REVIEW URRENT C OPINION Noninvasive ventilation and high-flow nasal oxygen for acute respiratory failure: is less more? Arnaud W. Thille a,b, Rémi Coudroy a,b, and Jean-Pierre Frat a,b Purpose of review High-flow nasal oxygen and noninvasive ventilation (NIV) are two strategies representing an alternative to standard oxygen in the management of respiratory failure. Recent findings Although high-flow nasal oxygen has shown promising results in patients with de-novo acute respiratory failure, further large clinical trials are needed to determine the best oxygenation strategy. As NIV may have deleterious effects, especially in patients generating strong inspiratory efforts, protective NIV using higher levels of positive-end expiratory pressure, more prolonged sessions and additional interfaces such as helmets should be assessed in the future. Whereas NIV is the first-line ventilation strategy in patients with acute exacerbation of chronic lung diseases, high-flow nasal oxygen could be an alternative to NIV after partial reversal of respiratory acidosis. To prevent severe hypoxemia during intubation of hypoxemic patients or to prevent postextubation respiratory failure in patients at high-risk of reintubation, NIV is the best strategy for preoxygenation or immediately after extubation in ICUs. Summary New large-scale clinical trials are needed to compare high-flow nasal oxygen with standard oxygen in patients with de-novo acute respiratory failure to determine the reference treatment. After which, more protective NIV could be assessed among the more severe patients. Keywords acute respiratory failure, high-flow nasal oxygen, noninvasive ventilation, respiratory insufficiency INTRODUCTION Reports on the first randomized clinical trials (RCTs) on noninvasive ventilation (NIV) were published in the 1990s and showed marked clinical improvement in patients with acute respiratory failure due to cardiogenic pulmonary edema or to chronic obstructive pulmonary disease (COPD) [1,2]. During the 2000s, the use of NIV in ICUs has been growing as a treatment for all forms of respiratory failure, especially in patients with de-novo acute respiratory failure, that is without underlying cardiac or chronic lung disease. Contrary to all expectations, a clinical trial published in 2004 suggested for the first time that patients treated by NIV for respiratory failure may have an increased risk of death as compared with standard oxygen [3]. In the 2010s, the first pilot studies appeared on high-flow nasal oxygen as an alternative to standard oxygen, and in 2015, a large clinical trial including 310 patients with de-novo acute respiratory failure radically transformed the existing paradigms [4]. Mortality of patients treated with high-flow nasal oxygen was found to be lower www.co-criticalcare.com than in patients treated with standard oxygen and above all, lower than in patients treated with highflow nasal oxygen alternating with NIV sessions, thereby suggesting deleterious effects of NIV. A post-hoc analysis of this study showed that patients generating large tidal volumes 1 h after NIV initiation (>9 ml/kg of predicted body weight) had higher mortality than those with lower tidal volumes [5]. Surprisingly, tidal volumes had never been reported in previous trials, and thereby seemed not to be considered as a criterion of respiratory severity. These findings reinforced the concept of patient self-inflicted, otherwise known as effort-dependent a Centre Hospitalier Universitaire de Poitiers, Médecine Intensive Réanimation and bCentre d’Investigation Clinique 1402 ALIVE, INSERM, Université de Poitiers, Poitiers, France Correspondence to Arnaud W. Thille, Service de Médecine Intensive Réanimation, CHU de Poitiers, 2 Rue la Milétrie, 86021 Poitiers Cedex, France. Tel: +33 549444007; e-mail: aw.thille@gmail.com Curr Opin Crit Care 2021, 27:60–65 DOI:10.1097/MCC.0000000000000785 Volume 27 Number 1 February 2021 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. Noninvasive ventilation and high-flow nasal oxygen Thille et al. KEY POINTS Although high-flow nasal oxygen has shown promising results in patients with de-novo acute respiratory failure, other studies are needed to recommend it as a first-line strategy of oxygenation. Whereas NIV may have deleterious effects, especially in patients with strong inspiratory efforts, ongoing research is aimed at assessing protective NIV using higher levels of positiveend expiratory pressure, more prolonged sessions and other interfaces such as a helmet. Whereas NIV is the first-line strategy of ventilation in patients with acute exacerbation of chronic lung disease with respiratory acidosis (pH 7.35), high-flow nasal oxygen could be an alternative to standard oxygen between NIV sessions or even an alternative to NIV after partial reversal of respiratory acidosis. To prevent severe hypoxemia during intubation of hypoxemic patients or to prevent postextubation respiratory failure in patients at high-risk of reintubation, NIV is the best strategy to apply for preoxygenation or immediately after extubation in ICUs. lung injury, meaning that despite moderate pressure-support levels, patients generating strong inspiratory efforts receive in return large tidal volumes, which worsen preexisting lung injury [6]. Therefore, assessment of respiratory effort might help to deliver a more protective noninvasive strategy