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Mechanisms of Ventilator-Induced Lung Injury (Part 1)
Although invasive mechanical ventilation saves tens of thousands of lives each year, it can also be harmful, causing or worsening acute respiratory distress syndrome (ARDS) when misapplied. The repetitive stretching of lung tissue during positive pressure ventilation can damage fragile alveoli already made vulnerable by pre-existing illness. This potentially lethal process has been called ventilator-induced lung injury.
The concept of positive pressure ventilation injuring the lungs was recognized as long ago as 1744 by John Fothergill, who observed that for a victim of respiratory arrest in a coal mine, mouth-to-mouth resuscitation should be used rather than bellows: “The lungs of one man may bear, without injury, as great a force as those of another man can exert; which by the bellows cannot always be determin'd.” In 1967, autopsies of mechanically ventilated patients showed parenchymal damage termed "respirator lung"; the acute respiratory distress syndrome (ARDS) was contemporaneously recognized as a disease process producing similar gross and histopathologic findings as so-called "respirator lung" (noncardiogenic pulmonary edema, inflammatory cell infiltration, diffuse alveolar damage and hyaline membrane formation). However, the idea that mechanical ventilation itself could cause or worsen lung injury did not gain wide acceptance for 30 more years, when a randomized trial published in 2000 showed that a lung-protective ventilator strategy improved survival among people with ARDS.
Plateau and Transpulmonary Pressures Demystified
During spontaneous breathing, the diaphragm's movement downward generates negative pressure and air is sucked into the lungs, as into an opening bellows. The pleural pressure is also negative (about -8 cm H2O) and tends to pull the lungs open. With neuromuscular blockade (paralysis), breathing efforts stop and the pleural pressure is about +1 cm H2O.
During mechanical ventilation, air is pumped in under positive pressure. The pleural pressure is still negative in non-paralyzed patients and helps to expand the lungs. Whether air gets sucked in (under negative pressure) or blown in (under positive pressure), either way it creates a positive pressure like any gas in a closed space. At all points in the respiratory cycle, the positive pressure of the air in the lungs (alveolar pressure) combined with the vacuum outside the lungs in the pleural space (pleural pressure which carries a negative value), act together to keep the lungs open. These forces are opposed by the resistance of the airways and the lungs' and chest wall's recoil. At end inspiration, the pressure holding open the lungs is called the transpulmonary pressure, which is the alveolar pressure (always positive) minus the pleural pressure (usually negative in non-paralyzed patients, so it's "added").
Pleural pressure can't be measured accurately or easily; it can be approximated by measuring esophageal pressure, but this is somewhat inconvenient and not widely performed. Alveolar pressure can't be measured easily either. To approximate alveolar pressure, the airway pressure (in the ventilator circuit) is measured at end-inspiration (during an "inspiratory pause"). The airway pressure at end-inspiration is called the plateau pressure.
Plateau pressure is essentially flawed as a clinical variable in that even when accurate, it can only measure the sum of alveolar pressures. But ventilator-associated lung injury is caused by regional lung overdistension, when in-flowing air follows the path of least resistance to overfill healthy, compliant alveoli rather than to noncompliant, diseased areas of lung.
Still, plateau pressure is a fair proxy for transpulmonary pressure -- as long as pleural pressure (which it does not consider) is not too negative, and resistive chest wall forces (which it does, though they're harmless to the lungs) are not too positive. Pleural effusions, ascites, or severe obesity can falsely elevate plateau pressure above alveolar pressure. High spontaneous breathing efforts generate high negative pleural pressures, which can significantly increase transpulmonary pressure despite a normal-appearing plateau pressure.
Plateau pressure should therefore be kept below 30 cm H2O, and preferably as low as possible, while considering the above factors in its interpretation.
Mechanisms of Ventilator Induced Lung Injury
Most ventilator-induced lung injury is believed to occur at high ventilator volumes (by regional lung over distention or what has been called barotrauma or volutrauma), but ventilator-induced lung injury can also occur when volumes are too low (through repetitive shear injury, called atelectrauma).
High Lung Volume Ventilator-Induced Lung Injury
Ventilation at high lung volumes can rupture alveoli and create gross barotrauma (pneumothorax, subcutaneous emphysema, and/or pneumomediastinum), but these complications are relatively uncommon. More often, ventilator induced lung injury from repetitive lung overdistention manifests more subtly as noncardiogenic pulmonary edema. When this edema becomes visible on plain chest films and is accompanied by significant hypoxemia (PaO2/FiO2 < 300 mm Hg), it is called ARDS (acute respiratory distress syndrome). It remains unclear exactly how this process occurs, but overdistension of alveoli is clearly involved, leading to the coinage "volutrauma" to describe the derangement. The term "acute lung injury" still has pathophysiologic utility but has been deprecated as a clinical diagnosis in favor of the term "mild ARDS."
Ventilator-Induced Lung Injury at Low Lung Volumes
"Atelectrauma" describes injury to lung parenchyma caused by stretching forces associated with repetitive opening and closing of alveoli. This damages the epithelial cells, which slough, leak proteinaceous fluid, and permit the development of hyaline membranes and pulmonary edema. Areas of inhomogeneity in diseased lungs -- where aerated lung borders on atelectatic tissue -- are most susceptible to further atelectraumatic injury during mechanical ventilation. This vulnerability is the rationale for using higher levels of positive end-expiratory pressure (PEEP) in patients with severe ARDS.
Biotrauma, Inflammation, and Multiorgan Failure from Ventilator-Induced Lung Injury
These mechanisms of injury create a pro-inflammatory milieu in the diseased lung, which can itself worsen and extend lung injury. Intracellular mediators (cytokines and other proteins) may be directly injurious, or result in the influx of neutrophils whose activities further damage the epithelium. The leaky epithelium permits translocation of bacteria, lipopolysaccharide, or inflammatory mediators from the alveoli into the bloodstream. This can trigger a massive systemic inflammatory response (infectious, non-infectious, or both) that results in multiple organ system failure, worsened ARDS, and death.
This systemic inflammation is at least as great a threat to life as impaired gas exchange for people with severe ARDS. Minimizing the ventilator's contribution to this deadly process should be a top therapeutic priority in the treatment of most people with lung injury.
Arthur Slutsky and V. Marco Ranieri. Ventilator-Induced Lung Injury. N Engl J Med 2013; 369:2126-36.