Abstract
Aim
Coronavirus disease (COVID‐19) spread worldwide, and was declared as a pandemic by the World Health Organization. Despite numerous studies in the last few years, the factors associated with the outcomes of patients with COVID‐19 requiring mechanical ventilation remain unclear. The prediction of ventilator weaning and mortality using the data obtained at the time of intubation could be beneficial for establishing appropriate treatment strategies and obtaining informed consent. In this study, we aimed to clarify the association between patient information at the time of intubation and the outcomes of intubated COVID‐19 patients.
Methods
This retrospective observational study used single‐center data from patients with COVID‐19. Patients with COVID‐19 who were admitted to Osaka Metropolitan University Hospital from April 1, 2020, to March 31, 2022, and under mechanical ventilation were included. The main outcome was defined as the factors related to ventilator weaning; a multivariate analysis was carried out to evaluate the association between patient information at the time of intubation and the outcome.
Results
In total, 146 patients were included in this study. The factors significantly associated with ventilator weaning were age (65–74 years old, adjusted odds ratio [OR], 0.168; 75 years and older, adjusted OR, 0.121), vaccination history (adjusted OR, 5.655), and Sequential Organ Failure Assessment (SOFA) respiration score (adjusted OR, 0.007) at the time of intubation.
Conclusion
Age, SOFA respiration score, and COVID‐19 vaccination history at the time of intubation could be associated with outcomes in patients with COVID‐19 requiring mechanical ventilation.
Keywords: COVID‐19, mechanical ventilation, prognostic factor, ventilator weaning
Short abstract
We performed a retrospective observational study used the single‐center data from patients with severe COVID‐19 requiring mechanical ventilation. Age, SOFA respiratory score, and COVID‐19 vaccination history at the time of intubation may be associated with outcomes in patients with COVID‐19 requiring mechanical ventilation.
INTRODUCTION
Coronavirus disease (COVID‐19) was declared as a pandemic on March 11, 2020 by the World Health Organization (WHO). 1 On December 2022, the WHO reported that the cumulative number of COVID‐19 cases had exceeded 600 million, and the cumulative number of deaths had exceeded 6 million. 2 In Japan, more than 20 million people have been infected, and more than 50,000 deaths were reported. 3 Although the number of COVID‐19 cases has shown a steady decline since the start of 2023, there is still a possibility of future increases. It is crucial that we maintain vigilance and address the disease with continued caution.
Coronavirus disease can be complicated by acute respiratory dysfunction syndrome, which can lead to respiratory failure requiring mechanical ventilation. In addition, it can induce excessive inflammatory reactions throughout the body, damage the vascular endothelial cells, cause thrombosis in the lungs, heart, kidneys, and brain, and lead to multiple organ failure, thus increasing the severity of infection. 4
Recently, numerous factors have been reported to be associated with COVID‐19 outcomes. Previous studies reported a strong relationship between history of chronic respiratory disease, 5 history of chronic kidney disease, 6 coronary risk factors such as age, obesity, history of smoking, history of hypertension, and history of diabetes, and poor outcomes. 7 A history of vaccination against COVID‐19 might also influence the outcome. 8
Drugs such as steroids, 9 remdesivir, 10 baricitinib, 11 and molnupiravir 12 have been associated with favorable outcomes among patients treated for COVID‐19. In addition, many cases of COVID‐19‐associated coagulopathy have been reported, 13 and antithrombotic drugs are often given in those with severe cases. These drugs are commonly used in many COVID‐19 treatment facilities in Japan, including our hospital.
As described above, various factors could be related to the outcomes of COVID‐19; however, most of the recommendations are based on the results of low‐grade studies. In addition, only a few studies have examined the relationship between patient information at the time of intubation and outcomes of those with severe COVID‐19 cases. 14 This study aimed to clarify the association between patient information at the time of intubation and outcomes of intubated COVID‐19 patients. The prediction of outcomes using the information collected at the time of intubation will help determine the possibility of achieving successful weaning from mechanical ventilation and the survival status at the time of intubation, which might be beneficial for establishing appropriate treatment plans, such as early tracheostomy and information sharing.
