Short Survival of Patients with Chronic Obstructive Pulmonary Disease and a Do-Not-Resuscitate Order Despite the Noninvasive Positive Pressure Ventilatory Support: A Retrospective Cohort Study in Taiwan

Abstract

Background:

Chronic obstructive pulmonary disease (COPD) progression leads to repeated acute exacerbations, gravely impacting patients’ quality of life. Although noninvasive positive pressure ventilation (NIPPV) reduces the work of breathing, intubation rate, and mortality in acute therapeutic care, its role and benefits in palliative care are unclear.

Aims:

To determine the overall survival (OS), hospital mortality, and ventilator-free survival for patients with COPD supported with NIPPV with a special emphasis on patients who signed a do-not-resuscitate (DNR) order.

Design:

A single-centered retrospective observational cohort study in Taiwan.

Setting/Participants:

In total, 209 patients with COPD with acute respiratory failure receiving NIPPV support.

Results:

OS was 4.8 months. For patients with a DNR, the median OS was 1.9 months, and hospital mortality was 51.0%, compared with 36.4 months and 23.3% for those without a DNR (both p < 0.001). The median ventilator-free survival periods among those liberated from ventilatory support were 3.1 and 9.0 months for patients with and without a DNR, respectively (p = 0.031). Patients with a DNR exhibited higher mortality compared with those without a DNR (adjusted hazard ratio [aHR]: 2.38; 95% confidence interval [CI]: 1.52–3.72; p < 0.001). Male sex (aHR: 2.00; 95% CI: 1.52–3.72; p < 0.001), using vasopressors (aHR: 2.03; 95% CI: 1.25–3.32; p = 0.005), and a bedridden status (aHR: 2.16; 95% CI: 1.37–3.41, p = 0.001) were associated with increased mortality.

Conclusions:

In patients with COPD with acute respiratory failure, those who signed a DNR order had high hospital mortality and short OS, despite NIPPV support. Therefore, providing hospice and palliative care options is essential to maximize these patients’ quality of life.

Key Message

In patients with chronic obstructive pulmonary disease with acute respiratory failure, those who signed a do-not-resuscitate order had high hospital mortality, despite noninvasive positive pressure ventilation support. Even if they managed to be liberated from the ventilatory support, the remaining ventilator-free survival period was dismal.

Introduction

Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitations that are usually associated with progressive shortness of breath leading to limitation in daily activities.¹ It is the fourth leading cause of death in the United States, responsible for more than 120,000 deaths annually and the third leading cause worldwide.^2,3 It is the seventh leading cause of death in Taiwan, associated with more than 5000 deaths yearly.⁴ Its high prevalence, chronicity, and progressive nature cause repeated acute exacerbations and respiratory failure. The need for respiratory therapies and multiple hospitalizations impacts the quality of life of patients and families.⁵

Noninvasive positive pressure ventilation (NIPPV) delivers positive pressure ventilation through a noninvasive interface (e.g., a face mask). It allows respiratory muscles to rest. As they have to exert less effort to breathe, and hence less oxygen consumption, there is less breathlessness. It is commonly used in patients with respiratory failure resulting from COPD acute exacerbations, pneumonia, or decompensated heart failure. Evidence from many randomized trials and meta-analyses supports NIPPV’s benefits in improving clinical outcomes in patients with COPD acute exacerbations and hypercapnic acidosis.^6–8 When facing acute respiratory failure, conventional invasive intubation and mechanical ventilation can be torturous for patients, and the risks of complications such as ventilator-induced lung injury, ventilator-associated pneumonia, and post-extubation sequelae are inevitable. NIPPV is a preferred method of ventilatory support in many patients with COPD exacerbations and respiratory failure, as it corrects hypercapnia and reduces mortality and the intubation rate.^9,10 Although NIPPV provides clear benefits for patients with COPD, it is also associated with many complications, which include leaking masks, claustrophobia, facial pressure ulcers, abdominal distention, vomiting and aspiration, discomfort associated with high airflow, and further sputum plugging.^11,12

The three general circumstances for which NIPPV is used in patients with advanced COPD are (1) for those who desire complete life-prolonging therapy, regardless of the prognosis (i.e., NIPPV, followed by invasive mechanical ventilation if NIPPV fails); (2) for those who wish for life-prolonging therapy but with limitations (i.e., patients with a do-not-intubate order); and (3) for supportive and palliative purposes.¹³ However, for patients with advanced COPD, especially those who have signed a do-not-resuscitate (DNR) order, whether NIPPV is beneficial has become an issue of debate.

