In this secondary analysis of critically ill COVID-19 patients we analyzed if the sustained oxygenation improvement after the first PP session could be associated to ICU outcome in terms of time to liberation from mechanical ventilation, complication rates and mortality. We found that, in severe COVID-19-related ARDS, the sustained PaO2/FiO2 improvement after the first prone positioning was progressively related a to lower mechanical ventilation time and ICU mortality.
Severe COVID-19 is characterized by dyspnea, a respiratory rate of 30 or more breaths per minute, a blood oxygen saturation of 93% or less, a PaO2/FiO2 ratio of less than 300 mmHg, or infiltrates in more than 50% of the lung field within 24 to 48 h from the onset of symptoms [21]. PP has been rapidly adopted by intensivists once the first wave spread out to the ICUs worldwide, mainly for its positive effect on arterial oxygen content. This can be consequence of several mechanisms, which are largely dependent on the stage of the disease. Despite its sound physiological basis, PP determines a variable oxygenation response across COVID-19 patients, some improving dramatically oxygenation and others not. Recruitment of dorsal lung regions due to the lung edema shift from vertebral to sternal lung, which, furthermore, continued to receive most pulmonary blood flow (at least in non COVID-19-related ARDS), is the main mechanism thought to be involved in the oxygenation improvement during PP [22]. When this happens, CRS improves, and DP decreases because of the wider surface available for ventilation.
When analyzing the oxygenation in COVID-19 patients returning to supine position after the first PP session, the variable persistence of oxygenation improvement was found both in noninvasively and invasively ventilated patients [7, 15, 16]. However, this finding has never been previously linked with patients’ outcome. We found that the sustained oxygenation improvement after the first PP session was independently associated with a reduced duration of mechanical ventilation and mortality rate.
In a previous study by Lee et al. [23] in non-COVID-19 ARDS, a sustained oxygenation after PP was associated to an improvement of respiratory system mechanics. In their paper, indeed, only responders increase CRS after resupination, while non-responders did not. In our population, responders had a slightly lower DP after PP, but both responders and non-responders had a comparable decrease in DP—and presumably in lung recruitment—after PP. Since the improvement in DP was not different between responders and non-responders, it cannot explain per se why the oxygenation increased only in the responders group.
To support this, a recent work by Haddam et al. found that the gas exchange improvement after PP could not be predicted by the variation of dorsal aeration measured by lung ultrasound [24]. Therefore, several mechanisms, beside lung recruitment, are involved in the PaO2/FiO2 increase following PP in ARDS and this is probably even more true for COVID-19-related ARDS, where the vascular impairment can be responsible for a defective hypoxic pulmonary vasoconstriction [4]. A new CT scan study comparing COVID-19 ARDS to an historical non-COVID ARDS population, found, indeed, that for comparable lung aeration and compliance, COVID-19 ARDS has a significantly higher percentage of hypoxemia [25]. This confirms the hypothesis that COVID-19-related ARDS is a specific “vasocentric” phenotype of ARDS [26]. The oxygenation response to PP may, therefore, be a hint of at partially preserved ventilation/perfusion matching and, therefore, an indirect sign of disease extension. Patients not improving oxygenation after PP may, therefore, highlight an extended damage of both the alveolar and vascular structures. A recent observational study demonstrated that transesophageal echocardiography monitoring is feasible, sensitive and promising in tracking individual hemodynamic response to PP, which may be unpredictably deleterious in some patients [27]. The heterogeneous effect on the right ventricle output may, indeed, help to understand the different responsiveness to PP seen in these patients. Future studies are needed to address this key physiopathological point.
Previous studies in non-COVID ARDS found that an oxygenation improvement after PP was marginally [13] or not associated [14] with mortality. Despite mortality was not the primary outcome of this study, we believe that the association between response to PP and mortality may be a peculiar characteristic of COVID-19-related ARDS and that further studies need to specifically address this point.
Non-responders had a prolonged duration of mechanical ventilation, an increased risk of death and a higher rate of tracheostomy compared to responders. This was not unexpected, since a reduced response to PP was independently associated to a higher risk of prolonged liberation from mechanical ventilation, while no differences were found in the complication rates.
Since the oxygenation response to the first PP can highlight patients at major risk of death, it may be used to inform who may benefit from a further level of assistance. Beside PP, indeed, other interventions can be used to increase oxygenation in COVID-19, like inhaled nitric oxide [5, 28], intravenous Almitrine [29], ECMO [30]. The reduced oxygenation response to PP may be, therefore, helpful to select patients needing alternative ventilatory treatment. Indeed, the only three patients that in our population underwent ECMO were in the non-responders group.
A prolonged time of prone positioning (36 h) was recently suggested to help preserving the oxygenation improvement after resupination [31]. In our population, both responders and non-responders had the same time of PP, but it is worth to explore in future studies if non-responders may need a prolonged session of prone positioning to fully exploit the potential of the maneuver. We found that a sustained oxygenation improvement after prone positioning was associated with better outcome; whether this was linked to a higher organ oxygen delivery, to a different stage of the disease or to a different mechanism linked to PP disease must be explored by future studies. Poor response to prone positioning, moreover, could be potentially used to identify patients that are at higher risk of prolonged weaning and, therefore, modify the policy of tracheostomy, sedation and ventilation. During prone positioning, all patients were paralyzed and ventilated in volume-controlled ventilation. Recent evidence [32] show that spontaneous breathing could be beneficial during prone position and the effect of spontaneous breathing during prone positioning in COVID-19 patients has to be explored. Moreover, despite no differences were found in driving pressure change, PEEP and recruitment may have played a role in some patients. Further studies are needed to assess the impact of PEEP [33], lung recruitment and/or recruitability [34, 35] on PP response.
Our study has several limitations. First, the ventilatory treatment and weaning were not standardized among participating, thus adding potential confounding factors. Second, for many variables, we asked the participating centers to collect the lowest values within the first 5 days of ICU stay, thus possibly missing important data on the precise time course of these variables. Third, several experimental COVID-19 therapies were tested in different centers during the conduction of present study. Forth, we did not evaluate thrombosis among complications, since this parameter can be difficult to be assessed, both for micro and macro thrombosis. Finally, we analyzed the response to the first prone positioning session. Further studies should evaluate if the response to subsequent PP sessions could be useful in predicting outcome. In our analysis, we grouped patients based on the oxygenation response to PP. Before performing the maneuver, no single variable was predictive of the response. Moreover, all patients started PP per clinical decision, and therefore, it is possible to assume that the severity of patients in the groups was the same and this was confirmed by the baseline characteristics of the groups. The only mechanical difference among the two groups in the first 5 days of ICU stay was the lowest Crs, since this was slightly higher in responders. Despite this, in both groups PP was decided on oxygenation and not on respiratory mechanics. Post-hoc power analysis revealed that the primary outcome (VFDs) had a power of 0.92, meaning that there is an 92% chance of detecting a difference as statistically significant, if in fact a true difference exists.