METHODS
Study design, study participants, eligibility, and setting
This retrospective observational study was undertaken at a single center in Japan. We included patients with COVID‐19 who were intubated and treated at Osaka Metropolitan University Hospital. This study cohort did not include patients who were intubated for illnesses other than COVID‐19. Intubation was indicated among patients who experienced dyspnea after receiving 5 L/min of oxygen. Patients admitted to our hospital between April 1, 2020 and March 31, 2022 were included. We excluded those with missing data on the day of intubation, who experienced cardiopulmonary arrest upon arrival, or whose life‐prolonging treatment was discontinued on the day of visit. We extracted the following data from the medical records, which could potentially influence the outcomes of COVID‐19 (see “Data collection”), and carried out a univariate analysis using these variables. For the multivariate analysis, we included variables that showed significant differences in the univariate analysis, as well as variables that have been reported to be associated with outcomes in previous studies. The study results were reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology statement. 15 An opt‐out method was used on the website to obtain patient consent. This study was carried out with the approval of the Osaka Metropolitan University Hospital Ethics Review Committee (2022–140).
Treatment for COVID‐19
Corticosteroids (methylprednisolone or dexamethasone), remdesivir, tocilizumab, baricitinib, molnupiravir, and antithrombotic drugs (low‐molecular‐weight or unfractionated heparin) were used for the treatment of COVID‐19. None of the patients who received molnupiravir underwent intubation and were excluded from the study. As COVID‐19 can be complicated by bacterial pneumonia, antibacterial drugs (mainly ceftriaxone) were concomitantly administered from the start of COVID‐19 treatment in all patients.
Data collection
Data were collected at the initiation of mechanical ventilation. The collected data were patients' baseline information (age, categorized into three groups: <65 , 65–74, and ≥75 years, sex, body mass index [BMI] above 30 kg/m2, 16 ethnicity, smoking history, and COVID‐19 vaccination history), medical history (diabetes, cardiovascular diseases including hypertension, chronic respiratory disease [asthma, chronic obstructive pulmonary disease, and interstitial pneumonia], chronic renal failure, end‐stage renal disease [requiring dialysis or kidney transplant], hematopoietic disease, malignant tumor, and history of chemotherapy in the last 12 months), hemoglobin A1c level on the day of intubation, Sequential Organ Failure Assessment (SOFA) scores on the day of intubation (respiration, coagulation, liver, cardiovascular, central nervous system, and renal scores), drugs given (steroids [methylprednisolone or dexamethasone], remdesivir, tocilizumab, baricitinib, molnupiravir, and antithrombotic agents e.g., unfractionated heparin, low‐molecular‐weight heparin, and nafamostat), and patient outcomes (ventilator weaning, mortality, and ventilator‐free days within 14 days after intubation).
Outcome
The factors related to ventilator weaning at our hospital were assigned as the primary outcome. The factors associated with mortality and ventilator‐free days within 14 days after intubation were assigned as the secondary outcomes. Successful weaning from the ventilator was regarded as a “favorable outcome,” while other cases were regarded as “poor outcomes.” We defined “ventilator weaning” as a combination of “extubation” and “removal of the mechanical ventilator from the tracheostomy tube”. There were no specific criteria for ventilator weaning; this decision was left to the discretion of the attending physician. If the mechanical ventilator was reattached to the tracheostomy tube within 72 h after removal, or if reintubation occurred within 72 h after extubation, the weaning was considered invalid.
Statistical analyses
For the statistical analysis of the two groups, Student's t‐test was used for normally distributed data and Mann–Whitney's U‐test for nonnormally distributed data. The normally distributed values were expressed as mean (standard deviation), while the nonnormally distributed values were expressed as median (first quartile–third quartile). Pearson's χ2‐test or Fisher's exact test was used to analyze the proportions. The relationship between the dependent and independent variables was assessed using logistic and linear regression analyses (both forced‐entry methods). The results of the logistic regression analysis were expressed as adjusted odds ratios (ORs), 95% confidence interval (CIs), and p values. The results of the linear regression analysis are expressed as beta, t, 95% CIs, and p values. All statistical analyses were undertaken using SPSS version 25.0 (IBM Corp). All tests were two‐tailed, and a p value of less than 0.05 was considered significant.
