The Protective Role of the Ratio of Arterial Partial Pressure of Oxygen and Fraction of Inspired Oxygen after Re-Supination in the Survival of Patients with Severe COVID-19 Pneumonia

1. INTRODUCTION

The benefits of the prone position in patients with acute respiratory failure have been documented since 1976 [1]. Improved gas exchange with an increased arterial oxygen partial pressure (PaO₂) and a decreased arterial partial pressure of carbon dioxide (PaCO₂) in Acute Respiratory Distress Syndrome (ARDS) is well described [2]. However, the most important thing regarding the prone position is the decrease in mortality when it is implemented early (< 48 hours); it is especially used once ARDS has been diagnosed, and for at least 16 hours in patients with severe hypoxemia (PaO₂/FiO₂ <150 mmHg) [3-5]. The pneumonia caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been identified as Coronavirus Disease 2019 (COVID-19). Up to 80% of COVID-19-related intubated patients have died [6, 7]. Therefore, guidelines for the care of critically ill adult patients with COVID-19 have recommended the use of the prone position [8]. The use of protective mechanical ventilation in terms of airway volume and pressure, including the prone position, is another strategy that can reduce the fatal outcome at 28 days (RR 0.74, 95% CI 0.61-0.88) [9]. Thus, the prone position should be accompanied by a low Tidal Volume (VT) [10], limiting plateau Pressure (Pplat) [11], Mechanical Power (MP) [12], Driving Pressure (DP) [13], and favorable Ventilatory Efficiency (VE) [14]. Together, these interventions could reduce the risk of Ventilator-induced Lung Injury (VILI), which is a reflection of inappropriate pressures and volumes, i.e., excessive stress and strain [15].

Invasive Mechanical Ventilation (IMV) in the supine position does not fully benefit lung function; the different gravitational forces between the dependent and nondependent regions cause the pleural Pressure (Ppl) to be more negative in non-dependent areas, which increases transpulmonary Pressure (Ptpl) and causes greater alveolar distension. In dependent areas, where Ppl is less negative, the opposite effect is obtained, and as a result, Ptpl is lower, translating into less alveolar distension [16]. Ventilation in the prone position favors the homogeneous distribution of Ptpl that generates more uniform ventilation, improves the diaphragmatic excursion of the dorsal region, and decreases the “mechanical effect” of the mediastinal structures (mainly the heart), redistributing ventilation. On the other hand, ventilation in the prone position causes redistribution of pulmonary blood flow, improving the ventilation/perfusion (V/Q) ratio [17]. Finally, respiratory mechanics benefit from improved distensibility of the chest wall and lung parenchyma. Together, these changes increase the PaO₂/FiO₂ ratio and decrease PaCO₂ [2, 18]. It has been proposed that a “prolonged” (more than 36 hours) prone position is safe and free of major adverse events in patients with ARDS secondary to SARS-CoV-2; likewise, the improvement could be greater and sustained [19]. However, in many patients, the improvement in the PaO₂/FiO₂ ratio is not sustained after resupination, which could be associated with patient outcomes. Therefore, our research aimed to determine survival by observing the change in the values of this index from the supine position to the prone position and vice versa.

2. MATERIAL AND METHODS

2.5. Statistical Analysis

Data have been reported as numbers (percentage) for categorical variables and mean (Standard Deviation (SD)) or median (interquartile range (IQR)) for continuous variables. The Shapiro‒Wilk test was used to evaluate the normality assumption of continuous variables. Non- normally distributed continuous variables were compared using the Mann‒Whitney U-test, and normally distributed continuous variables were compared with the Student’s t-test. The categorical variables between the groups were compared using the chi-square test or Fisher´s exact test. Friedman´s test was used to compare the PaO₂/FiO₂ ratio at T0, T1, T2, and T3 within each group, and if statistical significance was detected, multiple comparisons were carried out with Wilcoxon´s signed-rank test for post-hoc comparisons between the related values. The bivariate correlation between the variables under study was assessed using the Spearman correlation coefficient. A univariate Cox regression analysis was performed, and only the variables significantly associated with the non-survival of COVID-19 patients were entered into a multivariate model with a stepwise method. In this regard, the Hazard Ratios (HRs) together with 95% Confidence Intervals (CIs) were estimated. Receiver Operating Characteristic (ROC) curve analysis was applied to evaluate the predictive value of the PaO₂/FiO₂ ratio, considering the Area Under the Curve (AUC). The Kaplan-Meir survival curve to estimate survival according to the best cutoff point of the PaO₂/FiO₂ ratio at T3 was constructed. The statistical significance of the differences between the categories of PaO₂/FiO₂ ratio was calculated using the log-rank test. A p-value <0.05 was considered statistically significant. Statistical analysis was performed using R Studio (version 1.0.153), SPSS 25.0 (SPSS Inc., Chicago, IL, USA), and MedCalc (Software 8.1.1.0; Mariakerke, Belgium).

