Asynchrony Injures Lung and Diaphragm in Acute Respiratory Distress Syndrome*

Abstract

Objectives: 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. Design: Prospective randomized animal study. Setting: University research laboratory. Subjects: Eighteen New Zealand White rabbits. Interventions: 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. Conclusions: 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.

Setting positive end-expiratory pressure: role in diaphragm-protective ventilation

“…In turn, patient-ventilator asynchronies could have an adverse effect on the diaphragm. In a recent study in a rabbit ARDS model, reverse triggering and breath stacking resulted in both diaphragm and lung injury [8 ▪ ]. However, no indications of diaphragm myotrauma caused by patient-ventilator asynchronies were found in another study in pigs with ARDS [44].…”

“…Finally, certain types of patient-ventilator asynchrony may contribute to diaphragm myotrauma due to the occurrence of injurious eccentric (lengthening) contractions [7]. In an animal model of acute respiratory distress syndrome (ARDS), reverse triggering caused eccentric contractions of the diaphragm with concomitant diaphragm myotrauma [8 ▪ ]. This has been discussed in more detail in a recent narrative review [9].…”

Dyssynchronous diaphragm contractions impair diaphragm function in mechanically ventilated patients

“…The hypothesis of eccentric myotrauma as a mechanism of ventilator-induced diaphragm dysfunction is intriguing, but its clinical relevance remains uncertain. Pre-clinical studies have demonstrated that dyssynchronous diaphragm contractions are associated with acute diaphragm injury and dysfunction [ 5 – 7 ] and that eccentric loading results in acute diaphragmatic weakness [ 8 ]. Diaphragm biopsies in humans including mechanically ventilated patients manifest evidence of acute load-induced injury and inflammation [ 9 , 10 ], suggesting that load-induced injury occurs in this setting.…”

Lung and Diaphragm Protection During Mechanical Ventilation: Synchrony Matters*

“…In the current issue of Critical Care Medicine , Hashimoto et al (11) conducted an experimental study to test the hypothesis that some forms of dyssynchrony may cause lung and diaphragm injury. In a rabbit model of acute lung injury, the authors used phrenic nerve stimulation to induce breath stacking or reverse triggering for a period of 4 hours.…”

“…The clinical benefit of the lung-protective and diaphragm-protective approach, and of ameliorating these forms of dyssynchrony, remains to be tested in clinical trials. The work by Hashimoto et al (11) highlights the urgent need for these trials.…”