Delirium in terminally ill patients with interstitial lung diseases: a retrospective study

Introduction

Interstitial lung diseases (ILDs) are a general term for diseases in which the interstitium of the lungs is the center of involvement (1). Idiopathic pulmonary fibrosis (IPF), which is the most common form of ILDs, has a poor prognosis (2). Patients with ILDs frequently experience dyspnea, cough, and fatigue (3-5). Additionally, as the disease progresses, its symptoms worsen. Therefore, palliative care is necessary to improve their quality of life of patients with ILDs. However, compared to patients with lung cancer, patients with IPF do not receive sufficient palliative care (6,7).

Delirium is a neuropsychiatric condition primarily defined as the disturbance of consciousness that occurs acutely (8) and is common in patients with advanced illness, especially medically hospitalized older patients (9). Terminally ill patients with ILDs are vulnerable to delirium because of several factors, including hypoxemia, infection (10), the use of drugs such as corticosteroids (11,12) and opioids (13), dyspnea, and environmental changes attributable to hospitalization. Delirium is distressing for patients as well as their families and caregivers (14). Therefore, the prevention of delirium and management of its symptoms are essential to the palliative care of patients with ILDs. However, few studies have examined the prevalence of delirium among patients with ILDs (15,16). Additionally, no studies have examined the risk factors for delirium in these patients. Therefore, this study investigated the incidence of delirium among terminally ill patients with ILDs and risk factors for its development. We present this article in accordance with the STROBE reporting checklist (available at https://apm.amegroups.com/article/view/10.21037/apm-25-21/rc).

Methods

Study design

This retrospective, observational study was conducted to determine the prevalence and the risk factors for delirium in patients with ILDs during the last week of life. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Institutional Review Board of the National Hospital Organization (NHO) Kinki Chuo Chest Medical Center (approval No. Rin2022-083). We employed an opt-out approach whereby information about the study was made publicly available, and patients or their families were given the opportunity to refuse the use of their medical data for research purposes. Informed consent was obtained from all the patients.

Study setting and patients

Eligible study patients were those with ILDs who were admitted to the NHO Kinki Chuo Chest Medical Center between April 2020 and September 2022 and died during hospitalization. ILDs include idiopathic interstitial pneumonias (IIPs), fibrotic hypersensitivity pneumonitis (fHP), pneumoconiosis, and connective tissue disease-associated ILDs (CTD-ILDs). IIP was diagnosed based on the 2013 Idiopathic Interstitial Pneumonia Consensus Guidelines of the American Thoracic Society, European Respiratory Society (17). fHP was diagnosed based on the 2020 clinical practice guidelines of the American Thoracic Society, Japan Respiratory Society, and Latin American Thoracic Association (18). Patients with lung cancer, those who had delirium more than 7 days before the date of death, or who were hospitalized within 7 days before death and did not develop delirium were excluded.

Data collection

We collected the following demographic data from the medical records: age, sex, smoking history, presence of dementia, infection, type of hospitalization (emergency or scheduled), use of systemic corticosteroids and their dosages, use of opioids and their dosages, use of benzodiazepines, and physical restraint and etiology of ILDs. We defined dementia based on the patient’s treatment history. Emergency hospitalization was defined when the date of the decision to hospitalize the patient and date of hospitalization were the same. Newly diagnosed infections were defined as those that required antibiotic treatment during hospitalization. During this study, we defined the presence of dementia as a history of dementia reported during the admission interview or a history of antidementia medication use.

We also collected data regarding delirium during the last week of life and risk factors for delirium. Data regarding oxygen supplementation, laboratory data, respiratory function test results, use of opioids and their dosages, use of antibiotics, use of systemic corticosteroids and their dosages, use of benzodiazepines, and physical restraint were evaluated to determine whether they were risk factors for delirium. Dosages of drugs were defined as the maximum dose administered during one day. For patients with delirium, we assessed the dose of drugs for 6 days before the delirium onset. For patients without delirium, the maximum daily dose was assessed between 7 days and 13 days before death. We defined physical restraint as the use of mitt restraints or restraint belts for any reason during the same period when drug use was assessed. These data were collected before the development of delirium. Laboratory data included C-reactive protein (CRP), lactate dehydrogenase (LDH), albumin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, Krebs von den Lungen-6 (KL-6), sodium, potassium, blood urea nitrogen (BUN), creatinine, and hemoglobin levels. The respiratory function test results included the percentage of predicted forced vital capacity (FVC) and percentage of predicted diffusing capacity of the lungs for carbon monoxide (DL_CO).

