The NAVIGATE trial: early identification and management of mild acute hypoxemic failure, does timing matter outside ICUs?

Despite advances in the management of acute respiratory failure, severe hypoxemia remains a challenging complication among patients admitted to the hospital (1). In fact, hypoxemia is consistently associated with adverse clinical outcomes and an increased risk of death, regardless of whether it occurs in medical wards (2), during the postoperative period (3), or in intensive care units (ICUs) (4). Moreover, hypoxemia is a major component of respiratory failure, a condition defined by the inability of the respiratory system to maintain adequate gas exchange, frequently associated with signs of respiratory distress, which can rapidly become life-threatening and lead to ICU admission and the initiation of noninvasive respiratory support or invasive ventilation. Hypoxemia and signs of respiratory distress, i.e., polypnea, respiratory rate >25 breaths/min, use of the accessory respiratory muscles, or active abdominal contraction, are often used in clinical trials evaluating and comparing noninvasive respiratory supports in acute respiratory failure, and serving as inclusion criteria or predetermined criteria of intubation (5-8).

The NAVIGATE trial

In this line, the NAVIGATE trial evaluates whether adding early intermittent noninvasive ventilation (NIV) to standard oxygen therapy for hypoxemia associated or not with signs of respiratory distress can further mitigate its negative impact on patient prognosis (9). Monti et al. conducted a multicenter randomized controlled trial enrolling 523 patients admitted to general wards across 11 hospitals (in Italy, Greece and Kazakhstan) between 2012 and 2023. The trial evaluated early NIV compared with usual care in patients with mild acute respiratory failure, defined by a partial pressure of arterial oxygen (PaO₂)/fraction of inspired oxygen (FiO₂) ratio between 200 and 300 mmHg (9). The primary outcome was progression to severe respiratory failure, defined by PaO₂/FiO₂ ratio <200 mmHg, persistent marked dyspnea, use of accessory respiratory muscles, active abdominal contraction, or respiratory acidosis [partial pressure of arterial carbon dioxide (PaCO₂) >45 mmHg and pH <7.30]. In the intervention group, NIV was applied for two hours every eight hours for a minimum of 24 hours. High-flow nasal cannula oxygen was discouraged and not considered as NIV, and its use was classified as a protocol deviation. In the usual care group, NIV was initiated only in case of severe respiratory failure (primary outcome). The population was heterogeneous, including 40% of patients with pneumonia, while others had cardiogenic pulmonary edema or postoperative respiratory failure. Mild acute respiratory failure was characterized by hypoxemia in 96% of patients, whereas clinical signs of respiratory failure were present in only 30% of patients and mild decompensated hypercapnia in 2%. The authors planned primarily to initiate continuous positive airway pressure (CPAP) in case of acute hypoxemic respiratory failure and bilevel positive airway pressure (BiPAP) in case of acute hypercapnic respiratory failure. As a result, CPAP was the predominant mode of NIV in 90% of cases, delivered through an orofacial mask, while BiPAP was applied in 10% of cases. NIV was stopped in 15% of cases due to intolerance or refusal. The NAVIGATE trial demonstrated that early NIV can be safely performed, as it reduced progression to severe acute respiratory failure compared with usual care, 18% versus 28% (absolute difference −9.8, 95% confidence interval, −17 to −2.6, P=0.008). Early NIV compared with usual care likewise reduced both components of the primary outcome, severe hypoxemia (12% vs. 21%) and signs of severe respiratory distress (15% vs. 24%). However, no significant difference was observed in ICU admissions (8% vs. 7%), endotracheal intubation (5% vs. 4%), mortality rates (15% in both groups), or length of hospital stay (9 vs. 8 days).

This study has several strengths, including its large sample size, multicenter design, and its focus on NIV implementation outside ICUs, an area that remains understudied. Patient safety was supported by close collaboration between ward physicians and an emergency medical team responsible for identifying clinical deterioration and determining the need for ICU transfer or intubation.

