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Thille et al. Annals of Intensive Care (2024) 14:158 https://doi.org/10.1186/s13613-024-01389-w

Annals of Intensive Care

*Correspondence: Arnaud W. Thille [email protected]

Full list of author information is available at the end of the article

Abstract Background This narrative review was written by an expert panel to the members of the jury to help in the development of clinical practice guidelines on oxygen therapy.

Results According to the expert panel, acute hypoxemic respiratory failure was defined as PaO2 < 60 mm Hg or SpO2 < 90% on room air, or PaO2/FiO2 ≤ 300 mm Hg. Supplemental oxygen should be administered according to the monitoring of SpO2, with the aim at maintaining SpO2 above 92% and below 98%. Noninvasive respiratory supports are generally reserved for the most hypoxemic patients with the aim of relieving dyspnea. High-flow nasal cannula oxygen (HFNC) seems superior to conventional oxygen therapy (COT) as a means of avoiding intubation and may therefore be should probably be used as a first-line noninvasive respiratory support in patients requiring more than 6 L/min of oxygen or PaO2/FiO2 ≤ 200 mm Hg and a respiratory rate above 25 breaths/minute or clinical signs of respiratory distress, but with no benefits on mortality. Continuous positive airway pressure (CPAP) cannot currently be recommended as a first-line noninvasive respiratory support, since its beneficial effects on intubation remain uncertain. Despite older studies favoring noninvasive ventilation (NIV) over COT, recent clinical trials fail to show beneficial effects with NIV compared to HFNC. Therefore, there is no evidence to support the use of NIV or CPAP as first-line treatment if HFNC is available. Clinical trials do not support the hypothesis that noninvasive respiratory supports may lead to late intubation. The potential benefits of awake prone positioning on the risk of intubation in patients with COVID-19 cannot be extrapolated to patients with another etiology.

Conclusions Whereas oxygen supplementation should be initiated for patients with acute hypoxemic respiratory failure defined as PaO2 below 60 mm Hg or SpO2 < 90% on room air, HFNC should be the first-line noninvasive respiratory support in patients with PaO2/FiO2 ≤ 200 mm Hg with increased respiratory rate. Further studies are needed to assess the potential benefits of CPAP, NIV through a helmet and awake prone position in patients with acute hypoxemic respiratory failure not related to COVID-19.

Oxygen therapy and noninvasive respiratory supports in acute hypoxemic respiratory failure: a narrative review Arnaud W. Thille1,2*, Frédéric Balen3,4, Guillaume Carteaux5,6,7, Tahar Chouihed8,9, Jean-Pierre Frat1,2, Christophe Girault10, Erwan L’Her11, Nicolas Marjanovic2,12, Mai-Anh Nay13, Patrick Ray14, Matthieu Reffienna15, Leo Retenauer16, Antoine Roch17, Guillaume Thiery18,19 and Jennifer Truchot20

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Definition of acute hypoxemic respiratory failure Respiratory failure is defined as the failure of the respi- ratory system to perform its gas exchange functions, including oxygenation and carbon dioxide elimination. Acute hypoxemic respiratory failure, also referred to as type 1, specifically denotes oxygenation failure and refers to de novo respiratory failure, i.e. excluding hypoxemia caused by cardiogenic pulmonary edema and exacerba- tion of chronic lung diseases. The main etiology of such de novo respiratory failure is pneumonia [1]. Thus, acute hypoxemic respiratory failure does not encompass acute hypercapnic respiratory failure, also referred to as type 2, characterized by a ventilation failure defined by arte- rial carbon dioxide pressure (PaCO2) exceeding 45  mm Hg and pH below 7.35, indicative of respiratory acidosis. This review will not address the latter form of respiratory failure.

According to the panel of experts participating in these guidelines on oxygen therapy [2], acute hypoxemic respi- ratory failure can be defined as partial pressure of arterial oxygen (PaO2) less than 60 mm Hg or peripheral oxygen saturation measured by pulse oximetry (SpO2) less than 90% on room air, or a ratio of the partial pressure of arte- rial oxygen to the fraction of inspired oxygen (PaO2/FiO2) of 300 mm Hg or less ratio less in patients receiving oxy- gen therapy. Whereas FiO2 is not measured under con- ventional oxygen therapy (COT) delivered through nasal cannula or facemask, it can be best estimated using the following formula: FiO2 in % = Flow of oxygen (L/min) x 3 + 21% [3]. Regardless of the oxygenation strategy, hypoxemia can be considered as severe in patients with PaO2/FiO2 ratio equal to or below 100  mm Hg, moder- ate in patients with PaO2/FiO2 ratio between 101 and 200  mm Hg, and mild in patients with PaO2/FiO2 ratio between 201 and 300 mm Hg, as in patients with acute respiratory distress syndrome (ARDS) [4]. Clinical signs of acute hypoxemic respiratory failure include increased respiratory rate above 25 breaths per minute, activation of accessory respiratory muscles, paradoxical abdomi- nal respiration, cyanosis, dyspnea, and breathlessness. Several oxygenation strategies can be proposed as alter- natives to COT for oxygen supplementation, including high-flow nasal cannula oxygen therapy (HFNC), contin- uous positive airway pressure (CPAP), and noninvasive ventilation (NIV). Among patients with acute hypoxemic respiratory failure, a vast majority have pulmonary bilat- eral infiltrates on chest radiograph and could be con- sidered as having ARDS criteria [1, 5]. However, as the Berlin definition of ARDS stated that PaO2/FiO2 ratio had to be measured with positive airway pressure of at least 5 cmH2O [4], patients treated with COT or HFNC still cannot be considered as ARDS [6]. Indeed, positive airway pressure levels generated with HFNC are most often around 2–3  cm H2O and remain lower than the

levels required to reach ARDS criteria [7, 8]. To modify this definition, recent guidelines suggested considering patients treated with HFNC at a minimal 30 L/min flow as having ARDS if they have pulmonary bilateral infil- trates and PaO2/FiO2 ratio of 300 mm Hg or less [9].

Indications and targets for oxygen therapy Deleterious effects of hypoxemia While the deleterious effects of hypoxemia are widely known in clinical practice, this concept has been poorly evaluated. In a large retrospective cohort study includ- ing 152,680 patients admitted to 150 ICUs, hypoxemia occurring within the first 24  h following admission was associated with an increased risk of death [10]. The same findings were also reported in a systematic review including 7,410 critically ill children [11]. A more recent multicenter clinical trial comparing conservative oxy- gen therapy (PaO2 between 55 and 70 mm Hg and SpO2 between 88 and 92%) versus liberal oxygen therapy (PaO2 between 90 and 105 mm Hg and SpO2 of at least 96%) in mechanically ventilated ARDS patients was prematurely stopped after including 205 patients because of safety concerns [12]. Indeed, mortality was significantly higher in the arm receiving the lower oxygen therapy strategy. These findings lend credence to an oxygen administra- tion strategy that aims at avoiding hypoxemia by main- taining PaO2 above 70  mm Hg and SpO2 above 92% in patients with acute hypoxemic respiratory failure, even though most of the data come from mechanically venti- lated patients.

Deleterious effects of hyperoxia Animal studies have consistently shown that exposure to high FiO2 can cause respiratory failure and early death [13]. From the beginnings of artificial ventilation, there has been concern that high FiO2 values might induce pul- monary lesions [14]. Whereas ventilator-induced lung injury (VILI) is well- established [15], the specific pulmo- nary lesions attributable to oxygen toxicity remain hypo- thetical. Literature from the past 15 years has yielded extensive yet conflicting findings. The challenge in inter- preting the different clinical trials stems from their var- ied methodologies while some focused exclusively on mechanically ventilated patients, while others included any patients breathing spontaneously under oxygen. Additionally, oxygenation targets have varied, with some studies using SpO2 and others PaO2, often with significant overlap between the two targets (Table  1). A first seminal single-center clinical trial including 434 unselected patients admitted to an ICU showed that a higher oxygen strategy (SpO2 between 97 and 100%) significantly increased the risk of death as compared to a lower oxygen strategy (SpO2 between 94 and 98%) [16]. To date, this is the only randomized controlled

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trial showing increased risk of death with a higher oxy- gen strategy and subsequent clinical trials have found no significant differences in mortality between lower and higher oxygenation strategies [17–25]. Nevertheless, a recent clinical trial showed the potentially deleterious effects of higher oxygen strategy, with a decreased num- ber of days without life support in COVID-19 patients admitted to ICUs [17]. Furthermore, a separate clinical trial revealed that administration of maximal FiO2 (set at 100% for 24  h) in mechanically ventilated patients with septic shock led to a higher incidence of serious adverse events and a trend toward increased mortality, prompting the study to be stopped due to safety concerns [26]. Addi- tionally, in a large retrospective cohort study including 19,593 patients admitted to five ICUs in the United King- dom, exposure to hyperoxia (defined as PaO2 ≥ 100  mm Hg), no matter its duration, increased risk of death when compared to patients non-exposed to hyperoxia [27]. Nevertheless, even though hyperoxia may have deleteri- ous effects in critically ill patients, a recent meta-analysis pooling RCTs comparing higher versus lower oxygen- ation strategies suggested that it was still not possible to draw definitive conclusions about the effects on mortality [28]. Only studies targeting particularly high oxygenation levels have shown harmful effects on mortality [16, 26]. These findings support an oxygen administration strat- egy that aims at avoiding hyperoxia by maintaining PaO2 below 90–100 mm Hg and SpO2 below 98%.

Indications for oxygen therapy Supplemental oxygen is frequently administered in emer- gency departments (EDs) and more than half of patients admitted to ICUs receive oxygen therapy for hypoxemia [29]. Oxygen is a treatment for hypoxemia, not breath- lessness, and supplemental oxygen does not improve dyspnea and breathlessness in non-hypoxemic patients [30, 31]. Supplemental oxygen should be administered in patients with acute hypoxemic respiratory failure according to the monitoring of SpO2 values. In case of severe hypoxemia, oxygen therapy should be immedi- ately administered using a non-rebreathing reservoir mask at a flow rate of at least 15 L/min. For less severe cases, oxygen should be administered using nasal prongs when the flow rate is between 1 and 6 L/min, or using a standard facemask when the flow rate is between 6 and 10 L/min. To avoid deleterious effects of hypoxemia and hyperoxia, SpO2 values should be maintained above 92% and below 98%. However, technical problems and mea- surement biases, such as low peripheral blood flow, ane- mia, and skin pigmentation can significantly compromise the accuracy of SpO2 measurements [32–34]. Moreover, there may be considerable discrepancies in SpO2 mea- surements between different monitoring devices, with

Table 1 Main RCTs comparing different targets of oxygenation Study, year N patients – centers

Targets PaO2 (mm Hg) – SpO2 (%) higher vs. lower

Inclusion criteria: % of intubated patients

Mortality rates

Nielsen, 2024 [17] N = 726–13 centers

High PaO2 90 mm Hg vs. Low PaO2 60

COVID-19: 24% Mortality day- 90: higher 35% vs. lower 30%, p = 0.18

Van der Wal, 2023 [18]; N = 664–9 centers

High PaO2 110–150 mm Hg, SpO2 96–100% vs. Low PaO2 55–80, SpO2 91–94%

Patients receiv- ing MV > 24 h : 100%

Mortality day- 28: higher 35% vs. lower 39%, p = 0.34

Schmidt, 2022 [19] N = 789–2 centers

High PaO2 98–105 mm Hg vs. Low PaO2 68–75

After cardiac arrest: 100%

Mortality day- 90: higher 29% vs. lower 31%, p = NS

Semler, 2022 [20] N = 2541–1 center

High SpO2 98% (96–100) vs. Inter- mediate SpO2 94% (92–96) vs. Low SpO2 90% (88–92)

Patients receiv- ing MV: 100%

Mortality day- 28: higher 33% vs. intermediate 34% vs. lower 35%, p = NS

Gelissen, 2021 [22] N = 574–4 centers

Higher PaO2 105–135 mm Hg vs. Lower: PaO2 60–90

SIRS : 70% Mortality day- 90: higher 34% vs. lower 35%, p = 0.91

Mackle, 2020 [23] N = 1000–14 centers

High SpO2 > 90% vs. Low SpO2 > 90% and < 97%

Patients receiv- ing MV: 100%

Mortality day- 90: higher 33% vs. lower 35%, p = NS

Schjørring, 2020 [21] N = 2928–35 centers

High PaO2 90 mm Hg vs. Low PaO2 60

Patients with oxygen (> 10 L/ min): 59%

Mortality day- 90: higher 42% vs. lower 43%, p = 0.60

Barrot, 2020 [12] N = 201–13 centers

High PaO2 90–105 mm Hg, SpO2 ≥ 96% vs. Low PaO2 55–70, SpO2 88–92%

Patients with ARDS: 100%

Mortality day- 90: higher 30% vs. lower 44%, p < 0.05 *Stopped for safety reason

Yang, 2019 [24] N = 14–1 center

Higher PaO2 105–135 mm Hg vs. Lower PaO2 60–90

Expected ICU stay > 72 h: 85%

Mortality day- 28: higher 33% vs. lower 26%, p = 0.30

Asfar, 2017 [26] N = 442–22 centers

High FiO2 100% for 24 h vs. Low SpO2 88–95%

Septic shock: 100%

Mortality day- 28: higher 43% vs. lower 35%, p = 0.12 *Stopped for safety reason

Panwar, 2016 [25] N = 103–4 centers

Higher SpO2 ≥ 96% vs. Lower SpO2 88–92%

Patients receiv- ing MV > 24 h : 100%

Mortality day- 90: higher 37% vs. lower 40%, p = 0.74

Girardis, 2016 [16] N = 434–1 center

High PaO2 up to 150 mm Hg, SpO2 97–100 vs. Low PaO2 70–100, SpO2 94–98

Expected ICU stay > 72 h: 67%

Mortality ICU: higher 20% vs. lower 12%, p = 0.01

Abbreviations: RCT = Randomized Controlled Trials; PaO2 = Partial pressure of arterial oxygen; SpO2 = peripheral oxygen saturation measured by pulse oximetry; FiO2 = Fraction of inspired oxygen

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errors ranging from − 3% to + 1% relative to arterial oxy- gen saturation (SaO2) as the reference [35].

