Clinical progression of critically ill COVID-19 patients
A total of 633 mechanically ventilated patients admitted to 13 UK National Health Service (NHS) Trusts with 18 ICU sites between 01 March 2020 and 31 August 2020 had complete daily data up to ICU death or discharge (Fig. 1, Table S1). Baseline demographics (Fig. S1 and Table S5) were similar to the Intensive Care National Audit and Research Centre cohort  (Table S6). On initiation of mechanical ventilation, the severity of mild, moderate and severe hypoxaemia was 23.2%; 50.6%, and 26.2%, respectively, with mortality increasing with severity (Fig. 2, Table S7). On admission, increased severity was associated with higher settings for mechanical ventilation, higher severity of organ failure (including dynamic respiratory system compliance, oxygenation index (OI), and ventilatory ratio (VR)) (Table 1), and greater application of interventions (Table 2).
Determinants of mortality
Survival to ICU discharge was 57.7%. There was a difference in mortality between quartiles of patients admitted (peak: 31st March; median: 1st April 2020) during the first surge (P = 0.053). This showed the first quartile [1st–26th March 2020] of admitted patients during the surge had a mortality of 37.3%; the second quartile [27th March–2nd April 2020], 53%; the third quartile [3rd–9th April 2020], 43.4%; and the last quartile [10th April–31st August], 35.9% (see Fig. S1, Table S8). Admission respiratory SOFA increased across the pandemic quartile (P = 0.036). In those that died, active withdrawal of support occurred in 65% of patients (85/130), in the 13 sites which reported, and unanticipated cardiac arrest occurred in 11% of patients (13/122). There was an increased rate of reported withdrawal of life support in patients admitted during the second and third quartiles of the surge (first quartile, 55.9%; the second quartile, 73.8%; the third quartile, 71%; and the last quartile, 56.5%; P = 0.018). Patients who had life support withdrawn had a median age of 64(57–70) years, a length of mechanical ventilation of 11 (6–18) days; a last PaO2/FiO2 of 12.8 (10–19.5) kPa and had a higher application of prone intervention (72%). Median PaO2/FiO2 in non-survivors on the day of death was 12.3(8.9–18.4)kPa.
Our multivariate model showed clinical variables on ICU admission independently associated with mortality were higher age (HR 1.95 per decade, 95% CI 1.58–2.4), male gender (HR 2.05, 95% CI 1.17–3.61), higher lactate (HR 1.52 per quartile (0.6 mmol/L), 95% CI 1.21–1.92), and higher SOFA coagulation score (HR 1.95, 95% CI 1.17–3.26) (Fig. S2; Table S9). Over the first week, statistically significant interaction differences were noted in the group-wise ANOVA between survivors and non-survivors within several respiratory, inflammatory and coagulation parameters (Fig. S2; Table S10). Machine learning models using admission data predicted mortality with 60% accuracy. Predictive capacity increased to 74.5% and 76.3% accuracy, respectively, when longitudinal data from the first week were added to LR and 3MLP models (Fig. 3). Critically, using Explainability AI methods, we were able to identify key clinical parameters which started at relatively low importance at admission but then greatly increased and exceeded others in importance over the first week (Fig. 3): these were lower PaO2/FiO2, higher peak pressure, higher ventilatory ratio (VR), lower pH, higher lactate, lower platelet count, higher C-Reactive Protein (CRP), lower oxygen saturations, and higher PaCO2 (see Fig. S3).
Determinants of oxygenation
Movement across hypoxaemia severity groups (mild, moderate and severe PaO2/FiO2 group) showed deterioration in 31.4% of cases, stasis in 45.1%, and resolution in only 23.5% of patients over the first 7 days (Fig. 4 and Table S11). Overall, progression to a worse PaO2/FiO2 group occurred in twice the number of patients as compared to pre-COVID studies of ARDS (Table S11). ICU mortality in those who did not resolve hypoxaemia within the first week was significantly higher than those that did (60.4% versus 17.6%; P < 0.001; Fig. S4). Admission and time-course differences between resolvers and non-resolvers in demographic, ventilatory, physiological, and laboratory parameters are shown in Fig. S4 and Tables S12 and S13. Resolvers were younger [57 (47–64) vs 60 (54–67) years; P < 0.001] and showed a longer duration of symptoms prior to ICU admission 9.0 (7–14) vs 7 (6–11) days (P = 0.004). Multivariate regression showed that increased age and worse cardiovascular SOFA were associated with deteriorating hypoxaemia within the first week of IMV (Fig. S4; Table S14).
