The Land of Irrelevance #1 - The PReVENT Study
The first edition of The Land of Irrelevance is here! Today I recall PReVENT, a 2018 RCT published in JAMA.
Title: Effect of a Low vs Intermediate Tidal Volume Strategy on Ventilator-Free Days in Intensive Care Unit Patients Without ARDS.
Scenario: Mechanically ventilated patients without ARDS
Dominant Cause: Ventilatory failure
Dominant intervention: Mechanical ventilation
Hypothesis: In patients on mechanical ventilation for any reason except ARDS, a ventilation strategy with lower tidal volumes results in more days alive and free of mechanical ventilation on the 28th day.
Causal chain: The hypothesis may translate as (1) Higher tidal volumes cause alveolar mechanical stress. (2) Alveolar mechanical stress causes VILI. (3) VILI causes poor oxygenation. (4) Poor oxygenation causes prolonged mechanical ventilation and ultimately death. Statements 1 and 2 are in the realm of biological plausibility. Statement 3 is the assumption of a pre-clinical consequence of the former clauses. Statement 4 assumes a clinical effect resulting from the causal chain. For the study hypothesis to be true, all the stated mechanisms must be intense enough to cause the next in the chain AND the final assumption must be a dominant cause of death or prolonged MV.
Case: Marginal cause. Volume-induced alveolar damage although present, is not a dominant cause of death or prolonged MV.
Narrative:
During mechanical ventilation, whenever the inspiratory valve opens, some amount of mechanical energy is converted to kinetic energy as the gas flows through the airways. When the motion stops, that same amount of energy has fully dissipated into the lung tissues causing mechanical stress.
This is a sound statement of biological plausibility. The more energy, the more you harm the patient. Hence, I don't need clinical studies to decide whether I will ventilate parsimoniously. I always use less pressure and volume, and, because every inspiration is another insult, I try to use lower respiratory rates. The lower boundary of this strategy is hypoventilation, asynchrony, hypoxemia, etc.
However, in the clinical scenario, the effect of more or less volume/pressure/rate within a safe range is marginal. Let's examine the dominant and marginal causes.
The PReVENT study included patients intubated for more than 15 distinct reasons, but they all have one thing in common: they were alive at randomization because they were in mechanical ventilation. Ventilatory failure was the dominant cause of death in these patients, hence any form of MV is the dominant intervention if the outcome is mortality. Moreover, the 15+ causes of ventilatory insufficiency are also dominant determinants of mortality. Any other cause is marginally linked to mortality.
Please notice that the dominant causes of mortality and its treatments are present in all patients from randomization. Therefore, with the dominant causes and related treatments equally distributed in the study arms, the trial only tests the marginal effect of different tidal volumes within reasonable ranges. Due to the exponential distribution of the marginal effects size, the study intervention lies in the long tail of irrelevant interventions. In plain English, provided that everything that matters is addressed, don't expect a few more mL of air to kill someone. No RCT was needed.
For mistaking biological plausibility for clinical relevance, PReVENT rests forever in the windy fields of the Land of Irrelevance.