Taiwan enacted the Hospice Palliative Care Act in 2000, covering noncancer diseases such as COPD. This legislation provides a legal framework ensuring patients with COPD receive appropriate palliative care services. The Taiwan Ministry of Health and Welfare has announced the reference examples of the “Advance Directive for Palliative Care and Life-Sustaining Treatment Choices” and the “Medical Power of Attorney” forms.¹⁴ The National Health Insurance endorses various palliative care services to address different stages and needs of patients with COPD. Hospice wards are designed for patients in the advanced stages of COPD who require intensive symptom management and end-of-life care. They provide a comfortable environment where symptoms such as severe breathlessness and pain can be effectively managed, ensuring the patient’s dignity and quality of life during their final days. Home-based palliative care provides continuous care and support at home for stable, frail patients. This service aims to provide medical care and daily assistance, allowing patients to remain in a familiar environment. It also helps to reduce hospital readmissions and supports families in managing the patient’s symptoms. Outpatient services are suitable for patients with COPD in earlier stages who need regular medical follow-ups and symptom management without the need for hospitalization. The goal is to manage symptoms proactively, prevent complications, and maintain the patient’s quality of life through regular check-ups and interventions.

The importance and benefits of palliative care are emphasized in the National Institute for Health and Care Excellence COPD guidelines¹⁵ and also by the American Thoracic Society and European Respiratory Society.¹⁶ So far, there is no consensus or conclusions from related guidelines regarding using NIPPV in the palliative management of patients with COPD. Several studies explored the outcomes and predictors of COPD exacerbation.^17–20 However, the lack of evidence on the prognosis after the NIPPV administration makes it difficult to judge the timing of hospice compared with other terminal diseases, such as patients with cancer.²¹ In addition, despite the burden of the disease, palliative care is often not offered to or omitted from most patients with advanced COPD.^17,22–25 Therefore, this study aimed to establish mortality indicators and evaluate NIPPV’s role in the palliative care of patients with COPD.

Methods

Patients

Patients were included in the study if they had a COPD-related hospitalization and NIPPV use within the enrollment window. In this study, COPD-related hospitalizations were defined as inpatient records with a primary diagnosis of COPD or those with a primary diagnosis of other diseases, such as pneumonia or sepsis, and a secondary diagnosis of COPD. Patients had to have been diagnosed with COPD at least 6 months before hospitalization. The attending physicians judged a COPD diagnosis by considering clinical presentations, history of exposure to risk factors, and pulmonary function tests. Patients who were long-term dependent on NIPPV (defined as the need for NIPPV for more than 6 hours daily for more than 21 days) were not included.²⁶ The Joint Institutional Review Board of Taipei Medical University approved this study and waived the need for informed consent (N202106044).

Study design

This single-center, retrospective cohort study consisted of patients who had a COPD-related hospitalization followed by respiratory failure and NIPPV use between January 2017 and December 2019. The hospital admission date was the index date, and the earliest index date was in January 2017. The source of patient data was a database of Wang Fang Hospital (Taipei City, Taiwan). The DNR status of patients before the application of NIPPV was noted and recorded. Baseline demographics and clinical characteristics we evaluated included age, sex, body mass index, smoking status, and other comorbidities. Patients’ level of dependence on activities of daily living, consciousness level, administration of vasoactive agents, and the level of oxygen supplementation before NIPPV were also assessed and documented. After discharge, patients were followed until the end of December 2021.

Outcome assessments

The primary outcome of interest was long-term overall survival (OS). Secondary outcomes were successful liberation from NIPPV, hospital mortality, and ventilator-free survival for those liberated from ventilatory support. Successful liberation from NIPPV was defined as freedom from invasive or noninvasive ventilatory support for more than 5 days. When calculating ventilator-free survival, both invasive and noninvasive ventilations are considered valid outcome events.