of ventilation by mitigating patient effort and moderating subsequent tidal volumes. PATIENTS WITH DE-NOVO ACUTE RESPIRATORY FAILURE To highlight the role of patient respiratory effort, a physiological study including 30 patients with acute respiratory failure found monitoring of inspiratory effort using esophageal pressure measurements to be a major predictor of NIV failure [7 ]. The drop of esophageal pressure (DPes) reflecting the magnitude of inspiratory effort was markedly higher 2 h after NIV initiation among patients who failed NIV and required intubation than in those who improved under NIV. By contrast, a reduction in DPes of at least 10 cmH2O after 2 h of NIV was strongly associated with avoidance of intubation, and represented the most accurate predictor of treatment success, much more predictive than large tidal volumes exceeding 9 ml/kg or severity of hypoxemia (PaO2/FiO2). In a systematic review comparing intubation rates according to NIV protocol (14 trials gathering 750 patients), intubation rate was not influenced by duration of NIV sessions or type of ventilator, but && was lower when using high positive end-expiratory pressure (PEEP) levels (>6 cmH2O) [8]. Thereby, adjustment of high PEEP levels could be a major determinant of ventilator settings under NIV in view of decreasing inspiratory effort [9] and of promoting alveolar recruitment as is the case in patients with acute respiratory distress syndrome. When compared with the face mask, the helmet is an interface apparently more comfortable for patients (avoiding facial pressure points), and may thereby be an alternative enabling delivery of more prolonged NIV sessions with higher levels of pressure [10]. A physiological study of 15 patients with acute respiratory failure compared high-flow nasal oxygen with a flow at 50 l/min vs. NIV using helmet delivering high PEEP (at least 10 cmH2O) and high pressure-support levels (10–15 cmH2O) [11 ]. Compared with high-flow nasal oxygen, NIV with a helmet markedly improved oxygenation and significantly reduced dyspnea, respiratory rate, and patient effort, whereas comfort and PCO2 remained similar. Significantly, the beneficial physiological effects of helmet NIV were more pronounced in patients who made more vigorous spontaneous efforts (i.e., they exhibited a more pronounced reduction of spontaneous effort when switched to helmet NIV). However, the transpulmonary pressure swing seemed to be higher with a helmet than with high-flow nasal oxygen which may potentially worsen lung injury in some patients. Further clinical trials are needed to confirm physiological effects before it can be used safely in clinical practice. Despite improved understanding of physiological determinants, whether NIV is beneficial or deleterious remain controversial, and the latest clinical practice guidelines the experts were unable to offer a recommendation [12]. In a network meta-analysis including 3804 patients from 25 RCTs, treatment with NIV or with high-flow nasal oxygen were both associated with lower risk of endotracheal intubation. However, only NIV was associated with a lower risk of mortality as compared with oxygen (low certainty for helmet and moderate certainty for facemask) [13]. This finding does not necessarily mean that NIV is more effective than high-flow nasal oxygen in management of acute respiratory failure. Far more studies have been conducted on NIV than on high-flow nasal oxygen, and many NIV trials included mixed populations with COPD or postoperative patients, who are known to benefit from NIV, or immunocompromised patients, who might likewise show greater improvement with NIV. Up until now, the largest RCT including homogeneous patients with de-novo acute respiratory failure found a lower mortality with high-flow nasal oxygen than with NIV or standard oxygen [4]. 1070-5295 Copyright ß 2020 Wolters Kluwer Health, Inc. All rights reserved. && www.co-criticalcare.com Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. 61 Respiratory system In patients treated with high-flow nasal oxygen, calculation of the ROX index (ratio of SpO2/FIO2 to respiratory rate) has been proposed as an easy-to-use index facilitating the decision of intubation [14 ]. The diagnostic accuracy of this index has been assessed in a multicenter prospective observational cohort study including 191 patients treated with high-flow nasal oxygen (36% required intubation). Two hours after initiation of high-flow nasal oxygen, ROX index at least 4.88 was associated with lower risk of intubation, whereas ROX index less than 2.85 was a good predictor of intubation. On the other hand, modalities for separation from highflow nasal oxygen in patients improving have been poorly studied. A retrospective monocenter study including 190 patients treated with high-low nasal oxygen found that ROX index at least 9.2 and a criterion even easier to use, that is FiO2 of 40% or less at time of the separation, were the two best predictors of successful separation from high-flow nasal oxygen [15 ]. Lastly, patients included in future trials should be perfectly comparable in terms of respiratory severity, especially the PaO2/FiO2 ratio which is a good indicator of oxygenation. Whereas FiO2 is adjusted using NIV or high-flow nasal oxygen, it is not known under standard oxygen. The reliability of different inspired oxygen fraction estimation methods has been