Noninvasive respiratory supports for management of respiratory failure Several oxygenation strategies can be proposed as an alternative to COT in patients with acute hypoxemic respiratory failure. These oxygenation strategies, most often referred as noninvasive respiratory supports because of positive airway pressure and relief of respi- ratory effort include HFNC, CPAP, and NIV. Whereas supplemental oxygen should be offered to all patients with acute hypoxemic respiratory failure regardless of the level of breathlessness, noninvasive respiratory supports are reserved for the most hypoxemic patients with clini- cal signs of respiratory distress and are aimed at reliev- ing dyspnea. In most clinical trials assessing noninvasive respiratory supports in acute hypoxemic respiratory failure, the patients included had moderate-to-severe hypoxemia (PaO2/FiO2 ≤ 200  mm Hg), and either an increased respiratory rate above 25 breaths per minute or clinical signs of respiratory distress (Tables 2 and 3, and 4). These operational criteria could enable identification of the most severe forms of acute hypoxemic respiratory

failure, and help in deciding when to initiate a noninva- sive respiratory support.

High-flow nasal cannula oxygen therapy (HFNC) While COT cannot deliver FiO2 exceeding 60–70% in the upper airways [3], even with non-rebreathing face- mask and especially in patients generating strong efforts, HFNC can achieve FiO2 levels exceeding 80–90% [36]. Beyond improving oxygenation and enhancing comfort, dead space washout of the upper airways and, to a lesser extent, continuous delivery of low levels of positive air- way pressure can reduce work of breathing as compared with COT [37–39]. Indeed, relief of respiratory workload could be the main objective of noninvasive respiratory supports in severe forms of respiratory failure, possi- bly leading to improved outcomes [40]. The FLORALI study was the seminal study, showing clinical benefits of HFNC as compared to COT or NIV in patients with acute hypoxemic respiratory failure [1]. Whereas the risk of mortality was significantly lower with HFNC as com- pared with COT or NIV, the risk of intubation decreased only in patients with moderate-to-severe hypoxemia (PaO2/FiO2 ≤ 200 mm Hg), a finding suggesting that ben- eficial effects were more pronounced in patients with

Table 2 Main RCTs comparing high-flow nasal cannula oxygen therapy (HFNC) vs. conventional oxygen therapy (COT) in acute hypoxemic respiratory failure Study, year N centers

N Patients HFNC vs. COT Outcomes

Crimi, 2023 [51] 27 centers – wards

N = 362 – Mild-to-moderate COVID-19

HFNC (n = 181) vs. COT (n = 182)

Intubation day-28: HFNC 7% vs. COT 10% (p = NS) – Timing not specified Mortality day-28: HFNC 8% vs. COT 7% (p = 0.84)

Bouadma, 2022 [50] 19 centers – ICU

N = 333 –COVID-19

HFNC (n = 115) vs. COT (n = 109) vs. CPAP (n = 109)

Intubation day-28: HFNC 33% vs. COT 29% vs. CPAP 31% (p = NS) – Timing not specified Mortality day-60: HFNC 26% vs. COT 29% vs. CPAP 28% (p = NS)

Nazir, 2022 [52] 1 center – ICU

N = 120 - Mild-to-moderate COVID-19

HFNC [60] vs. COT (n = 60)

Intubation: HFNC 3% vs. COT 13% (p = NS) – Timing not specified Mortality: HFNC 5% vs. COT 8% (p = NS)

Perkins, 2022 [49] 48 centers – ICUs and wards

N = 783 – COVID-19

HFNC (415) vs. COT (n = 368)

Intubation day-30: HFNC 41% vs. COT 42% (p = 0.86) – Timing: HFNC 1 day [0–3] vs. COT 1 day [0–3] (p = 0.82) Mortality day-30: HFNC 19% vs. COT 20% (p = 0.66)

Frat, 2022 [48] 34 centers – ICU

N = 711 – COVID-19

HFNC (n = 357) vs. COT (n = 354)

Intubation day-28: HFNC 45% vs. COT 53% (p = 0.04) – Timing: HFNC 36 h [12–84] vs. COT 26 h [12–54] (p = 0.10) Mortality ICU: HFNC 10% vs. COT 11% (p = 0.60)

Ospina-Tascón, 2021 [47] 3 centers – ICU

N = 199 – COVID-19

HFNC (n = 99) vs. COT (n = 100)

Intubation day-28: HFNC 34% vs. COT 51% (p = 0.03) – Timing: HFNC 22 h [13–60] vs. COT 29 h [14–58] (p = 0.69) Mortality day-28: HFNC 8% vs. COT 16% (p = 0.11)

Andino, 2020 [42] 1 center – ICU

N = 46 – Acute hypoxemic respira- tory failure

HFNC (n = 24) vs. COT (n = 24)

Intubation: HFNC 33% vs. COT 63% (p = 0.04) – Timing not specified Mortality: HFNC 25% vs. COT 18% (p = 0.70)

Azoulay, 2018 [41] 32 centers – ICU

N = 776 – Immuno-compromised

HFNC (n = 388) vs. COT (n = 388)

Intubation: HFNC 39% vs. COT 44% (p = 0.17) – Timing not specified Mortality day-28: HFNC 36% vs. COT 36% (p = 0.94)

Frat, 2015 [1] 24 centers – ICU

N = 310 – Acute hypoxemic respira- tory failure

HFNC (n = 106) vs. COT (n = 94) vs. NIV (n = 110)

Intubation day-28: HFNC 38% vs. COT 47% vs. NIV 50% (p = 0.18) – Tim- ing: HFNC 27 h [8–46] vs. COT 15 h [5–39] vs. NIV 27 h [8–53] (p = 0.27) Mortality ICU: HFNC 11% vs. COT 19% vs. NIV 25% (p = 0.047)

Values are given in mean ± standard deviation or median [25ème – 75ème percentiles]

Abbreviations: RCT = Randomized Controlled Trials; COT = Conventional Oxygen Therapy; HFNC = High-Flow Nasal Cannula oxygen therapy; CPAP = Continuous Positive Airway Pressure; ICU = Intensive Care Unit; NS = Not Significant

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greater respiratory severity. In another large-scale clinical trial including immunocompromised patients, HFNC did not show any difference in terms of intubation or mor- tality as compared with COT [41] Another small-scale study reported lower intubation rates with HFNC than with COT [42]. Despite these contradictory results, clini- cal practice guidelines drawn up before the COVID-19 pandemic suggested the utilization of HFNC as opposed to COT or NIV in patients with acute hypoxemic respira- tory failure, although this was only a conditional recom- mendation [43]. HFNC was widely used for management of respiratory failure during the COVID-19 pandemic. The first retrospective observational studies conducted in China and then in Europe suggested decreased risk

of intubation with HFNC as compared with COT, while no reduction in mortality was observed [44–46]. After which, 6 clinical trials compared HFNC vs. COT in acute hypoxemic respiratory failure due to COVID-19 (Table 2) [47–52]. Two of them showed lower intubation rates with HFNC without reduction of mortality [47, 48], while a third one showed benefits on mortality or intubation but only in the subgroup of the most hypoxemic patients [49]. A recent meta-analysis pooling these random- ized controlled trials confirmed that HFNC significantly reduced the risk of intubation compared with COT with- out changes in mortality rates in patients with respiratory failure due to COVID-19 [53]. However, early initiation of HFNC in the specific population with mild hypoxemia seems pointless, and HFNC should be considered mainly in patients with moderate-to-severe hypoxemia (PaO2/ FiO2 ratio ≤ 200  mm Hg) [1, 51, 54]. A large-scale clini- cal trial (1110 patients planned to be included) compar- ing HFNC and COT is currently ongoing in patients with moderate-to-severe hypoxemia and will probably make it possible to reinforce or not the recommendation for the use of HFNC as first-line therapy in acute hypoxemic respiratory failure (NCT04468126).

Continuous positive airway pressure (CPAP) Whereas CPAP significantly improves oxygenation and increases end-expiratory lung volumes compared with COT and even HFNC, it has almost no effect on work of breathing in acute hypoxemic respiratory failure not related to cardiogenic pulmonary edema [55–57]. In 2000, a first clinical trial did not show any benefit of CPAP over COT (Table 3) [58]. Two other trials failed to show a decrease risk of intubation with CPAP delivered through a helmet vs. COT [59, 60]. Thereafter, a small- scale clinical trial including 40 patients with hematologic malignancy found that CPAP decreased the need for intubation and mortality when administered early in the ward as compared with COT [61]. More recently, a large platform trial conducted during the COVID-19 pan- demic showed significantly lower intubation rates with CPAP through a facemask as compared with COT, a dif- ference not observed between HFNC and COT [49]. This trial revived the interest in this noninvasive respiratory support which was nonetheless not as frequently used for management of respiratory failure [29]. However, another clinical trial conducted during the COVID-19 pandemic did not replicate these results, showing similar intubation and mortality rates for CPAP, COT or HFNC [50]. However, these recent studies have highlighted fre- quent discomfort using CPAP, leading to discontinuation of this respiratory support in approximately 15 to 20% of cases [49, 50]. Although discomfort may be lower when CPAP is delivered with a helmet, only a few small-scale

Table 3 Main RCTs comparing CPAP vs. COT or HFNC in acute hypoxemic respiratory failure Study, year N centers

N Patients CPAP vs. COT or HFNC

Outcomes

Bouadma, 2022 [50] 19 centers – ICU

N = 333; COVID-19

CPAP facemask (n = 109) vs. COT (n = 109) vs. HFNC (n = 115)

Intubation day-28: CPAP 31% vs. COT 29% vs. HFNC 33% (p = NS) – Timing not specified Mortality day-60: CPAP 28% vs. COT 29% vs. HFNC 26% (p = NS)

Perkins, 2022 [49] 48 centers – ICUs and wards

N = 733; COVID-19

CPAP facemask (n = 377) vs. COT (n = 356)

Intubation day-30: CPAP 33% vs. COT 41% (p = 0.03) – Timing: CPAP 2 days [1–4] vs. COT 1 day [0–4] (p = 0.03) Mortality day-30: CPAP 17% vs. COT 19% (p = 0.65)

Brambilla, 2014 [59] 4 centers

N = 81; Pneumonia

CPAP helmet (n = 40) vs. COT (n = 41)

Intubation: CPAP 5% vs. COT 2% (p = NS) – Timing not specified Mortality hospital: CPAP 5% vs. 17% (p = 0.15)

Squadrone, 2010 [61] 1 center – wards

N = 40; Hematologic with respira- tory failure

CPAP helmet (n = 20) vs. COT (n = 20)

Intubation: CPAP 10% vs. COT 70% (p < 0.01) – Tim- ing not specified Mortality hospital: CPAP 15% vs. 25% (p < 0.01)

Cosentini, 2010 [60] 1 center – wards

N = 47; Pneumonia

CPAP helmet (n = 20) vs. COT (n = 27)

No patient was intubated or died

Delclaux, 2000 [58] 6 centers – ICU

N = 123; Acute hypoxemic respiratory failure

CPAP facemask (n = 62) vs. COT (n = 61)

