Determination of PaO2/FiO2 after 24 h of invasive mechanical ventilation and ΔPaO2/FiO2 at 24 h as predictors of survival in patients diagnosed with ARDS due to COVID-19

Study design and site

A retrospective cohort study was conducted using physical and electronic medical records of patients diagnosed with ARDS due to COVID-19. The study was carried out at Hospital III Daniel Alcides Carrión, located in the district of Calana in Tacna, in southern Peru. This third-level referral hospital belongs to the Tacna Social Security Health Care Network (EsSalud). It has a capacity of 28 beds in intensive care units (ICU) (EsSalud, 2022). The study period was from April 2020 to April 2021. The writing of the manuscript was carried out following the recommendations of STROBE to inform observational studies (Vandenbroucke et al., 2007).

Study population

The study population included critically ill adult patients (≥18 years) diagnosed with ARDS due to COVID-19 on IMV and hospitalized in the ICU. Diagnosis of COVID-19 was made by real-time polymerase chain reaction (RT-PCR) or positive nasopharyngeal swab antigenic rapid test. The diagnosis of ARDS was made according to what was proposed in the Berlin criteria (Ranieri et al., 2012). The patients who could not confirm the diagnosis of COVID-19, who were still in the ICU during data collection, and in whom complete data were not available in their medical record records were excluded. The sample included all patients who met the eligibility criteria within the study period.

Hospital management

As part of the institutional protocol for critical patient ventilatory management in our hospital, all patients admitted to IMV underwent initial programming with the following parameters in pressure-controlled mode: (a) tidal volume 6-8ml/kg of ideal weight, (b) Positive end-expiratory pressure (PEEP): 8–12 cmH2O, (c) Respiratory rate (RR) for Carbon dioxide arterial pressure (PaCO2) between 35 and 50 mmHg and or pH >7.2 and (d) FiO2 for pulse oximetry saturation (SatO2) between 92–96%. Additionally, all patients were placed in the prone position for 48 to 72 continuous hours, which was suspended when PaO2/FiO2 was ≥200 mmHg with PEEP ≤10 and FiO2 ≤40%. Likewise, all patients received sufficient analgesia to allow the coupling to the IMV, associated with neuromuscular blockade during the prone period. On the other hand, those patients who, after coming out of pronation, presented a PaO2/FiO2 <150 or a 20% decrease in PaO2/FiO2 with respect to PaO2/FiO2 in prone (with or without posterior dense pulmonary infiltrates evidenced in the multicut computerized tomography) were subjected again to another cycle of prone.

We decided to evaluate all the patients who underwent MV and were admitted to the ICU and met the inclusion criteria. We calculated the statistical power of the collected sample (200 patients) based on the study by Schuijt et al. (2021a), who reported mortality at 28 days in patients with severe ARDS on the second day after admission to IMV of 44.3% and 28.6% in patients with mild ARDS, also reported a ratio of unexposed to exposed of 6.21 (764/123). With a confidence level of 95% and 200 participants in the study sample and a non-exposed/exposed ratio of 3, calculated the statistical power was at 53.5%.

Data collection

After reviewing all physical and digital medical records, patients were evaluated from hospital admission to outcome (medical discharge or death). Sociodemographic, clinical, ventilatory (before access to the IMV and 24 h later), laboratory and imaging characteristics that the radiologists reported at the time of admission to the IMV were collected, the calculation of the extent of parenchymal involvement was performed by a semi-quantitative scoring used in previous studies  (Chang et al., 2005; Pan et al., 2020). To calculate lung damage, the average percentage of lung damage reported for each lobe was used (from 0 to 100%). Complications and therapies administered during the ICU stay were also evaluated.

Two researchers conducted data collection; Each one entered the data independently; A third researcher supervised and compared the data collected; when he found any error, the third researcher reviewed the medical history and corrected the error. The coded data collection forms were entered into the Microsoft Excel v.2016 program and performed the statistical analysis with the STATA V17.0 (StatCorp, College Station, TX, USA) and Prism 9 (GraphPad, San Diego, CA, USA) software.

