aerosolized prostacyclin in acute respiratory distress syndrome. Am J Respir Crit Care Med. 1996;153(3):991 [MEDLINE]
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