Intubation: CPAP 34% vs. COT 39% (p = 0.53) – Tim- ing not specified Mortality ICU: CPAP 21% vs. COT 25% (p = 0.63)

Values are given in mean ± standard deviation or median [25ème – 75ème percentiles]

Abbreviations: RCT = Randomized Controlled Trials; ICU = Intensive Care Unit; ED = Emergency Department; RF = Respiratory Failure; ARDS = Acute Respiratory Distress Syndrome; COPD = Chronic Obstructive Pulmonary Disease; CPE = Cardiogenic Pulmonary Edema; COT = Conventional Oxygen Therapy; HFNC = High-Flow Nasal Cannula oxygen therapy; NIV = Non-Invasive Ventilation; NS = Not Significant

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Table 4 Main RCTs comparing NIV vs. COT or HFNC in acute hypoxemic respiratory failure Study, year N centers

N Patients NIV vs. COT or HFNC Outcomes

Coudroy, 2022 [78] 29 ICUs

N = 299; Immuno- Compromised – COPD/CPE: No

NIV facemask + HFNC (n = 145) vs. HFNC (n = 154)

Intubation day-28: NIV 46% vs. HFNC 51% (p = 0.44) – Timing: NIV 29 h [9–72] vs. HFNC 20 h [5–58] (p = 0.24) Mortality day-28: NIV 35% vs. 36% (p = 0.83)

Grieco, 2021 [79] 4 ICUs

N = 109; COVID-19 – COPD/CPE: No

NIV helmet (n = 55) vs. HFNC (n = 54)

Intubation: NIV 30% vs. HFNC 51% (p = 0.03) – Timing: NIV 29 h [8–71] vs. HFNC 21 h [4–65] (p = 0.45) Mortality day-28: NIV 15% vs. 18% (p = 0.80)

Nair, 2021 [77] 1 ICU

N = 109; COVID-19 – COPD/CPE: No

NIV facemask (n = 54) vs. HFNC (n = 55)

Intubation day-7: NIV 46% (n = 25) vs. HFNC 27% (n = 15) (p = 0.045) – Timing not specified Mortality hospital: NIV 46% (n = 25) vs. 29% (n = 16) (p = 0.06)

He, 2019 [76] 21 ICUs

N = 200; Mild Acute Respiratory Distress Syndrome – COPD/CPE: No

NIV facemask (n = 102) vs. COT (n = 98)

Intubation: NIV 9% vs. COT 7% (p = 0.66) – Timing: NIV 4.7 ± 6.7 days vs. COT 2.6 ± 2.9 (p = 0.38) Mortality ICU: NIV 7% vs. 7% (p = 0.72)

Doshi, 2018 [75] 5 EDs

N = 204; Acute hypoxemic respiratory failure – COPD: 39%

NIV facemask (n = 100) vs. HFNC (n = 104)

Intubation at 72 h: NIV 13% vs. HFNC 7% (p = 0.13) – Timing: NIV 2.5 h [1.0-6.4] vs. HFNC 4.0 h [2.1–5.5] (p = NS)

Lemiale, 2015 [74] 28 ICUs

N = 374; Immuno- Compromised – COPD/CPE: No

NIV facemask ± HFNC (n = 191) vs. COT or HFNC (n = 183)

Intubation day-28: NIV 38% vs. COT or HFNC 45% (p = 0.20) – Tim- ing not specified Mortality day-28: NIV 24% vs. 27% (p = 0.47)

Frat, 2015 [1] 24 ICUs

N = 310; Acute hypoxemic respiratory failure – COPD/CPE: No

NIV facemask (n = 110) vs. COT (n = 94) or HFNC (n = 106)

Intubation day-28: NIV 50% vs. COT 47% or HFNC 38% (p = 0.18) – Timing: NIV 27 h [8–53] vs. COT 15 h [5–39] or HFNC 27 h [8–46] (p = 0.27) Mortality ICU: NIV 25% vs. COT 19% or HFNC 11% (p = 0.047)

Zhan, 2012 [80] 10 ICUs

N = 40; Mild Acute Respiratory Dis- tress Syndrome – COPD/CPE: No

NIV facemask (n = 21) vs. COT (n = 19)

Intubation: NIV 5% vs. COT 21% (p = 0.17) – Timing not specified Mortality ICU: NIV 5% vs. 26% (p = 0.08)

Ferrer, 2003 [68] 3 ICUs

N = 105; Acute hypoxemic respiratory failure – CPE: 29%

NIV facemask (n = 51) vs. COT (n = 54)

Intubation: NIV 25% vs. COT 52% (p = 0.03) – Timing not specified Mortality ICU: NIV 18% vs. 39% (p = 0.03)

Hilbert, 2001 [69] 1 ICU

N = 52 Immuno-compromised – COPD/CPE: No

NIV facemask (n = 26) vs. COT (n = 26)

Intubation: NIV 46% vs. COT 77% (p = 0.03) – Timing: NIV 63 ± 16 h vs. COT 51 ± 23 h (p = NS) Mortality ICU: NIV 38% vs. 69% (p = 0.03)

Antonelli, 2000 [70] 1 ICU

N = 40 Immuno- compromised – CPE: 22.5% – Hypercapnia 25%

NIV facemask (n = 20) vs. COT (n = 20)

Intubation: NIV 20% vs. COT 70% (p = 0.02) – Timing not specified Mortality ICU: NIV 20% vs. 50% (p = 0.05)

Martin, 2000 [71] 1 ICU

N = 61 Pneumonia – COPD: 38%

NIV facemask (n = 32) vs. COT (n = 29)

Intubation: NIV 28% vs. COT 59% (p = 0.02) – Timing not specified Mortality ICU: NIV 16% vs. 34% (p = 0.14)

Confalonieri, 1999 [72] 3 ICUs

N = 56 Acute hypoxemic RF – COPD: 41%

NIV facemask (n = 28) vs. COT (n = 28)

Intubation: NIV 21% vs. COT 50% (p = 0.03) – Timing: NIV 44 ± 24 h vs. COT 42 ± 13 h (p = NS) Mortality hospital: NIV 25% vs. 21% (p = NS)

Wood, 1998 [82] 1 ED

N = 27; Acute hypoxemic respiratory failure – CPE 37% - COPD 22%

NIV facemask (n = 16) vs. COT (n = 11)

Intubation: NIV 44% vs. COT 45% (p = 0.93) – Timing: NIV 26 ± 27 h vs. COT 4.8 ± 6.9 h (p = 0.055) Mortality hospital: NIV 25% vs. 0% (p = 0.12)

Kramer, 1995 [73] 1 ICU

N = 31; Acute hypoxemic respiratory failure – COPD: 74%

NIV facemask (n = 16) vs. COT (n = 15)

Intubation: NIV 31% vs. COT 73% (p = 0.03) – Timing not specified Mortality hospital: NIV 6% vs. 13% (p = NS)

Wysocki, 1995 [81] 1 ICU

N = 41; Acute hypoxemic respiratory failure – CPE 34% – Hypercapnia 41%

NIV facemask (n = 21) vs. COT (n = 20)

Intubation: NIV 62% vs. O2 70% (p = 0.88) – Timing: NIV 16 ± 24 h vs. O2 17 ± 25 h (p = 0.75) Mortality ICU: NIV 33% vs. O2 50% (p = 0.46)

Values are given in mean ± standard deviation or median [25ème – 75ème percentiles]

Abbreviations: RCT = Randomized Controlled Trials; ICU = Intensive Care Unit; ED = Emergency Department; RF = Respiratory Failure; ARDS = Acute Respiratory Distress Syndrome; COPD = Chronic Obstructive Pulmonary Disease; CPE = Cardiogenic Pulmonary Edema; COT = Conventional Oxygen Therapy; HFNC = High-Flow Nasal Cannula oxygen therapy; NIV = Non-Invasive Ventilation; NS = Not Significant

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clinical trials have compared CPAP-helmet vs. COT, with contradictory results [59–61].

Noninvasive ventilation (NIV) The early 1990s saw the first studies demonstrating the benefits of NIV through a facemask over COT in patients with acute exacerbation of chronic obstructive pulmo- nary disease [62–64] or cardiogenic pulmonary edema [65–67]. Later, in the 90–2000  s, several small-scale clinical trials involving patients with acute hypoxemic respiratory failure reported lower intubation rates with NIV compared COT (Table 4) [68–73]. From 2015, new clinical trials including larger populations (between 100 and more than 300 patients) compared NIV with HFNC [1, 74–79]. None of them reported beneficial effects of NIV with facemask as compared to HFNC [1, 74–78]. Two clinical trials have even shown deleterious effects of NIV with higher intubation or mortality rates than with HFNC [1, 77].

Whereas COT was used as control group in all the old studies showing beneficial effects of NIV [68–73, 80], HFNC was used in more recent studies as a con- trol group [1, 74–79]. Given the potential superiority of HFNC over COT in reducing intubation [1, 43, 47, 48, 53], it is probably more difficult to show the superior- ity of NIV over HFNC than over COT. Moreover, the older studies included heterogeneous populations with a number of patients with underlying chronic lung dis- ease or with cardiogenic pulmonary edema [68, 70–73, 81, 82], i.e. situations where NIV is particularly effective. By contrast, these patients were systematically excluded in more recent studies [1, 74, 76–79]. Lastly, the number of included patients was markedly lower in older than in most recent studies, with results appearing particularly contradictory in immunocompromised patients [69, 70, 74, 78]. Whereas two clinical trials conducted in 2000s showed superiority of NIV over COT on a sample of 40–50 patients [69, 70], two large-scale trials conducted more recently and including approximately 300 patients did not find any superiority of NIV over COT or HFNC [74, 78].

The interface may also significantly impact the out- come of NIV. Whereas NIV is most frequently delivered in ICUs with a facemask, it may also be delivered with a helmet. Potential advantages of a helmet include deliv- ering higher pressures (inspiratory and expiratory) than with a facemask due to fewer leaks, and more prolonged sessions of NIV due to a more comfortable interface without face pressure points [83]. Several physiological studies have shown that NIV through helmet improved oxygenation, decreased patient inspiratory effort and relieved dyspnea as compared to HFNC [57, 84]. A recent clinical trial showed lower rates of intubation with NIV through helmet than with HFNC in patients with acute

hypoxemic respiratory failure due to COVID-19 [79]. Two other randomized controlled trials have compared NIV through helmet versus NIV through facemask with contradictory results [85, 86]. In a first trial including 83 patients, the risks of intubation and mortality sig- nificantly decreased with NIV-helmet as compared to NIV-facemask [85]. In a more recent trial including 320 patients with acute hypoxemic respiratory failure due to COVID-19, NIV-helmet did not decrease the risk of intu- bation or mortality as compared to usual respiratory sup- ports that included NIV-facemask in approximately 70% of cases and HFNC in 75% of cases [86].

Thereby, this strategy cannot be recommended to date, and further studies are needed to assess the clinical effi- cacy of this interface. Indeed, even though NIV through helmet seems to be an effective noninvasive respira- tory support in terms of oxygenation, work of breathing and relief of dyspnea, to date only one clinical trial has compared NIV through a helmet vs. HFNC [79]. How- ever, a large-scale clinical trial (1200 patients planned to be included) comparing NIV through helmet, CPAP through helmet and HFNC in patients with acute respi- ratory failure is currently ongoing, and will probably make it possible to better specify the clinical benefits of each strategy, and the respective effects of the ventilation mode and the interface (NCT05089695).

Lastly, it has been suggested that the magnitude of inspiratory effort relief under NIV may be a good pre- dictor of NIV success [40, 84]. However, measurement of inspiratory effort is not performed in daily practice and whether the escalation to NIV may be personalized according to a patient’s inspiratory effort remains to be determined [87].

Which first-line noninvasive respiratory support should we propose in acute hypoxemic respiratory failure? To summarize, HFNC seems superior over COT to avoid intubation and should probably be used as a first-line treatment in patients with acute hypoxemic respiratory failure requiring more than 6 L/min of oxygen (i.e. FiO2 at least 40%) or PaO2/FiO2 ≤ 200  mm Hg and a respira- tory rate above 25 breaths per minute or clinical signs of respiratory distress, despite no benefits on mortality. Given that its beneficial effects on intubation remain uncertain, especially when compared with HFNC, CPAP cannot currently be recommended as a first-line of non- invasive respiratory support strategy in patients with acute hypoxemic respiratory failure. Despite older stud- ies favoring NIV over COT, recent clinical trials fail to show beneficial effects with NIV as compared to HFNC. Although HFNC is easier to use than NIV, it is not avail- able in all units, especially in emergency rooms. NIV or even CPAP may therefore be proposed as alternatives to COT in acute hypoxemic respiratory failure if HFNC is

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not available or in situations with constraints as was the case during the pandemic. By contrast, there is no evi- dence to support the use of NIV or CPAP as first-line treatment if HFNC is available. The main limitation of such recommendations could be their restricted applica- bility to low-income countries due to costs or constraints, the choice of the noninvasive respiratory support decided according to the availability on site.

