Early invasive ventilation as a lung-protective strategy in acute hypoxemic respiratory failure

High spontaneous respiratory drive in acute hypoxemic respiratory failure 

There is increasing concern that continued vigorous spontaneous respiratory efforts may be harmful in the presence of severe lung injury. The adverse impact of using high tidal volumes during invasive mechanical ventilation is well known. The swings in transpulmonary pressure (airway pressure – pleural pressure), representing lung stress, are comparable with spontaneous, controlled, or partially supported breathing when similar tidal volumes are delivered.1 Thus, high tidal volumes may be equally injurious with spontaneous or assisted breaths compared to controlled breaths. Patients with de novo acute hypoxemic respiratory failure (AHRF) may have a strong respiratory drive, leading to the generation of large spontaneous tidal volumes. 

How does a high spontaneous respiratory drive cause harm?

Besides the adverse effects related to high transpulmonary pressures, the alveolar pressure may drop significantly lower than the end-expiratory pressure during spontaneous breathing. The intravascular pressure within the pulmonary blood vessels decreases proportionally; however, the pleural pressure decreases to a greater extent, thus, increasing the transmural pulmonary vascular pressure. The increase in the transmural pulmonary vascular pressure combined with increased capillary permeability results in leakage of fluid from within the capillaries and may lead to pulmonary edema. These changes may be similar to the pathophysiology of negative-pressure pulmonary edema, characterized by high airway resistance, leading to the a precipitous drop in the airway and alveolar pressures.2 In patients with injured lungs, there may be regional variations in transpulmonary pressures. This may lead to movement of air from the non-dependent to dependent areas of the lung during the early inspiratory phase of spontaneous respiratory efforts (the pendulluft phenomenon). Overstretch injury to the dependent lung may occur due to this phenomenon.3 The adverse consequences arising from a continued high respiratory drive have been termed patient self-inflicted lung injury (P-SILI).4

Use of NIV in AHRF

The use of non-invasive ventilation (NIV) as the initial modality of ventilatory support has increased several-fold over the years. There is well-established evidence for the benefit of NIV use in acute respiratory failure due to exacerbation of chronic obstructive pulmonary disease and in cardiogenic pulmonary edema. However, improved outcomes with NIV use in patients with AHRF with no pre-existing cardiopulmonary disease (de novo acute respiratory failure) is less certain. 

From a physiological perspective, there appears to be a strong rationale for the application of NIV in AHRF. Oxygenation may improve with alveolar recruitment, and the work of breathing may improve, thereby ameliorating the subjective feeling of dyspnea. These positive effects may avoid the need for intubation and invasive ventilation, and thus, improve clinical outcomes. However, there is increasing concern regarding possible harm from NIV use in AHRF, especially in pneumonia and acute respiratory distress syndrome (ARDS). Bellani et al. performed a sub-analysis of the LUNG-SAFE study, a large observational study that evaluated the management of patients with ARDS. NIV failure was strongly correlated with the severity of ARDS. Furthermore, on propensity-matched analysis, among patients with a PaO2/FiO2 ratio <150, ICU mortality was higher with NIV compared to invasive mechanical ventilation. The magnitude of the decrease in the PaO2/FiO2 ratio between days 1 and 2 was an independent predictor of mortality on multivariate analysis.5 In the FLORALI study that compared high-flow nasal oxygen with NIV or standard oxygen therapy through a non-rebreather face mask in patients with AHRF, 58% of patients failed NIV and required intubation by 28 days.6

Possible reasons for NIV failure in AHRF

Evidence from observational studies suggests that failure of NIV, followed by invasive ventilation, is associated with worse clinical outcomes, including higher overall mortality.7,8 

The apparent adverse impact of NIV may be a confounding effect related to higher underlying severity of illness. The transient salutary effects of NIV on gas exchange and the subjective feeling of dyspnea could delay intubation when the underlying disease process may actually be worsening.  It is also possible that interruption of NIV, even for short periods of time, may offset alveolar recruitment and reduction in the work of breathing, leading to worsening of the clinical situation. 

Does the use of analgesic and sedative agents as adjunctive treatment lead to NIV failure? Muriel et al. evaluated 842 patients who underwent NIV in a multicentric study. Analgesics or sedative use alone was not associated with NIV failure; however, the combined use of both analgesics and sedatives was significantly associated with failure of NIV. On multivariate analysis, the 28-d mortality was also higher with combined analgesic and sedative use.9

In patients with an increased respiratory drive, it may be impossible to limit tidal volumes within the “lung-protective” range during NIV use. Carteaux et al., in a prospective observational study, evaluated 62 patients who underwent NIV for AHRF. An algorithmic approach was utilized to limit the tidal volume to 6–8 ml/kg of ideal body weight. However, the tidal volume delivered was higher across all NIV sessions (median tidal volume, 9.8 ml/kg; interquartile range, 8.1–11.1 ml/kg). The tidal volume was significantly higher in patients who failed NIV and required intubation, compared to those who succeeded [10.6 ml/kg (9.6–12.0) vs. 8.5 ml/kg (7.6–10.2)]. A threshold tidal volume of 9.5 ml/kg was the most accurate predictor of NIV failure with 82% sensitivity, and 87% specificity.10

Early invasive ventilation as a part of a lung-protective strategy

Identification of patients who may benefit from early invasive ventilation as part of a lung-protective strategy is crucial, to prevent possible harm from P-SILI due to enhanced respiratory drive. Abolition of spontaneous respiratory efforts with the use of neuromuscular blockers has been shown to reduce the pro-inflammatory response in patients with ARDS.11 The use of continuous neuromuscular blockade with cis-atracurium during the first 48 h of mechanical ventilation was evaluated in the ACURASYS study. The adjusted 90-d mortality, the primary outcome, was significantly lower with continuous neuromuscular blockade compared to the control group.12 These studies reinforce the possibililty of improved outcomes with a fully controlled ventilator strategy in severe ARDS.  

