Postintubation Decline in Oxygen Saturation Index Predicts Mortality in COVID-19: A Retrospective Pilot Study

Background Acute respiratory failure from COVID-19 pneumonia is a major cause of death after SARS-CoV-2 infection. We investigated whether PaO2/FiO2, oxygenation index (OI), SpO2/FiO2, and oxygen saturation index (OSI), commonly used to assess the severity of acute respiratory distress syndrome (ARDS), can predict mortality in mechanically ventilated COVID-19 patients. Methods In this single-centered retrospective pilot study, we enrolled 68 critically ill mechanically ventilated adult patients with confirmed COVID-19. Physiological variables were recorded on the day of intubation (day 0) and postintubation days 3 and 7. The association between physiological parameters, PaO2/FiO2, OI, SpO2/FiO2, and OSI with mortality was assessed using multiple variable logistic regression analysis. Receiver operating characteristic analysis was conducted to evaluate the performance of the predictive models. Results The ARDS severity indices were not statistically different on the day of intubation, suggesting similar baseline conditions in nonsurviving and surviving patients. However, these indices were significantly worse in the nonsurviving as compared to surviving patients on postintubation days 3 and 7. On intubation day 3, PaO2/FiO2 was 101.0 (61.4) in nonsurviving patients vs. 140.2 (109.6) in surviving patients, p=0.004, and on day 7 106.3 (94.2) vs. 178.0 (69.3), p < 0.001. OI was 135.0 (129.7) in nonsurviving vs. 84.8 (86.1) in surviving patients (p=0.003) on day 3 and 150.0 (118.4) vs. 61.5 (46.7) (p < 0.001) on day 7. OSI was 12.0 (11.7) vs. 8.0 (10.0) (p=0.006) on day 3 and 14.7 (13.2) vs. 6.5 (5.4) (p < 0.001) on day 7. Similarly, SpO2/FiO2 was 130 (90) vs. 210 (90) (p=0.003) on day 3 and 130 (90) vs. 230 (50) (p < 0.001) on day 7, while OSI was 12.0 (11.7) vs. 8.0 (10.0) (p=0.006) on day 3 and 14.7 (13.2) vs. 6.5 (5.4) (p < 0.001) on day 7 in the nonsurviving and surviving patients, respectively. All measures were independently associated with hospital mortality, with significantly greater odds ratios observed on day 7. The area under the receiver operating characteristic curve (AUC) for mortality prediction was greatest on intubation day 7 (AUC = 0.775, 0.808, and 0.828 for PaO2/FiO2, OI, SpO2/FiO2, and OSI, respectively). Conclusions Decline in oxygenation indices after intubation is predictive of mortality in COVID-19 patients. This time window is critical to the outcome of these patients and a possible target for future interventions. Future large-scale studies to confirm the prognostic value of the indices in COVID-19 patients are warranted.


Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is known to invade the pulmonary alveolar epithelial cells primarily [1]. While most infected patients have mild to no symptoms, some develop acute hypoxemic respiratory failure that can progress to multiorgan failure and death [2]. Early studies on critically ill patients with coronavirus disease 2019 (COVID-19) revealed long mechanical ventilation times, with one study among New York City patients reporting a median of 18 days and others up to 59 days of mechanical ventilation [3,4]. Even patients with milder form of the disease may require prolonged respiratory support; one study reported an average of 14.6 days of mechanical ventilation in patients who survived COVID-19 pneumonia [4]. It is important to identify patients who are at greatest risk of major complications so that appropriate treatments are provided earlier in the disease process. is will also aid providers in discussing compassionate palliative care and end of life decisions with the patients and their families. As such, a better understanding of the prognosis and course of the severe coronavirus disease 2019 (COVID- 19) is critical for resource allocation and medical management.
An important pathological feature of the lungs obtained on autopsy from patients with COVID-19 is the presence of diffuse alveolar damage and widespread signs of thrombosis, similar to findings in patients with acute respiratory distress syndrome (ARDS) [5,6]. e clinical presentation and respiratory mechanics of COVID-19 pneumonia are also largely comparable to other forms of ARDS, although a less aggressive "normal compliance" type of COVID-19 has been described [7]. Accordingly, clinicians have applied physiological measures of ARDS severity to COVID-19 patients, without any evidence to support their prognostic values. One important example is the ratio of arterial oxygen tension (PaO 2 ) to fraction of inspired oxygen (FiO 2 ), or the PaO 2 /FiO 2 ratio. Besides classifying the severity of ARDS, the PaO 2 /FiO 2 ratio also has prognostic value, being associated with mortality according to the ARDS Definition Task Force [8]. Mild ARDS (PaO 2 /FiO 2 200-300) is associated with 27% mortality, while moderate (PaO 2 /FiO 2 100-200) and severe (PaO 2 /FiO 2 < 100) ARDS are associated with 32% and 45% mortality rates, respectively.
Another physiological index used to stratify the severity of pulmonary dysfunction in ARDS is the product of the mean alveolar pressure (MAP) and the reciprocal of the PaO 2 /FiO 2 ratio, known as oxygenation index (OI) [9,10]. OI has also been validated as an independent predictor of mortality in patients with ARDS [11]. Incorporating MAP into its calculation, the OI has the advantage to also reflect alterations in lung mechanics contributing to lung injury. It is routinely used in the care of adult and pediatric patients [12]. However, both PaO 2 /FiO 2 and OI rely on invasive blood gas analysis. Consequently, oxygenation indices that are based on noninvasive pulse oximetry, namely, the SpO 2 / FiO 2 ratio and oxygen saturation index (OSI), were also examined and subsequently validated [13][14][15]. Due to the noninvasive nature of these measurements, they may be of greater clinical value than their invasive counterparts.
Although the clinical and prognostic values of the above oxygenation indices are well established in ARDS, they have yet not been validated in COVID-19 patients. We conducted a retrospective pilot study to explore the association of OI and OSI with survival in a subgroup of COVID-19 patients with significant lung injury and acute respiratory failure requiring mechanical ventilation. Additionally, studying survivors compared to nonsurvivors, we assessed how oxygenation varied over the first 7 days following intubation to establish the value of PaO 2 /FiO 2 , OI, SpO 2 /FiO 2, and OSI as early predictors of outcome. We hypothesized that oxygenation indices are better in COVID-19 survivors as compared to nonsurvivors upon intubation and will continue to improve as patients progressively recover.

Study Design and Population.
e study was conducted at the Boston Medical Center, the largest safety-net hospital in Boston and a level 1 academic trauma center. e study protocol was approved by the Boston Medical Center Institutional Review Board. e requirement for written informed consent was waived given the retrospective nature of the study. All consecutive adult patients with confirmed COVID-19 infection who were admitted to the medical and surgical intensive care units between 3/1/2020 and 6/30/2020 for acute hypoxemic respiratory failure and required mechanical ventilation were enrolled in the study. Patients who were admitted for reasons other than respiratory failure were excluded. Patients who were discharged to another facility, and for whom the primary outcome (survivor vs nonsurvivor) was unknown, were also excluded. We defined day 0 as the day of intubation and initiation of mechanical ventilation.
All patients met the Berlin criteria for ARDS and were treated according to a standard institution-wide, lungprotective ventilation protocol. Specifically, mechanical ventilation was managed by the clinical team of intensivists and respiratory therapists according to the ARDSnet recommendations for titration of PEEP/FiO 2 and to maintain a plateau pressure of <30 cm H 2 O. Contemporary national guidelines were followed for the management of COVID-19. It included empiric antibiotic treatment with azithromycin, administration of hydroxychloroquine, and immunomodulation with the interleukin-6 receptor inhibitor tocilizumab, interleukin-1 receptor antagonist anakinra, the antiviral agent remdesivir, and anticoagulation, when appropriate. Prone positioning, neuromuscular blocking agents, and inhaled nitric oxide were also employed at the discretion of the treating clinicians.

Data Collection.
Demographic data, medical history, preadmission medications, and diagnoses were extracted from each enrolled patient's electronic medical record. Clinical data were also extracted from the electronic medical records until extubation or death, whichever occurred first. Data included patients' vital signs, laboratory parameters, and clinical imaging including chest X-rays. Ventilator settings and arterial blood gas (ABG) parameters were recorded at a daily reference time of approximately 18:00. Special attention was paid to avoiding data collection within 30 minutes of respiratory interventions including suctioning of the endotracheal tube, recruitment maneuvers, bronchoscopies, and acute changes in ventilator settings. Calculated variables included the Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) score, Charlson Comorbidity Index (CCI), respiratory compliance (Crs), PaO 2 /FiO 2 , SpO 2 /FiO 2 , OI, and OSI. OI was calculated as (mean airway pressure × FiO 2 × 100)/PaO 2 , and OSI was calculated as (mean airway pressure × FiO 2 × 100)/SpO 2 . Higher OI and OSI values indicate worse oxygenation [11]. Anonymized records were entered into a secure cloud-based data entry online platform (StudyTRAX, Macon, GA) and subsequently extracted for analysis.

