Background: Whether respiratory physiology of COVID-19-induced respiratory failure is different from acute respiratory distress syndrome (ARDS) of other etiologies is unclear. We conducted a single-center study to describe respiratory mechanics and response to positive end-expiratory pressure (PEEP) in COVID-19 ARDS and to compare COVID-19 patients to matched-control subjects with ARDS from other causes. Methods: Thirty consecutive COVID-19 patients admitted to an intensive care unit in Rome, Italy, and fulfilling moderate-to-severe ARDS criteria were enrolled within 24 h from endotracheal intubation. Gas exchange, respiratory mechanics, and ventilatory ratio were measured at PEEP of 15 and 5 cmH₂O. A single-breath derecruitment maneuver was performed to assess recruitability. After 1:1 matching based on PaO₂/FiO₂, FiO₂, PEEP, and tidal volume, COVID-19 patients were compared to subjects affected by ARDS of other etiologies who underwent the same procedures in a previous study. Results: Thirty COVID-19 patients were successfully matched with 30 ARDS from other etiologies. At low PEEP, median [25th–75th percentiles] PaO₂/FiO₂ in the two groups was 119 mmHg [101–142] and 116 mmHg [87–154]. Average compliance (41 ml/cmH₂O [32–52] vs. 36 ml/cmH₂O [27–42], p = 0.045) and ventilatory ratio (2.1 [1.7–2.3] vs. 1.6 [1.4–2.1], p = 0.032) were slightly higher in COVID-19 patients. Inter-individual variability (ratio of standard deviation to mean) of compliance was 36% in COVID-19 patients and 31% in other ARDS. In COVID-19 patients, PaO₂/FiO₂ was linearly correlated with respiratory system compliance (r = 0.52 p = 0.003). High PEEP improved PaO₂/FiO₂ in both cohorts, but more remarkably in COVID-19 patients (p = 0.005). Recruitability was not different between cohorts (p = 0.39) and was highly inter-individually variable (72% in COVID-19 patients and 64% in ARDS from other causes). In COVID-19 patients, recruitability was independent from oxygenation and respiratory mechanics changes due to PEEP. Conclusions: Early after establishment of mechanical ventilation, COVID-19 patients follow ARDS physiology, with compliance reduction related to the degree of hypoxemia, and inter-individually variable respiratory mechanics and recruitability. Physiological differences between ARDS from COVID-19 and other causes appear small.

Background: The effects of awake prone position on the breathing pattern of hypoxemic patients need to be better understood. We conducted a crossover trial to assess the physiological effects of awake prone position in patients with acute hypoxemic respiratory failure. Methods: Fifteen patients with acute hypoxemic respiratory failure and PaO₂/FiO₂ < 200 mmHg underwent high-flow nasal oxygen for 1 h in supine position and 2 h in prone position, followed by a final 1-h supine phase. At the end of each study phase, the following parameters were measured: arterial blood gases, inspiratory effort (ΔP_ES), transpulmonary driving pressure (ΔP_L), respiratory rate and esophageal pressure simplified pressure–time product per minute (sPTP_ES) by esophageal manometry, tidal volume (V_T), end-expiratory lung impedance (EELI), lung compliance, airway resistance, time constant, dynamic strain (V_T/EELI) and pendelluft extent through electrical impedance tomography. Results: Compared to supine position, prone position increased PaO₂/FiO₂ (median [Interquartile range] 104 mmHg [76–129] vs. 74 [69–93], p < 0.001), reduced respiratory rate (24 breaths/min [22–26] vs. 27 [26–30], p = 0.05) and increased ΔP_ES (12 cmH₂O [11–13] vs. 9 [8–12], p = 0.04) with similar sPTP_ES (131 [75–154] cmH₂O s min⁻¹ vs. 105 [81–129], p > 0.99) and ΔP_L (9 [7–11] cmH₂O vs. 8 [5–9], p = 0.17). Airway resistance and time constant were higher in prone vs. supine position (9 cmH₂O s arbitrary units⁻³ [4–11] vs. 6 [4–9], p = 0.05; 0.53 s [0.32–61] vs. 0.40 [0.37–0.44], p = 0.03). Prone position increased EELI (3887 arbitrary units [3414–8547] vs. 1456 [959–2420], p = 0.002) and promoted V_T distribution towards dorsal lung regions without affecting V_T size and lung compliance: this generated lower dynamic strain (0.21 [0.16–0.24] vs. 0.38 [0.30–0.49], p = 0.004). The magnitude of pendelluft phenomenon was not different between study phases (55% [7–57] of V_T in prone vs. 31% [14–55] in supine position, p > 0.99). Conclusions: Prone position improves oxygenation, increases EELI and promotes V_T distribution towards dependent lung regions without affecting V_T size, ΔP_L, lung compliance and pendelluft magnitude. Prone position reduces respiratory rate and increases ΔP_ES because of positional increases in airway resistance and prolonged expiratory time. Because high ΔP_ES is the main mechanistic determinant of self-inflicted lung injury, caution may be needed in using awake prone position in patients exhibiting intense ΔP_ES. Clinical trail registeration: The study was registered on clinicaltrials.gov (NCT03095300) on March 29, 2017.