RESULTS
Flowchart of patient selection process
A flowchart of the patient selection process is shown in Figure 1. A total of 163 patients with COVID‐19 were included in this study. We excluded 10 patients with missing data, 6 patients who experienced cardiopulmonary arrest upon arrival, and 1 patient whose life‐prolonging treatment was discontinued on the day of visit. The number of eligible patients was 146; among them, 98 patients had a favorable outcome, while 48 patients had a poor outcome.
FIGURE 1.
One hundred sixty‐three patients with COVID‐19 were included in this study. We excluded 10 patients with missing data, 6 patients who experienced cardiopulmonary arrest upon arrival, and 1 patient whose life‐prolonging treatment was discontinued on the day of visit. The number of eligible patients was 146; among them, 98 patients had a favorable outcome, while 48 patients had a poor outcome.
Patients' characteristics
Table 1 shows the characteristics of the patients with COVID‐19 who were admitted and intubated in our hospital. Significant differences were observed between favorable and poor outcomes in terms of age, cardiovascular diseases including hypertension, SOFA respiration, renal scores, and treatment with baricitinib. A total of 113 patients were discharged from our hospital alive, while 33 died. The median number of ventilator‐free days within 14 days after intubation was 3.
TABLE 1.
Baseline characteristics of patients with COVID‐19 at the time of intubation and outcomes.
| Total | Favorable outcome | Poor outcome | p value | |||||
|---|---|---|---|---|---|---|---|---|
| (n = 146) | (n = 98) | (n = 48) | ||||||
| Age, years | Median (IQR) | 63 | (55–74) | 58 | (53–70) | 73 | (64–79) | <0.001 |
| <65 | n (%) | 77 | (52.7) | 65 | (66.3) | 12 | (25.0) | <0.001 |
| 65–74 | n (%) | 35 | (24.0) | 19 | (19.4) | 16 | (33.3) | 0.064 |
| ≥75 | n (%) | 34 | (23.3) | 14 | (14.3) | 20 | (41.7) | <0.001 |
| Male | n (%) | 123 | (84.2) | 85 | (86.7) | 38 | (79.2) | 0.238 |
| Body mass index | Median (IQR) | 24 | (22.0–27.4) | 24.4 | (22.3–27.9) | 23.5 | (21.5–27.1) | 0.420 |
| ≥30 | n (%) | 26 | (17.8) | 17 | (17.3) | 9 | (18.8) | 0.835 |
| Ethnicity | ||||||||
| Japanese | n (%) | 145 | (99.3) | 98 | (100.0) | 47 | (97.9) | 0.329 |
| Others | n (%) | 1 | (0.7) | 0 | (0.0) | 1 | (2.1) | 0.329 |
| Smoking history | n (%) | 41 | (28.1) | 26 | (26.5) | 15 | (31.3) | 0.551 |
| Vaccination history | n (%) | 16 | (11.0) | 13 | (13.3) | 3 | (6.3) | 0.145 |
| Medical history | ||||||||
| Diabetes mellitus | n (%) | 47 | (32.2) | 35 | (35.7) | 12 | (25.0) | 0.193 |
| Cardiovascular diseases including hypertension | n (%) | 83 | (56.8) | 50 | (51.0) | 33 | (68.8) | 0.042 |
| Chronic respiratory disease | n (%) | 22 | (15.1) | 14 | (14.3) | 8 | (16.7) | 0.706 |
| Chronic kidney disease | n (%) | 25 | (17.1) | 13 | (13.3) | 12 | (25.0) | 0.077 |
| End‐stage kidney disease a | n (%) | 12 | (8.2) | 7 | (7.1) | 5 | (10.4) | 0.543 |
| Hematopoietic disease | n (%) | 5 | (3.4) | 3 | (3.1) | 2 | (4.2) | 0.664 |
| Malignant neoplasm | n (%) | 15 | (10.3) | 9 | (9.2) | 6 | (12.5) | 0.535 |
| Receiving chemotherapy in the last 12 months | n (%) | 2 | (1.4) | 1 | (1.0) | 1 | (2.1) | 0.551 |