Is it the same in patients with do-not-intubate (DNI) order? Initiation of a noninvasive respiratory support in patients with acute hypoxemic respiratory failure and a do- not-intubate order is frequent. In a systematic review of observational studies including more than 10,000 patients with acute respiratory failure treated with NIV or HFNC, the overall rate of do-not-intubate orders was 27% [88]. However, two clinical situations must be dis- tinguished. The first is when there is a reasonable pros- pect of survival. In this case, the goal of the non-invasive respiratory support is hospital survival, even though a decision has been made to forgo intubation in case of respiratory worsening. The second case scenario is an end-of-life setting and the goal of the treatment is symp- tom alleviation and quality of dying. In the first situation, the choice should be the same as for patients with full resuscitation code leading to intubation in case of respi- ratory worsening. In a systematic review including more than 2,000 patients with a do-not-intubate order, overall survival rate was 56% at hospital discharge and 32% at 1-year [89]. Whereas hospital survival reached 68% for chronic obstructive pulmonary disease and cardiogenic pulmonary edema, it was only 41% for pneumonia, and 37% for patients with malignancy. Although few studies have evaluated the quality of life of survivors, it would not be altered when compared with baseline. In a pro- spective observational cohort study, the prevalence of anxiety, depression, and post-traumatic stress disorder- related symptoms in patients with do-not-intubate order were similar to those who were treated without do-not- intubate order [90].

In the end-of-life setting, a randomized controlled trial compared NIV vs. COT for management of acute respiratory failure in 200 patients with a life expectancy of less than 6 months [91]. Although dyspnea decreased more rapidly with NIV than with COT and morphine consumption was reduced, NIV was discontinued due to poor tolerance in 11% of cases, mainly related to mask intolerance and anxiety. NIV impairs the ability to communicate, and therefore, does not appear to be compatible with the psychological and spiritual needs of patients in this setting. Consequently, NIV cannot be recommended in terminally ill patients. Several clinical trials have shown that HFNC was superior to COT for dyspnea alleviation, and reduced dyspnea to the same

extent as NIV [92–95], and several observational studies have used HFNC in first-line treatment as an alternative to NIV [96–98]. Given its good tolerance and its efficacy on dyspnea, HFNC could be considered as the first-line noninvasive respiratory support for management of acute respiratory failure in end-of life settings.

Other treatments Positioning and mobilization are part of the adjuvant treatments that can be offered in patients with acute hypoxemic respiratory failure.

What are the potential beneficial effects of awake prone positioning (APP)? As prone positioning has been shown to improve sur- vival in intubated patients with acute respiratory distress syndrome (ARDS) [99], during the COVID-19 pandemic “awake” prone positioning (APP) was used early in non- intubated patients with acute respiratory failure [100– 102]. These first observational studies showed significant improvement in oxygenation and reduction in respira- tory rate without major complications. Following which, several clinical trials compared APP vs. usual care on the risk of intubation and mortality (Table  5) [103–109]. In these clinical trials, APP was started in ICUs or hospi- tal wards, in patients treated with COT, HFNC or NIV, with a wide range of respiratory severity and APP dura- tion. Consequently, intubation rates ranged from 10 to 40%. By pooling all RCTs, several meta-analyses showed that APP was associated with a significant decreased risk of intubation without improving survival [110, 111]. In fact, these findings are mainly driven by one large meta- trial showing a decreased risk of intubation [109]. In this meta-trial pooling 6 different RCTs conducted in six countries and including 1111 patients, a decreased risk of intubation was significant in only one participating country (Mexico) where APP sessions were much lon- ger. A post-hoc analysis of this Mexican study suggested that APP sessions lasting at least 8 h/day were associated with treatment success [112]. With the exception of this study, no other randomized controlled trial has shown a significant reduction in the risk of intubation or mortal- ity using APP. However, thanks to this large-scale positive study, meta-analyses are favor APP, with beneficial effects on oxygenation and on the risk of intubation, especially using prolonged APP sessions in the most severe patients [110]. The potential benefits of APP on the risk of intuba- tion in patients with COVID-19 cannot be extrapolated to patients with another etiology of acute hypoxemic respiratory failure. Thus, further clinical trials are needed to assess APP in patients with acute hypoxemic respira- tory failure from various causes.

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Is physiotherapy a beneficial adjuvant measure? To date, no randomized controlled trial has assessed the impact of physiotherapy in patients with acute hypox- emic respiratory failure. However, some techniques can be proposed to improve the clinical condition or comfort of patients during the management of respiratory failure. Motor physiotherapy such as exercises in bed, sitting on a chair, cycloergometer could help to reduce the shunt effect caused by parenchymal consolidations through alveolar recruitment. Several studies have evaluated the effects of physical activity on lung aeration using electri- cal impedance tomography [113–115]. In these studies, however, the changes in ventilation distribution were not sustained over time and regressed after the various inter- ventions. Guidelines from the American Association for Respiratory Care and the British Thoracic Society have

specified the role of respiratory physiotherapy [116, 117]. Bronchial clearance techniques should be reserved for patients with bronchial congestion and sputum difficul- ties. Respiratory physiotherapy should be tailored rather than routinely offered to all patients with acute hypox- emic respiratory failure. Among the various techniques used for respiratory physiotherapy, none has been shown to be superior to another, and the choice of the technique must take into account the patient’s tolerance, preference and clinical condition [118]. However, the physiothera- pist can legitimately participate in the installation and monitoring of devices such as aerosol therapy or non- invasive ventilation [119, 120]. In all cases, the benefit- risk balance should be evaluated before and during each physiotherapy session.

Indications for invasive mechanical ventilation Patient self-inflicted lung injury associated with noninvasive respiratory supports After several small-scale studies showing beneficial effects of NIV, a large-scale clinical trial including more than 300 patients showed for the first time higher mor- tality rates with NIV than with HFNC [1]. A post-hoc analysis of this study suggested that large tidal volumes generated by the patient from NIV initiation (exceeding 9.5 ml/kg of predicted body weight) were associated with increased risk of death [121]. This finding was consistent with another observational study [122], and that gave

Table 5 Main multicenter RCTs comparing awake prone positioning (APP) vs. standard position in acute hypoxemic respiratory failure due to COVID-19 Study, year N patients – centers

Noninvasive respiratory support and APP duration

Outcomes

Nay, 2023 (103) N = 267–12 centers

Under COT (96%) or HFNC: usual care (n = 132) vs. APP (n = 135) for 90 min/d [30–133]

Intubation: APP 7% vs. 10% (p = NS) Mortality: APP 0% vs. 3% (p = NS)

Alhazzani, 2022 (104) N = 400–21 centers

Under HFNC (70%), COT, or NIV: usual care (n = 195) vs. APP (n = 205) for 4.8 h/d [1.8-8.0]

Intubation day-30: APP 34% vs. 41% (p = NS) Mortality day-60: APP 22% vs. 24% (p = NS)

Fralick, 2022 (105) N = 248–15 centers

Under HFNC or NIV: usual care (n = 122) vs. APP (n = 126) for 6 h [1.5–12.8] within the first 72 h

Intubation: APP 5% vs. 4% (p = NS) Mortality: APP 1% vs. 1% (p = NS)

Gopalakrishnan, 2022 (106) N = 502–1 center

Room air or COT: usual care (n = 245) vs. APP (n = 257) for 4.3 h ± 2.9/d

Intubation: APP 10% vs. 10% (p = NS) Mortality: APP 16% vs. 15% (p = NS)

Qian, 2022 (107) N = 501–2 centers

Under COT (66%), NIV or HFNC: usual care (n = 243) vs. APP (n = 258) for 4.2 h/d [1.8–6.7]

Intubation: APP 12% vs. 12% (p = NS) Mortality: APP 21% vs. 23% (p = NS)

Rosén, 2021 (108) N = 75–3 centers

Under HFNC or NIV: stan- dard (n = 39) vs. APP (n = 36) for 9.0 h/d [4.4–10.6]

Intubation day-30: APP 33% vs. 33% (p = NS) Mortality day-30: APP 17% vs. 8% (p = NS)

Ehrmann, 2021 (109) N = 1111–6 countries

Under HFNC: standard (n = 557) vs. APP (n = 564) for 5.0 h/d [1.6–8.8]

Intubation day-28: APP 33% vs. 40% (p = 0.004) Mortality day-28: APP 21% vs. 24% (p = NS)

Values are given in mean ± standard deviation or median [25ème – 75ème percentiles]

Abbreviations: RCT = Randomized Controlled Trials; APP = Awake Prone Positioning; COT = Conventional Oxygen Therapy; HFNC = High-Flow Nasal Cannula oxygen therapy; NIV = Non-Invasive Ventilation; NS = Not Significant

Table 6 Major and minor criteria for intubation proposed to the committee using Delphi method. The presence of only one major criterion should lead to consider immediate intubation whereas combination of several minor criteria should prompt intubation Major criteria - Cardiac or respiratory arrest - Altered consciousness defined as a Glasgow coma scale < 9 - Persistent hypoxemia despite maximal oxygen delivery or maximal inspired fraction of oxygen (FiO2) defined as PaO2 < 60 mm Hg, PaO2/ FiO2 < 60 mm Hg, or SpO2 < 88% - Respiratory acidosis defined as pH < 7.20 Minor criteria 1. Clinical signs of Respiratory distress with increased accessory muscle activity 2. Increased respiratory rate > 30 breaths per minute 3. Persistent hypoxemia despite maximal oxygen delivery or maximal inspired fraction of oxygen (FiO2) defined as PaO2 < 100 mm Hg; PaO2/ FiO2 < 100 mm Hg; or SpO2 < 92% 4. Episodes of oxygen desaturation defined as SpO2 < 86% 5. Intolerance to device delivering oxygen 6. Abundant secretions 7. Respiratory acidosis defined as pH < 7.30 8. Agitation 9. Altered consciousness defined as Glasgow coma scale < 12 10. Shock requiring with increased lactate level at least 2 mmol/L

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birth to the concept of “PSILI” for Patient Self-Inflicted Lung Injury [123]. Patients producing strong inspiratory efforts generate large tidal volumes under NIV, and that may lead to worsening of lung injury by increasing trans- pulmonary pressures, in the same way that large tidal vol- umes are harmful in patients with ARDS under invasive mechanical ventilation [124, 125]. However, such large tidal volumes observed in patients treated with NIV may simply reflect respiratory disease severity, and one can- not exclude the possibility that effects of NIV may be different according to severity. An observational study suggested that NIV may be associated with an increased risk of death in the most severe patients, i.e. patients with ARDS and a PaO2/FiO2 ratio below 150  mm Hg [126]. Similarly, another observational study showed that patients who still had significant inspiratory efforts after NIV initiation had increased risk of intubation as compared to the others [40]. Although tidal volumes do not increase when switching form COT to HFNC [37], patients with strong inspiratory efforts could still develop lung injury, regardless of the type of noninvasive respi- ratory support [123]. Up until now, no clinical trial has shown any benefit to switch from a noninvasive respira- tory support to another according to tidal volumes or intensity of effort.

Criteria for intubation Most clinical trials comparing different noninvasive respiratory supports have proposed pre-specified crite- ria for intubation to ensure the consistency of indications across sites and reduce the risk of delayed intubation. Criteria for intubation usually include worsening respi- ratory failure, hemodynamic failure and neurological failure. Major and minor criteria for intubation were determined by experts using a Delphi method and pro- posed to the guideline panel (Table  6). The presence of only one major criterion should lead to consider imme- diate intubation whereas a combination of several minor criteria should prompt intubation.

Timing of intubation Several observational studies have suggested that late or delayed intubation may be associated with increased risk of death [127–130]. However, there may be a major bias of interpretation between late intubation and delayed intubation. Delayed intubation means a delay between occurrence of criteria for intubation and the decision to intubate. Late intubation can occur without being delayed, for example when criteria for intubation emerge later due to secondary worsening. An observational study including more than 800 patients treated with NIV has showed that patients intubated early (i.e. within the first 12 h after ICU admission) had markedly higher severity at admission than those intubated later [128]. However,

the severity assessed at the time of intubation was simi- lar for both early and late intubations, meaning that intu- bation was late but not delayed. Thereby, late intubation could be associated with worse outcomes simply because it indicates failure of the initial treatment. Randomized controlled trials are the best way to answer the question of whether the use of noninvasive respiratory supports risks delaying intubation. Among all randomized con- trolled trials that compared HFNC vs. COT, none showed significantly later intubation with HFNC than with COT (Table 2). Similarly, among all randomized controlled tri- als that compared NIV vs. HFNC or COT, none showed significant later intubation than with one of those respi- ratory supports (Table  4). Only one RCT showed later intubation with CPAP than with COT in patients with respiratory failure due to COVID-19, knowing that 40% of patients were treated in the hospital wards and not in ICUs due to a wave of the pandemic (Table  3) [49]. Therefore, although late intubation per-se may be asso- ciated with poor outcomes, randomized controlled trials do not show that noninvasive respiratory supports may lead to late or delayed intubation.