Outcomes

The primary and secondary outcomes were the percentage of patients with delirium and risk factors for delirium, respectively. Delirium was defined as a Nursing Delirium Screening Scale (Nu-DESC) score ≥2 (19). The five components of the Nu-DESC score were inferred and qualified retrospectively based on the descriptive notes provided in the medical records by physicians and nurses. Patient records were reviewed independently by five physicians (Yusuke Kuze, A.Y., K.K., T.K., and H.S.), with each physician responsible for reviewing a portion of the data.

Statistical analysis

Continuous data are presented as median [interquartile range (IQR)], and categorical data are presented as frequencies and proportions. For the risk factor analysis, we calculated the risk ratios and 95% confidence intervals (CIs) for potential risk factors for delirium by comparing patients with and without delirium. The risk factors analyzed, including high levels of CRP, LDH, BUN, creatinine, AST, ALT, KL-6, hyponatremia, hypokalemia, hypoalbuminemia, hyperbilirubinemia, and anemia, corticosteroid dose. The cutoff value was defined as Common Terminology Criteria for Adverse Events grade >1. The CRP and KL-6 cutoff values were defined by the receiver-operating characteristic curve (CRP level ≥4.49 mg/dL; KL-6 level ≥638 IU/L). In Japan, high-dose intravenous methylprednisolone therapy (≥500 mg/day) is commonly used in the treatment of acute exacerbations of ILDs (20). Since such high doses are frequently administered in clinical practice, we evaluated whether methylprednisolone ≥500 mg/day was a potential risk factor for delirium in our study. Statistical significance was determined when the 95% CI of the risk ratio did not include 1.0. All statistical analyses were performed using EZR, which is a modified version of the R commander software designed to add statistical functions that are frequently used in biostatistics (21).

Results

Patients

A total of 85 patients were included in this study. The baseline characteristics of the 85 patients included in the analysis are shown in Table 1. The median age of the patients was 78 years, and the majority of patients were male. The most frequent etiology of ILDs was unclassifiable interstitial pneumonia, followed by IPF and CTD-ILDs. Four patients had dementia. Delirium was present in 38 patients (44.7%). The median doses of corticosteroids (equivalent to prednisolone) among patients who used corticosteroids were 45, 42.5, and 45 mg for all patients, patients with delirium, and patients without delirium, respectively. The median dose of opioids (equivalent to oral morphine) among patients who used opioids was 24, 39, and 12 mg for all patients, patients with delirium, and patients without delirium, respectively.

Laboratory data and respiratory function test results for the 85 patients included in the analysis are shown in Table 2. The median serum sodium and potassium levels were 138 mEq/L and 4.2 mEq/L, respectively. The median CRP level was 3.92 mg/dL, and the median LDH was 289 IU/L. The median albumin level was relatively low at 2.7 g/dL. Renal function markers showed a median BUN of 21.8 mg/dL and creatinine of 0.69 mg/dL. Liver enzyme levels (AST and ALT) and total bilirubin were within normal to mildly elevated ranges. The median KL-6 level was 986 IU/L, which reflects interstitial lung inflammation. The respiratory function test results, available for 32 patients, showed a median %FVC of 52.3% and a median %DL_CO of 41%, indicating moderate to severe impairment.

