Respiratory drive in the acute respiratory distress syndrome: pathophysiology, monitoring, and therapeutic interventions

Abstract

Neural respiratory drive, i.e., the activity of respiratory centres controlling breathing, is an overlooked physiologic variable which affects the pathophysiology and the clinical outcome of acute respiratory distress syndrome (ARDS). Spontaneous breathing may offer multiple physiologic benefits in these patients, including decreased need for sedation, preserved diaphragm activity and improved cardiovascular function. However, excessive effort to breathe due to high respiratory drive may lead to patient self-inflicted lung injury (P-SILI), even in the absence of mechanical ventilation. In the present review, we focus on the physiological and clinical implications of control of respiratory drive in ARDS patients. We summarize the main determinants of neural respiratory drive and the mechanisms involved in its potentiation, in health and ARDS. We also describe potential and pitfalls of the available bedside methods for drive assessment and explore classical and more "futuristic" interventions to control drive in ARDS patients.

Fig. 1

Metabolic hyperbola, brain and ventilation curves in health and ARDS. The metabolic hyperbola is the relationship between ventilation and the resultant PaCO₂ for a given level of metabolic CO₂ production and dead space. Increased dead space or CO₂ production will shift the hyperbola up. The ventilation curve describes the actual effect of changing PaCO₂ on resultant minute ventilation. ARDS can shift the ventilation curve to the right (lower minute ventilation despite higher PaCO₂) due to increased respiratory load and muscle weakness. Finally, the brain curve (also known as the "controller curve", "CO₂ sensitivity curve" or "ventilation gain curve") describes the minute ventilation theoretically requested by the neural respiratory drive for a given PaCO₂. During ARDS, this is shifted to the left (higher minute ventilation despite lower PaCO₂) due to multiple concomitant pathologic conditions, including acidosis, inflammation and others. a In health, brain and ventilation curves overlap and the ventilation response (i.e., the change in minute ventilation induced by a change in PaCO₂) reflects the neural respiratory drive. The metabolic hyperbola is obtained assuming a dead space of 0.3 and a metabolic CO₂ production (VCO₂) of 200 ml/min. Brain and ventilation curves are overlapping and are calculated assuming at PaCO₂ of 39.5 mmHg, a ventilation of 6.5 l/min, linearly increasing to 30 l/min at a PaCO₂ of 49 mmHg. b In ARDS, the metabolic hyperbola is shifted upward due to increase of dead space (0.5) and VCO₂ (250 ml/min). The listed factors cause the brain and ventilation curves to be shifted in opposite directions and diverge. Please, note that a single ARDS patient will be characterized by both curves at the same time: the brain curve will correspond to the theoretical ventilation/PaCO₂ correlation desired by the neural respiratory drive, while the ventilation curve will be the actual ventilation/PaCO₂ correlation measured by spirometer and blood gas analysis. Brain and ventilation curves are calculated assuming a ventilation of 6.5 l/min at 28 mmHg PaCO₂ (increasing to 30 l/min at 33 mmHg PaCO₂) and a ventilation of 5 l/min at 40 mmHg PaCO₂ (increasing to 25 l/min at 52 mmHg PaCO₂), respectively

Fig. 2

Schematic representation of control of respiratory drive in ARDS. The figure shows the key triggers of respiratory drive and the anatomic targets where these triggers exert their effects. In the centre, the descending cascade from neural respiratory drive to breathing effort and lung stress is represented, together with the main factors that may cause a dissociation between drive and effort (i.e., muscle function) and between drive, effort and lung stress (i.e., neuromechanical coupling and respiratory mechanics)

Fig. 3

Potential dissociation between neural respiratory drive (P_0.1) and respiratory effort (P_es) under pathologic conditions. The figure shows simulated identical waveforms for airway pressure (P_aw) during supported breaths but with different simulated oesophageal pressure (P_es) waveforms. P_0.1 (i.e., the negative airway pressure generated by occlusion occurring during the first 0.1 s of an inspiration) reflects the intensity of neural respiratory drive. Oesophageal pressure swings (ΔP_es) allow quantification of respiratory effort. However, in patients with high chest wall elastance, ΔP_es underestimates effort. In the presence of muscular weakness, high drive may be associated with “normal” or even low effort (right panel)