Statistical Analysis.
e primary outcome variable was death before hospital discharge; therefore, all patients were categorized as survivors or nonsurvivors and followed until death or hospital discharge. Because this was a pilot study, a sample size sufficient to assess the feasibility of the retrospective methods was required as opposed to the global COVID-19 patients. Categorical variables were presented as counts and percentages. Continuous variables were presented as mean ± standard deviation (SD) or median with interquartile range (IQR) and compared between groups (survivors vs nonsurvivors) using t-tests or Mann-Whitney U/log-rank tests, respectively. Categorical variables were presented as proportions and compared between groups using chi-squared tests. Independent-samples Kruskal-Wallis test was used to compare the distribution of Crs, PaO 2 /FiO 2 , SpO 2 /FiO 2 , OI, and OSI in surviving and nonsurviving patients, with the Bonferroni correction to preserve the overall type I error at 0.05.
Related-samples Wilcoxon signed rank test was used to compare change in respiratory indices over time. Multivariable logistic regression modeling was used to assess the association between Crs, PaO 2 /FiO 2 , SpO 2 /FiO 2 , OI, and OSI on postintubation days 0, 3, and 7 and in-hospital mortality, adjusting for age, CCI, and sex. Receiver operating characteristic curves were used to analyze prognostic value for mortality for PaO 2 /FiO 2 , SpO 2 /FiO 2 , OI, and OSI on days 0, 3, and 7. Statistical analyses were completed using SPSS Statistics 26 (IBM Corporation, Chicago, IL), SAS (SAS Institute, Cary, NC), and a two-sided significance level of <0.05 was used for statistical inference.

Results
A total of 498 patients with confirmed COVID-19 pneumonia were admitted to our hospital between March 1, 2020, and June 30, 2020, of whom 119 required ICU admission and 68 met inclusion criteria for this study ( Figure 1 irty-two (47%) patients were successfully extubated and discharged from the hospital, while 36 (53%) expired within 17 [IQR 9] days after hospital admission.
Demographic characteristics and clinical data for each group of patients are summarized in Table 1. Most patients had a variety of comorbid conditions, with the common diagnoses being diabetes mellitus (39% in survivors and 74% in nonsurvivors), coronary artery disease with a history of myocardial infarction (3% in survivors and 28.6% in nonsurvivors), congestive heart failure (12.1% in survivors and 25.7% in nonsurvivors), and cerebrovascular disease and chronic obstructive pulmonary disease. Advanced age, CCI score, history of MI, and preexisting diabetes were associated with an increased risk of mortality, while other clinical characteristics on ICU admission were not. Average ICU length of stay was 13.7 (7.7) in survivors and 15.8 (8.5) in nonsurvivors (p � 0.365) and hospital length of stay was 21.6 (10.2) and 16.9 (8.7), p � 0.086, respectively.
Crs, PaO 2 /FiO 2 , SpO 2 /FiO 2 , OI, and OSI were not significantly different between survivors and nonsurvivors on the day of intubation or day 0 ( Table 2) On postintubation day 3, the Crs and PaO 2 /FiO 2 and SpO 2 /FiO 2 were higher and OI and OSI were lower in survivors as compared to nonsurvivors (Table 2). e group difference in these pulmonary variables was even greater on day 7 (p � 0.007 for Crs and <0.001 for all oxygenation indices), with markedly better (lower) OI and OSI in the survivors as compared to nonsurvivors.
In a multivariate logistic regression model, Crs, PaO 2 / FiO 2 , SpO 2 /FiO 2 , OI, and OSI on intubation days 3 and 7, respectively, were associated with death when adjusted for age, CCI score, and sex ( We tested the individual performance of OI, OSI, PaO 2 / FiO 2 , and SpO 2 /FiO 2 on intubation days 0, 3, and 7 to predict hospital mortality by calculating the AUC of the receiver operating characteristic curves (Figure 2 and Table 4). While all indices had only moderate performance for mortality prediction on the intubation day (AUC ranging from 0.544 and 0.605), they were significant predictors of Critical Care Research and Practice mortality on postintubation days 3 and 7 with excellent performance of both the arterial blood gas-dependent variables and the noninvasive pulse oximeter-derived indices: AUC was 0.684 (95% CI: 0.546-0.822) and 0.808 (95% CI: 0.697-0.919) on days 3 and 7 for OI and 0.655 (95% CI: 0.514-0.797) and 0.828 (95% CI: 0.724-0.932) for OSI. Given the report of a better performance of OI and OSI in young patients, we also analyzed the receiver operating characteristic (ROC) curve for patients younger than 60 years of age to determine if discrimination was improved. Although the analysis was limited by the lower number of these patients, the AUC of the ROC curves were even better in this group of younger patients: AUC for OI was 0.802 (95% CI: 0.604-1.000) and 1.000 (95% CI: 1.000-1.000) and for OSI 0.733 (95% CI: 0.517-0.949) and 1.000 (95% CI: 1.000-1.000) on days 3 and 7, respectively.