Statistical analysis

Baseline assessments were summarized and compared between the groups with and without DNR orders. Intergroup differences were compared with independent sample t-tests for a normal distribution, the Mann-Whitney U test for a non-normal distribution, and Chi-squared tests or Fisher’s exact tests for categorical variables. The Cox proportional hazard model was applied to determine multivariate relationships between survival times and covariates. Potential confounders included age, sex, body mass index, cigarette smoking, baseline comorbidities, performance status of ambulation and feeding, bedsores, a DNR order, the consciousness level, vasopressor use, fraction of oxygen (FiO₂) support, and the arterial carbon dioxide partial pressure before administration of NIPPV. Kaplan-Meier survival curves were plotted and compared using the Wilcoxon test. Statistical significance was accepted with a two-sided p < 0.05. All statistical analyses were performed with R program vers. 4.1 (R Foundation).

Results

Patient demographics and clinical characteristics

In total, 209 eligible patients admitted between January 2017 and December 2019 were included in the study. Their mean age was 82.0 ± 10.9 years. Male patients accounted for 71.7%. Of these, 17.2% were active smokers, and another 39.7% had quit smoking. The most observed comorbidities were congestive heart failure (55.0%), chronic kidney disease (28.7%), coronary heart disease (22.0%), diabetes mellitus (21.5%), and stroke (19.1%). Among all hospitalizations, the most common causes of respiratory failure were pneumonia (43.1%) and COPD acute exacerbations (33.0%). Regarding physical performance, 47.8% of the population were either nasogastric- or Foley catheter-dependent, and a high proportion had bedsores of various degrees (42%). Fifty patients (23.9%) were bedridden, and 67 (32.1%) were wheelchair bound. Consciousness, graded via the Glasgow Coma Scale, was severely (≤8), moderately (9–11), and mildly (12–14) impaired for 51 (24.4%), 46 (22.0%), and 28 (13.4%) patients, respectively. Of the total 209 patients, 149 (71.3%) had signed a DNR order, and 60 (28.7%) had not (Table 1). In the DNR group, 84% of patients were 75 or older, and 50% were more than 85 years old, compared with the non-DNR group’s 58% and 33%, respectively (p = 0.001). Congestive heart failure, chronic kidney disease, and dementia were more prevalent in the DNR group. Proportions of patients who were bedridden and wheelchair bound in the DNR group were also higher than those in the non-DNR group (28.2% and 37.6% compared with 13.3% and 18.3%, p < 0.001). More (60.7%) patients in the DNR group had a poor consciousness level (moderate or lower), compared with 27% in the non-DNR group (p < 0.001).

Table 1.

Clinical Characteristics of 209 Patients with COPD Who Had Acute Respiratory Failure Supported with NIPPV

	Do-not-resuscitate order		p-Value
	No (n = 60)	Yes (n = 149)	p-Value
Age (year)	78 (67.5–86.75)	85 (79.5–90.5)	0.042
<75	25 (41.7%)	25 (16.8%)	0.001
75–84	15 (25.0%)	50 (33.6%)
≥85	20 (33.3%)	74 (49.7%)
Sex			0.181
Female	13 (21.6%)	46 (30.9%)
Male	47 (78.3%)	103 (69.1%)
Body mass index (kg/m²)	22.0 ± 4.7	21.2 ± 5.2	0.315
Smoking status			0.028
Current active smokers	16 (26.7%)	20 (13.4%)
Ex-smokers	17 (28.7%)	66 (44.3%)
Non-smokers	27 (45.0%)	63 (42.3%)
Main diagnosis			0.232
Pneumonia	26 (43.3%)	64 (43.0%)
Acute exacerbation of COPD	20 (33.3%)	49 (32.9%)
Sepsis	6 (10.0%)	15 (10.1%)
Decompensated heart failure	2 (3.3%)	7 (4.7%)
Acute kidney injury	3 (5.0%)	5 (3.4%)
Cancer	1 (1.7%)	6 (4.0%)
Stroke	2 (3.3%)	1 (0.7%)
Others	0	2 (1.3%)
Comorbidities
Chronic heart failure	24 (40.0%)	91 (61.1%)	0.006
Chronic kidney disease	9 (15.0%)	51 (34.2%)	0.005
End-stage renal disease	3 (5.0%)	4 (2.7%)	0.412
Coronary artery disease	10 (16.7%)	36 (24.2%)	0.237
Diabetes mellitus	14 (23.3%)	31 (20.8%)	0.688
Previous stroke	12 (20.0%)	28 (18.8%)	0.841
Dementia	4 (6.7%)	31 (20.8%)	0.014
Activities of daily living deficit
Nasogastric feeding	20 (33.3%)	67 (45.0%)	0.123
Indwelling Foley catheter	17 (28.3%)	54 (36.2%)	0.275
Bedsores	21 (35.0%)	67 (45.0%)	0.187
Ambulation functional status			<0.001
Unaided walkers	16 (26.7%)	20 (13.4%)
Walking with assistant devices	25 (41.7%)	31 (20.8%)
Wheelchair-bound	11 (18.3%)	56 (37.6%)
Bed-ridden	8 (13.3%)	42 (28.2%)
Glasgow coma scale			<0.001
3–8 (severely impaired)	9 (15.0%)	58 (38.9%)
9–11 (moderately impaired)	7 (11.7%)	34 (22.8%)
12–14 (mildly impaired)	11 (18.3%)	17 (11.4%)
15 (fully alert)	36 (60.0%)	48 (32.2%)
Vasopressors	4 (6.7%)	20 (13.4%)	0.231
FiO₂ demand			0.208
21–39%	33 (55.0%)	62 (41.6%)
40–59%	10 (16.7%)	30 (20.1%)
60–100%	17 (28.3%)	57 (38.3%)
PaCO₂ (mmHg)	64.6 ± 18.4	66.2 ± 28.2	0.717
NIPPV outcomes			<0.001
Successful weaning	33 (55.0%)	77 (51.7%)
Ventilator dependence	4 (6.7%)	10 (6.7%)
Invasive mechanical ventilation	23 (38.3%)	0
Death	0	62 (41.6%)
In-hospital mortality	14 (23.3%)	76 (51.0%)	<0.001
Hospital stay (day)	19 (10.25–38.25)	17 (10–30)	0.419

