Patients who develop hypoxemic respiratory failure and require OTI have greater inflammatory activity prior to intubation and develop radiological worsening of the lung injury. Furthermore, risk factors for hospital mortality prior to respiratory failure were higher SAPS-3 values and a longer time for tracheal intubation from the onset of symptoms.
Through the analysis of the relationship since the onset of symptoms, temporal surveillance of inflammatory markers as well as radiological evolution was possible. Intubation performed 15 days after the onset of symptoms demonstrated worsening survival.
The appropriate time for OTI is a central concern since in addition to hypoxemia, the patient outside of invasive mechanical ventilation may present a higher ventilatory effort, leading to high transpulmonary pressures, stress and strain, which may culminate in the development of Patient Self-Inflicted Lung Injury (P-SILI) and thus potentiate lesions in an already diseased lung (15–17).
The prolonged time for OTI often correlates with the use of non-invasive ventilatory support, however its use is not without risks (18). Respiratory fatigue, pulmonary atelectasis and inflammatory activity (biotrauma) can be exacerbated, causing damage to distant organs in addition to the already sick respiratory system, worsening the patient's prognosis (5, 16–21). It is known that patients with exacerbated COPD managed with non-invasive ventilatory support undergo intubation in up to 15–20% of cases, a number that is already high, however in patients with hypoxemic respiratory failure these numbers jump to 40–60% of failure rate with the non-invasive method (22, 23). As an aggravating factor, these patients with hypoxemic respiratory failure who progress to OTI will have higher mortality (22, 24), which is one of the reasons for the extreme importance of their monitoring in relation to method failure, whether through tidal volume in patients using NIV or ROX Index in patients using HFNC (2, 25). At the beginning of the Covid-19 pandemic, the indication was to intubate immediately (26, 27). However, with greater understanding of the disease, it was seen that these patients tolerated a degree of hypoxemia with few clinical manifestations, causing these patients to undergo invasive mechanical ventilation later (28). Therefore, later guidelines recommended that patients, before being intubated, undergo therapy with non-invasive ventilatory support (26).
Even with a physiological rationale for P-SILI in patients on NIV, a meta-analysis of more than 8,000 patients with Covid-19 suggested that the timing of intubation may not have an impact on mortality. However, given the great heterogeneity of the studies analyzed on the topic, this cannot be considered a certainty (29).
The cutoff point for early and late intubation is divided between 24 and 48 hours depending on the source used. Studies that used 24 hours after ICU admission as a cutoff found no significant differences in mortality (19, 30). Studies that used 48 hours as a cutoff point reported contradictory results, with some observing a higher mortality rate in patients intubated after this period and others finding no significant differences (31). In another publication, both cutoff points were analyzed in a prospective paired analysis study in Spain, showing an increased risk of mortality in patients undergoing invasive mechanical ventilation both after 24 and 48 hours (32). A retrospective observational study including only 40 patients with Covid-19 found lower mortality in patients intubated before 50 hours after ICU admission, but it is clear that the small sample size does not allow definitive conclusions to be drawn about the best time for intubation (33).
In the present study, unlike other existing studies, the temporal analysis takes place not from hospital or ICU admission, but rather with the onset of Covid-19 symptoms, providing a more detailed analysis of the patient whether in terms of their clinical, radiological or laboratories trends. Analyzing the numbers presented, the median from the onset of symptoms to hospitalization was 10 days and the median from the onset of symptoms to OTI was 11 days, the fact indicates that OTI occurred 24 hours after hospitalization, corroborating all studies which showed a positive influence from this early intervention. Assessing the time window for OTI from the onset of symptoms provides a more accurate perspective on the evolution of the disease from the appearance of the first signs of infection and can help with early identification of rapidly deteriorating patients. This makes it possible to implement interventions before the condition reaches more advanced stages.
ICU arrival time can vary significantly between patients and some may be admitted late due to factors such as access to medical care, initial screening or individual characteristics of the disease. By starting the count from the symptoms, these variations are sought to be mitigated. Analysis from the onset of symptoms allows for a more in-depth understanding of how the initial immunological response may influence the need for OTI and other clinical outcomes.
Regarding inflammatory markers, we found higher values of CRP, IL-6 and D-dimer in patients undergoing OTI. The topic of hyperinflammatory and hypoinflammatory patterns of ARDS has been increasingly studied in recent years and it is known that patients with greater inflammatory activity throughout the disease require higher doses of vasoactive drugs, administration of fluids, PEEP values as well as they have higher mortality (34–36). The importance of constant assessment of the patient in relation to their fluid needs is highlighted here, since at the same time that hyperinflammatory patients need to use higher PEEP values in an attempt to correct their hypoxemia, these same individuals also receive a greater amount of fluids, which can in itself worsen the lung ventilation/perfusion relationship, leading to worsening hypoxemia.
Furthermore, we found an association of patients with greater inflammatory activity and failure to non-invasive pulmonary ventilation strategies and the consequent need for OTI. In addition, we also showed that patients infected by SARS-CoV-2 and who presented a hyperinflammatory pattern had a greater presence of pulmonary consolidations on chest CT. These points are worth highlighting, since today there is much discussion about the ARDS phenotype, but little is known about what to do about it. Many studies today focus on whether a personalized approach to treating ARDS is valid, as occurs in oncology, as there are still doubts about its impact on the clinical outcome of these individuals (36, 37).
Although this study has points that deserve to be highlighted, such as a representative sample in a highly specialized hospital, follow-up for 1 year, thus including different phases of the pandemic and avoiding possible biases related to variations in treatments, available resources and knowledge of the disease throughout the period, it also contains some limitations such as its observational character being only a generator of hypotheses without actually verifying the real causal condition (38). Furthermore, the collection was carried out in a single center, which does not allow the generalization of the study, the reason for intubation was not registered and there is a lack of data regarding the treatments carried out on patients during hospital admission that could impact mortality. However, the sample was homogeneous with robust statistical analysis, adjusted for several demographic and greater severity variables for these patients; in the same way, the consecutive collection of patients prevented the possibility of selection bias.