Proning Responder or Not? This Is the Question.

“Primum…docui…quae sint morbo mortique necesse est multa volare (1).” More than 2,000 years later, in the era of coronavirus disease 2019 (COVID-19), Latin poet Lucretius’s verses sound prophetic when thinking to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia outbreak: an unknown disease that we had to face suddenly. Knowing only little of its physiopathology, physicians all over the world started to treat such patients with the therapeutic and management instruments whose efficacy had been established in “similar” settings and progressively focused on those showing better results in terms of outcome and survival rate. A key point, immediately evident since the beginning of the so-called “first wave” in winter 2020, was that severe respiratory failure requiring ICU admission develops in greater than 40% of patients presenting with COVID-19 infection (2); however, a debate is still ongoing if COVID-related acute respiratory distress syndrome (C-ARDS) has different features than acute respiratory distress syndrome (ARDS) from other causes (2, 3).

Prone positioning (PP) is a rescue therapy that consists in keeping mechanically ventilated patients face down for long sessions, usually greater than 12 hours. PP is applied to ARDS patients with severe hypoxia refractory to conventional mechanical ventilation (4, 5). In this issue of Critical Care Medicine, Camporota et al (6) present a retrospective, observational study conducted on 376 adult patients admitted to ICU with ARDS, mechanically ventilated and made undergo PP: 220 had COVID-19–related ARDS and 156 patients ARDS from other causes. The study was aimed at describing differences between C-ARDS and ARDS, quantifying the response to PP and evaluate variables associated with survival, if any. The study focus only on the first PP session, presenting data on gas exchange and respiratory mechanics collected before and after proning. Patients response to PP was analyzed against ICU and hospital outcome to test the hypothesis that oxygenation response is greater in C-ARDS and mainly when applied early. The results show that in both groups in about 80% of patients there was a significant increase in oxygenation after the first PP and that in C-ARDS, an earlier application of PP was independently associated with improved survival.

PP was first reported in the 1970s (5) and since then achieved an established role in ARDS treatment (4), as confirmed by countless trials. Actually, PP may be beneficial for several reasons: 1) In the PP, gas exchange is improved because lung compression by the heart and abdominal organs is reduced as compared with supine position, while blood and air flow distribute more evenly. 2) With improved lung function, less support from the ventilator is needed to achieve adequate oxygen levels. This may reduce the risk of ventilator-induced lung injury, which occurs from overinflation and excess stretching of certain portions of the lungs. 3) PP may improve heart function in some patients. In the PP, venous return increases and lung vessels’ constriction decreases. This may help the heart pump better, resulting in improved oxygen delivery to the body. 4) Because the mouth and nose are facing down, secretions produced by the disease process in the lung may drain better (7).

PP application in routine practice, however, was reported to be quite low (8), probably because its benefit/risk ratio is not fully perceived by staff physicians and nurses often overwhelmed by the burden of daily workload. SARS-CoV-2 pneumonia outbreak lead rapidly to the evidence that PP could be beneficial in many of these patients, and not only in the intubated ones, so that a new challenge arose, made compelling by the enormous amount of patients requiring hospital admission, that is to persuade both intensivists and nonintensivists to prone their patients inside and outside the ICUs. Actually, a huge amount of literature is being published on PP in awake COVID patients, showing overall encouraging results (9, 10), while unexpectedly, less trials focuses on intubated patients, probably because they are equated to “classical” ARDS ones (11).

Camporota et al (6) tackle on this point by comparing C-ARDS versus ARDS and their findings do underline that C-ARDS is not fully superimposable to ARDS.

An affectionate reproach that could be made to Camporota et al (6) is that they used a “classical” vertical algorithm to present their data, while COVID-19 is everything but a classical disease and thus probably requires a more transversal approach.

