Study design and setting
The J-PICS study was a prospective, multicenter, observational cohort study of mechanically ventilated patients, conducted in 16 ICUs across 14 hospitals of Japan. Five of the 16 ICUs were university-affiliated hospitals and the others were tertiary teaching hospitals. The median number of ICU beds was 10 [interquartile range (IQR), 8–15]. All ICUs were mixed ICUs and were managed by intensivists. The study protocol was approved by the Kobe City Medical Center General Hospital (KCGH) ethics committee and the ethics committees of all participating hospitals (KCGH approval number: Zn181008). Written informed consent was obtained from all patients or authorized surrogates. The J-PICS study has been registered at UMIN-CTR (registration number: UMIN000034072).
Study population and eligibility criteria
All consecutive adult ICU patients who were expected to receive mechanical ventilation for more than 48 hours between April 01, 2019 and September 30, 2019 were recruited in the study. The patients who received noninvasive mechanical ventilation were also enrolled. Eligibility criteria were assessed next morning at 8:00 am after admission in the ICUs. The patients with the following conditions were excluded from the study: 1) patients who had primary brain injury that was likely to result in conscious or cognitive disorder (e.g., traumatic brain injury, subarachnoid hemorrhage, acute stroke, post cardiac arrest, meningitis, and encephalitis); 2) patients with pre-admission diagnosis of dementia; 3) patients who received home ventilation prior to admission; 4) patients with end-stage cancer; 5) patients with withdraw/withhold status; 6) expected death within 24 h; 7) second or subsequent readmission to ICU during the study period; 8) patients who had no family members; 9) patients who did not speak Japanese; and 10) the patients who could not be followed-up (e.g., did not live in Japan and/or homeless).
Variables and measurements
The following demographic and hospital data of the patients were collected: age, sex, body mass index, Charlson comorbidity index (CCI) [18], clinical frailty scale [19], do not attempt resuscitation code status at the time of ICU admission, educational level, employment status, marital status, patient’s residential living status before admission, history of treatment with benzodiazepines and steroids, source of admission to ICU, and primary diagnosis at the time of ICU admission. The number of patients with sepsis and acute respiratory distress syndrome (ARDS) was also recorded. Sepsis and ARDS were diagnosed on the basis of Sepsis-3 [20] and Berlin definition [21], respectively. The severity of illness was measured using the Acute Physiology and Chronic Health Evaluation (APACHE II) score and Sequential Organ Failure Assessment (SOFA) score [22] within 24 hours of ICU admission. The management data in the ICU, including the use of inotropes or vasopressors, paralytic agents except during intubation, renal replacement therapy, extracorporeal membrane oxygenation (ECMO), intra-aortic balloon pumping, and tracheostomy were also collected. The data for the use of inotropes, vasopressors, and paralytic agents were collected during the first four days of ICU admission. The data on patient outcomes, including ICU mortality; in-hospital mortality; length of stay in ICU; length of stay in hospital; duration of mechanical ventilation; occurrence of delirium, diagnosed by the Confusion Assessment Method for the Intensive Care Unit [23] for the first four days; and discharge status among survivors were collected.
Patient-reported outcomes
Six months after ICU admission, the authors sent the questionnaires by post to all patients except those who died. Patient-reported data were collected centrally by mail. If the participants did not revert, the lead author asked each participating institution to attempt a contact via telephone to return the questionnaire.
The patient-reported outcome survey evaluated the physical and mental functions of patients through the assessment of HRQOL and cognitive functions. HRQOL was assessed using the SF-36 questionnaire [24–26], which is available in the Japanese language [27,28]. At the time of enrolment in the study after ICU admission, the patients’ baseline SF-36 questionnaire was completed by a proxy (4-week recall assessment before the patients’ current acute illness). At 6 months after ICU admission, SF-36 questionnaire was obtained by mail from the patient or proxy. The SF-36 questionnaire has established acceptability, reliability, and validity in critically ill patient populations and as a surrogate-completed proxy measure [29–36]. SF-36 questionnaire is a comprehensive 36-item survey of HRQOL with two summary scales, physical component scale (PCS) and mental component scale (MCS), with scores ranging from 0 to 100. A higher score indicates better physical and mental functions. Both scales were transformed to a normalized scale using norm-based scoring (NBS) with 50 as the population mean and 10 points representing one standard deviation. The scores were calculated based on the standard methods [37]. The missing data were treated using the standard methods. If a patient answered more than half of the items on the subscale, the missing data were replaced with the mean of the subscale. In contrast, if a patient answered less than half items on the subscale, the data of the answered questions were excluded [37].
Cognitive functioning was assessed using the Short-Memory Questionnaire (SMQ) [38]. The SMQ was to be completed by a proxy, similar to the Informant Questionnaire on Cognitive Decline in the Elderly [39]. The SMQ is the only questionnaire filled by a proxy that has been translated and established in the Japanese language [40]. The SMQ is a 12-item questionnaire with scores ranging from 4 to 46. A score less than 40 indicates cognitive dysfunction.
The primary outcome was the occurrence of PICS 6 months after ICU admission. The definition of PICS was any of the following criteria: 1) decline in physical status, indicated by PCS score decrease of ≥ 10 points; 2) decline in mental status, indicated by MCS score decrease of ≥ 10 points; or 3) cognitive function impairment, indicated by decline in SMQ score and SMQ score < 40 at 6 months after ICU admission. A 10-point change was considered clinically important in a previous study in the ICU setting [36,41]. For the assessment of subjective significance of SF-36 score change, participants also answered anchor questions on whether their physical and mental status had improved, worsened, or unchanged on a 7-point Likert scale (from large negative change to large positive change) [42–44] at 6 months. The questions related to patients’ employment status at 6 months were also asked.
Statistical analyses
Since the analyses focused on patient-reported outcomes at 6 months, participants who were lost to follow-up and who died before 6 months were excluded from the final analysis. Continuous variables are presented as median and interquartile range. Categorical variables are presented as absolute value and percentage. A univariate analysis was performed using the Wilcoxon signed-rank test for continuous variables, and the chi-squared test or Fisher’s exact test, if the number was less than 10, was used for categorical variables. Multivariate logistic regression model was used to identify the factors associated with the occurrence of PICS. Multivariate analysis included the following variables as confounding factors: age, APACHE II score, CCI, and educational status [7, 45–47]. The risk of PICS is expressed as odds ratio (OR) with 95% confidence interval (CI). The number of missing data have been reported, and no assumptions have been made except for SF-36 questionnaire data. The changes in SF-36 PCS, MCS, and SMQ scores between baseline and 6 months after ICU admission were compared using the Wilcoxon signed-rank test. The subjective significance of change in SF-36 PCS and MCS was assessed by an anchor-based question with a Global Assessment Rating as large negative change, moderate negative change, small negative change, no change, small positive change, moderate positive change, and large positive change in physical and mental status. Each Global Assessment Rating change is expressed as median and IQR change in SF-36 PCS or MCS scores.
Further, we conducted a sensitivity analysis, wherein, we did not use the baseline PCS, MCS, and SMQ data. We compared PCS and MCS scores at 6 months to NBS. In this analysis, the definition of PICS was any of the following criteria: 1) physical status; PCS score < 10; 2) mental status; MCS score < 50; or 3) cognitive function; SMQ score at 6 months < 40.
The differences with P value less than 0.05 (two-sided) were considered statistically significant. All data were analyzed using JMP 15.1.0 (SAS Institute Inc., Cary, NC, USA).