Respiratory drive heterogeneity associated with systemic inflammation and vascular permeability in acute respiratory distress syndrome

Abstract

Background: In acute respiratory distress syndrome (ARDS), respiratory drive often differs among patients with similar clinical characteristics. Readily observable factors like acid-base state, oxygenation, mechanics, and sedation depth do not fully explain drive heterogeneity. This study evaluated the relationship of systemic inflammation and vascular permeability markers with respiratory drive and clinical outcomes in ARDS.

Methods: ARDS patients enrolled in the multicenter EPVent-2 trial with requisite data and plasma biomarkers were included. Neuromuscular blockade recipients were excluded. Respiratory drive was measured as P_ES0.1, the change in esophageal pressure during the first 0.1 s of inspiratory effort. Plasma angiopoietin-2, interleukin-6, and interleukin-8 were measured concomitantly, and 60-day clinical outcomes evaluated.

Results: 54.8% of 124 included patients had detectable respiratory drive (P_ES0.1 range of 0-5.1 cm H₂O). Angiopoietin-2 and interleukin-8, but not interleukin-6, were associated with respiratory drive independently of acid-base, oxygenation, respiratory mechanics, and sedation depth. Sedation depth was not significantly associated with P_ES0.1 in an unadjusted model, or after adjusting for mechanics and chemoreceptor input. However, upon adding angiopoietin-2, interleukin-6, or interleukin-8 to models, lighter sedation was significantly associated with higher P_ES0.1. Risk of death was less with moderate drive (P_ES0.1 of 0.5-2.9 cm H₂O) compared to either lower drive (hazard ratio 1.58, 95% CI 0.82-3.05) or higher drive (2.63, 95% CI 1.21-5.70) (p = 0.049).

Conclusions: Among patients with ARDS, systemic inflammatory and vascular permeability markers were independently associated with higher respiratory drive. The heterogeneous response of respiratory drive to varying sedation depth may be explained in part by differences in inflammation and vascular permeability.

Keywords: Acute respiratory distress syndrome; Hypnotics and sedatives; Mechanical ventilation; Respiratory mechanics; Work of breathing.

Fig. 1

Association of circulating inflammatory biomarkers angiopoietin-2, interleukin-6, and interleukin-8, with respiratory drive. To facilitate data visualization, the range of P_ES0.1 across tertiles of biomarker values is shown

Fig. 2

Association of circulating plasma concentration of inflammatory biomarkers angiopoietin-2, interleukin-6, and interleukin-8, with respiratory drive in univariable and multivariable models. Adjusted model 1 includes the biomarker of interest and measures of lung mechanics (tidal volume scaled to predicted body weight, end-inspiratory transpulmonary pressure, end-expiratory transpulmonary pressure), chemoreceptor input (pH, PaCO₂, PaO₂) and sedation depth (Richmond agitation-sedation score [RASS]). Adjusted model 2 includes all covariates in adjusted model 1 plus clinical markers of inflammation (maximum temperature and white blood cell count in the 24 h preceding enrollment) and an index of multiorgan dysfunction (sequential organ failure assessment [SOFA]). The biomarker of interest was entered as a continuous log-transformed variable into each model. Additional sensitivity analyses with alternative model formulations are reported in the online supplement

Fig. 3

Respiratory drive and survival. Kaplan–Meier plots. Patients were classified as having low drive if P_ES0.1 was less than 0.5 cm H₂O, moderate drive if between 0.5–2.9 cm H₂O, and high drive if 3.0 cm H₂O or higher. P_ES0.1 refers to the change in esophageal pressure, a surrogate of pleural pressure, during the first 0.1 s (100 ms) of patient inspiratory effort

Fig. 4

Factors contributing to respiratory drive heterogeneity in acute respiratory failure. Inflammation and associated vascular permeability are key determinants of respiratory drive in critical illness that may explain why some critically ill patients experience refractory high drive despite accounting for other clinically observable factors, including even deep sedation. High drive in turn may cause patient self-inflicted lung injury (P-SILI) that increases inflammatory signaling, creating a positive feedback loop. Blue denotes chemoreceptor inputs. Green denotes pulmonary mechanoreceptor inputs. Purple denotes supratentorial inputs. Red denotes inflammatory input