Patient-ventilator asynchrony is often observed during mechanical ventilation and is associated with higher mortality. We hypothesized that patient-ventilator asynchrony causes lung and diaphragm injury and dysfunction.


Prospective randomized animal study.


University research laboratory.


Eighteen New Zealand White rabbits.


Acute respiratory distress syndrome (ARDS) model was established by depleting surfactants. Each group (assist control, breath stacking, and reverse triggering) was simulated by phrenic nerve stimulation. The effects of each group on lung function, lung injury (wet-to-dry lung weight ratio, total protein, and interleukin-6 in bronchoalveolar lavage), diaphragm function (diaphragm force generation curve), and diaphragm injury (cross-sectional area of diaphragm muscle fibers, histology) were measured. Diaphragm RNA sequencing was performed using breath stacking and assist control (n = 2 each).

Measurements and Main Results: 

Inspiratory effort generated by phrenic nerve stimulation was small and similar among groups (esophageal pressure swing ≈ –2.5 cm H2O). Breath stacking resulted in the largest tidal volume (>10 mL/kg) and highest inspiratory transpulmonary pressure, leading to worse oxygenation, worse lung compliance, and lung injury. Reverse triggering did not cause lung injury. No asynchrony events were observed in assist control, whereas eccentric contractions occurred in breath stacking and reverse triggering, but more frequently in breath stacking. Breath stacking and reverse triggering significantly reduced diaphragm force generation. Diaphragmatic histology revealed that the area fraction of abnormal muscle was ×2.5 higher in breath stacking (vs assist control) and ×2.1 higher in reverse triggering (vs assist control). Diaphragm RNA sequencing analysis revealed that genes associated with muscle differentiation and contraction were suppressed, whereas cytokine- and chemokine-mediated proinflammatory responses were activated in breath stacking versus assist control.


Breath stacking caused lung and diaphragm injury, whereas reverse triggering caused diaphragm injury. Thus, careful monitoring and management of patient-ventilator asynchrony may be important to minimize lung and diaphragm injury from spontaneous breathing in ARDS.

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