| SOFA score | ||||||||
| Respiration | Median (IQR) | 2 | (2–3) | 2 | (1–3) | 3 | (2–3) | <0.001 |
| Coagulation | Median (IQR) | 0 | (0–1) | 0 | (0–1) | 0 | (0–0) | 0.159 |
| Liver | Median (IQR) | 0 | (0–0) | 0 | (0–0) | 0 | (0–0) | 0.094 |
| Cardiovascular | Median (IQR) | 0 | (0–0) | 0 | (0–0) | 0 | (0–0) | 0.153 |
| Central nervous system | Median (IQR) | 0 | (0–0) | 0 | (0–0) | 0 | (0–0) | 0.306 |
| Renal | Median (IQR) | 0 | (0–1) | 0 | (0–0) | 0 | (0–1) | 0.020 |
| Laboratory data | ||||||||
| HbA1c (%) | Median (IQR) | 6.2 | (5.8–7.2) | 6.3 | (5.8–7.3) | 6.2 | (5.9–7.0) | 0.663 |
| Therapeutic drug | ||||||||
| Steroid | n (%) | 143 | (97.9) | 96 | (98.0) | 47 | (97.9) | 1.000 |
| Remdesivir | n (%) | 124 | (84.9) | 87 | (88.8) | 37 | (77.1) | 0.064 |
| Tocilizumab | n (%) | 16 | (11.0) | 9 | (9.2) | 7 | (14.6) | 0.327 |
| Balicitinib | n (%) | 45 | (30.8) | 37 | (37.8) | 8 | (16.7) | 0.010 |
| Molnupiravir | n (%) | 0 | (0.0) | 0 | (0.0) | 0 | (0.0) | N/A c |
| Antithrombotic drug | n (%) | 141 | (96.6) | 96 | (98.0) | 45 | (93.8) | 0.598 |
| Outcome | ||||||||
| Weaning of mechanical ventilation | n (%) | 98 | (67.1) | 98 | (100.0) | 0 | (0.0) | |
| Mortality | n (%) | 33 | (22.6) | 0 | (0.0) | 33 | (68.8) | |
| Ventilator‐free days within 14 days after intubation | Median (IQR) | 3 | (0–8) | 7 | (3–9) | 0 | (0–0) | |
Abbreviations: HbA1c, hemoglobin A1C; N/A, not applicable; SOFA, Sequential Organ Failure Assessment.
aRequiring hemodialysis or kidney transplantation.
Primary outcome
We examined the factors associated with weaning from mechanical ventilation using a multivariate logistic regression model (Table 2). In addition to age and male sex, existing cardiovascular diseases including hypertension, SOFA respiration scores, and renal scores at intubation were used as independent variables as they were significantly different in univariate analyses (Table 1), while BMI, vaccination history, and existing chronic kidney disease were used as independent variables; these variables were suggested to be associated with the outcomes in previous studies, as mentioned in the introduction. In this study, age, vaccination history, and SOFA respiration score were significantly associated with ventilator weaning.
TABLE 2.
Multivariate regression analysis of factors associated with weaning of patients with COVID‐19 from mechanical ventilation.
| Variable | Adjusted OR | 95% CI | p value |
|---|---|---|---|
| Age, years | |||
| <65 | 1.000 | (reference) | |
| 65–74 | 0.168 | 0.060–0.476 | 0.001 |
| ≥75 | 0.121 | 0.039–0.372 | <0.001 |
| Male | 1.279 | 0.427–3.832 | 0.661 |
| BMI ≥ 30 | 0.849 | 0.276–2.607 | 0.774 |
| Vaccination history | 5.655 | 1.030–31.054 | 0.046 |
| Existing CVD including hypertension | 1.086 | 0.437–2.701 | 0.859 |
| Existing CKD | 1.172 | 0.281–4.890 | 0.827 |
| SOFA respiration score on intubation | 0.007 | 0.337–0.839 | 0.007 |
| SOFA renal score on intubation | 0.708 | 0.444–1.130 | 0.148 |
Note: The forced‐entry method was adopted as the variable imputation method for multivariate analysis. The p value for the analytical model was <0.001. Hosmer–Lemeshow test: p = 0.088; the model predictive value was 67.1%.