Discussion
In this retrospective observational pilot study of 68 critically ill patients with confirmed COVID-19 pneumonia, we present evidence to suggest that PaO 2 /FiO 2, SpO 2 /FiO 2 , OI, and OSI can serve as predictors of mortality after intubation. While difference in oxygenation was marginal and did not reach clinical or statistical significance on the day of intubation, suggesting comparable baseline characteristics in survivors and nonsurvivors, survivors rapidly distinguished themselves with a higher PaO 2 /FiO 2 and SpO 2 /FiO 2 and lower OI and OSI within 3 days. Lung compliance followed the same trend and was significantly higher in survivors on days 3 and 7 with no significant difference between the two groups on day 0.

e Importance of Prognostication in the Critically Ill COVID-19 Patients.
In patients with COVID-19 infection, it is particularly difficult to provide accurate prognostic information, as the case fatality rate has been quite variable ranging from 0.7% in Germany to about 10% in Italy [16]. Decisions about goals of care and life-sustaining treatments are made by incorporating available medical and prognostic data with the preferences of each patient and his or her surrogate. is process depends on the clinician's ability to provide understandable and accurate prognostic information. Existing mortality data must be considered for each specific condition and appropriately applied to the individual patient. Mortality rates between 24% and 67% have been reported in patients requiring hospital admission [17,18]. COVID-19 patients who require ICU admission and intubation have a particularly high mortality rate, but besides preexisting risk factors such as age, cardiovascular disease, diabetes, and COPD, no clinical prognostic tools have been validated for identifying those at greater risk of death [19,20]. e findings reported herein confirm the prognostic value of PaO 2 /FiO 2 and OI in these patients and can therefore serve as an important tool to guide therapeutic management and goals of care discussions and decisionmaking conversations for COVID- 19   respiratory failure. However, clinicians should consider the dynamic nature of the oxygenation indices, and the need to wait at least 3 days after intubation for a more reliable prognostication. ese metrics can then serve as additional data points to inform resource allocation in crisis scenarios when access to therapeutic measures is limited or the number of critically ill COVID-19 patients overwhelms the hospitals and health providers.

e Importance of Respiratory Mechanics.
Although previous studies have established the importance of oxygenation indices and lung mechanics in patients with ARDS, these important findings have not been validated in COVID-19 patients. e Berlin definition of ARDS uses the PaO 2 / FiO 2 ratio as the primary measure of ARDS severity, but some studies have failed to validate it as an independent predictor of mortality [21,22]. It is argued that the outcome in ARDS is affected not only by the degree of oxygenation impairment but also by the mechanical properties of the lungs and the impact of ventilator-induced lung injury (VILI). Integrating both airway pressure and oxygenation into a single index, OI and OSI, might be more powerful predictors of death in ARDS patients [23,24]. is is of particular importance in COVID-19 pneumonia, given the reported heterogeneity in Crs [7], and respiratory mechanics were therefore expected to have an even greater prognostic relevance. Nevertheless, our results showed that, despite differences in compliance between survivors and nonsurvivors on intubation days 3 and 7, PaO 2 /FiO 2 and SpO 2 / FiO 2 remain as powerful as OI and OSI in predicting mortality, possibly suggesting that the primary determinant of mortality is the degree of oxygenation impairment as opposed to respiratory mechanics.