Analyzed variables

Statistical analysis

Categorical variables were described as absolute and relative frequency, and quantitative variables as mean/standard deviation or median/interquartile range depending on whether their distribution was normal or not. The Chi-square or Fisher’s exact statistical tests were used for the bivariate analysis between the categorical variables and the results. For the quantitative variables, the Student’s t-test was used if the assumptions were fulfilled or, failing that, the Mann–Whitney U test. For the comparison with the degrees of severity of ARDS, the ANOVA or Kruskal Wallis statistical tests were used according to the normality of the variables.

We investigated the predictive capacity of ΔPaO2/FiO2 24 h and PaO2/FiO2 24 h after IMV as a predictor of survival in patients with ARDS due to COVID-19. First, we calculated the Receiver Operating Characteristic (ROC) curves, the ROC curve (area under the curve, AUC) area, and the corresponding Youden indices. The highest Youden index identified the optimal cut-off point. Next, the 95% CI was calculated by bootstrapping a thousand repetitions, thereby generating dichotomous exposure variables for ΔPaO2/FiO2 24 h and PaO2/FiO2 24 h after IMV. Then, we calculated the sensitivity, specificity, and odds ratio with their respective 95% CI of the established cut-off points to predict survival. In addition, the differences between the ROC curves were tested using the Chi-square test (Safari et al., 2016).

Finally, to answer our hypothesis, we used Cox proportional hazards models to find the crude and adjusted hazard ratios (aHR) and their respective 95% confidence intervals (95% CI). The variables ΔPaO2/FiO2 24 h, PaO2/FiO2 24 h of IMV, and ARDS severity before IMV and after 24 h of IMV, as they were not independent of each other, were analyzed individually in different adjusted regressions (one for each variable). In the adjusted model, we included the variables: age, sex, number of comorbidities, septic shock, acute renal failure, positive end-expiratory pressure, plateau pressure, driving pressure, and date of admission. These variables were selected for clinical plausibility as they could influence the outcome. The proportionality of the multivariate model had a value of p = 0.452.

Ethical aspects

This research followed the international guidelines of the Declaration of Helsinki. The research protocol was evaluated and approved by the ethics committee of the Faculty of Health Sciences of the Private University of Tacna (Identification code: N391-2021-UPT/FACSA-D). Due to the retrospective observational nature of the study, they did not request informed consent. All information was coded to maintain the anonymity of the participants, and only the researchers had access to the data.

Characteristics of the study population

Of the 235 medical records examined, 35 did not meet our inclusion criteria (25 were still hospitalized and 10 had incomplete data), so a total of 200 medical records of patients with ARDS secondary to COVID-19 undergoing IMV and who were admitted to the ICU; of these the 79% (n = 158) were male, and the mean age was 54.29 (SD: 12.19) years. A total of 78% (n = 159) of those admitted had at least one comorbidity, and the most frequent were obesity (59%), hypertension (26.5%), and diabetes mellitus type 2 (21.50%). The median length of hospital stays, time in the ICU, and time in IMV was 20 (IQR: 14–28) days, 10 (IQR: 5.5–16) days, and 10 (IQR: 6–16) days, respectively (Table 1).

At the time of hospital admission, the median SatO2 and PaO2/FiO2 were 88% (IQR: 84.5–90) and 245.5 (IQR: 165.5–297), respectively, and the mean extent of pulmonary involvement on chest tomography was 61.34% (SD: 14.02). At the time of admission to IMV, the median PaO2/FiO2 was 91.5 (IQR: 70–129.5); likewise, 58.5% of patients were admitted to IMV with a diagnosis of severe ARDS, and the median SOFA score at admission was 4 (IQR: 3–5) points. Regarding the laboratory data, the median of lymphocytes, procalcitonin, and lactate dehydrogenase were 675.65 (IQR: 480–1070.4) cells/mm3, 0.14 (IQR: 0.06–0.37) ng/mL, and 757.5 (IQR: 587.5–990.5) IU/L, respectively (Table 1).

At 24 h after admission to IMV, the median PaO2/FiO2 was 240 (IQR: 200–301.5), and the 24 h ΔPaO2/FiO2 was 141 (105–193). Concerning ventilatory parameters, the median values for PEEP, plateau pressure, and driving pressure were 12 (IQR: 10.5–14), 28 (IQR: 26–31), and 16 (IQR: 15–18), respectively. Likewise, 74.5% of patients admitted to IMV were classified as having mild ARDS at 24 h (Table 1).