Heterogeneity of patient population

The patient population was heterogeneous, including patients with acute hypoxemic respiratory failure, acute hypercapnic respiratory failure, cardiogenic pulmonary edema and postoperative respiratory failure. However, the underlying pathophysiology is consistently different among these causes of acute respiratory failure. Acute hypoxemic respiratory failure is typically characterized by oxygenation failure and is primarily caused by viral or bacterial pneumonia. Recent clinical trials have excluded cardiogenic pulmonary edema or chronic respiratory diseases from this setting due to their substantially different outcomes (8,10). The operational definition and classification of acute hypoxemic respiratory failure is primarily based on the degree of hypoxemia, as clinical signs of respiratory failure alone do not accurately reflect severity. Recent guidelines on oxygen therapy in this setting have proposed a pragmatic definition of hypoxemia to guide oxygen initiation in ICUs: PaO₂ <60 mmHg or pulse oximetry (SpO₂) <92% on room air (6). Severity of hypoxemia can be assessed while breathing spontaneously with PaO₂/FiO₂ (6,7,11-13). Similarly, to the definition of acute respiratory distress syndrome (ARDS), and regardless of the oxygen strategy applied, hypoxemia is considered as severe when the PaO₂/FiO₂ ratio is below or equal to 100 mmHg, moderate when the PaO₂/FiO₂ ratio is between 101 and 200 mmHg, and mild when PaO₂/FiO₂ ratio is between 201 and 300 mmHg (6,7,11).

In contrast, acute hypercapnic respiratory failure occurs in patients with underlying chronic respiratory disease, chronic cardiac disease, or in cases of severe, late-stage de novo acute hypoxemic respiratory failure accompanied by clinical signs of respiratory muscle exhaustion. Therefore, it is not encompassed by acute hypoxemic respiratory failure (5,6). Acute hypercapnic respiratory failure is characterized by ventilation failure, defined by respiratory acidosis with arterial carbon dioxide (PaCO₂) exceeding 45 mmHg and pH below 7.35 (6).

Acute hypoxemic and hypercapnic respiratory failure differ not only in their physiological mechanisms but also in terms of their respective outcomes. Acute hypoxemic respiratory failure carries the highest risk profile, with intubation rates ranging from 10% to 50%, and mortality rates from 10% to 35% (6,7,10,14). Conversely, acute hypercapnic respiratory failure is associated with lower intubation rates, ranging from 10% to 20%, and mortality rates below 15%, as well as cardiogenic pulmonary edema with intubation rates ranging from 5% to 10% and mortality below 15% (14). The postoperative period is also a high-risk time for respiratory failure, due to diaphragmatic dysfunction and atelectasis. Intubation rates can reach 30%, especially after cardiothoracic surgery or abdominal surgery, with mortality rates around 5% and 10% (14-17).

Generalization of NIV outside ICUs

For “patient-centered outcomes”

The findings of the NAVIGATE trial showed that early NIV reduced progression to severe acute respiratory failure. While the trial was not designed and powered to detect differences in secondary outcomes, it revealed no significant impact on critical clinical endpoints, including intubation rates, mortality, or ICU admission. Additionally, other patient-centered outcomes such as comfort or patient-reported dyspnea were not assessed, despite their importance in evaluating other aspects of NIV benefit (10,18,19). Although severe respiratory distress was documented and recorded, these evaluations appear primarily clinician-based rather than patient-reported, limiting their ability to fully evaluate the patient experience and potential individual benefits.

These limitations align with current guideline recommendations, which explicitly discourage the use of NIV in patients with acute hypoxemic respiratory failure (6,14,15,20). The uncertainty extends to CPAP, for which evidence remains inconsistent, with conflicting results on intubation reduction and no benefit on mortality compared with standard oxygen or high-flow nasal cannula oxygen, including during the coronavirus disease 2019 (COVID-19) pandemic (21-24). The physiological characteristics and constraints of NIV may explain the conflicting results reported in clinical studies comparing NIV with other oxygenation supports in acute hypoxemic respiratory failure. NIV may worsen existing lung injury due to the synchronization between the high and prolonged inspiratory effort generated by the patient and the pressure-support level delivered by the ventilator, resulting in high transpulmonary pressure and potential alveolar distension (patient self-inflicted lung injury concept) (4,25-27). By comparison, high-flow nasal cannula oxygen results in decreased inspiratory effort without increasing transpulmonary pressure (28,29). Given its beneficial effect on intubation risk, high-flow nasal cannula oxygen has been proposed as first-line oxygen therapy in patients with acute hypoxemic respiratory failure (6).