Where to manage patients receiving noninvasive respiratory support? The huge influx of ICU patients during the COVID- 19 pandemic led intensivists to treat a large number of patients with noninvasive respiratory supports out- side ICUs due to the limited number of available beds [46, 49, 131]. These patients were treated in wards with HFNC, CPAP or NIV, and only those requiring intuba- tion were admitted to an ICU, with intubation rates around 30–40% [49]. In an observational study including 608 patients in 10 hospitals in the Netherlands during the pandemic, initiation of HFNC outside ICUs was shown to be safe, and intubation or mortality rates did not differ between patients treated first in ICUs and those treated first outside ICUs [132]. In a French observational study, 85 patients with acute hypoxemic respiratory failure due to COVID-19 received open valve CPAP treatment in intermediate care units from non-ICU staff who were trained using a simple short tutorial video [133]. In a retrospective study conducted in Italy before the pan- demic, patients were treated with CPAP or NIV outside ICUs without major complication [134]. However, these patients were managed by a rapid response team with a daily visit in collaboration with ward staff highly experi- enced in noninvasive respiratory supports. The pandemic has shown that initiation of noninvasive respiratory sup- port outside ICUs was feasible and potentially safe for patients with respiratory failure, especially when the hos- pital faces such constraints. However, intubation rates in patients with acute hypoxemic respiratory failure range from 30 to 50%, and in more than half of cases occur

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within the first 24 h (Tables 2 and 3 and Table 4). There- fore, these patients should be closely monitored in ICUs rather than in wards, if ICU beds are available.

Conclusion Oxygen supplementation should be initiated for patients with acute hypoxemic respiratory failure defined as PaO2 below 60  mm Hg or SpO2 < 90% on room air. HFNC should be the first-line noninvasive respiratory support in patients with moderate-to-severe hypoxemia (PaO2/ FiO2 ≤ 200 mm Hg). Further studies are needed to assess potential benefits of CPAP, NIV through a helmet and awake prone position, especially in patients with acute hypoxemic respiratory failure not related to COVID-19.

Abbreviations RCT Randomized Controlled Trials COT Conventional Oxygen Therapy HFNC High-Flow Nasal Cannula oxygen therapy NIV Non-Invasive Ventilation ICU Intensive Care Unit NS Not Significant

Acknowledgements We thank Jeffrey Arsham (CHU de Poitiers, Poitiers, France) for reviewing and editing the original English-language manuscript.

Author contributions Pr. Arnaud W. Thille had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors contributed to drafting of the work, revising it critically for important intellectual content and approved the final version of the manuscript. All authors give their agreement to be accountable for all aspects of the work, and ensure the accuracy and integrity of any part of the work.

Funding None.

Data availability Not applicable.

Declarations

Ethics approval and consent to participate Not applicable.

Consent for publication Not applicable.

Competing interests AWT, MAN, JPF received fees from Fisher&Paykel (travel expense coverage to attend scientific meetings and payments for lectures). GC received personal fees from Air Liquide Medical System, GE Healthcare, Dräger, Fisher&Paykel, Medtronic and Lowenstein.

Author details 1Service de Médecine Intensive Réanimation, CHU de Poitiers, Poitiers, France 2INSERM CIC-1402, IS- ALIVE, Université de Poitiers, Poitiers, France 3CHU de Toulouse, Service des Urgences, Toulouse, France 4INSERM, CERPOP – EQUITY, Toulouse, France 5Assistance Publique-Hôpitaux de Paris, CHU Henri Mondor-Albert Chenevier, Service de Médecine Intensive Réanimation, Créteil, France 6Faculté de Santé, Groupe de Recherche Clinique CARMAS, Université Paris Est-Créteil, Créteil, France 7INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, France

8CHRU de Nancy, Service des Urgences, Nancy, France 9Université de Lorraine, UMRS 1116, Nancy, France 10CHU-Hôpitaux de Rouen, Service de Médecine Intensive Réanimation, Normandie Univ, GRHVN UR, Rouen 3830, France 11CHU de Brest, Service de Médecine Intensive Réanimation, Brest, France 12CHU de Poitiers, Service d’Accueil des Urgences, Poitiers, France 13CHU d’Orléans, Service de Médecine Intensive Réanimation, Orléans, France 14CHU de Dijon, Service des Urgences, Dijon, France 15Hôpital Foch, Service de Réanimation polyvalente, Suresnes, France 16Assistance Publique-Hôpitaux de Paris, Hôpital de la Pitié-Salpêtrière, Service des Urgences, Paris, France 17CHU de Marseille, Hôpital Nord, Service de Médecine Intensive Réanimation, Marseille, France 18CHU de Saint-Etienne, Service de Médecine Intensive Réanimation, Saint-Etienne, France 19Research on Healthcare Performance RESHAPE, INSERM U1290, Université Claude Bernard Lyon 1, Lyon, France 20Assistance Publique – Hôpitaux de Paris, Hôpital Cochin, Service des Urgences, Université Paris-Cité, Paris, France

Received: 11 June 2024 / Accepted: 2 October 2024

References 1. Frat JP, Thille AW, Mercat A, Girault C, Ragot S, Perbet S, et al. High-flow

oxygen through nasal cannula in acute hypoxemic respiratory failure. N Engl J Med. 2015;372(23):2185–96. PubMed PMID: 25981908. Epub 2015/05/20.

2. Helms J, Catoire P, Abensur Vuillaume L, Bannelier H, Douillet D, Dupuis C, et al. Oxygen therapy in acute hypoxemic respiratory failure: guidelines from the SRLF-SFMU consensus conference. Ann Intensiv Care. 2024;14(1):140. PubMed PMID: 39235690. Pubmed Central PMCID: PMC11377397. Epub 2024/09/05.

3. Coudroy R, Frat JP, Girault C, Thille AW. Reliability of methods to estimate the fraction of inspired oxygen in patients with acute respiratory failure breathing through non-rebreather reservoir bag oxygen mask. Thorax. 2020;75(9):805–7. PubMed PMID: 32522764. Epub 2020/06/12.

4. Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, et al. Acute respiratory distress syndrome: the Berlin definition. JAMA. 2012;307(23):2526–33. PubMed PMID: 22797452.

5. Coudroy R, Frat JP, Boissier F, Contou D, Robert R, Thille AW. Early identification of Acute Respiratory Distress Syndrome in the absence of positive pressure ventilation: implications for revision of the Berlin Criteria for Acute Respira- tory Distress Syndrome. Crit Care Med. 2018;46(4):540–6. PubMed PMID: 29271843.

6. Arrivé F, Coudroy R, Thille AW. Early identification and diagnostic approach in acute respiratory distress syndrome (ARDS). Diagnostics (Basel, Switzerland). 2021;11(12). PubMed PMID: 34943543. Pubmed Central PMCID: PMC8700413. Epub 2021/12/25.

7. Parke RL, Eccleston ML, McGuinness SP. The effects of flow on airway pres- sure during nasal high-flow oxygen therapy. Respir Care. 2011;56(8):1151–5. PubMed PMID: 21496369. Epub 2011/04/19.

8. Groves N, Tobin A. High flow nasal oxygen generates positive airway pressure in adult volunteers. Australian Crit care: Official J Confederation Australian Crit Care Nurses. 2007;20(4):126–31. PubMed PMID: 17931878. Epub 2007/10/13.

9. Matthay MA, Arabi Y, Arroliga AC, Bernard G, Bersten AD, Brochard LJ, et al. A New Global Definition of Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med. 2024;209(1):37–47. PubMed PMID: 37487152. Epub 2023/07/24.

10. Eastwood G, Bellomo R, Bailey M, Taori G, Pilcher D, Young P, et al. Arterial oxygen tension and mortality in mechanically ventilated patients. Intensive Care Med. 2012;38(1):91–8. PubMed PMID: 22127482. Epub 2011/12/01.

11. Raman S, Prince NJ, Hoskote A, Ray S, Peters MJ. Admission PaO2 and mortal- ity in critically Ill children: a cohort study and systematic review. Pediatric Critical Care Med J Soc Critical Care Med World Federation Pediatric Intensive and Crit Care Soc. 2016;17(10):e444–50. PubMed PMID: 27509363. Epub 2016/08/11.

12. Barrot L, Asfar P, Mauny F, Winiszewski H, Montini F, Badie J, et al. Liberal or conservative oxygen therapy for acute respiratory distress syndrome. N Engl J Med. 2020;382(11):999–1008. PubMed PMID: 32160661. Epub 2020/03/12.

Page 12 of 15Thille et al. Annals of Intensive Care (2024) 14:158

13. Hochberg CH, Semler MW, Brower RG. Oxygen toxicity in critically ill adults. Am J Resp Crit Care Med. 2021;204(6):632–41. PubMed PMID: 34086536. Pubmed Central PMCID: PMC8521700. Epub 2021/06/05.

14. Nash G, Blennerhassett JB, Pontoppidan H. Pulmonary lesions associated with oxygen therapy and artificial ventilation. N Engl J Med. 1967;276(7):368–74. PubMed PMID: 6017244. Epub 1967/02/16.

15. Dreyfuss D, Saumon G. Ventilator-induced lung injury: lessons from experi- mental studies. Am J Respir Crit Care Med. 1998;157(1):294–323. PubMed PMID: 9445314.

16. Girardis M, Busani S, Damiani E, Donati A, Rinaldi L, Marudi A, et al. Effect of conservative vs conventional oxygen therapy on Mortality among patients in an intensive care unit: the oxygen-ICU randomized clinical trial. JAMA. 2016;316(15):1583–9. PubMed PMID: 27706466. Epub 2016/10/19.

17. Nielsen FM, Klitgaard TL, Siegemund M, Laake JH, Thormar KM, Cole JM et al. Lower vs higher oxygenation target and days alive without life support in COVID-19: the HOT-COVID randomized clinical trial. JAMA. 2024 Mar 19. PubMed PMID: 38501214. Pubmed Central PMCID: PMC10951852. Epub 2024/03/19.

18. van der Wal LI, Grim CCA, Del Prado MR, van Westerloo DJ, Boerma EC, Rijnhart-de Jong HG, et al. Conservative versus liberal oxygenation targets in Intensive Care Unit patients (ICONIC): a Randomized Clinical Trial. Am J Respir Crit Care Med. 2023;208(7):770–9. PubMed PMID: 37552556. Pubmed Central PMCID: PMC10563190. Epub 2023/08/08.

19. Schmidt H, Kjaergaard J, Hassager C, Mølstrøm S, Grand J, Borregaard B, et al. Oxygen targets in Comatose survivors of Cardiac arrest. N Engl J Med. 2022;387(16):1467–76. PubMed PMID: 36027567. Epub 2022/08/27.

20. Semler MW, Casey JD, Lloyd BD, Hastings PG, Hays MA, Stollings JL, et al. Oxygen-saturation targets for critically ill adults receiving mechanical ventila- tion. N Engl J Med. 2022;387(19):1759–69. PubMed PMID: 36278971. Pubmed Central PMCID: PMC9724830. Epub 2022/10/25.

21. Schjørring OL, Klitgaard TL, Perner A, Wetterslev J, Lange T, Siegemund M, et al. Lower or higher oxygenation targets for Acute Hypoxemic Respiratory failure. N Engl J Med. 2021;384(14):1301–11. PubMed PMID: 33471452. Epub 2021/01/21.

22. Gelissen H, de Grooth HJ, Smulders Y, Wils EJ, de Ruijter W, Vink R, et al. Effect of Low-Normal vs high-normal oxygenation targets on Organ Dysfunction in critically ill patients: a Randomized Clinical Trial. JAMA. 2021;326(10):940–8. PubMed PMID: 34463696. Pubmed Central PMCID: PMC8408761. Epub 2021/09/01.

23. Mackle D, Bellomo R, Bailey M, Beasley R, Deane A, Eastwood G, et al. Con- servative oxygen therapy during mechanical ventilation in the ICU. N Engl J Med. 2020;382(11):989–98. PubMed PMID: 31613432. Epub 2019/10/16.