COPD, chronic obstructive pulmonary disease; NIPPV, noninvasive positive pressure ventilation.

Therapies

Twenty-four of 209 patients (11.5%) required vasoactive agent support for hemodynamic stability. Severe hypoxemic respiratory failure, requiring oxygen support with a value of the FiO₂ of >0.6, was observed in 74 patients (35.4%). No statistical difference regarding the partial pressure of carbon dioxide or FiO₂ demand was observed between the DNR and non-DNR groups.

In-hospital outcomes

During hospitalization, 110 (52.6%) patients had been successfully weaned off of NIPPV. Fourteen patients (6.7%) became ventilator dependent, whereas 23 (11%) received endotracheal intubation and mechanical ventilation (Fig. 1). Of the 23 patients shifted to invasive mechanical ventilation, three (13.0%) were successfully weaned off mechanical ventilation, six became ventilator-dependent, and 14 died before discharge. The proportions of patients successfully weaned off NIPPV were comparable between the DNR and non-DNR groups. However, most (86.1%) of the patients who failed to be weaned off of NIPPV in the DNR group died, whereas those in the non-DNR group were shifted to invasive mechanical ventilation. Hospital mortality of the DNR group (51.0%) was much higher than that of the non-DNR (23.3%) group.

FIG. 1.

Outcomes of 209 patients with chronic obstructive pulmonary disease supported with noninvasive positive pressure ventilation for acute respiratory failure.

Overall survival and ventilator-free survival

Overall survival

The median OS for the 209 patients with COPD who underwent NIPPV support was 4.3 months. For patients who had signed a DNR, the median OS was much shorter (1.9 months) than those without a DNR (36.4 months) (p < 0.001, Fig. 2A). OS periods for patients who were bedridden (1.0 months) and wheelchair bound (3.2 months) were shorter than those of walkers (23.2 months, p < 0.001, Fig. 2B). The multivariate relationship between OS and covariates is shown in Table 2. After adjustment, male patients had a higher mortality risk (adjusted hazard ratio [aHR]: 2.00; 95% confidence interval [CI]: 1.31–3.04). Patients who had signed a DNR order (aHR: 2.38; 95% CI: 1.52–3.72) and required vasoactive agents (aHR: 2.03; 95% CI: 1.25–3.32) had shorter OS periods. Bedridden individuals also had a higher mortality rate (aHR: 2.16; 95% CI: 1.37–3.41). Severe hypoxemic respiratory failure requiring oxygen support with FiO₂ of ≥0.6 was associated with a marginally higher risk of mortality (aHR: 1.41; 95% CI: 0.99–2.01).

FIG. 2.

