Factors associated with delirium among survivors of acute respiratory distress syndrome: a nationwide cohort study

This study is a nationwide population-based cohort study. It was conducted in accordance with the Strengthening of the Reporting of Observational Studies in Epidemiology guidelines. The study protocol was approved by the Institutional Review Board (IRB) (X-2008-630-903), and the National Health Insurance Service (NHIS) permitted data sharing after approval of the study protocol (NHIS-2021-1-424). The requirement of informed consent was waived by the IRB because anonymized data was used in this study.

Data (demographic, socioeconomic, and treatment data of all Korean individuals in the sole and public health insurance system in South Korea) was obtained from the NHIS database. All diagnoses of diseases had to be registered by physicians using the International Statistical Classification of Diseases and Related Health Problems, Tenth revision (ICD-10) codes in the NHIS database. The prescription information of all procedures and/or drugs also had to be registered in the NHIS database. These registrations enable patients to receive financial support for treatment expenses by the government.

All adult patients (aged ≥ 18 years) who were admitted to the ICU for ARDS (J80) between January 1, 2010, and December 31, 2019, were eligible. Patients with a main diagnosis or secondary diagnosis of ARDS were included because ARDS is a clinical syndrome that may occur concurrently with other main diseases such as pneumonia, sepsis, or pancreatitis [13]. The main diagnosis of each patient was determined by the NHIS after hospital discharge or death, as a disease requiring close follow-up or emergency treatment during the patient’s hospitalization. If a patient was admitted to the ICU with a diagnosis of ARDS ≥ 2 times during the study period, only the first ICU admission was considered in this study. To focus on delirium during hospitalization, patients with ARDS who died within 60 days after hospitalization were excluded because 60-day mortality is a common primary endpoint for patients with severe ARDS [14]. Therefore, patients with ARDS who survived ≥ 60 days after the diagnosis of ARDS were considered ARDS survivors and included in the final analysis.

The primary endpoint was the diagnosis of delirium during hospitalization and was evaluated from the date of ARDS diagnosis to 60 days after ARDS diagnosis. The ICD-10 code, F05, was used to extract delirium diagnoses. In South Korea, DSM-5 criteria isusually used for diagnosis of delirium in ICU [2], and the registration of ICD-10 codes of delirium enable the financial support of treatment. Moreover, most medical staff in Korean ICUs used Korean version of confusion assessment method for the ICU (CAM-ICU) routinely for screening and assessment of delirium during ICU stays [15]. The ARDS survivors who were diagnosed with delirium constituted the delirium group, while the remaining patients constituted the control group. The secondary endpoint was 1-year all-cause mortality, which was evaluated from the date of ARDS diagnosis to one year after ARDS diagnosis. To better follow up the patients with ARDS for at least one year after ARDS diagnosis, the exact date of death was extracted until December 31, 2020.

First, the prevalence of delirium among ARDS survivors and the factors associated with delirium were investigated. Second, the association between development of delirium during hospitalization among ARDS survivors and 1-year all-cause mortality was examined.

The following variables were considered covariates in this study: age and sex were demographic variables. Household income level and employment status at the time of ARDS treatment was included to reflect patients’ socioeconomic status. The patients were divided into four groups according to household income levels using quartile ratios. Household income level was registered annually in the NHIS database to determine insurance premiums in South Korea. The admitting department was included as a covariate and classified into two groups (internal medicine and non-internal medicine). Length of hospitalization (day) and total cost of hospitalization (United States dollars) were covariates. Since higher case volume centers are related to better survival outcomes of patients with ARDS [16], the annual case volume of ICU admission for ARDS treatment was considered a covariate. All patients with ARDS were divided into four groups using quartile ratios, based on the hospital in which they were admitted for ARDS treatment: Q1 ≤ 4; Q2, 5–14; Q3, 15–28; and Q4 ≥ 28. A main diagnosis of ARDS was considered as a covariate, and diagnoses of shock (R57) or sepsis (A40, A41, and R65.2) were also considered as covariates. If a patient with ARDS had a main diagnosis of sepsis and a secondary diagnosis of ARDS, the diagnosis was sepsis-associated ARDS. To reflect the comorbidity status of patients with ARDS, the Charlson comorbidity index (CCI) was calculated using registered ICD-10 codes within one year before the date of ARDS diagnosis (Additional file 1: Table S1). All patients were divided into four groups according to their CCI scores (0–1, 2–3, 4–5, and ≥ 6). Concurrent psychiatric illnesses such as depression (F32, F33, and F34.1), anxiety disorder (F40 and F 41), post-traumatic stress disorder (F43.1), alcohol abuse (F10), and other substance abuse (F11–19) were considered because of the close relationship between concurrent psychiatric disorders and development of delirium among hospitalized patients [17, 18]. Moreover, underlying disability at admission for ARDS was extracted and considered as a covariate. In South Korea, all disabilities should be registered in the NHIS database to receive various benefits under social welfare programs. The disabilities were divided into two groups such as brain disability and non-brain disability, because delirium is common in patients with neurological disease [19]. Regarding treatment, extracorporeal membrane oxygenation support, neuromuscular blockade use, continuous renal replacement therapy use, duration of mechanical ventilation (day), and cardiopulmonary resuscitation experience were considered as covariates. Information regarding benzodiazepine continuous infusion (midazolam, diazepam, and lorazepam), opioid continuous infusion, and propofol infusion were collected as covariates. Admission to isolated ICU was also collected and considered as a covariate, because isolation in ICU was known as environmental risk factor of delirium in ICU [20].