3. RESULTS

98 patients with a diagnosis of severe COVID-19 pneumonia were included in the statistical analysis; they were classified as survivors and non-survivors (Fig. 1). Demographic and clinical characteristics by subgroup are described in Table 1. The survivor group had a median age of 60.4 years old ±14.75 compared to 66 years old ±11.09 in the non-survivor group; the difference exhibited statistical significance.

Among the variables that were considered of interest for the clinical evolution of patients with severe COVID-19 pneumonia, sex, age, medical comorbidities, Pressure plateau (Pplat), Driving Pressure (ΔP), Compliance of the Respiratory System (CrS), Mechanical Power (MP), and Ventilatory Ratio (VR) stood out (Table 1). In all patients, the following variables were calculated: the PaO₂/FiO₂ ratio was measured pre-proning (T0), 30 min to 1 hour (T1), and 48 h after prone positioning (T2), and 30 min to 1 h after resupination (T3). The findings have emphasized a PaO2/FIO2 value in the highest T3 in the survivors group compared to non-survivors, i.e., 182mmHg (105.5mmHg) and 108.5mmHg (68mmHg), respectively (p=0.001; Table 1).

The univariate and multivariate analyses of the variables of interest have highlighted age (>55 years old) with HR 1.045 (95% CI 1.016-1.074; p=0.001) to lead to fatal outcomes. Likewise, T3 (after re-supination (after 48 hours in prone position)) has exhibited an HR of 0.993 (95% CI 0.989-0.998; p=0.006; Table 2).

When comparing the PaO₂/FiO₂ in the groups of survivors and non-survivors, T2 stood out as 251.5mmHg and 208.5mmHg, respectively (p= 0.032), and T3 as 182mmHg and 108.5mmHg, respectively (p <0.001; Fig. 2). The dynamic changes in the PaO₂/FiO₂ ratio at T0, T1, T2, and T3 within each group were also evaluated in this study. With the Friedman test, it was highlighted that the group of survivors presented high levels of PaO₂/FiO₂ for time T0, T1, T2, and T3 compared to the group of non-survivors (T0 = 87 (45.25), T1 = 180 (66.5), T2= 251.5 (115.25), T3= 182 (105.5), consecutively (p <0.00001 in all cases)) (Fig. 3). On the other hand, the PaO₂/FiO₂ ratio was increased at T2 compared to T0, T1, and T3 in the non-survivors )T0= 70.5 (30.75) vs. T1= 160 (85.5) vs. T2= 208.5 (136.25) vs. T3= 108.5 (68), p <0.00001). Through the ROC curve analysis, the ratio was compared at different times (Fig. 4A-D). Additionally, the results of the Area Under the Curve (AUC), best cutoff point, Youden´s index, Sensitivity (S), Specificity (Sp), Positive and Negative Predictive Values (PPV, NPV), and likelihood ratios for the PaO₂/FiO₂ ratio at T0, T1, T2, and T3 are shown in Table 3.

The PaO₂/FiO₂ ratio at time T3 of <129mmHg presented an AUC of 0.782 with S and Sp of 67.8% and 80.9%, respectively (Table 3). The PaO₂/FiO₂ ratio at T0 was positively correlated with age (r= 0.266, p= 0.008), whereas the PaO₂/FiO₂ ratio at T1 (r= 0.126, p= 0.215), T2 (r= 0.135, p= 0.184), and T3 (r= 0.165, p= 0.105) showed no significant correlation with age (Fig. 5A-D). A Kaplan‒Meier survival curve was plotted (Fig. 6) according to the best cutoff point (≤129mmHg) of the PaO₂/FiO₂ ratio at T3, which demonstrated a lower survival over time (p= 0.015).

