PReVENT

Clinical Question

In mechanically ventilated patients without ARDS, does a low tidal volume ventilation strategy (4-6 mL/kg PBW) as compared to an intermediate tidal volume strategy (8-10 mL/kg PBW) decrease the number of ventilator-free and alive days?

Bottom Line

In mechanically ventilated patients without ARDS, low tidal volume ventilation (4-6 mL/Kg PBW) had no effect on mortality or ventilator-free and alive days when compared to an intermediate tidal volume ventilation (8-10 mL/Kg PBW).

Major Points

Current international guidelines recommend using mechanical ventilation with low tidal volumes (less than 6-8 mL/Kg) for patients with ARDS, but the benefit of low tidal volume ventilation for patients without ARDS remains less certain. Two previous RCTs found tidal volume reduction to be associated with a lower number of pulmonary complications in patients without ARDS. Additionally, two individual patient data meta-analyses suggested that tidal volume reduction may shorten length of mechanical ventilation as well as ICU and hospital length of stay.

However, low tidal volume ventilation is not without risks. Lower tidal volumes could lead to higher sedation requirements due to higher respiratory rate or patient-ventilator asynchrony (along with associated self-inflicted lung injury) and longer duration of mechanical ventilation. In addition, it has been suggested that low tidal volumes may increase the risk of delirium in some patients.

Design

• Multicenter, randomized, controlled trial
• N= 961
  • Low Tidal Volume Strategy (n=477, with 2 patients lost to follow up)
  • Intermediate Tidal Volume Strategy (n=484, with 4 patients lost to follow up)
• Setting: 6 university and non university ICUs in the Netherlands
• Enrollment: September 2014 to August 2017
• Follow-up: 90 days
• Analysis: Intention-to-treat
• Primary outcome: ventilator-free days and alive at day 28, defined as:
  • The total number of days that a patient was alive and free from mechanical ventilation 28 days after randomization

Population

Inclusion Criteria

• Intubated and ventilated adult ICU patients (over 18 years of age) with an expected need for ventilator support >24 hours
  • Patients who already received ventilation before ICU admission were included if they could be enrolled within 1 hour of ventilation in the ICU

Exclusion Criteria

• Patients with ARDS at start of ventilation, according to the Berlin definition
  • Patients with a PaO2/FiO2 between 200 and 300 mmHg were accepted into the trial, but patients with a PaO2/FiO2 less than 200 mmHg within the first hour of ventilation were excluded, unless fluid overload or cardiac failure were the cause of hypoxia
• Age younger than 18 years
• Pregnant patients
• Ventilation lasting >12 hours directly preceding admission to the ICU
• Increased and uncontrollable intracranial pressure (of ≥ 18 mmHg)
• New pulmonary thromboembolism
• Previously randomized in PReVENT or other interventional trials
• History of pulmonary disease
  • GOLD classification III or IV COPD
  • Status asthmaticus
  • Previous pneumectomy or lobectomy
  • Premorbid restrictive pulmonary disease with evidence of chronic interstitial infiltration on previous chest radiographs

Baseline Characteristics

Baseline characteristics were similar between low and intermediate tidal volume strategy:

• Median age (68 vs 67 years old)
• SOFA score (8 vs 8)
• Medical reason for admission (82.7% vs 83.6%)
• Median time between start of ventilation in the ICU and randomization was 0.57 hours (0.23-1.00)
• Reason for intubation:
  • Cardiac arrest 23.1% vs 24.8%
  • Post-operative ventilation 17.2% vs 16.3%
  • Pneumonia 16.1% vs 15.9%
  • Sepsis 10.5% vs 9.5%
• Median time between start of ventilation in ICU and randomization

Interventions

Low Tidal Volume Strategy

• Patients were initiated with tidal volume of 6ml/Kg PBW with either volume controlled or pressure support modes
• If volume controlled, tidal volume was decreased by 1 mL/Kg every hour until a minimum of 4 mL/Kg
• If pressure support, the minimum pressure was 5 cm H2O
  • If tidal volume increased to >8mL/Kg PBW despite 5cm H2O, the pressure was not lowered
• Tidal volume could be increased in increments of 1 mL/kg PBW per hour in patients receiving volume-controlled or pressure support ventilation in the case of:
  • Severe dyspnea, identified by:
    • Increasing levels of discomfort with or without the need for increased sedation
    • Respiratory rate >35 breaths per min
    • Patient-ventilator asynchrony
  • Uncontrollable acidosis <7.25