In C-ARDS patients, oxygenation deteriorated from intubation at a greater extent than in non-C-ARDS, so that preproning they had a worst Pao2/Fio2 (13.0 vs 14.1 kPa; p = 0.017). However, in C-ARDS the median time from intubation to PP was longer (2.0 vs 1.0 d; p = 0.03). The question is: why C-ARDS patients were put prone later? Or also, why did attending physicians decide to prone them at a worst level of Pao2/Fio2 than non-COVID-19–related ARDS? This is perhaps the key to understand the whole process. The writer does not have an answer to this question, but some hypothesis: too many patients, staff shortage, the need to have on duty less-trained physicians and nurses, maybe. All over the world, patients’ care was highly conditioned by structural problems. It is important to underline that the study by Camporota et al (6) was conducted in seven European ICUs from March 2020 to May 2020, during the first violent COVID-19 outbreak that utterly stroke Europe, when our knowledge on COVID-19 physiopathology was at its dawn. Furthermore, the disproportionate number of patients with acute hypoxic respiratory failure compared with the available resources forced clinicians to assist patients by noninvasive techniques outside ICUs, keeping spontaneous breathing preserved despite dramatically impaired gas exchanges.

The proportion of responders to PP was similar between ARDS and C-ARDS (79% vs 76%; p = 0.5). Camporota et al (6) correctly report that responders had earlier PP (1.4 vs 2.5 d; p = 0.06) and that when PP was performed less than 24 hours from intubation, it achieved the greater improvement in oxygenation (11 vs 7 kPa; p = 0.002). However, let’s try to switch this statement to the following: the earlier PP is performed, the better do patients respond to it. Which is confirmed by the subsequent: variables independently associated with the “responder” category were the Pao2/Fio2 preproning and the time interval between intubation and proning. Data that authors do not discuss in the article, but that could help to understand their results are showed in Table 2 (6): in C-ARDS patients, the median time from hospital to ICU admission was 1 day, from hospital admission to proning was 5.4 days, from intubation to proning was 2 days. Interestingly, there was no difference between the two groups as regards the intubation to proning interval. This implies that time from ICU admission to intubation was 2.4 days, against 1.8 days in ARDS from other causes!

Actually, 32.1% of C-ARDS patients received noninvasive ventilation (NIV) versus only 1.3% of conventional ARDS before intubation, and this point matters a lot. Inspiratory effort can promote self-inflicted lung injury that in turn may affect lung injury evolution and thus the effects of PP. Would this actually mean a difference in terms of survival/mortality? In literature, data reporting then need to recognize timely the need to switch from NIV to invasive mechanical ventilation are quite strong (11), while no substantial improvement is obtained when invasive mechanical ventilation is prompted only after NIV failure, go in this direction.

The overall mortality reported by Camporota et al (6) was 45%, with no significant difference between the two groups. It is striking to observe that among the variables independently associated with mortality, besides age and Pao2/Fio2 change after PP, easily understandable, there is precisely the time interval between hospital admission and proning, which could be interpreted as an indirect evidence that what happens between ICU admission and intubation is important as well.

Two more considerations could be added: 1) “Mechanical power” is a very intriguing and fascinating measure (12). Furthermore, looking at plateau pressure and driving pressure is essential to be sure that clinicians are applying protective ventilation strategies (13). But also, in future prospective studies would be interesting to measure the presence of eventually airway opening pressure and especially, among different phenotypes (such as L and H) (14), distinguish patients recruiters from patients non recruiters (recruitment:inflation ratio > or < 0.5) (14, 15), especially during (or after) a PP session. For C-ARDS and the evolution of the related physiopathology, stating that “high peep worsens dead space, so keep it low” is not precise, as widely demonstrated, since in C-ARDS, the potential for lung recruitment shows large variability (15). If a patient “opens” his lungs at 13 cm H2O or if he does not recruit, this suggests that we are dealing with clusters of different patients and/or phenotypes with different response to PP. 2) Indeed, a type L pneumonia can evolve/convert in days into type H, therefore using the first pronation to evaluate a response that should allow to discern between responders and nonresponders might represent an “incomplete” picture of the pathology, according to laboratory work (reactive C protein, dimers), fluid balance and degree of ventilation to perfusion mismatch. Lung water, inflammation response, microthrombi, and pulmonary infiltrates do not reveal themselves in 1 day. The C-ARDS evolves in proportion to the type of therapy and the ventilatory strategy. Thus, a picture taken on day 1 of the same patient will be different from the one taken on day 3 (especially if mixing up day 1 data from patients admitted to ICU after 10 d of NIV and maybe several more days of wards with data patients intubated and admitted directly to ICU).

In conclusion, we agree with the authors, PP is useful anytime, if this is the message. In addition to that, the main difference between C-ARDS and ARDS are the phenotypes and evolution over time (rather than the solely physiologic response to first pronation).