4. DISCUSSION

In this study, our goal was to avoid both hypoxemia and hyperoxemia. PaO₂ levels between 60-100mmHg [23] and peripheral oxygen saturation (SpO₂) between 92% and 96% indicate COVID-19 infection in patients [24]. An SpO₂ of < 92% has been reported to indicate an increased risk of mortality (HR 1.62; 95% CI 1.02-2.56) [25] as well as an SpO₂ > 96% (RR 1.21; 95% CI 1.03-1.43) [26]. When possible, besides SpO₂, the sigmoid shape of the oxygen dissociation curve should be considered. Pulse oximetry between 92% and 96% can represent a PaO₂ between 60 and 200 mmHg, which can be an extremely different value with an important connotation regarding the treatment [27].

Variations in PaO₂/FiO₂ when placing the patient in the prone position or at weaning are important, but the benefit of this position goes beyond a variable. It has been documented that there is a 53% increase in PaO₂/FiO₂ in patients with moderate to severe ARDS; 12 hours after its start, the prone position improves survival HR 0.11 (95% CI 0.05-0.25, p=<0.001) [28]. In contrast, the decrease in the PaO₂/FiO₂ value upon returning to the supine position is associated with an increase in the need for tracheostomy and even mortality. In addition, the “sustained improvement” of PaO₂/FiO₂ when returning to the supine position is independently associated with extubation success (RR 1.563, 95% CI 1.329-1.838, p = <0.001) [29]. Similar to this, our research has demonstrated higher PaO₂/FiO₂ values at both T2 and T3 in the survivor group. However, only the PaO₂/FiO₂ ratio at T3 (HR= 0.993; 95% CI 0.989-0.998, p= 0.006) has been an independent predictor of death in COVID-19 patients with ARDS. The survivor group had a higher level of CRS (35.92 ± 9.15 vs. 30.37 ±9.38, p <0.005) than the non-survival group. This variable has been reported to be associated with discharge from the ICU at 28 days, but to not be a predictor of mortality [30].

The elimination of CO₂ is as important as the increase in oxygenation. Recruitment of well-perfused but poorly ventilated units decreases shunts and, thus, favors CO₂ elimination. The Ventilatory Ratio (VR) is a simple parameter that assesses alveolar ventilation. Its normal value is ~1, without units. The VR is mainly determined by dead-space fraction (VD/VT) and is an independent predictor of mortality. Among patients with ARDS, VR has been found to be higher in non-survivors [31]. Among patients with COVID-19 who required invasive mechanical ventilation, the increase in VR from ICU admission compared to day 3 was associated with mortality (OR 1.4, CI 1.01-1.07, p= 0.030), regardless of PaO₂/FiO₂ variations (OR 0.99, CI 0.95-1.02, p= 0.47) [32]. Dead space could predict mortality in patients with ARDS [33]; however, in our patient population, there were no differences in VR between the survivors and non-survivors or in PPLAT, DP, and MP between the survivors and non-survivors. Thus, it can be stated that a prolonged prone position (~48 hours) is viable, and at a greater number of hours, the benefits are greater, and there is no increase in the inherent risks of this anatomical position. Even a prolonged prone position could be useful for preserving oxygenation improvement after resupination [34-36].

The limitations of our study are stated as follows: the study was carried out at a single center, it was retrospective, the sample size was small, the mechanical ventilation protocol was not standardized (although the protective ventilation strategy was used), and we did not report adverse events of any kind regarding the prolonged prone position. However, our strength is that we have reported patients to share homogeneous baseline characteristics.

CONCLUSION

The results obtained in this study, although analyzed retrospectively, have suggested the dynamic evolution of lung disease in severe COVID-19 pneumonia, with age being an independent variable for fatal outcomes; however, what was most notable is the evolution of the ratio PaO₂/FiO₂ at different times in the clinical evolution, that is, the PaO₂/FiO₂ values measured in T2 could translate the gasometric paremeters’ response to the orotracheal intubation maneuver and prone position, but the T3 time (re-supination) was the most predictive for the final outcome.

REFERENCES