The application, median start date and duration of the first episode of each intervention and for each site is shown in Figs. S5, S6 and Table S15. The reported ideal body weight overestimated our calculated ideal body weight derived from reported height (http://ardsnet.org) in 92.6% of patients (Fig. S7). Hence, median tidal volume per kg on actual ideal body weight was 7.0 [IQR 6.0–8.4] mL/kg across all breaths and 5.6 [IQR 4.7–6.6] mL/kg on reported ideal body weight. Survivors and non-survivors showed the same distribution of tidal volume variation. Over 65% of reported PEEP values were set outside ± 1cmH2O and 53% set outside ± 2cmH2O of the ARDSNet PEEP-FiO2 tables (Fig. S7). Patients with BMI < 40 had a higher set PEEP than recommended by the PEEP-FiO2 table. In contrast, patients with BMI > 40 had a lower set PEEP than recommended by the PEEP-FiO2 table. Inhaled nitric oxide and prostacyclin were commenced on day 6 (3–9) and 7 (3–15) and were continued for 4 (2–7) days and 3 (1–7) days, respectively. Tracheostomy was performed in 29% at a median 14(9–18) days in patients mainly likely to survive (40% versus 10.9%; P < 0.001). Application of high PEEP, NMBA, and prone position was significantly higher during the second and third quartiles (Table S8). Corticosteroid usage increased across the surge whereas use of diuresis reduced (Table S8).
Responsiveness to open lung and prone interventions
Changes in PEEP were widespread over the first 7 days of IMV with both increases and decreases leading to unpredictable changes in PaO2/FiO2 (Fig. S7). We analysed the immediate change in PaO2/FiO2 over 36 h around the first prone intervention. Indeed, there were both positive and negative changes in PaO2/FiO2 in response to prone intervention over the first 36 h (Fig. S8). Improvements in oxygenation in response to prone position was found to decrease the later the prone episode was initiated after intubation (Fig. S8; Spearman r = − 0.16, P = 0.012). Patients that resolved hypoxaemia in the first week had prone position applied significantly earlier (2 [1–5] vs 4 [2–7] days; P = 0.007) than those that did not resolve. Importantly, in those that received no prone position, there were a higher number of missed opportunities to prone in non-resolvers compared to resolvers (6 [3–13] versus 1 [0–4] opportunities per patient; P < 0.001; Table S12).
Only 44.4% of patients maintained a mean PaO2/FiO2 > 20 kPa over 7 days after the initiation of prone position. Mortality was significantly higher in prone non-responders than in responders (69.5% versus 31.1%, P < 0.001 as seen in Fig. 5 and Table S16). Time series analysis showed that non-responders showed worse mean airway pressure, worse oxygenation index (OI), higher platelet count and higher alkaline transaminase (ALT) over the first week of prone position (Fig. S8 and Table S17). Multivariate analysis showed non-responders to be older with a higher pre-pronation peak pressure (OR 1.42[1.06–1.91]; P < 0.05), higher respiratory component (OR 1.71[1.17–2.5]; P < 0.01) and higher cardiovascular component (OR 1.36[1.04–1.75]; P < 0.05) of the sequential organ failure assessment (SOFA) score and raised lactate (OR 1.33[0.99–1.79]; P = 0.057) (Fig. S8 and Tables S18 and S19). Whilst there were no significant differences in the duration of IMV prior to the first prone period, the duration of the first period, or the number of future prone periods between responders and non-responders; non-responders had a higher number of missed prone opportunities (prior to first prone position event) than responders (3 [1–7] versus 2 [1–5] opportunities per patient; P < 0.05; Table S16).
Clinical implementation gap in proning interventions
The application of prone position occurred in 49.5% of patients and was applied on day 2 (1–5) and lasted 2 (1–4) days. Prone position was applied earlier in patients with greater severity on admission [mild: 4 (2–8) days; moderate 4 (2–7) days; severe: 2(1–4) days after onset of IMV; P < 0.001]. While patients that did not undergo prone position may overall have had a milder disease, we found that 76% of patients who had moderate hypoxaemia and 46% who had severe, at any stage of admission, did not undergo prone position at all. We measured the opportunity to apply prone position when there was a PaO2/FiO2 < 20 kPa, with an FiO2 ≥ 0.6, and a PEEP ≥ 5cmH2O, as per the PROSEVA study 20. In patients who received no prone positioning, there was 1 (IQR 0–2) prone opportunity per patient ignored during the first 48 h and 3 (IQR 1–10) during the whole patient journey. In patients who received prone interventions, there were on average 3 (IQR 1–6) prone opportunities per patient before prone initiation that were missed. There was no difference in the number of prone sessions between survivors and non-survivors, however, patients who died without receiving prone position had a greater number of missed prone opportunities [7 (3–15) versus 2(0–6); P < 0.001; Table S7]. Patients admitted before the peak of the surge had a lower application of prone position, a greater duration of IMV prior to application of first prone position and a tendency towards having more missed prone opportunities.