Acute respiratory distress syndrome (ARDS) is a leading cause of disability and mortality worldwide, and while no specific etiologic interventions have been shown to improve outcomes, noninvasive and invasive respiratory support strategies are life-saving interventions that allow time for lung recovery. However, the inappropriate management of these strategies, which neglects the unique features of respiratory, lung, and chest wall mechanics may result in disease progression, such as patient self-inflicted lung injury during spontaneous breathing or by ventilator-induced lung injury during invasive mechanical ventilation. ARDS characteristics are highly heterogeneous; therefore, a physiology-based approach is strongly advocated to titrate the delivery and management of respiratory support strategies to match patient characteristics and needs to limit ARDS progression. Several tools have been implemented in clinical practice to aid the clinician in identifying the ARDS sub-phenotypes based on physiological peculiarities (inspiratory effort, respiratory mechanics, and recruitability), thus allowing for the appropriate application of personalized supportive care. In this narrative review, we provide an overview of noninvasive and invasive respiratory support strategies, as well as discuss how identifying ARDS sub-phenotypes in daily practice can help clinicians to deliver personalized respiratory support and potentially improve patient outcomes.

PEEP can potentially modulate inspiratory effort (ΔPes), which is the major determinant of self-inflicted lung injury. Does high PEEP reduce ΔPes in moderate-to-severe ARDS patients on assisted ventilation? Sixteen patients with PaO₂/FiO₂≤200 mmHg and ΔPes≥10 cmH₂O underwent a randomized sequence of four ventilator settings: PEEP=5 cmH₂O or PEEP=15 cmH₂O + synchronous (pressure support ventilation, PSV) or asynchronous (pressure-controlled intermittent mandatory ventilation, PC-IMV) inspiratory assistance. ΔPes, respiratory system, lung and chest-wall mechanics were assessed with esophageal manometry and occlusions. PEEP-induced alveolar recruitment and overinflation, lung dynamic strain and tidal volume distribution were assessed with electrical impedance tomography. ΔPes was not systematically different at high vs. low PEEP (PSV: median 20 [15-24] cmH₂O vs. 15 [13-23], p=0.24; PC-IMV: 20 [18-23] vs. 19 [17-25], p=0.67). Similarly, respiratory system and transpulmonary driving pressure, tidal volume, lung/chest-wall mechanics and pendelluft extent were not different between study phases. High PEEP resulted in lower or higher ΔPes, respiratory system and transpulmonary driving pressure according to whether this increased or decreased respiratory system compliance, respectively (r=-0.85, p<0.001; r=-0.75, p<0.001; r=-0.80, p<0.001, respectively). PEEP-induced changes in respiratory system compliance were driven by its lung component and were dependent on the extent of PEEP-induced alveolar overinflation (r=-0.66, p=0.006). High PEEP caused variable recruitment and systematic redistribution of tidal volume towards dorsal lung regions, thereby reducing dynamic strain in ventral areas (PSV: 0.49 [0.37-0.83] vs. 0.96 [0.62-1.56], p=0.003; PC-IMV: 0.65 [0.42-1.31] vs. 1.14 [0.79-1.52], p=0.002). All results were consistent during synchronous and asynchronous inspiratory assistance. The impact of high PEEP on ΔPes and lung stress is inter-individually variable according to different effects on respiratory system and lung compliance resulting from alveolar overinflation. High PEEP may help mitigate the risk of self-inflicted lung injury solely if it increases lung/respiratory system compliance.