Overall survival of 209 patients with chronic obstructive pulmonary diseases supported with noninvasive positive pressure ventilation for acute respiratory failure stratified by (A) having a do-not-resuscitate order and (B) ambulation functional status. Ventilator-free survival of 113 patients with chronic obstructive pulmonary disease and acute respiratory failure who were successfully liberated from ventilatory support stratified by (C) having a do-not-resuscitate order and (D) ambulation functional status.

Table 2.

Multivariate Cox Regression for Predictors of Overall Survivals for 209 Patients with COPD Who Had Acute Respiratory Failure Supported with NIPPV

	aHR	95% CI		p-Value
Male sex	2.00	1.31	3.04	0.001
Vasopressors	2.03	1.25	3.32	0.005
DNR orders	2.38	1.52	3.72	<0.001
FiO₂ ≥ 0.6	1.41	0.99	2.01	0.058
Ambulation functional status				0.003
Walkers (unaided or with assistant devices)	Ref
Wheelchair-bound	1.25	0.81	1.91	0.313
Bed-ridden	2.16	1.37	3.41	0.001

aHR, adjusted hazard ratio; CI, confidence interval; DNR, do-not-resuscitate; FiO₂, fraction of oxygen.

Ventilator-free survival

For the 113 patients who were successfully liberated from ventilatory support, the median ventilator-free survival was 4.1 months. The ventilator-free survival times were 3.1 and 9.0 months for patients with and those without a DNR order, respectively (p = 0.031, Fig. 2C). Ventilator-free survival periods of patients who were bedridden (2.3 months) and wheelchair bound (2.6 months) were substantially shorter than that of walkers (8.5 months, p = 0.017, Fig. 2D). The multivariate Cox regression revealed that male sex (aHR: 2.36; 95% CI: 1.39–3.99) and having a DNR order (aHR: 1.74; 95% CI: 1.06–2.85) were associated with shorter ventilator-free survival periods (Table 3). Patients dependent on nasogastric tube feeding had shorter ventilator-free survival (aHR: 2.33; 95% CI: 1.47–3.67).

Table 3.

Multivariate Cox Regression for Predictors of Ventilator-Free Survivals for 113 Patients with COPD Who Successfully Weaned off Ventilatory Support

	aHR	95% CI		p-Value
Male sex	2.36	1.39	3.99	0.001
DNR orders	1.74	1.05	2.85	0.029
Dependent on nasogastric feeding	2.33	1.47	3.67	<0.001

Discussion

Main findings and key determinants for survival

In this retrospective cohort study, we provide critical information about the hospitalization of COPD patients with acute respiratory failure and NIPPV support. This study was designed to establish risk factors for mortality and survival and evaluate NIPPV’s role in the palliative care of patients with COPD. During hospitalization, the leading causes of respiratory failure were pneumonia and COPD acute exacerbations. Over half of the patients with COPD (52.6%) managed to be weaned off of NIPPV during hospitalization, while about 7% became permanently ventilator dependent. A high prevalence of comorbidities was shown in this study, especially congestive heart failure and chronic kidney disease. The existence and severity of comorbidities were already well-established mortality predictors from previous studies.^{18–20,27,28}

The main risk factors identified by this study were male sex, physical performance, administration of vasoactive agents, and DNR status. It should be emphasized that the DNR status is a marker of the severity of illness and underlying prognosis rather than a direct cause of shortened survival. The OS period for patients with COPD with acute respiratory failure and NIPPV support was about 4.8 months (144 days). For male patients, the risk of mortality was twice that of females. Those who were bedridden or wheelchair bound faced a much shorter survival period than those who were ambulatory, with an average of about one and three months, respectively, compared with two years. A similar trend remained even if these patients had successfully been weaned off of NIPPV support. The average ventilator-free survival periods of the bedridden and wheelchair-bound populations were 2.3 and 2.6 months, respectively, compared with 8.5 months for the ambulatory group. Bedridden patients had more than double the mortality risk, whereas patients who used wheelchairs were 25% more likely to encounter mortality than their ambulatory counterparts. Similar results were also observed in the group receiving vasoactive agents than those not, with more than double the mortality risk.