24. Yang X, Shang Y, Yuan S. Low versus high pulse oxygen saturation directed oxygen therapy in critically ill patients: a randomized controlled pilot study. J Thorac Disease. 2019;11(10):4234–40. PubMed PMID: 31737308. Pubmed Central PMCID: PMC6837987. Epub 2019/11/19.

25. Panwar R, Hardie M, Bellomo R, Barrot L, Eastwood GM, Young PJ, et al. Conservative versus liberal oxygenation targets for mechanically ventilated patients. A pilot Multicenter Randomized Controlled Trial. Am J Respir Crit Care Med. 2016;193(1):43–51. PubMed PMID: 26334785. Epub 2015/09/04.

26. Asfar P, Schortgen F, Boisramé-Helms J, Charpentier J, Guérot E, Megarbane B, et al. Hyperoxia and hypertonic saline in patients with septic shock (HYPERS2S): a two-by-two factorial, multicentre, randomised, clinical trial. Lancet Respiratory Med. 2017;5(3):180–90. PubMed PMID: 28219612. Epub 2017/02/22.

27. Palmer E, Post B, Klapaukh R, Marra G, MacCallum NS, Brealey D, et al. The Association between Supraphysiologic Arterial Oxygen Levels and mortality in critically ill patients. A Multicenter Observational Cohort Study. Am J Respir Crit Care Med. 2019;200(11):1373–80. PubMed PMID: 31513754. Pubmed Central PMCID: PMC6884048. Epub 2019/09/13.

28. Klitgaard TL, Schjørring OL, Nielsen FM, Meyhoff CS, Perner A, Wetterslev J, et al. Higher versus lower fractions of inspired oxygen or targets of arterial oxy- genation for adults admitted to the intensive care unit. Cochrane Database Syst Rev. 2023;9(9):CD012631. PubMed PMID: 37700687. Pubmed Central PMCID: PMC10498149. Epub 2023/09/13.

29. SRLF trial group. Hypoxemia in the ICU: prevalence, treatment, and outcome. Ann Intensiv Care. 2018;8(1):82. PubMed PMID: 30105416. Pubmed Central PMCID: PMC6089859. Epub 2018/08/15.

30. Hasegawa T, Ochi T, Goya S, Matsuda Y, Kako J, Watanabe H, et al. Efficacy of supplemental oxygen for dyspnea relief in patients with advanced progressive illness: a systematic review and meta-analysis. Respiratory Invest. 2023;61(4):418–37. PubMed PMID: 37105126. Epub 2023/04/28.

31. O’Driscoll BR, Howard LS, Earis J, Mak V. BTS guideline for oxygen use in adults in healthcare and emergency settings. Thorax. 2017;72(Suppl 1):ii1–90. PubMed PMID: 28507176. Epub 2017/05/17.

32. Thrush DN, Downs JB, Hodges M, Smith RA. Does significant arterial hypox- emia alter vital signs? J Clin Anesth. 1997;9(5):355–7. PubMed PMID: 9257199. Epub 1997/08/01.

33. Zeballos RJ, Weisman IM. Reliability of noninvasive oximetry in black subjects during exercise and hypoxia. Am Rev Respir Dis. 1991;144(6):1240–4. PubMed PMID: 1741533. Epub 1991/12/01.

34. Bickler PE, Feiner JR, Severinghaus JW. Effects of skin pigmentation on pulse oximeter accuracy at low saturation. Anesthesiology. 2005;102(4):715–9. PubMed PMID: 15791098. Epub 2005/03/26.

35. Blanchet MA, Mercier G, Delobel A, Nayet E, Bouchard PA, Simard S, et al. Accuracy of multiple pulse oximeters in stable critically ill patients. Respir Care. 2023;68(5):565–74. PubMed PMID: 36596654. Pubmed Central PMCID: PMC10171338. Epub 2023/01/04.

36. Sim MA, Dean P, Kinsella J, Black R, Carter R, Hughes M. Performance of oxygen delivery devices when the breathing pattern of respiratory failure is simulated. Anaesthesia. 2008;63(9):938–40. PubMed PMID: 18540928.

37. Mauri T, Turrini C, Eronia N, Grasselli G, Volta CA, Bellani G, et al. Physiologic effects of High-Flow Nasal Cannula in Acute Hypoxemic Respiratory failure. Am J Respir Crit Care Med. 2017;195(9):1207–15. PubMed PMID: 27997805.

38. Moller W, Celik G, Feng S, Bartenstein P, Meyer G, Oliver E, et al. Nasal high flow clears anatomical dead space in upper airway models. J Appl Physiol (Bethesda Md: 1985). 2015;118(12):1525–32. PubMed PMID: 25882385. Pubmed Central PMCID: PMC4482836. Epub 2015/04/18.

39. Delorme M, Bouchard PA, Simon M, Simard S, Lellouche F. Effects of High- Flow Nasal Cannula on the work of breathing in patients recovering from Acute Respiratory failure. Crit Care Med. 2017;45(12):1981–8. PubMed PMID: 28857852.

40. Tonelli R, Fantini R, Tabbì L, Castaniere I, Pisani L, Pellegrino MR, et al. Early Inspiratory Effort Assessment by Esophageal Manometry predicts noninva- sive ventilation outcome in De Novo Respiratory failure. A pilot study. Am J Respir Crit Care Med. 2020;202(4):558–67. PubMed PMID: 32325004. Pubmed Central PMCID: PMC7427381. Epub 2020/04/24.

41. Azoulay E, Lemiale V, Mokart D, Nseir S, Argaud L, Pène F, et al. Effect of High- Flow Nasal Oxygen vs Standard Oxygen on 28-Day mortality in immunocom- promised patients with Acute Respiratory failure: the HIGH Randomized Clini- cal Trial. JAMA. 2018;320(20):2099–107. PubMed PMID: 30357270. Pubmed Central PMCID: PMC6583581. Epub 2018/10/26.

42. Andino R, Vega G, Pacheco SK, Arevalillo N, Leal A, Fernández L et al. High- flow nasal oxygen reduces endotracheal intubation: a randomized clinical trial. Therapeutic Adv Resp Dis. 2020 Jan-Dec;14:1753466620956459. PubMed PMID: 32976085. Pubmed Central PMCID: PMC7522841. Epub 2020/09/26.

43. Oczkowski S, Ergan B, Bos L, Chatwin M, Ferrer M, Gregoretti C et al. ERS clini- cal practice guidelines: high-flow nasal cannula in acute respiratory failure. Eur Respir J. 2022;59(4). PubMed PMID: 34649974. Epub 2021/10/16.

44. Wang K, Zhao W, Li J, Shu W, Duan J. The experience of high-flow nasal can- nula in hospitalized patients with 2019 novel coronavirus-infected pneumo- nia in two hospitals of Chongqing, China. Ann Intensiv Care. 2020;10(1):37. PubMed PMID: 32232685. Pubmed Central PMCID: PMC7104710. Epub 2020/04/02.

45. Bonnet N, Martin O, Boubaya M, Levy V, Ebstein N, Karoubi P, et al. High flow nasal oxygen therapy to avoid invasive mechanical ventilation in SARS-CoV-2 pneumonia: a retrospective study. Ann Intensiv Care. 2021;11(1):37. PubMed PMID: 33638752. Pubmed Central PMCID: PMC7910764. Epub 2021/02/28.

46. Demoule A, Vieillard Baron A, Darmon M, Beurton A, Géri G, Voiriot G et al. High flow nasal canula in critically ill severe COVID-19 patients. Am J Respir Crit Care Med. 2020. PubMed PMID: 32758000. Epub 2020/08/08.

47. Ospina-Tascón GA, Calderón-Tapia LE, García AF, Zarama V, Gómez-Álvarez F, Álvarez-Saa T, et al. Effect of High-Flow Oxygen Therapy vs Conventional Oxygen Therapy on Invasive Mechanical Ventilation and clinical recov- ery in patients with severe COVID-19: a randomized clinical trial. JAMA. 2021;326(21):2161–71. PubMed PMID: 34874419. Pubmed Central PMCID: PMC8652598. Epub 2021/12/08.

48. Frat JP, Quenot JP, Badie J, Coudroy R, Guitton C, Ehrmann S, et al. Effect of High-Flow Nasal Cannula Oxygen vs Standard Oxygen Therapy on Mortality in patients with respiratory failure due to COVID-19: the SOHO-COVID Ran- domized Clinical Trial. JAMA. 2022;328(12):1212–22. PubMed PMID: 36166027. Pubmed Central PMCID: PMC9516287. Epub 2022/09/28.

49. Perkins GD, Ji C, Connolly BA, Couper K, Lall R, Baillie JK, et al. Effect of nonin- vasive respiratory strategies on intubation or mortality among patients with

Page 13 of 15Thille et al. Annals of Intensive Care (2024) 14:158

Acute Hypoxemic respiratory failure and COVID-19: the RECOVERY-RS Ran- domized Clinical Trial. JAMA. 2022;327(6):546–58. PubMed PMID: 35072713. Epub 2022/01/25.

50. Bouadma L, Mekontso-Dessap A, Burdet C, Merdji H, Poissy J, Dupuis C, et al. High-dose dexamethasone and oxygen support strategies in Intensive Care Unit patients with severe COVID-19 Acute Hypoxemic Respiratory failure: the COVIDICUS Randomized Clinical Trial. JAMA Intern Med. 2022;182(9):906–16. PubMed PMID: 35788622. Pubmed Central PMCID: PMC9449796. Epub 2022/07/06.

51. Crimi C, Noto A, Madotto F, Ippolito M, Nolasco S, Campisi R et al. High-flow nasal oxygen versus conventional oxygen therapy in patients with COVID-19 pneumonia and mild hypoxaemia: a randomised controlled trial. Thorax. 2022. PubMed PMID: 35580898. Pubmed Central PMCID: PMC9157330. Epub 2022/05/18.

52. Nazir N, Saxena A. The effectiveness of high-flow nasal cannula and standard non-rebreathing mask for oxygen therapy in moderate category COVID- 19 pneumonia: Randomised controlled trial. Afr J Thorac Crit care Med. 2022;28(1). PubMed PMID: 35692457. Pubmed Central PMCID: PMC9178776. Epub 2022/06/14.

53. Le Pape S, Savart S, Arrivé F, Frat JP, Ragot S, Coudroy R, et al. High-flow nasal cannula oxygen versus conventional oxygen therapy for acute respiratory failure due to COVID-19: a systematic review and meta-analysis. Ann Intensiv Care. 2023;13(1):114. PubMed PMID: 37994981. Pubmed Central PMCID: PMC10667189. Epub 2023/11/23.

54. Thille AW, Frat JP. High-flow nasal oxygen: benefits are hard to show in COVID-19 patients with mild hypoxaemia. Thorax. 2023;78(4):321–2. PubMed PMID: 36598078. Epub 2023/01/05.

55. L’Her E, Deye N, Lellouche F, Taille S, Demoule A, Fraticelli A, et al. Physiologic effects of noninvasive ventilation during acute lung injury. Am J Respir Crit Care Med. 2005;172(9):1112–8. PubMed PMID: 16081548.

56. Vargas F, Saint-Leger M, Boyer A, Bui NH, Hilbert G. Physiologic effects of High-Flow nasal cannula oxygen in critical care subjects. Respir Care. 2015;60(10):1369–76. PubMed PMID: 25944940. Epub 2015/05/07.

57. Menga LS, Delle Cese L, Rosà T, Cesarano M, Scarascia R, Michi T, et al. Respec- tive effects of Helmet pressure support, continuous positive Airway pressure, and Nasal High-Flow in Hypoxemic Respiratory failure: a randomized cross- over clinical trial. Am J Respir Crit Care Med. 2023;207(10):1310–23. PubMed PMID: 36378814. Pubmed Central PMCID: PMC10595442. Epub 2022/11/16.

58. Delclaux C, L’Her E, Alberti C, Mancebo J, Abroug F, Conti G, et al. Treat- ment of acute hypoxemic nonhypercapnic respiratory insufficiency with continuous positive airway pressure delivered by a face mask: a randomized controlled trial. JAMA. 2000;284(18):2352–60. PubMed PMID: 11066186. Epub 2000/11/07.

59. Brambilla AM, Aliberti S, Prina E, Nicoli F, Del Forno M, Nava S, et al. Helmet CPAP vs. oxygen therapy in severe hypoxemic respiratory failure due to pneumonia. Intensive Care Med. 2014;40(7):942–9. PubMed PMID: 24817030. Epub 2014/05/13.

60. Cosentini R, Brambilla AM, Aliberti S, Bignamini A, Nava S, Maffei A, et al. Helmet continuous positive airway pressure vs oxygen therapy to improve oxygenation in community-acquired pneumonia: a randomized, controlled trial. Chest. 2010;138(1):114–20. PubMed PMID: 20154071. Epub 2010/02/16.