Intermediate Tidal Volume Strategy

• Patients were initiated with tidal volume of 10ml/Kg PBW with either volume controlled or pressure support modes
  • In volume controlled mode, if plateau pressure >25 cm H2O, tidal volume was decreased by 1mL/Kg PBW per hour, to a minimum of 8 ml/kg PBW
  • In pressure support mode, pressure support level was adjusted to reach the target tidal volume while keeping the maximum airway pressure <25 cm H2O

Outcomes

Comparisons are Low Tidal Volume Strategy vs. Intermediate Tidal Volume Strategy.

Primary Outcomes

Median Ventilator-free days and alive at day 28

21 days (IQR, 0-26) (mean difference, –0.27 [95% CI −1.74 to 1.19] P = 0.71)

Secondary Outcomes

Median ICU length of stay

6 days (IQR, 3-12) (mean difference, 0.39 [95% CI −1.09 to 1.89] P = 0.58)

Median Hospital length of stay

14 days (IQR, 6-26) vs. 15 days (8-26) (mean difference, -0.60 [95% CI −3.52 to 2.31] P = 0.68)

ICU Mortality

29.3% vs. 25.1% (RR, 1.11 [95% CI 0.96 to 1.27] P= 0.15)

Hospital Mortality

31.7% vs. 28.9% (RR, 1.06 [95% CI 0.93 to 1.22] P= 0.35)

28-day Mortality

34.9% vs. 32.1% (RR, 1.12 [95% CI 0.90 to 1.40] P= 0.30)

90-day Mortality

39.1% vs. 37.8% (RR, 1.07 [95% CI 0.87 to 1.31] P= 0.54)

Development of ARDS

3.8% vs. 5% (RR, 0.86 [95% CI 0.59 to 1.24] P= 0.38)

Development of pneumonia

4.2% vs. 3.7% (RR, 1.07 [95% CI 0.78 to 1.47] P= 0.67)

Pneumothorax

1.8% vs. 1.3% (RR, 1.16 [95% CI 0.73 to 1.84] P= 0.55)

Atelectasis

11.4% vs. 11.2% (RR, 1.00 [95% CI 0.81 to 1.23] P= 0.94)

Extrapulmonary infection

4.5% vs. 6% (RR, 0.84 [95% CI 0.60 to 1.18] P= 0.28)

Extrapulmonary sepsis

2.7% vs. 3.5% (RR, 0.87 [95% CI 0.56 to 1.33] P= 0.50)

Delirium

43.4% vs. 36.6% (RR, 1.15 [95% CI 0.99 to 1.34] P= 0.06)

Need for tracheostomy

11.3% vs. 10.7% (RR, 1.03 [95% CI 0.84 to 1.26] P= 0.78)

Subgroup Analysis

There was a significant interaction in the effect of tidal volume on the Median Ventilator-free days and alive at day 28 in patients intubated inside the ICU (mean difference, –2.50 [IQR, –4.63 to –0.36]) vs patients intubated outside the ICU (mean difference, 1.45 [IQR –0.52 to 3.43]; P for interaction = .01).

Criticisms

• There was inadequate overall separation between the low vs intermediate ventilation strategies after day 1.
  • This could mean the PReVENT trial was underpowered to detect any true difference between low and intermediate volume ventilation strategies
• Selection bias was likely introduced due to the fact that many eligible patients missed entry into the trial (704/2734 of the total eligible patients or 26%), and many refused consent (304/2734 of the total eligible patients or 11%).
• The patient population consisted of all non-ARDS patients (with exceptions below), which means any benefit in sub groups may be not been detected.
  • Patients with severe COPD, status asthmaticus, previous pneumonectomy or lobectomy, and premorbid restrictive pulmonary disease were excluded and therefore results cannot be applied to these populations.
• Blinding the treating clinicians for ventilation strategies is difficult, and may have led to other non-measured changes in management biasing the results.

Funding

• This study was an investigator-initiated trial, but funded by the ZonMW (Zorgonderzoek Medische Wetenschappen) which is a part of the NWO (Nederlandse Organisatie voor Wetenschappelijk Onderzoek; the Dutch Organization for Scientific Research).