Marginal benefit of the palliative use of NIPPV in overall and ventilator-free survival for patients with COPD

When stratifying patients with COPD into DNR versus non-DNR groups, the DNR group was generally much older (83.2% were aged 75 years or older) and had a poorer physical performance status (two-thirds of them were bedridden or wheelchair bound), with a more impoverished state of consciousness and a higher percentage of comorbidities. More than half of this group experienced in-hospital mortality, much higher than the non-DNR group (51.0% vs. 23.3%). Patients with a DNR status also had a much shorter OS period, almost 20 times shorter than those who did not have a DNR (1.9 vs. 36.4 months). Even if these patients had successfully been weaned off of ventilatory support, the DNR group still had a much shorter ventilatory-free survival period, almost three times shorter than the non-DNR group (3.1 vs. 9.0 months). The aHR of 2.38 further confirmed the risk of poor outcomes to be more than twofold that of the non-DNR group. The DNR status was an important predictor for ventilator-free survival. These risk factors are compatible with evidence from previous studies and systematic reviews.^{18–20,28,29} Furthermore, despite having NIPPV support, the general trend of survival affected by these risk factors remained relatively similar. Given the extremely short survival, end-of-life treatment planning should be incorporated at the time of original clarification of goals of care when the DNR order was entered.

NIPPV remains an important option for patients with COPD experiencing acute respiratory failure. However, for patients with end-stage COPD who have signed a DNR, the use of NIPPV should focus on alleviating symptoms rather than prolonging life. Although evidence from previous studies supports the benefits of NIPPV in reducing mortality and the need for intubation in patients with acute respiratory failure in situations with COPD exacerbation,^9,10,29 the benefits may be limited in palliative care for patients with advanced COPD. The evidence regarding the quality of life of these patients is also insufficient. If a patient does not show improvement within a reasonable time frame and requires continuous 24-hour use of NIPPV, this can significantly impact their quality of life. In such cases, the palliative care team should offer alternative palliative treatment options, such as transitioning to high-flow nasal cannula or using narcotic agents. Risk factors identified in this study indicated that a much shorter survival period is inevitable if they are present in patients with COPD with acute respiratory failure and NIPPV support. Even if a patient manages to be liberated from ventilatory support, the subsequent ventilatory-free survival period is still short. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) report and many studies nowadays emphasize the importance of hospice and palliative care, as the quality of life in patients with advanced COPD is often neglected.^1,22–24 GOLD recommends “that all clinicians managing patients with COPD should be aware of the effectiveness of palliative approaches to symptom control and use them in their practice.”¹ As a result, while providing high-quality care and a comprehensive treatment regimen, it is essential to consider the options of hospice and palliative management, even for those who have successfully been weaned off mechanical ventilation, so that patients can have and maintain a better quality of life in the last mile of their lives.

Study limitations

The study is limited by its single-centered design and relatively few participants. The patients enrolled were mainly those with advanced age, with a mean age of 82.0 ± 10.9 years. Applying the conclusion directly to COPD populations with different age distributions requires special caution.

Additionally, we realize that using a standardized scale like the Eastern Cooperative Oncology Group (ECOG) performance status to assess the level of ambulation and functional status would be beneficial for uniformity and accuracy. However, ECOG was not routinely evaluated and recorded in our cohort. This lack of standardized assessment is acknowledged as a limitation of our study.

Conclusions

In patients with COPD and acute respiratory failure, male sex, a bedridden or wheelchair-bound status, a need for vasoactive agent usage, and a DNR status have a higher risk of mortality and much shorter survival periods. Patients who present with these conditions also have short ventilatory-free survival periods after successful liberation from ventilatory support. The DNR status is a marker of the severity of illness and underlying prognosis rather than a direct cause of shortened survival. The extremely short OS for the DNR group further highlights the urgency of initiating palliative care for this population. When making shared decisions for these patients and considering the pros and cons of NIPPV, it is reasonable to provide hospice and palliative support options to achieve the best quality of life in their remaining lifetime.

Footnotes

Authors’ Contributions

W.C.: Writing—original draft (equal) and data collection and analysis (equal). Y.-T.C.: Writing—original draft (equal) and data collection and analysis (equal). V.-D.N.: Review and editing (equal). H.-C.L.: Writing—review and editing (equal). C.-W.T.: Review and editing (equal). L.-L.C.: Writing—review and editing (equal). C.-H.L.: Conceptualization (supporting) and writing—reviewing (supporting). J.-H.C.: Conceptualization (lead) and writing—review and editing (equal).

Author Disclosure Statement

All authors declare no conflicts of interest.

Funding Information

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Abbreviations Used

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