61. Squadrone V, Massaia M, Bruno B, Marmont F, Falda M, Bagna C, et al. Early CPAP prevents evolution of acute lung injury in patients with hematologic malignancy. Intensive Care Med. 2010;36(10):1666–74. PubMed PMID: 20533022. Epub 2010/06/10.

62. Brochard L, Isabey D, Piquet J, Amaro P, Mancebo J, Messadi AA, et al. Reversal of acute exacerbations of chronic obstructive lung disease by inspiratory assistance with a face mask. N Engl J Med. 1990;323(22):1523–30. PubMed PMID: 2122253.

63. Brochard L, Mancebo J, Wysocki M, Lofaso F, Conti G, Rauss A, et al. Nonin- vasive ventilation for acute exacerbations of chronic obstructive pulmonary disease. N Engl J Med. 1995;333(13):817–22. PubMed PMID: 7651472.

64. Lightowler JV, Wedzicha JA, Elliott MW, Ram FS. Non-invasive positive pres- sure ventilation to treat respiratory failure resulting from exacerbations of chronic obstructive pulmonary disease: Cochrane systematic review and meta-analysis. BMJ (Clinical Res ed). 2003;326(7382):185. PubMed PMID: 12543832.

65. Bersten AD, Holt AW, Vedig AE, Skowronski GA, Baggoley CJ. Treatment of severe cardiogenic pulmonary edema with continuous positive airway pres- sure delivered by face mask. N Engl J Med. 1991;325(26):1825–30. PubMed PMID: 1961221. Epub 1991/12/26.

66. Masip J, Betbese AJ, Paez J, Vecilla F, Canizares R, Padro J et al. Non-invasive pressure support ventilation versus conventional oxygen therapy in acute cardiogenic pulmonary oedema: a randomised trial. Lancet (London, Eng- land). 2000 Dec 23–30;356(9248):2126–32. PubMed PMID: 11191538. Epub 2001/02/24.

67. Masip J, Roque M, Sanchez B, Fernandez R, Subirana M, Exposito JA. Nonin- vasive ventilation in acute cardiogenic pulmonary edema: systematic review and meta-analysis. JAMA. 2005;294(24):3124–30. PubMed PMID: 16380593. Epub 2005/12/29.

68. Ferrer M, Esquinas A, Leon M, Gonzalez G, Alarcon A, Torres A. Noninvasive ventilation in severe hypoxemic respiratory failure: a randomized clinical trial. Am J Respir Crit Care Med. 2003;168(12):1438–44. PubMed PMID: 14500259.

69. Hilbert G, Gruson D, Vargas F, Valentino R, Gbikpi-Benissan G, Dupon M, et al. Noninvasive ventilation in immunosuppressed patients with pulmonary infil- trates, fever, and acute respiratory failure. N Engl J Med. 2001;344(7):481–7. PubMed PMID: 11172189.

70. Antonelli M, Conti G, Bufi M, Costa MG, Lappa A, Rocco M, et al. Noninvasive ventilation for treatment of acute respiratory failure in patients undergoing solid organ transplantation: a randomized trial. JAMA. 2000;283(2):235–41. PubMed PMID: 10634340.

71. Martin TJ, Hovis JD, Costantino JP, Bierman MI, Donahoe MP, Rogers RM, et al. A randomized, prospective evaluation of noninvasive ventilation for acute respiratory failure. Am J Respir Crit Care Med. 2000;161:807–13. PubMed PMID: 10712326.

72. Confalonieri M, Potena A, Carbone G, Porta RD, Tolley EA, Umberto Meduri G. Acute respiratory failure in patients with severe community-acquired pneumonia. A prospective randomized evaluation of noninvasive ventilation. Am J Respir Crit Care Med. 1999;160:1585–91. PubMed PMID: 10556125.

73. Kramer N, Meyer TJ, Meharg J, Cece RD, Hill NS. Randomized, prospective trial of noninvasive positive pressure ventilation in acute respiratory failure. Am J Respir Crit Care Med. 1995;151(6):1799–806. PubMed PMID: 7767523.

74. Lemiale V, Mokart D, Resche-Rigon M, Pene F, Mayaux J, Faucher E, et al. Effect of Noninvasive Ventilation vs Oxygen Therapy on Mortality among Immunocompromised patients with Acute Respiratory failure: a Randomized Clinical Trial. JAMA. 2015;314(16):1711–9. PubMed PMID: 26444879. Epub 2015/10/08.

75. Doshi P, Whittle JS, Bublewicz M, Kearney J, Ashe T, Graham R, et al. High- velocity nasal insufflation in the treatment of respiratory failure: a Random- ized Clinical Trial. Ann Emerg Med. 2018;72(1):73–83. e5. PubMed PMID: 29310868. Epub 2018/01/10.

76. He H, Sun B, Liang L, Li Y, Wang H, Wei L, et al. A multicenter RCT of noninva- sive ventilation in pneumonia-induced early mild acute respiratory distress syndrome. Crit Care (London England). 2019;23(1):300. PubMed PMID: 31484582. Pubmed Central PMCID: PMC6727327. Epub 2019/09/06.

77. Nair PR, Haritha D, Behera S, Kayina CA, Maitra S, Anand RK, et al. Comparison of High-Flow Nasal Cannula and Noninvasive Ventilation in Acute Hypox- emic respiratory failure due to severe COVID-19 pneumonia. Respir Care. 2021;66(12):1824–30. PubMed PMID: 34584010. Epub 2021/09/30.

78. Coudroy R, Frat JP, Ehrmann S, Pène F, Decavèle M, Terzi N, et al. High-flow nasal oxygen alone or alternating with non-invasive ventilation in critically ill immunocompromised patients with acute respiratory failure: a randomised controlled trial. Lancet Respiratory Med. 2022;10(7):641–9. PubMed PMID: 35325620. Epub 2022/03/25.

79. Grieco DL, Menga LS, Cesarano M, Rosà T, Spadaro S, Bitondo MM, et al. Effect of Helmet Noninvasive Ventilation vs High-Flow Nasal Oxygen on days Free of respiratory support in patients with COVID-19 and moderate to severe hypoxemic respiratory failure: the HENIVOT Randomized Clinical Trial. JAMA. 2021;325(17):1731–43. PubMed PMID: 33764378. Epub 2021/03/26.

80. Zhan Q, Sun B, Liang L, Yan X, Zhang L, Yang J, et al. Early use of noninvasive positive pressure ventilation for acute lung injury: a multicenter randomized controlled trial. Crit Care Med. 2012;40(2):455–60. PubMed PMID: 22020236. Epub 2011/10/25.

81. Wysocki M, Tric L, Wolff MA, Millet H, Herman B. Noninvasive pressure support ventilation in patients with acute respiratory failure. A randomized compari- son with conventional therapy. Chest. 1995;107(3):761–8. PubMed PMID: 7874950.

82. Wood KA, Lewis L, Von Harz B, Kollef MH. The use of noninvasive positive pressure ventilation in the emergency department: results of a randomized clinical trial. Chest. 1998;113(5):1339–46. PubMed PMID: 9596317.

83. Antonelli M, Conti G, Esquinas A, Montini L, Maggiore SM, Bello G, et al. A multiple-center survey on the use in clinical practice of noninvasive

Page 14 of 15Thille et al. Annals of Intensive Care (2024) 14:158

ventilation as a first-line intervention for acute respiratory distress syndrome. Crit Care Med. 2007;35(1):18–25. PubMed PMID: 17133177. Epub 2006/11/30.

84. Grieco DL, Menga LS, Raggi V, Bongiovanni F, Anzellotti GM, Tanzarella ES, et al. Physiological comparison of High-Flow Nasal Cannula and Helmet Non- invasive Ventilation in Acute Hypoxemic Respiratory failure. Am J Respir Crit Care Med. 2020;201(3):303–12. PubMed PMID: 31687831. Epub 2019/11/07.

85. Patel BK, Wolfe KS, Pohlman AS, Hall JB, Kress JP. Effect of Noninvasive Ventila- tion delivered by Helmet vs Face Mask on the rate of endotracheal intubation in patients with Acute Respiratory Distress Syndrome: a Randomized Clinical Trial. JAMA. 2016;315(22):2435–41. PubMed PMID: 27179847.

86. Arabi YM, Aldekhyl S, Al Qahtani S, Al-Dorzi HM, Abdukahil SA, Al Harbi MK, et al. Effect of Helmet Noninvasive Ventilation vs Usual respiratory support on Mortality among patients with Acute Hypoxemic respiratory failure due to COVID-19: the HELMET-COVID randomized clinical trial. JAMA. 2022;328(11):1063–72. PubMed PMID: 36125473. Pubmed Central PMCID: PMC9490511. Epub 2022/09/21.

87. Grieco DL, Munshi L, Piquilloud L. Personalized noninvasive respiratory support for acute hypoxemic respiratory failure. Intensive Care Med. 2023;49(7):840–3. PubMed PMID: 37115260. Epub 2023/04/28.

88. Wilson ME, Mittal A, Karki B, Dobler CC, Wahab A, Curtis JR, et al. Do-not- intubate orders in patients with acute respiratory failure: a systematic review and meta-analysis. Intensive Care Med. 2020;46(1):36–45. PubMed PMID: 31659387. Pubmed Central PMCID: PMC7223954. Epub 2019/10/30.

89. Wilson ME, Majzoub AM, Dobler CC, Curtis JR, Nayfeh T, Thorsteinsdottir B, et al. Noninvasive ventilation in patients with Do-Not-Intubate and Comfort- measures-only orders: a systematic review and Meta-analysis. Crit Care Med. 2018;46(8):1209–16. PubMed PMID: 29498939. Epub 2018/03/03.

90. Azoulay E, Kouatchet A, Jaber S, Lambert J, Meziani F, Schmidt M, et al. Nonin- vasive mechanical ventilation in patients having declined tracheal intubation. Intensive Care Med. 2013;39(2):292–301. PubMed PMID: 23184037. Epub 2012/11/28.

91. Nava S, Ferrer M, Esquinas A, Scala R, Groff P, Cosentini R, et al. Palliative use of non-invasive ventilation in end-of-life patients with solid tumours: a randomised feasibility trial. Lancet Oncol. 2013;14(3):219–27. PubMed PMID: 23406914.

92. Hui D, Morgado M, Chisholm G, Withers L, Nguyen Q, Finch C, et al. High-flow oxygen and bilevel positive airway pressure for persistent dyspnea in patients with advanced cancer: a phase II randomized trial. J Pain Symptom Manag. 2013;46(4):463–73. PubMed PMID: 23739633. Pubmed Central PMCID: PMC3795985. Epub 2013/06/07.

93. Ruangsomboon O, Dorongthom T, Chakorn T, Monsomboon A, Praphru- etkit N, Limsuwat C, et al. High-Flow Nasal Cannula Versus Conventional Oxygen Therapy in relieving Dyspnea in Emergency Palliative patients with Do-Not-Intubate Status: a randomized crossover study. Ann Emerg Med. 2020;75(5):615–26. PubMed PMID: 31864728. Epub 2019/12/23.

94. Xu Z, Li P, Zhang C, Ma D. Effect of heated humidified high-flow nasal can- nula (HFNC) oxygen therapy in dyspnea patients with advanced cancer, a randomized controlled clinical trial. Supportive care cancer: Official J Multi- national Association Supportive Care Cancer. 2022;30(11):9093–100. PubMed PMID: 35984511. Epub 2022/08/20.

95. Hui D, Hernandez F, Urbauer D, Thomas S, Lu Z, Elsayem A, et al. High-Flow Oxygen and High-Flow Air for Dyspnea in Hospitalized patients with Cancer: a pilot crossover Randomized Clinical Trial. Oncologist. 2021;26(5):e883–92. PubMed PMID: 33289276. Pubmed Central PMCID: PMC8100563. Epub 2020/12/09.

96. Peters SG, Holets SR, Gay PC. High-flow nasal cannula therapy in do- not-intubate patients with hypoxemic respiratory distress. Respir Care. 2013;58(4):597–600. PubMed PMID: 22781059. Epub 2012/07/12.

97. Smesseim I, Mooij-Kalverda K, Hessels L, Korevaar DA, Atasever B, de Graaff H, et al. High flow nasal cannula for acute respiratory failure due to COVID- 19 in patients with a ‘do-not-intubate’ order: a survival analysis. Clin Respir J. 2023;17(2):115–9. PubMed PMID: 36584670. Pubmed Central PMCID: PMC9880618. Epub 2022/12/31.