The strategy of mechanical ventilation has been refined in the past two decades with emphasis on lung-protective strategies, including the use of low tidal volumes, and increasing focus on optimizing transpulmonary and driving pressures (driving pressure = Pplat – PEEP). In this context, the important question arises whether persistence with NIV or other assisted modes of ventilation could lead to harm, compared with a strategy of early intubation, and controlled, lung-protective mechanical ventilation in patients with AHRF. Importantly, the crucial question regarding the appropriate timing of invasive ventilation needs to be investigated, considering the evidence of poor outcomes with NIV failure in AHRF. 

The bottom line 

  • Continued vigorous spontaneous respiratory efforts may lead to harm in the injured lung.
  • Although there is a sound physiological rationale for NIV use in AHRF, adverse clinical outcomes are becoming increasingly evident, especially in patients with ARDS.
  • NIV failure and the generation of high tidal volumes during NIV have been associated with poor outcomes.
  • A PaO2/FiOratio of <150 and the combined use of sedatives and analgesics are risk factors for NIV failure.
  • Early invasive ventilation using a lung-protective strategy combined with the use of neuromuscular blockade in the initial phase of ventilation may lead to improved outcomes. 


1.         Bellani G, Grasselli G, Teggia-Droghi M, et al. Do spontaneous and mechanical breathing have similar effects on average transpulmonary and alveolar pressure? A clinical crossover study. Crit Care. 2016;20. doi:10.1186/s13054-016-1290-9

2.         Bhattacharya M, Kallet RH, Ware LB, Matthay MA. Negative-Pressure Pulmonary Edema. Chest. 2016;150(4):927-933. doi:10.1016/j.chest.2016.03.043

3.         Yoshida T, Torsani V, Gomes S, et al. Spontaneous effort causes occult pendelluft during mechanical ventilation. Am J Respir Crit Care Med. 2013;188(12):1420-1427. doi:10.1164/rccm.201303-0539OC

4.         Brochard L, Slutsky A, Pesenti A. Mechanical Ventilation to Minimize Progression of Lung Injury in Acute Respiratory Failure. Am J Respir Crit Care Med. 2017;195(4):438-442. doi:10.1164/rccm.201605-1081CP

5.         Bellani G, Laffey JG, Pham T, et al. Noninvasive Ventilation of Patients with Acute Respiratory Distress Syndrome. Insights from the LUNG SAFE Study. Am J Respir Crit Care Med. 2017;195(1):67-77. doi:10.1164/rccm.201606-1306OC

6.         Frat J-P, Thille AW, Mercat A, et al. High-Flow Oxygen through Nasal Cannula in Acute Hypoxemic Respiratory Failure. N Engl J Med. 2015;372(23):2185-2196. doi:10.1056/NEJMoa1503326

7.         Demoule A, Girou E, Richard J-C, Taille S, Brochard L. Benefits and risks of success or failure of noninvasive ventilation. Intensive Care Med. 2006;32(11):1756-1765. doi:10.1007/s00134-006-0324-1

8.         Schnell D, Timsit J-F, Darmon M, et al. Noninvasive mechanical ventilation in acute respiratory failure: trends in use and outcomes. Intensive Care Med. 2014;40(4):582-591. doi:10.1007/s00134-014-3222-y

9.         Muriel A, Peñuelas O, Frutos-Vivar F, et al. Impact of sedation and analgesia during noninvasive positive pressure ventilation on outcome: a marginal structural model causal analysis. Intensive Care Med. 2015;41(9):1586-1600. doi:10.1007/s00134-015-3854-6

10.       Carteaux G, Millán-Guilarte T, De Prost N, et al. Failure of Noninvasive Ventilation for De Novo Acute Hypoxemic Respiratory Failure: Role of Tidal Volume*. Crit Care Med. 2016;44(2):282-290. doi:10.1097/CCM.0000000000001379

11.       Forel J-M, Roch A, Marin V, et al. Neuromuscular blocking agents decrease inflammatory response in patients presenting with acute respiratory distress syndrome. Crit Care Med. 2006;34(11):2749-2757. doi:10.1097/01.CCM.0000239435.87433.0D

12.       Papazian L, Forel J-M, Gacouin A, et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010;363(12):1107-1116. doi:10.1056/NEJMoa1005372

1 thought on “Early invasive ventilation as a lung-protective strategy in acute hypoxemic respiratory failure”

  1. I have often wondered about the risks vs benefits of early intubation in someone who has been on NIV for more than a day, has tachypnea, requires sedation and needs moderately high FiO2. It is a fairly common problem. The argument to continue NIV, in my mind, has always been simplistic – That endotracheal intubation has its own risks.
    This is a thought provoking article, which I thoroughly enjoyed reading. Thank you.

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