Temporal Evolution of Oxygenation Indices in Intubated COVID-19 Patients.
As stated earlier, we were surprised to find that despite differences in baseline clinical characteristics, the ARDS indices (PaO 2 /FiO 2 , OI, and OSI) did not significantly differ between survivors and nonsurvivors on intubation day 0. ese findings differ from previous studies of the oxygenation indices, which reported their prognostic power at the time of ARDS diagnosis [15,25]. It is plausible that, given the initially comparable oxygenation indices in our COVID-19 patients, the pulmonary disease burden may not have been significantly different between the survivor and nonsurvivor groups at the time of intubation. However, over the course of only three days, nonsurvivors were clearly distinguished with significantly worse oxygenation indices as compared to survivors, suggesting significant progression in their pulmonary disease and lung injury. It is of course impossible to determine the cause of the observed divergence in disease progression, but this finding may indicate a time window that is critical to the outcome of intubated COVID-19 patients and potentially a target for future interventions.

e Simplicity of Noninvasive Pulse Oximetry for Assessment of the ARDS Severity.
e importance of a continuous assessment of oxygenation is well recognized. Still, it is often limited to recording oxygen saturation or intermittently reviewing blood gas parameters, both of which are critically dependent on the fraction of inspired oxygen. By calculating the PaO 2 /FiO 2 and SpO 2 /FiO 2 ratios as well as the oxygenation and oxygen saturation indices, our study extends the role of such physiological indices as relevant estimates of disease severity. Also, it validates these measurements as valuable prognostic tools in critically ill COVID-19 patients. Importantly, we show that noninvasive measures, such as SpO 2 /FiO 2 and OSI, derived from pulse oximetry, are equally predictive of outcome when compared to those obtained from arterial blood gas values.

Critical Care Research and Practice
Moreover, SpO 2 /FiO 2 is as powerful a predictor as OSI, obviating the need to routinely incorporate pulmonary mechanics in the assessment of the severity of respiratory failure in COVID-19 patients. e effects of therapeutic interventions, as well as prognostication and identification of patients who will benefit the most from continued mechanical ventilation and ICU care, can all be guided by a simple calculation of the SpO 2 /FiO 2 .

Use of SpO 2 /FiO 2 to Guide
erapeutic Approach to Intubated COVID-19 Patients. While the pathophysiology of ARDS has been extensively studied, its treatment is currently mostly based on supportive intensive care and prevention of VILI. Mortality from the disease ranges from 30 to 60% [11]. e COVID-19-related lung injury is no exception being, at best, only marginally controlled by the currently accepted standard treatments, including antibiotic, antiviral, and immunomodulatory agents. Lung-protective ventilation using small tidal volumes with permissive hypercapnia remains the cornerstone of ARDS management, as it facilitates the goal of minimizing VILI. Lung recruitment strategies, careful optimization of the positive end expiratory pressure (PEEP), pulmonary vasodilators, and prone positioning are also employed to optimize ventilation distribution as well as ventilationperfusion matching in COVID-19 patients [26]. Evidence to support novel antiviral and anti-inflammatory therapies continues to evolve, as does the data on convalescent plasma, immune globulin, and monoclonal antibodies. e therapeutic and respiratory effects of these treatments might be guided by their impact on pulmonary compliance and oxygenation indices, including a simple calculation of SpO 2 /FiO 2 .

Strengths and Limitations of the Study.
e strengths of this study include the unique burden of COVID-19 in the

Conclusions
Our study validates the prognostic power of the oxygenation indices PaO 2 /FiO 2 , SpO 2 /FiO 2 , OI, and OSI in severely ill COVID-19 patients. Early calculation of these simple metrics can help predict the clinical course of the patient's disease, assist in prognostication, and guide therapeutic interventions.

Data Availability
e patient data used to support the findings of this study are restricted by the BMC and MGH Institutional Review Boards in order to protect patient privacy. Data are available from Drs. Nozari or Pinciroli for researchers who meet the criteria for access to confidential data.

Ethical Approval
is hospital registry study was approved by the Institutional Review Board at Boston Medical Center.

Consent
Consent was waived.

Conflicts of Interest
e authors declare that they have no conflicts of interest.

Authors' Contributions
SM and MV contributed to conception and design, data collection, analysis of data, and writing and revision of the manuscript. AG contributed to analysis of data, revision of the manuscript, and statistical expertise. AP and NF contributed to data collection and revision of the manuscript. RC, GR, RP, AN, and SQ contributed to analysis of data and revision of the manuscript. RO contributed to analysis of data and revision of the manuscript and provided administrative support. AN contributed to conception and design, analysis of data, writing and revision of the manuscript, and supervision.