However, the efficacy of NIV is well-established in acute hypercapnic respiratory failure due to cardiogenic pulmonary edema and acute exacerbation of chronic obstructive lung disease. In this setting, NIV significantly reduces intubation and mortality, leading to strong recommendations for its use (14). The physiologic rationale is that NIV effectively unloads the respiratory muscles, thereby reducing inspiratory effort and alleviating the work of breathing (30,31). In addition, it enhances cardiopulmonary interaction, entailing improved cardiac output and reduced preload, which are particularly beneficial in left ventricular failure (32). NIV has also proven beneficial in the postoperative setting, reducing reintubation rates after extubation, particularly among patients undergoing thoracic and abdominal surgery (14,16,17).

Although noninvasive respiratory supports have historically been evaluated and proven to be efficient in ICUs, their use has been increasingly expanded to emergency departments and general wards, a trend that became particularly pronounced during the COVID-19 pandemic. Use of noninvasive respiratory supports outside ICUs has been driven by rising ICU demand and limited resources, prompting healthcare systems to reconsider the boundaries of advanced respiratory support delivery (22,33). In this high-risk patients with acute hypoxemic respiratory failure managed outside ICUs (general wards, sub-ICUs, intermediate care units and high-dependency units), a systematic review and meta-analysis based mainly on retrospective studies reported that among the 3,377 patients included, noninvasive respiratory supports initiated outside ICUs resulted in intubation in 55% of the patients receiving “full-treatment” and a mortality rate of 19%, excluding those subject to “limitations of care” (33). A multicenter randomized clinical trial including 364 patients across 27 centers with mild acute hypoxemic respiratory failure (defined by PaO₂/FiO₂ between 200 and 300 mmHg and signs of acute respiratory failure) due to COVID-19 infection compared the initiation of high-flow nasal cannula oxygen with standard oxygen outside the ICU (34). The primary outcome was the rate of escalation (need for CPAP, NIV or invasive mechanical ventilation), which did not significantly differ between groups, 30% vs. 39% in the high-flow nasal cannula oxygen and in the standard group, respectively, nor did it significantly differ in terms of the rates of ICU admission (8% vs. 11%), or intubation (2% vs. 4%). Similarly, there were no significant differences in time to escalation, length of hospital stay, or mortality. These results suggest that while noninvasive respiratory supports are feasible outside ICUs, their efficacy in improving clinical outcomes remains uncertain.

For “collective benefits”

Otherwise, the use of noninvasive respiratory support outside ICUs may be justified by improvements in collective benefits, such as reduced ICU bed occupancy and decreased demand for ICU resources (i.e., sedatives and invasive ventilation equipment). However, this approach is only feasible if the care workload remains manageable. In the NAVIGATE trial, the impact of NIV implementation in the general wards on care workload was not evaluated. The absence of an effect on outcomes such as ICU admission, intubation, or mortality raises questions regarding the routine use of NIV outside ICUs, where nurse-to-patient ratios are lower than in ICUs and continuous monitoring, such as pulse-oximetry, is not consistently available. NIV application requires substantial organizational resources, specialized equipment and close monitoring, all of which may be difficult to safely ensure outside a critical care environment. When focusing on the results, early NIV use prevented prolonged NIV exposure (>12 hours per day) in approximately 12% of patients in the usual care group, without translating into improvements in hard outcomes. This finding suggests that early NIV initiation in all patients with mild acute respiratory failure may help avoid unnecessary escalation of NIV in a small-scale subset of patients, albeit at the cost of increased care burden and without clear patient-centered benefit.

What should we remember from the NAVIGATE trial?

The NAVIGATE trial provides important insight into the feasibility and short-term physiological impact of early NIV initiation in general wards for patients with mild acute respiratory failure. Although early NIV reduced progression to severe respiratory failure, its impact on clinically meaningful outcomes such as ICU admission, intubation, or mortality is uncertain. These findings underscore the complexity of managing hypoxemia outside ICUs and suggest that preventing physiological deterioration does not necessarily translate into improved patient outcomes. Rather than supporting routine NIV use in general wards, the trial reinforces the importance of careful patient selection and timely transfer to ICUs when appropriate. Ultimately, the key question is not whether NIV can be delivered outside ICUs, but whether it should be, in whom, and for what benefit. Future studies should prioritize patient-centered outcomes, assess NIV as well as high-flow nasal cannula oxygen, which may impose a lower care burden, and evaluate pragmatic implementation strategies so as to ensure that expanding access to noninvasive respiratory support does not come at the expense of safety or meaningful benefit.

Supplementary

The article’s supplementary files as

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.