Optimal Ventilator Strategies in Acute Respiratory Distress Syndrome

Michael C. Sklar, MD; Bhakti K. Patel, MD; Jeremy R. Beitler, MD, MPH; Thomas Piraino, RRT; Ewan C. Goligher, MD, PhD


Semin Respir Crit Care Med. 2019;40(1):81-93. 

In This Article

Optimizing Tidal Volume

Lower tidal volumes (VT) attenuate biophysical lung injury by several mechanisms. Preventing frank overdistension (volutrauma/barotrauma),[1–3] decreasing tidal shear strain in regions of mechanical heterogeneity,[4,5] and reducing cyclic opening and collapse of small airways/alveoli (atelectrauma)[6–8] all reduce cellular and extracellular matrix injury.[9–11] Multicenter trials have demonstrated that targeting VT of 6 mL/kg predicted body weight (PBW), compared with 12 mL/kg PBW, expedites resolution of multiple organ failures, lessens systemic inflammation, and improves survival in patients with ARDS.[1,2,12,13]

However, while 6 is superior to 12 mL/kg PBW, the ideal VT strategy in ARDS is unknown. Two mechanistic human studies have found lowering VT below 6 mL/kg PBW by means of extracorporeal life support as needed to maintain adequate gas exchange may attenuate systemic inflammation in select patients with severe ARDS and poor respiratory system compliance.[14,15] The recently published EOLIA trial aimed to address this question by randomizing patients with severe ARDS to conventional mechanical ventilation (CMV) or extracorporeal membrane oxygenation.[16] This trial was stopped early by the data safety monitoring board and failed to demonstrate a statistical difference in the primary outcome of mortality at 60 days. Reanalysis of the EOLIA trial suggested that this biological signal with ultra-low VT for very severe ARDS may translate to clinical benefit.[16,17] Readers are guided to the accompanying section on mechanical circulatory support for more details.

Existing data indicate that no arbitrary VT threshold, even if scaled to PBW, is universally protective for all patients.[18–20] Rather, an ideal VT strategy likely must incorporate two related patient-specific factors: mechanics and biology.[21]

Several approaches have gained interest recently for adjusting VT according to mechanics. Perhaps most immediately clinically accessible is airway driving pressure, defined as plateau pressure minus positive end-expiratory pressure (PEEP). Airway driving pressure is equivalent mathematically to VT scaled to the individual patient's respiratory system compliance (VT/CRS) (Figure 1). It was highly correlated with mortality independent of VT in a secondary analysis of multiple ARDS randomized trials.[22] Airway driving pressure also appears highly correlated with VT scaled to lung compliance (transpulmonary driving pressure = VT/CL).[23] Typical transpulmonary driving pressure is roughly 5 to 10 cm H2O with normal spontaneous breathing in healthy individuals,[24,25] indicating the usual amount of global stress experienced across the lung in health. However, transpulmonary driving pressure can be substantially higher in patients with ARDS due to changes in compliance of the injured lung.[21,26] Targeting healthy normal driving pressure during ARDS has intuitive appeal for this reason, but its role for enhancing lung protection remains to be tested directly in prospective clinical trials.

Figure 1.

Driving pressure and compliance. Top panel: respiratory pressures generated during a volume-controlled ventilation breath with an end-inspiratory pause. After generation of the peak inspiratory pressure, a pause allows for static conditions and the measurement of plateau pressure. The difference between the plateau and end-expiratory pressure is the airway driving pressure. Respiratory system compliance is the tidal volume divided by the driving pressure. Bottom panel: the effect of compliance on driving pressure. On this pressure–volume graph, compared with curve B, curve A illustrates a patient with increased respiratory system compliance and as a result at a given tidal volume there is reduced driving pressure.

Volume-based strategies for individualizing VT to mechanics include scaling VT to either functional residual capacity (FRC) measured at end-expiration (VT/FRC) or inspiratory capacity (IC) measured during a maximal insufflation maneuver (VT/IC). FRC-based approaches use computed tomography imaging, nitrogen wash-out/wash-in, or helium dilution to measure end-expiratory lung volume,[26–28] after which VT might be set to equal a certain percentage of that volume. Of course, FRC may change rapidly with any adjustment in ventilator pressures or volumes and with the evolution of ARDS, requiring frequent reassessment. While important research tools, feasibility and availability of the techniques may limit broad clinical application. Measuring IC can be done at bedside with any modern ventilator able to report volume change in response to change in pressure,[23] but lung recruitment and hyperinflation may complicate measurement, and limited data exist on this approach. As with driving pressure, no threshold has been proposed nor strategy tested prospectively for scaling V T to these volume-based measures.

Indeed, it is likely that no universal threshold for lung protection exists regardless of how V T is scaled to patient-specific mechanics. Rather, the extent to which a given V T causes lung injury likely also depends on concomitant biological risk, including endothelial injury/activation, local/systemic inflammation, a primary alveolar epithelial insult, and heterogeneous distribution of injury patterns further confounding the ability to personalize lung protective ventilation.[29–31]

Currently, no clinically available, well-validated metric to assess risk of biophysical injury is available. Lung injury prediction scores from clinical data have not identified risk of ARDS with sufficient accuracy for clinical use,[32,33] and similar is likely true of risk of biophysical injury in established ARDS. Both instances likely require incorporating molecular markers of lung injury to assess patient-specific risk.[34] Two potential plasma markers of promise are soluble receptor for advanced glycation end-products (sRAGE), a marker of alveolar epithelial injury,[35–38] and angiopoietin-2, a marker of vascular endothelial injury.[39–41] Whether these or other biomarkers, alone or in combination, identify risk of biophysical injury with sufficient reliability for clinical use remains to be tested.

Ideally, biomarker(s) might facilitate risk stratification for biophysical injury and allow the clinician to weigh risks/benefits of adjusting VT. Even if threshold mechanical and biological measures are established, lung protection is not the sole goal in titrating VT. Maintaining lower sub-physiologic VT requires escalating cointerventions that carry their own risks. Deeper sedation and/or neuromuscular blockade may be required to facilitate patient tolerance and suppress ventilatory drive, which in turn increase risk of delirium and disuse atrophy of the diaphragm and other skeletal muscle.[42–45] Extreme lowering of VT (e.g., 3 mL/kg PBW) may require extracorporeal life support to facilitate adequate gas exchange, which may heighten risk of hemorrhage, hematological, and neurological complications.[46]

To truly individualize V T for patient-centered benefit will require (1) identifying who is at risk of biophysical injury, (2) developing an approach for titrating V T to risk, and (3) weighing clinically the tradeoff between further lung protection and escalating cointerventions required for lowering V T. Research in lung mechanics and biology is advancing toward that goal at an increasingly rapid pace, with clinical protocols ready for testing on the horizon.