Abbreviations; BMI, body mass index; CI, confidence interval; CKD, chronic kidney disease; CVD, cardiovascular disease; OR, odds ratio; SOFA, Sequential Organ Failure Assessment.
Secondary outcome
We examined the factors associated with mortality and ventilator‐free days within 14 days after intubation using multiple logistic regression and multiple linear regression models. The same primary outcome variables were used as independent variables. Age and SOFA respiration score were associated with mortality (Table 3). Higher age group and respiration and renal SOFA scores were significantly associated with a decreased number of ventilator‐free days. Vaccination history was associated with increased number of ventilator‐free days (Table 4).
TABLE 3.
Multivariate regression analysis of factors associated with mortality among patients with COVID‐19 requiring mechanical ventilation.
| Variable | Adjusted OR | 95% CI | p value |
|---|---|---|---|
| Age, years | |||
| <65 | 1.000 | (reference) | |
| 65–74 | 5.405 | 1.643–17.786 | 0.005 |
| ≥75 | 6.531 | 1.884–22.637 | 0.003 |
| Male | 0.775 | 0.246–2.443 | 0.664 |
| BMI ≥ 30 | 1.813 | 0.552–5.947 | 0.326 |
| Vaccination history | 0.404 | 0.070–2.342 | 0.312 |
| Existing CVD including hypertension | 0.962 | 0.351–2.633 | 0.940 |
| Existing CKD | 0.614 | 0.133–2.828 | 0.532 |
| SOFA respiration score on intubation | 2.384 | 1.362–4.173 | 0.002 |
| SOFA renal score on intubation | 1.491 | 0.929–2.394 | 0.098 |
Note: The forced‐entry method was adopted as the variable imputation method for multivariate analysis. The p value for the analytical model was <0.001. Hosmer–Lemeshow test: p = 0.290; the model predictive value was 77.4%.
Abbreviations: BMI, body mass index; CI, confidence interval; CKD, chronic kidney disease; CVD, cardiovascular disease; OR, odds ratio; SOFA, Sequential Organ Failure Assessment.
TABLE 4.
Multivariate regression of factors associated with ventilation‐free days within 14 days of intubation of patients with COVID‐19.
| Variable | Beta | t | 95% CI | p value |
|---|---|---|---|---|
| Age, years | ||||
| <65 | (reference) | |||
| 65–74 | −2.493 | −3.468 | −3.915 to −1.071 | 0.001 |
| ≥75 | −2.449 | −3.181 | −3.972 to −0.927 | 0.002 |
| Male | −0.717 | −0.906 | −2.282–0.848 | 0.366 |
| BMI ≥ 30 | 0.426 | 0.541 | −1.131–1.983 | 0.589 |
| Vaccination history | 2.175 | 2.296 | 0.302–4.047 | 0.023 |
| Existing CVD including hypertension | −1.104 | −1.778 | −2.333–0.124 | 0.078 |
| Existing CKD | 0.538 | 0.521 | −1.503–2.578 | 0.603 |
| SOFA respiration score on intubation | −1.027 | −0.253 | −1.620 to −0.435 | 0.001 |
| SOFA renal score on intubation | −0.803 | −0.224 | −1.482 to −0.124 | 0.021 |
Note: The forced‐entry method was adopted as the variable imputation method for multivariate analysis. The p value of the regression equation was <0.001. R, 0.572; R 2, 0.327; adjusted R 2, 0.282.
Abbreviations: BMI, body mass index; CI, confidence interval; CKD, chronic kidney disease; CVD, cardiovascular disease; SOFA, Sequential Organ Failure Assessment.