Risk factors related to delirium

The risk ratios of potential risk factors for delirium among the 85 patients are shown in Table 3. Patients with dementia had a significantly higher risk of delirium compared to those without dementia (risk ratio, 2.38; 95% CI: 1.84–3.08), and patients who were physically restrained also had a higher risk of delirium compared to those without restraint (risk ratio, 2.32; 95% CI: 1.53–3.52). Use of corticosteroids, opioids, benzodiazepines, and high-dose methylprednisolone (≥500 mg/day) was not significantly associated with delirium.

Discussion

During our study, we found that almost half of the patients with ILDs (44.7%) developed delirium at the end of life. Additionally, we found that dementia and physical restraint were risk factors for delirium.

The important finding of our study was that the prevalence of delirium among patients with ILDs before death was 44.7%. One retrospective study that examined differences in symptoms of lung cancer and ILDs found that the prevalence of delirium 7 days before death was 11% (2 of 18 patients) in the ILDs group (16). Another retrospective study that examined end-of-life care for patients with IPF revealed that the prevalence of delirium during the last week of life was 19% (11 of 59 patients) (15). The prevalence of delirium in our study was higher than that previously reported. This discrepancy may be attributable to differences in the methods of diagnosing of delirium. Delirium was diagnosed based on information in the medical records that was provided by nurses during one study (16); however, the diagnostic criteria used during another study were not described (15). Based on a previous study, we diagnosed delirium based on Nu-DESC scores ≥2 (19). Although this diagnostic tool has not yet been validated, it seems more objective than other methods used to diagnose delirium (15,16). Additionally, the sample size of our study was larger than that of the aforementioned studies [18 patients (16) and 59 patients (15)]. Because of the high frequency of delirium in this study, attention should be focused on delirium in patients with end-stage ILDs.

We found that dementia was a risk factor for delirium during the last week of life. Furthermore, previous studies identified dementia as a risk factor for delirium (10,22). Patients with ILDs tend to be elderly, and the mean age of patients with IPF is older than 70 years (23). Therefore, the possibility of dementia should be considered when encountering terminally ill patients with ILDs. Dementia is a non-modifiable risk factor for delirium; however, identifying dementia in terminally ill patients with ILDs allows us to prepare both non-pharmacological and pharmacological interventions for delirium and to inform the patient’s family about its potential occurrence.

We also found that physical restraint was a risk factor for delirium. Physical restraint contributes to delirium by inducing immobility, increasing psychological distress, and disrupting the sleep-wake cycle, all of which are known precipitating factors for cognitive impairment. Consistent with our results, previous studies found that restraint was associated with delirium in adults (24). In addition, physical restraint can cause other adverse events other than delirium, including skin injuries, neurofunctional impairment, post-traumatic stress disorder, and deep vein thrombosis (25,26). Therefore, unnecessary physical restraint should be avoided in patients with ILDs.

Opioids are sometimes administered to terminally ill patients with ILDs to manage cough and dyspnea (5). Opioids act on the central nervous system by altering neurotransmitter release and neuronal activity, which can lead to neuropsychiatric effects such as cognitive impairment and delirium, especially in patients with advanced cancer. Additionally, opioids may disrupt the normal sleep-wake cycle, further increasing the risk of delirium (27).

For patients with cancer, an oral morphine-equivalent dose more than 90 mg has been associated with delirium (28,29). However, opioids were not associated with delirium in our study. Furthermore, in our study, the mean oral morphine-equivalent dose for patients who used opioids was 24 mg. Therefore, lower doses of opioids may result in the absence of association between opioid use and delirium.

Corticosteroids are occasionally administered to treat ILDs. Corticosteroids can precipitate limbic-hypothalamic-pituitary-adrenal axis dysfunction, dopaminergic system inhibition, or have a direct toxic effect on different brain regions, particularly the hippocampus, which may hamper selective attention and memory function and thus increase the odds of transitioning to delirium (30). For patients with cancer, a dexamethasone-equivalent dose more than 15 mg (prednisolone-equivalent dose of almost 100 mg) (31) is associated with delirium (29). However, in the present study, corticosteroid use and intravenous high-dose methylprednisolone therapy (≥500 mg daily for 3 consecutive days) were not associated with delirium. Additionally, in this study, the mean oral prednisolone-equivalent dose was 12.5 mg. Therefore, lower doses of corticosteroids may result in the absence of an association between corticosteroid use and delirium.

