This prospective observational study aims to help making light on the effectiveness of H-CPAP in patients who developed CARDS during hospitalization in RICU.
The patient’s sample did not show differences among waves for socio-demographic features (Table 1). In the first wave, less compromised patients fare worse (more patients with diabetes, neoplasia and chronic renal failure and more smokers in the second and in the third waves). During the second and third pandemic waves, the hospital mortality for patients admitted with CARDS was significantly reduced compared to the first pandemic period. H-CPAP success increased and DNI number decreased.
In the first wave, most patients were treated with systemic corticosteroids. Instead, in the second and third waves, practically all patients received corticosteroids following new clinical trials [21] and our previous experience in the steroid use in severe CAP [11][22]. In the first wave, PaO2/FiO2 in oxygen was significantly lower and d-dimer significantly higher. These were demonstrated to be independent risk factors for adverse outcomes [23][24] and the result is also confirmed by our study.
In addition, d-dimer at admission, worst d-dimer and worst IL-6 were significantly higher in the first wave suggesting more severe inflammation. Worst PaO2/FiO2 in H-CPAP was significantly lower in the first wave. No differences were found between the first PaO2/FiO2 in H-CPAP among the three waves and the patients with preARDS and mild, moderate, and severe ARDS at admission were equally distributed during the different waves, but the parameter was obtained with PEEP progressively decreasing.
Helmet success and survival/death outcomes have progressively improved in the three waves reflecting a slight progressive reduction in patient severity associated with improved clinical management (practically 100% steroid in the second and third waves; daily d-dimer monitoring for PE diagnosis; progressive increase in prone position).
DNI order was considered only in cases that needed intubation and has decreased during the three waves due to higher availability of ICU beds (equal percentage of patients transferred to ICU in the different waves despite higher patients severity in the first period).
CARDS has a biphasic trend confirmed in all three waves (Fig. 2).
The two stages of the disease correspond to the initially worsening trend of most of our patients, from admission to subsequent days of hospitalization and they are likely to switching from L (low elastance, low lung weight, low recruitability - ground glass opacities at CT, preserved lung compliance) to H (high elastance, high lung weight, high recruitability - extensive densification at CT) CARDS [25] [26] [27].
Probably, in the first stage of the disease, improvement in oxygenation through the application of PEEP or pronation is mainly not due to the recruitment, but to the redistribution of perfusion in the lungs (25) (28).
In the second stage of the disease, the application of PEEP recruits non aerated alveoli in dependent pulmonary regions, stabilizes the airways and reduces the inhomogeneity of lung volume distribution [18]. PEEP can be applied in spontaneously breathing patients in form of CPAP [29].
The most important complications are shown in Table E1. The increased frequency of PE diagnosis in the second and third waves is explained by daily d-dimer monitoring and a higher use of CT Angiography.
Low PaO2/FiO2 ratio during H-CPAP, high FiO2 and average helmet PEEP were important factors of H-CPAP failure as a result of more severe AHRF; as already known, the mortality rate of ARDS increases with the severity of hypoxemia [3].
An increase of 1000 unit in d-dimer level (more severe “cytokine storm”) reduces the H-CPAP success of 9.5% [24].
A widespread use of steroids in our center could play a role in good clinical outcomes. Our study shows that the assumption of steroids increases the chance to H-CPAP success of almost 14 times, confirming what has been demonstrated in the RECOVERY TRIAL [21], a large multicenter randomized controlled trial (RCT) where patients receiving dexamethasone had a reduced death rate especially on mechanical ventilation.
Also for the second outcome, survival/death, the worst PaO2/FiO2 ratio during H-CPAP and the assumption of steroids were the best predictors. In our study there is a lower probability of death (77%) with respect to patients who did not undergo steroid therapy (Table 2).
Prone position in non-intubated spontaneously breathing patients is widely applied alongside NIRS. Its effectiveness in reducing intubation rate and mortality and its tolerability, timing and optimal duration are still not completely clear [30]. Prone position has gradually been increased in the three waves based on early suggestions in the literature [30][31].
Prone position determined in our patients a meaningful increase in PaO2/FiO2 value, although this improvement does not represent a good prognostic factor in itself. This response could give patients a chance to overcome the critical phase of CARDS and avoid intubation. We want to emphasize the fact that, despite the extremely low values of worst PaO2/FiO2 ratio recorded 82 (15.9%) mild, 202 (39.2%) moderate, 231 (44.9%) severe CARDS, 70% of our patients were finally discharged without need of IMV. In mild patients H-CPAP had a success of 98.8%, in moderate of 93% and, in severe patients, of 41%. In addition, 89 out of 231 patients in the “severe CARDS” group, were transferred to ICU and, of these, 44 finally survived, with a final mortality rate of 39.8%, in agreement with the mortality rate described for patients with severe non-COVID-19 ARDS in ICU (45%). We underline that, in our group of patients, mortality rates in mild and moderate ARDS are inferior to those reported in literature [3][8], considering the different features of patients admitted to ICUs (i.e. multiorgan failure).
Many management models for non invasive treatment of CARDS in RICU have been proposed in literature [32][33][31].
To our knowledge, up to now, this is the only study entirely carried out in RICU on patients all with CARDS and all treated with H-CPAP in the three COVID-19 waves.
We may therefore assume that the proper management in RICU, the use of H-CPAP as NIRS, prone position, large steroid use affect the prognosis of patients CARDS [34].
A constant clinical and parametric monitoring during hospitalization by the pulmonologist in RICU is critical in promptly recognition and treatment of every possible worsening in clinical conditions, an event than can arise even later in the course of the disease. In fact, the majority of patients moved to a worse CARDS class during hospitalization (Fig. 2).
Furthermore, our data seem to exclude a possible delay in intubation timing due to H-CPAP treatment and this is remarked by a mortality rate of almost 50% in patients finally admitted to ICU, substantially comparable with 55% of all Lombardy ICUs [7] and other countries experience [35].
In addition we must remember that, even if delayed intubation is associated with increased mortality in patients with AHRF [35][36], it is also true that premature intubation when NIRS is adequate, exposes patients to potentially unnecessary risks associated with IMV [16][37]. Our study has several limitations that can limit the generalizability of our results, among them being monocentric, the lack of control group and the peculiar setting of the study, characterized by an emergency pandemic situation with continuous changes in scientific evidence. Nevertheless, further multicentric and more trials are needed in order to confirm these data. In addition, the Berlin Definition of ARDS required that patients must be in IMV in moderate and severe ARDS, with the exception of mild ARDS in which patients can receive CPAP ≥ 5 cmH2O. In our study, ARDS was classified as moderate or severe during H-CPAP.