assessed in 262 patients with acute hypoxemic respiratory failure breathing spontaneously through nonrebreather reservoir bag oxygen mask [16 ]. As compared with inspired oxygen fraction measured inside the mask, the most accurate estimation method was the following: 21% þ oxygen flow rate (in l/min) 3. Other estimation methods overestimated inspired oxygen fraction and hypoxemia severity. & & & PATIENTS WITH CORONAVIRUS DISEASE 2019 In patients with respiratory failure related to coronavirus disease 2019 (COVID-19), several studies have reported promising results using high-flow nasal oxygen or NIV to avoid intubation, with intubation rates ranging from 20 over 50% [17,18,19 ,20]. Given the small number of studies and low level of evidence, the best oxygenation strategy remains to be determined. In a cohort of 146 COVID-19 patients treated with high-flow nasal oxygen in ICUs, the intubation rate was 56% and ICU mortality was 25% [19 ]. Using a propensity score-matched analysis, patients treated with highflow nasal oxygen seemed to have lower intubation rates than those not receiving high-flow nasal oxygen. One of these studies suggests that these strategies are even feasible outside ICUs and are associated & & 62 www.co-criticalcare.com with favorable outcomes notwithstanding a risk of staff contamination [18]. However, several in vitro studies assessing bio-aerosol dispersion with a manikin found that the exhaled smoke dispersion distance using high-flow nasal oxygen at 60 l/min was similar compared with an oxygen mask at 15 l/min, and even lower than when using nonrebreathing and Venturi masks [21]. IMMUNOCOMPROMISED PATIENTS The use of NIV is still recommended in management of immunocompromised patients with acute respiratory failure [12]. However, the strength of this recommendation is only conditional given the moderate certainty of evidence. The largest RCT performed up until now found no beneficial effects of NIV in terms of intubation and mortality rates as compared with oxygen alone [22]. The mortality of immunocompromised patients requiring intubation is particularly high, and could explain a particular indication of NIV in this context to avoid intubation at all costs. Nevertheless, NIV does not seem more efficient in immunocompromised patients than in other patients. In a study including 208 patients treated by NIV for acute hypoxemic respiratory failure, the risk of intubation was not higher in immunocompromised patients than in the others using propensity-matched analysis, whereas their risk of death was increased by 2.6-fold in the ICU [23]. In this population, the most effective strategy of oxygenation is not clearly established. A large multicenter trial compared high-flow nasal oxygen vs. standard oxygen in 778 immunocompromised patients with acute hypoxemic respiratory failure [24 ]. Overall intubation and day-28 mortality rates did not differ between the two groups of treatment. However, a high proportion of patients died without prior intubation, meaning that they had a do-not-intubate order, and this might have mitigated the potential beneficial effects of high-flow nasal oxygen for patients treated for acute respiratory failure with full code ICU management. As previous studies did not necessarily use protective NIV, a study protocol aiming to compare protective NIV, that is using prolonged sessions with high levels of PEEP and targeting low tidal volumes vs. high-flow nasal oxygen therapy alone in a large RCT has been designed [25]. This multicenter trial planned to include 300 immunocompromised patients with acute hypoxemic respiratory failure and to assess the day-28 mortality rate as main outcome. In the absence of NIV superiority, we could assume that NIV may no longer be recommended for management of && Volume 27 Number 1 February 2021 Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. Noninvasive ventilation and high-flow nasal oxygen Thille et al. acute respiratory failure in immunocompromised patients. PATIENTS WITH CHRONIC LUNG DISEASE NIV is obviously the first-line strategy of ventilation in patients with acute exacerbation of chronic lung disease with respiratory acidosis (pH 7.35) [12]. The usual rate of intubation in patients with COPD treated with NIV in ICUs is around 15%. The HACOR score (including heart rate, acidosis, consciousness, oxygenation, and respiratory rate) collected 1–2 h after NIV initiation may help to predict the risk of NIV failure [26]. In a cohort of 500 COPD patients, the higher the HACOR score the higher the risk of intubation, at a rate exceeding 50% in patients with a HACOR score above five points. This score could be of use in deciding intubation because in most at-risk patients intubation delayed beyond 48 h has been associated with increased hospital mortality. Highflow nasal oxygen could be an alternative to standard oxygen between NIV sessions or even an alternative to NIV after partial reversal of respiratory acidosis. In a randomized crossover physiologic study including 30 COPD patients recovering from an episode of acute respiratory failure, switching from NIV to standard oxygen increased respiratory rate and work of breathing, which was estimated using diaphragm ultrasonography, whereas it remained stable when switching from NIV to high-flow nasal oxygen at 50 l/min, and resulted in improved comfort [27]. In another physiological study including 