Positive End Expiratory Pressure in Adults with Acute Lung Injury and Acute Respiratory Distress Syndrome

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Mercat A, et al. "Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial". JAMA. 2008. 299(6):646-655.
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Clinical Question

In patients with acute respiratory distress syndrome treated with low tidal volume, Does high PEEP (increased recruitment) vs. moderate PEEP (minimal distention) affect 28-day mortality ?

Bottom Line

Adjusting PEEP to higher levels to achieve a plateau pressure of 28-30 did not improve 28 day, 60 day, and in-hospital mortality; and required more IV fluids. However was associated wit less ventilator free days, and organ-failure free days without increased incidence of pneumothorax.

Major Points

Reducing ventilator induced lung injury is pivotal in management of ARDS patients. Higher PEEP can lead to alveolar recruitment and better oxygenation. At the same time, Higher PEEP can cause lung hyperinflation. The ideal clinical strategy to optimize PEEP and limit ventilator induced tissue stress is controversial. This study was terminated early due to failure of higher PEEP to reduce absolute mortality by 10%.

Guidelines

Design

  • Multi-center, randomized, controlled trial
  • N=768
    • Minimal distention (n=282)
    • Increased recruitment (n=285)
  • Setting: 37 intensive care units in France
  • Enrollment: September 16, 2002, and December 12, 2005
  • Mean follow-up: 60 days
  • Analysis: Intention-to-treat
  • Primary outcome:
 28 day mortality 
  • Secondary outcome:
 60 day mortality
 In-hospital mortality
 Ventilator free days 
 Organ failure free days (between day 1-28) 
 Proportion of patients who developed pneumothorax required chest tube by day 28

Population

Inclusion Criteria

  • patients with adult respiratory distress syndrome, on mechanical ventilation for less than 48 hours

ARDS was defined as: P/F ratio < 300 bilateral acute chest infiltrate less likely due to left atrial hypertension

Exclusion Criteria

  • Age less than 18 years
  • Females with known pregnancy
  • Participation in another trial within 30 days before meeting the eligibility criteria
  • High intracranial pressure
  • Sickle cell disease
  • Severe chronic respiratory disease requiring long-term oxygen therapy or home mechanical ventilation
  • Actual body weight exceeding 1 kg/cm of height
  • Severe burns
  • Severe chronic liver disease (Child-Pugh class C),
  • Bone marrow transplant or chemotherapy-induced neutropenia
  • Pneumothorax
  • Expected duration of mechanical ventilation shorter than 48 hours
  • Decision to withhold life-sustaining treatment.

Baseline Characteristics

mean [SD]

  • Mean age: 59.9 [15.4 years]
  • 95% were ventilated with a total PEEP of 5 or more at inclusion
  • 84% had a PaO2:FIO2 equal to or lower than 200 mm Hg
  • Septic shock in 60 vs. 63 %
  • Causes of lung injury were mainly; pneumonia 50 vs. 52%, aspiration 23 vs 20% , intra-abdominal sepsis 7 vs. 8 %

Interventions

  • 6 ml/kg ideal body weight tidal volume in both groups
  • FiO2 was used to achieve oxygenation target
  • Randomized to minimal distention (5-9 of PEEP --> lowest inspiratory plateau pressure) or higher recruitment (PEEP titrated to achieve inspiratory plateau pressure of 28-30)
  • No recruitment maneuver were allowed or recommended
  • Similar weaning protocol was used for both arms

Outcomes

Comparisons are minimal distention vs. higher recruitment

Primary Outcomes

28-day mortality
31.2% (95% CI, 26.5%-35.8%) vs 27.8% (95% CI, 23.3%-32.3%)
Relative risk [RR], 1.12 [95% CI, 0.90-1.40] [P = .31]

Secondary Outcomes

60-day mortality
RR, 1.10 [95% CI, 0.92-1.32]
Hospital mortality
RR, 1.10 [95% CI, 0.92-1.32]
Ventilator-free days
Median, 3 [IQR, 0-17] vs. 7 [IQR, 0-19]; P = .04)
Organ failure–free days
Median, 2 [IQR, 0-16]vs. 6 [IQR, 0-18]; P = .04


Subgroup Analysis

28-day mortality differences according to pre-randomization PaO2/FiO2 quartiles were not statistically significant P=0.4


Adverse Events

Pneumothorax between day 1 and day 28
5.8% vs 6.6 P=0.57
volume resuscitation in the first 72 hours
0.5 liters vs 1 P < 0.001

Criticisms

  • Unblinded nature of the study and use of adjunctive interventions left to the discretion of the attending physician in case of severe hypoxemia are possible confounders
  • PEEP was adjusted based on pulmonary pressure and volume independent of oxygenation
  • The investigators did not include a formal evaluation of compliance with the protocols, and prespecified secondary analyses that accounted for intersite variation in compliance, and that may have provided insight into the failure to detect a difference in mortality

Funding

  • Centre Hospitalier Universitaire d’Angers and supported by a grant from
  • The Ministère de la santé (Programme Hospitalier de Recherche Clinique 2001)
  • The Association National pour le Traitement à Domicile de l’Insuffisance Respiratoire (ANTADIR)

Further Reading

ALVEOLI 2004, Brower RG, Lanken PN, MacIntyre N, et al; 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 Jul 22;351(4):327-36.

LOVs 2008, Meade MO, Cook DJ, Guyatt GH, et al; Lung Open Ventilation Study Investigators. Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2008 Feb 13;299(6):637-45. doi: 10.1001/jama.299.6.637.

Express 2008, Mercat A, Richard J-CM, Vielle B, et al; Expiratory Pressure (Express) Study Group. Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2008;299(6):646-655 ART investigators writing group. 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; 318(14):1335-1345.

OLA 2016, Kacmarek RM, Villar J, Sulemanji D, et al. Open Lung Approach for the Acute Respiratory Distress Syndrome: A Pilot, Randomized Controlled Trial. Critical care medicine. 2016; 44(1):32-42

ART 2017, ART investigators writing group. 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; 318(14):1335-1345.