Limitations

This study had some limitations. First, this was a single-center, retrospective study. However, the number of patients in our study was larger than that of previous studies. Second, we defined delirium as Nu-DESC scores ≥2. However, there is a validated diagnostic tool to diagnosing delirium is not available for retrospective studies. Third, we scored transient symptoms as also being included in the Nu-DESC item. This may have resulted in the overdiagnosis of delirium. Fourth, multiple evaluators did not review a single patient’s medical records independently when assessing delirium using the Nu-DESC, and only one physician determined the Nu-DESC score of each patient group. Therefore, differences in the evaluation processes of the evaluators were possible. Fifth, dementia was not diagnosed using formal diagnostic criteria during our study. However, we included patients with previously diagnosed dementia and those whose medical records indicated that they used antidementia drugs. Therefore, some patients with dementia may have been identified as not those without dementia in our study, and physical restraint may have been used for these patients. In addition, because dementia and delirium share overlapping symptoms such as disorientation, inattention, and altered mental status, some cases of dementia-related behaviors might have been misclassified as delirium. This concern is particularly relevant since Nu-DESC, although widely used for delirium screening, has not been validated specifically for use in patients with dementia. Therefore, the association between dementia and delirium in our findings should be interpreted with caution due to the potential for diagnostic misclassification. Sixth, we did not analyze the actual dosages of benzodiazepines. This was due to inconsistent documentation of administration timing and dosing in the medical records. Patients exposed to daily doses of benzodiazepines greater than 2 mg (lorazepam equivalents) have been reported to have an increased risk of developing delirium (29). The absence of dosage analysis may have led to an underestimation of their impact. Seventh, while anticholinergic medications are known contributors to delirium and may be used in ILD patients experiencing excessive respiratory secretions, their administration was not consistently documented in our data and thus could not be analyzed. Eighth, while physical restraint was identified as a risk factor for delirium, it is also possible that restraint was implemented in response to early signs of agitation or delirium. Therefore, the causal relationship should be interpreted with caution. Nineth, this study did not include multivariate statistical analyses such as logistic regression due to the limited sample size. As a result, we were unable to adjust for potential confounding factors. Future studies with larger cohorts should incorporate multivariate models to more accurately identify independent risk factors for delirium. Finally, we only included terminally ill patients with ILDs. Therefore, the results of our study cannot be generalized to all patients with ILDs.

Conclusions

Delirium is prevalent among terminally ill patients with ILDs, and dementia and physical restraint may be risk factors for delirium. Physicians may be considered the risk factors for delirium and prepare for its development in patients with ILDs.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://apm.amegroups.com/article/view/10.21037/apm-25-21/rc

Data Sharing Statement: Available at https://apm.amegroups.com/article/view/10.21037/apm-25-21/dss

Peer Review File: Available at https://apm.amegroups.com/article/view/10.21037/apm-25-21/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-25-21/coif). T.T. has received lecture fees from Shionogi, not related to this work. T.A. has received research funding from Sekisui Medical and Sysmex, not related to the present study. He has also received lecture fees from Boehringer Ingelheim, Shionogi, AstraZeneca, and Sekisui Medical. Y.I. has received a research grant from the Japanese Ministry of Health, Labour and Welfare. He has served as a consultant, advisor, or steering committee member for Savara, Boehringer Ingelheim, Roche, Shionogi, Taiho Pharmaceutical, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma, CSL Behring, Vicore Pharma AB, AbbVie, and Avalyn Pharma. He has also received lecture fees from Boehringer Ingelheim, Shionogi, Kyorin Pharmaceutical, Nobelpharma, GlaxoSmithKline (GSK), and AstraZeneca. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Institutional Review Board of the National Hospital Organization (NHO) Kinki Chuo Chest Medical Center (approval No. Rin2022-083, approval date: December 15, 2022). Informed consent was obtained from all the patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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