98. Epstein AS, Hartridge-Lambert SK, Ramaker JS, Voigt LP, Portlock CS. Humidi- fied high-flow nasal oxygen utilization in patients with cancer at Memorial Sloan-Kettering Cancer Center. J Palliat Med. 2011;14(7):835–9. PubMed PMID: 21599530. Pubmed Central PMCID: PMC5586152. Epub 2011/05/24.

99. Guerin C, Reignier J, Richard JC. Prone positioning in the acute respiratory dis- tress syndrome. N Engl J Med. 2013;369(10):980–1. PubMed PMID: 24004127.

100. Elharrar X, Trigui Y, Dols AM, Touchon F, Martinez S, Prud’homme E, et al. Use of Prone Positioning in Nonintubated patients with COVID-19 and

Hypoxemic Acute Respiratory failure. JAMA. 2020;323(22):2336–8. PubMed PMID: 32412581. Pubmed Central PMCID: PMC7229532. Epub 2020/05/16.

101. Coppo A, Bellani G, Winterton D, Di Pierro M, Soria A, Faverio P, et al. Feasibility and physiological effects of prone positioning in non-intubated patients with acute respiratory failure due to COVID-19 (PRON-COVID): a prospec- tive cohort study. Lancet Respiratory Med. 2020;8(8):765–74. PubMed PMID: 32569585. Pubmed Central PMCID: PMC7304954. Epub 2020/06/23.

102. Sartini C, Tresoldi M, Scarpellini P, Tettamanti A, Carcò F, Landoni G, et al. Respiratory parameters in patients with COVID-19 after using Noninvasive Ventilation in the prone position outside the Intensive Care Unit. JAMA. 2020;323(22):2338–40. PubMed PMID: 32412606. Pubmed Central PMCID: PMC7229533. Epub 2020/05/16.

103. Nay MA, Hindre R, Perrin C, Clément J, Plantier L, Sève A, et al. Prone position versus usual care in hypoxemic COVID-19 patients in medical wards: a ran- domised controlled trial. Crit Care (London England). 2023;27(1):240. PubMed PMID: 37330512. Pubmed Central PMCID: PMC10276908. Epub 2023/06/18.

104. Alhazzani W, Parhar KKS, Weatherald J, Al Duhailib Z, Alshahrani M, Al-Fares A, et al. Effect of Awake Prone Positioning on Endotracheal Intubation in patients with COVID-19 and Acute Respiratory failure: a Randomized Clinical Trial. JAMA. 2022;327(21):2104–13. PubMed PMID: 35569448. Pubmed Central PMCID: PMC9108999. Epub 2022/05/16.

105. Fralick M, Colacci M, Munshi L, Venus K, Fidler L, Hussein H et al. Prone positioning of patients with moderate hypoxaemia due to covid-19: multicentre pragmatic randomised trial (COVID-PRONE). BMJ (Clinical Res ed). 2022;376:e068585. PubMed PMID: 35321918. Pubmed Central PMCID: PMC8941343. Epub 2022/03/25.

106. Gopalakrishnan M, Khichar S, Saurabh S, Vijayvergia P, Thangaraju K, Tripathi S et al. Effectiveness of early awake self proning strategy in non-intubated patients with COVID-19 hypoxemia: an open-labelled randomized clinical trial from Jodhpur, India. Monaldi archives for chest disease = Archivio Mon- aldi per le malattie del torace. 2022;93(4). PubMed PMID: 36524853. Epub 2022/12/17.

107. Qian ET, Gatto CL, Amusina O, Dear ML, Hiser W, Buie R, et al. Assessment of Awake Prone Positioning in hospitalized adults with COVID-19: a Nonran- domized Controlled Trial. JAMA Intern Med. 2022;182(6):612–21. PubMed PMID: 35435937. Pubmed Central PMCID: PMC9016608. Epub 2022/04/19.

108. Rosén J, von Oelreich E, Fors D, Jonsson Fagerlund M, Taxbro K, Skorup P, et al. Awake prone positioning in patients with hypoxemic respiratory failure due to COVID-19: the PROFLO multicenter randomized clinical trial. Crit Care (London England). 2021;25(1):209. PubMed PMID: 34127046. Pubmed Central PMCID: PMC8200797. Epub 2021/06/16.

109. Ehrmann S, Li J, Ibarra-Estrada M, Perez Y, Pavlov I, McNicholas B, et al. Awake prone positioning for COVID-19 acute hypoxaemic respiratory failure: a ran- domised, controlled, multinational, open-label meta-trial. Lancet Respiratory Med. 2021;9(12):1387–95. PubMed PMID: 34425070. Epub 2021/08/24.

110. Li J, Luo J, Pavlov I, Perez Y, Tan W, Roca O, et al. Awake prone positioning for non-intubated patients with COVID-19-related acute hypoxaemic respira- tory failure: a systematic review and meta-analysis. Lancet Respiratory Med. 2022;10(6):573–83. PubMed PMID: 35305308. Epub 2022/03/20.

111. Wang J, Chen D, Deng P, Zhang C, Zhan X, Lv H, et al. Efficacy and safety of awake prone positioning in the treatment of non-intubated spontaneously breathing patients with COVID-19-related acute respiratory failure: a system- atic review and meta-analysis. J Intensive Med. 2023;3(4):365–72. PubMed PMID: 37362868. Pubmed Central PMCID: PMC10063156. Epub 2023/06/26.

112. Ibarra-Estrada M, Li J, Pavlov I, Perez Y, Roca O, Tavernier E, et al. Factors for success of awake prone positioning in patients with COVID-19-induced acute hypoxemic respiratory failure: analysis of a randomized controlled trial. Crit Care (London England). 2022;26(1):84. PubMed PMID: 35346319. Pubmed Central PMCID: PMC8958810. Epub 2022/03/30.

113. Eimer C, Freier K, Weiler N, Frerichs I, Becher T. The Effect of Physical Therapy on Regional Lung function in critically ill patients. Front Physiol. 2021;12:749542. PubMed PMID: 34616313. Pubmed Central PMCID: PMC8488288. Epub 2021/10/08.

114. Yuan S, Chi Y, Long Y, He H, Zhao Z. Effect of position change from the Bed to a wheelchair on the Regional Ventilation distribution assessed by electrical impedance tomography in patients with respiratory failure. Front Med. 2021;8:744958. PubMed PMID: 34805212. Pubmed Central PMCID: PMC8600076. Epub 2021/11/23.

115. Hickmann CE, Montecinos-Munoz NR, Castanares-Zapatero D, Arriagada- Garrido RS, Jeria-Blanco U, Gizzatullin T, et al. Acute effects of sitting out of Bed and Exercise on Lung Aeration and Oxygenation in critically ill subjects. Respir Care. 2021;66(2):253–62. PubMed PMID: 32994357. Epub 2020/10/01.

Page 15 of 15Thille et al. Annals of Intensive Care (2024) 14:158

116. Strickland SL, Rubin BK, Haas CF, Volsko TA, Drescher GS, O’Malley CA. AARC Clinical Practice Guideline: effectiveness of Pharmacologic Airway Clearance Therapies in hospitalized patients. Respir Care. 2015;60(7):1071–7. PubMed PMID: 26113566. Epub 2015/06/27.

117. Bott J, Blumenthal S, Buxton M, Ellum S, Falconer C, Garrod R, et al. Guidelines for the physiotherapy management of the adult, medical, spontaneously breathing patient. Thorax. 2009;64(Suppl 1):i1–51. PubMed PMID: 19406863. Epub 2009/05/07.

118. Wilson LM, Morrison L, Robinson KA. Airway clearance techniques for cystic fibrosis: an overview of Cochrane systematic reviews. The Cochrane database of systematic reviews. 2019;1(1):CD011231. PubMed PMID: 30676656. Pubmed Central PMCID: PMC6353051 the active cycle of breathing tech- nique. One author (LM) has contributed to the review on oscillating devices. Epub 2019/01/25.

119. Santambrogio M, Lazzeri M, Bonitta G, Guarise R, Simonetta E, Blasi F et al. Hospital staff practical skills and theoretical knowledge in inhaled aerosol therapy: a single centre cross-sectional observational study. Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace. 2021;91(1). PubMed PMID: 33501819. Epub 2021/01/28.

120. Vaudan S, Ratano D, Beuret P, Hauptmann J, Contal O, Garin N. Impact of a dedicated noninvasive ventilation team on intubation and mortality rates in severe COPD exacerbations. Respir Care. 2015;60(10):1404–8. PubMed PMID: 26152474. Epub 2015/07/15.

121. Frat JP, Ragot S, Coudroy R, Constantin JM, Girault C, Prat G, et al. Predictors of intubation in patients with Acute Hypoxemic respiratory failure treated with a noninvasive oxygenation strategy. Crit Care Med. 2018;46(2):208–15. PubMed PMID: 29099420.

122. Carteaux G, Millan-Guilarte T, De Prost N, Razazi K, Abid S, Thille AW, et al. Failure of noninvasive ventilation for De Novo Acute Hypoxemic Respiratory failure: role of tidal volume. Crit Care Med. 2016;44(2):282–90. PubMed PMID: 26584191.

123. Brochard L, Slutsky A, Pesenti A. Mechanical ventilation to minimize progres- sion of Lung Injury in Acute Respiratory failure. Am J Respir Crit Care Med. 2017;195(4):438–42. PubMed PMID: 27626833. Epub 2016/09/15.

124. de Prost N, Ricard JD, Saumon G, Dreyfuss D. Ventilator-induced lung injury: historical perspectives and clinical implications. Ann Intensiv Care. 2011;1(1):28. PubMed PMID: 21906379. Pubmed Central PMCID: 3224506.

125. Carteaux G, Parfait M, Combet M, Haudebourg AF, Tuffet S, Mekontso Dessap A. Patient-self inflicted Lung Injury: a practical review. J Clin Med. 2021;10(12). PubMed PMID: 34205783. Pubmed Central PMCID: PMC8234933. Epub 2021/07/03.

126. Bellani G, Laffey JG, Pham T, Madotto F, Fan E, Brochard L, 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. PubMed PMID: 27753501.

127. Carrillo A, Gonzalez-Diaz G, Ferrer M, Martinez-Quintana ME, Lopez-Martinez A, Llamas N, et al. Non-invasive ventilation in community-acquired pneumo- nia and severe acute respiratory failure. Intensive Care Med. 2012;38(3):458– 66. PubMed PMID: 22318634.

128. Duan J, Han X, Bai L, Zhou L, Huang S. Assessment of heart rate, acidosis, consciousness, oxygenation, and respiratory rate to predict noninvasive ven- tilation failure in hypoxemic patients. Intensive Care Med. 2017;43(2):192–9. PubMed PMID: 27812731. Epub 2016/11/05.

129. Dumas G, Lemiale V, Rathi N, Cortegiani A, Pène F, Bonny V, et al. Survival in immunocompromised patients ultimately requiring invasive mechanical ventilation: a pooled individual Patient Data Analysis. Am J Respir Crit Care Med. 2021;204(2):187–96. PubMed PMID: 33751920. Epub 2021/03/23.

130. Kang BJ, Koh Y, Lim CM, Huh JW, Baek S, Han M, et al. Failure of high-flow nasal cannula therapy may delay intubation and increase mortality. Intensive Care Med. 2015;41(4):623–32. PubMed PMID: 25691263. Epub 2015/02/19.

131. Franco C, Facciolongo N, Tonelli R, Dongilli R, Vianello A, Pisani L et al. Fea- sibility and clinical impact of out-of-ICU noninvasive respiratory support in patients with COVID-19-related pneumonia. Eur Respir J. 2020;56(5). PubMed PMID: 32747398. Epub 2020/08/05.

132. Janssen ML, Türk Y, Baart SJ, Hanselaar W, Aga Y, van der Steen-Dieperink M, et al. Safety and Outcome of High-Flow Nasal Oxygen Therapy outside ICU set- ting in hypoxemic patients with COVID-19. Crit Care Med. 2024;52(1):31–43. PubMed PMID: 37855812. Pubmed Central PMCID: PMC10715700. Epub 2023/10/19.

133. Carteaux G, Pons M, Morin F, Tuffet S, Lesimple A, Badat B, et al. Continuous positive airway pressure for respiratory support during COVID-19 pandemic: a frugal approach from bench to bedside. Ann Intensiv Care. 2021;11(1):38. PubMed PMID: 33655452. Pubmed Central PMCID: PMC7924341. Epub 2021/03/04.

134. Moretto F, Fracazzini M, Verdina F, Ferrante D, Baino S, Grossi F et al. One-year follow up of noninvasive respiratory support in General wards. Respiratory Care. 2022. PubMed PMID: 35853702. Epub 2022/07/20.

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