During the ICU stay, 29% (n = 58) of the patients presented a nosocomial infection, with pneumonia associated with IMV being the most frequent (75.86%); however, 98.5% of the patients’ received antibiotics. Furthermore, 14.5% of the patients developed acute renal failure, and 51% required renal replacement therapy. Finally, 51 patients (25.5%) of those admitted to IMV died (Table 2).

Bivariate analysis according to the severity of ARDS

Significant differences were observed concerning greater severity of ARDS after 24 h in IMV in elderly patients, a greater number of comorbidities. The most frequent in this group were heart failure, chronic kidney disease, and immunosuppression. The clinical and ventilatory characteristics associated with greater severity of ARDS were, entering the emergency room with minor oxygen saturation, requiring vasopressors, a higher percentage of lung damage, and a higher SOFA score (Table S1).

Bivariate analysis according to death

In the bivariate analysis, statistically significant differences were observed concerning mortality in patients with older age, with the presence of 1 or more comorbidities, and among them, mainly type 2 diabetes mellitus, heart failure, and chronic kidney disease. It was also observed that those who died had a more extended stay in the ICU (median: 14 days vs nine days) and IMV (median: 15 days vs eight days), lower SatO2, lower PaO2/FiO2 at hospital admission, a greater pulmonary involvement in the chest tomography and a higher score in the SOFA score. Likewise, the patients who died presented a lower PaO2/FiO2 before entering IMV (median: 68 vs 95; p < 0.001) and in the same way, at 24 h after IMV, PaO2/FiO2 and ΔPaO2/FiO2 24 h were lower in the deceased with a median of 190 vs 260 (p < 0.001) and a median of 106 vs. 152.2 (p < 0.001), respectively, than in the survivors (Fig. 1). At 24 h, the proportion of patients with mild ARDS was 84.56% in the survivors and 45% in the deceased (p < 0.001). (Table 1). It was also observed that deceased patients presented higher plateau pressure, driving pressure, and higher PEEP values at 24 h of IMV and a higher incidence of ventilator-associated pneumonia, septic shock, arrhythmias, and acute renal failure (Table 2).

Determination of predictive value of PaO2/FiO2 24 h after IMV and ΔPaO2/FiO2 24 h

PaO2/FiO2 24 h after IMV has an AUC ROC of 0.75 (95% CI [0.66–0.83]), with 222.5 (95% CI [175.85–269.14]) being the best cut-off point to determine survival, with a sensitivity and specificity of 74.5% (IC 95% 66.7–81.3) and 68.6% (IC 95% [54.1–80.9]), respectively. Similarly, the AUC ROC of ΔPaO2/FiO2 24 h was 0.70 (95% CI [0.61–0.78]), with a cut-off point of 109.5 (95% CI [85.43–133.56]), whose sensitivity and specificity were 81.2% (IC 95% [74–87.1]) and 56.9% (42.2–70.7), respectively. Although the AUC ROC of PaO2/FiO2 24 h after IMV was higher than ΔPaO2/FiO2 24 h, no statistically significant differences were observed between both curves (p = 0.054) (Fig. 2, Table 3).

Multivariable model

In the crude Cox regression analysis, the variables associated with mortality were moderate ARDS (cHR: 2.68, 95% CI [1.49–4.83]) and severe ARDS (cHR: 13.98, 95% CI [5.59-34-93]) at 24 h of IMV, ΔPaO2/FiO2 24 h <109.5 (HRc: 3.70, CI 95% [2.12–6.46]), PaO2/FiO2 24 h after IMV <222.5 (HRc: 3.41, CI 95% [1.88–6.19]).

In the adjusted model, an aHR 3.32 (95% CI [1.87–6.07]) was obtained for ΔPaO2/FiO2 24 h <109.5, an aHR 2.87 (95% CI [1.48–5.57]) for PaO2/FiO2 24 h <222.5 after IMV and an aHR: 2.18 (CI 95% [1.13–4.12]) and aHR: 9.81 (CI 95% [3.43–28.04]) for moderate and severe ARDS after 24 h of IMV, respectively (Table 4).