12 hypercapnic COPD patients who had clinical improvement after initial treatment with NIV, work of breathing measured using esophageal pressure under high-flow nasal oxygen at 30 l/min was similar to work of breathing measured under NIV [28 ]. However, flow higher than 30 l/min was associated with increased work of breathing in half of patients, suggesting that a flow rate at 30 l/min could be the best setting in COPD patients recovering from acute respiratory failure. In a prospective pilot study including 50 COPD patients recovering from an episode of acute hypercapnic respiratory failure, switch from NIV to high-flow nasal oxygen at least 8 h a day and during the night led to significantly decreased PaCO2 in patients with pure COPD whereas it has no effect on patients with associated obstructive sleep apnea [29]. & PREOXYGENATION OF HYPOXEMIC PATIENTS The risk of severe hypoxemia (most often defined as pulse oximetry below 80%) is particularly frequent during the intubation procedure, especially in previously hypoxemic patients, with the ultimate complication being the risk of cardiac arrest related to hypoxia. Preoxygenation with the aim of increasing functional residual capacity and oxygen reserves to obtain the highest level of SpO2 before intubation may prevent severe hypoxemia. A large-scale RCT has compared preoxygenation with NIV or high-flow nasal oxygen in 314 hypoxemic patients requiring intubation in 28 ICUs [30 ]. Severe hypoxemia episodes were particularly frequent (26% of patients) but did not differ between the two methods. However, severe hypoxemia occurred less frequently after preoxygenation with NIV than with high-flow oxygen among the 242 patients with moderate-to-severe hypoxemia (PaO2/FiO2 200 mmHg) before intubation (24 vs. 35%; P ¼ 0.0459 after adjustment). These results were confirmed in a recent network meta-analysis of randomized trials including 959 patients from seven studies suggesting that NIV was safe and probably the most effective preoxygenation method compared with standard or high-flow nasal oxygen [31]. Consequently, although there is no a strong certainty in the evidence, NIV may be suggested for preoxygenation of most hypoxemic patients before intubation in ICUs. Another RCT has shown that continuation of bagmask ventilation in ICU patients between induction and intubation helped to decrease the risk of severe hypoxia compared with no ventilation [32]. This study is particularly interesting because it goes against popular belief and suggests that continuation of ventilation during the apnea phase is not harmful despite a theoretical risk of inhalation. Considering that NIV may be the most effective preoxygenation strategy, it should be delivered using pressure-assist controlled ventilation (with a back-up respiratory rate of 10 cycles/min) rather than using pressure-support ventilation to continue positive pressure ventilation during apnea between induction and intubation. && AFTER EXTUBATION In a large clinical trial, 641 patients extubated after at least 24 h of mechanical ventilation and considered at high-risk of reintubation, that is older than 65 years or with underlying chronic cardiac or lung disease, were randomly assigned to receive high-flow nasal oxygen alone or alternating with NIV sessions for 48 h after extubation with the aim of preventing respiratory failure [33 ]. The proportion of patients who developed postextubation respiratory failure or required reintubation was significantly lower with NIV than with high-flow nasal oxygen alone. Whereas the most recent international clinical practice guidelines recommend NIV after extubation patients at high-risk of extubation failure in ICUs, the strength of this recommendation was only conditional given the moderate certainty of evidence 1070-5295 Copyright ß 2020 Wolters Kluwer Health, Inc. All rights reserved. && www.co-criticalcare.com Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. 63 Respiratory system [12]. This recent RCT further reinforces certainty and could consequently change clinical practice and contribute to the establishment of a strong recommendation on preventive NIV after extubation of patients at high-risk of reintubation in ICUs. IN CONCLUSION The use of NIV as first-line strategy of ventilation is particularly efficient to treat respiratory failure in patients with chronic lung disease, or to prevent respiratory failure after extubation, while highflow nasal oxygen maybe an alternative to standard oxygen between NIV sessions. In patients with denovo acute respiratory failure the best oxygenation strategy remains uncertain. Only one RCT has reported lower risk of mortality with high-flow nasal oxygen compared with all other strategies of oxygenation. Protective NIV using high levels of PEEP and low levels of pressure-support or delivered through helmet might be an alternative for future research. Acknowledgements We thank Jeffrey Arsham (CHU de Poitiers, Poitiers, France) for reviewing and editing the original Englishlanguage article. Financial support and sponsorship None. Conflicts of interest A.W.T. reported receiving grants from the French Ministry of Health and personal fees (payment for lectures and travel expense coverage to attend scientific meetings) from Fisher & Paykel Healthcare, Maquet-Getinge, GE Healthcare, and Covidien. 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