Background: There is growing interest towards the use of helmet noninvasive ventilation (NIV) for the management of acute hypoxemic respiratory failure. Gas conditioning through heat and moisture exchangers (HME) or heated humidifiers (HHs) is needed during facemask NIV to provide a minimum level of humidity in the inspired gas (15 mg H ₂ O/L). The optimal gas conditioning strategy during helmet NIV remains to be established. Methods: Twenty patients with acute hypoxemic respiratory failure (PaO ₂ /FiO ₂ < 300 mmHg) underwent consecutive 1-h periods of helmet NIV (PEEP 12 cmH ₂ O, pressure support 12 cmH ₂ O) with four humidification settings, applied in a random order: double-tube circuit with HHs and temperature set at 34 °C (HH34) and 37 °C (HH37); Y-piece circuit with HME; double-tube circuit with no humidification (NoH). Temperature and humidity of inhaled gas were measured through a capacitive hygrometer. Arterial blood gases, discomfort and dyspnea through visual analog scales (VAS), esophageal pressure swings (Δ P _ES ) and simplified pressure–time product (PTP _ES ), dynamic transpulmonary driving pressure (Δ P _L ) and asynchrony index were measured in each step. Results: Median [IqR] absolute humidity, temperature and VAS discomfort were significantly lower during NoH vs. HME, HH34 and HH37: absolute humidity (mgH ₂ O/L) 16 [12–19] vs. 28 [23–31] vs. 28 [24–31] vs. 33 [29–38], p < 0.001; temperature (°C) 29 [28–30] vs. 30 [29–31] vs. 31 [29–32] vs 32. [31–33], p < 0.001; VAS discomfort 4 [2–6] vs. 6 [2–7] vs. 7 [4–8] vs. 8 [4–10], p = 0.03. VAS discomfort increased with higher absolute humidity ( p < 0.01) and temperature ( p = 0.007). Higher VAS discomfort was associated with increased VAS dyspnea ( p = 0.001). Arterial blood gases, respiratory rate, ΔP _ES , PTP _ES and ΔP _L were similar in all conditions. Overall asynchrony index was similar in all steps, but autotriggering rate was lower during NoH and HME ( p = 0.03). Conclusions: During 1-h sessions of helmet NIV in patients with hypoxemic respiratory failure, a double-tube circuit with no humidification allowed adequate conditioning of inspired gas, optimized comfort and improved patient–ventilator interaction. Use of HHs or HME in this setting resulted in increased discomfort due to excessive heat and humidity in the interface, which was associated with more intense dyspnea. Trail Registration Registered on clinicaltrials.gov (NCT02875379) on August 23rd, 2016.

Acute hypercapnic respiratory failure is a life-threatening condition caused by alveolar hypoventilation. It is mostly caused by an acute exacerbation of chronic obstructive pulmonary disease or conditions yielding muscle dysfunction. Noninvasive ventilation through a facemask is the cornerstone first-line strategy to support hypercapnic patients with acidemia, and current guidelines strongly recommend this intervention to improve survival and long-term clinical outcomes. Because of its benefits related to carbon dioxide washout from the upper airways and the enhanced comfort, high-flow nasal oxygen has been proposed as a respiratory support strategy in patients with hypercapnic respiratory failure, both as an alternative to and in combination with noninvasive ventilation. When compared to noninvasive ventilation as a first-line intervention, high-flow nasal oxygen shows a higher rate of failure. Hence, if not contraindicated, the use of noninvasive ventilation should be preferred. After the resolution of acidemia with noninvasive ventilation, high-flow nasal oxygen showed promising physiological effects compared to conventional oxygen. During weaning from mechanical ventilation in patients with or at risk of developing hypercapnia, high-flow nasal oxygen showed encouraging results, especially when applied alternating with sessions of noninvasive ventilation. Optimal settings of high-flow nasal oxygen in hypercapnic patients include the use of a smaller-size cannula, flows ranging between 30 and 40 L/min, and FiO₂ adjusted to obtain SpO₂ between 88% and 92%. Specific interfaces, such as asymmetric cannulas, may further enhance the benefits of a high flow in terms of carbon dioxide clearance. In this narrative review, we provide an updated overview of the physiological rationale and clinical evidence concerning the use of high-flow nasal oxygen in patients with acute hypercapnic respiratory failure.