DISCUSSION
In this study, we examined the association between information at the time of intubation and outcomes of patients with COVID‐19 requiring mechanical ventilation using multivariate analysis and found significant associations between outcomes of age, vaccination history, and SOFA respiration score.
Previous studies have suggested a relationship between age, respiratory status at the time of intubation, and the outcome of COVID‐19. 17 , 18 Additionally, this study found a significant association between COVID‐19 vaccination history and COVID‐19 outcomes in patients requiring mechanical ventilation. A meta‐analysis reported that a history of COVID‐19 vaccination was associated with the reduction in COVID‐19 exacerbation and mortality. 19 Our study showed that COVID‐19 vaccination can inhibit the progression of COVID‐19 after the initiation of mechanical ventilation.
This study showed a significant association between renal function at the time of intubation and ventilator‐free days within 14 days after intubation. During the PubMed database search, we were unable to find studies that examined the association between the outcomes of COVID‐19 requiring mechanical ventilation and renal function on the day of intubation. The pathogenesis of kidney injury caused by COVID‐19 can be explained by the following two possible mechanisms: ischemia of the kidney due to thrombogenesis 4 and entry of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) into the body. The SARS‐CoV‐2 virus enters the body through the angiotensin converting enzyme‐2 (ACE2) receptor. The lungs and proximal renal tubules express high levels of ACE2 receptors. 20 In patients with COVID‐19, SARS‐CoV‐2 fragments were detected in the urine within 2–3 weeks after infection, 20 and histological changes in ACE2 receptors in the proximal tubules and podocytes were reported. 20 , 21 , 22 The SARS‐CoV‐2 virus could directly cause renal damage. 22 A previous study undertaken by the European Renal Association–European Dialysis and Transplantation Association showed that a history of chronic kidney disease might affect the outcome of patients with severe COVID‐19. 6 However, the medical history of chronic kidney disease did not have a significant association with ventilator‐free days in this study. The existence of acute kidney injury as a comorbidity in patients with COVID‐19 might reflect the intensity of the infection. The occurrence of acute kidney injury could have exacerbated the outcome.
Although this was a single‐center study in Japan, the variables related to the outcomes were not significantly different from those reported in other countries. No correlation was observed between obesity and cardiovascular disease in this study, which have been associated with outcomes in previous studies. 6 Racial differences and medications, as well as the lack of cases, might have influenced our results. If a larger number of cases were included, it might be possible to identify the accurate factors associated with the outcomes.
As most of the participants in this study were Japanese, it is difficult to generalize these results to other countries in terms of race and treatment policies. However, our results can be possibly generalized to medical institutions managing patients with COVID‐19 requiring mechanical ventilation in Japan.
Limitations
This study has some limitations. First, we did not discuss the different variants of SARS‐CoV‐2, the type and number of times that COVID‐19 vaccination was given, or the interval between vaccination and the onset of COVID‐19. Second, the patients’ treatments were not sufficiently recorded until they were admitted to our hospital. Third, we were unable to monitor the subsequent outcomes of the patients who were transferred to our hospital. Fourth, a significant but unadjustable difference was observed between favorable and poor outcomes associated with the use of baricitinib. Finally, as this was an observational study, confounding factors could have existed.
CONCLUSION
Age, SOFA respiration score, and COVID‐19 vaccination history at the time of intubation could be associated with outcomes in patients with COVID‐19 requiring mechanical ventilation.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.
ETHICS STATEMENT
Approval of the research protocol: This study was approved by the Institutional Review Board of Osaka Metropolitan University Hospital (approval number: 2022–140).
Informed consent: We applied an opt‐out method on the website to obtain patient consent.
Registry and registration no. of the study/trial: N/A.
Animal studies: N/A.
ACKNOWLEDGMENTS
We thank Mari Shimokawa for her support in contributing to the acquisition of the data. We would like to thank Editage for English language editing.
Deguchi R, Nishimura T, Matsuo K, Wakita F, Kawamoto A, Uchida K, et al. Factors associated with the outcome of patients with COVID‐19 requiring mechanical ventilation: A single‐center observational study in Japan. Acute Med Surg. 2023;10:e868. 10.1002/ams2.868
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.