Implications for post critical illness trial design: sub-phenotyping trajectories of functional recovery among sepsis survivors

Abstract

Background Patients who survive critical illness suffer from a significant physical disability. The impact of rehabilitation strategies on health-related quality of life is inconsistent, with population heterogeneity cited as one potential confounder. This secondary analysis aimed to (1) examine trajectories of functional recovery in critically ill patients to delineate sub-phenotypes and (2) to assess differences between these cohorts in both clinical characteristics and clinimetric properties of physical function assessment tools. Methods Two hundred ninety-one adult sepsis survivors were followed-up for 24 months by telephone interviews. Physical function was assessed using the Physical Component Score (PCS) of the Short Form-36 Questionnaire (SF-36) and Activities of Daily Living and the Extra Short Musculoskeletal Function Assessment (XSFMA-F/B). Longitudinal trajectories were clustered by factor analysis. Logistical regression analyses were applied to patient characteristics potentially determining cluster allocation. Responsiveness, floor and ceiling effects and concurrent validity were assessed within clusters. Results One hundred fifty-nine patients completed 24 months of follow-up, presenting overall low PCS scores. Two distinct sub-cohorts were identified, exhibiting complete recovery or persistent impairment. A third sub-cohort could not be classified into either trajectory. Age, education level and number of co-morbidities were independent determinants of poor recovery (AUROC 0.743 ((95%CI 0.659–0.826), p < 0.001). Those with complete recovery trajectories demonstrated high levels of ceiling effects in physical function (PF) (15%), role physical (RP) (45%) and body pain (BP) (57%) domains of the SF-36. Those with persistent impairment demonstrated high levels of floor effects in the same domains: PF (21%), RP (71%) and BP (12%). The PF domain demonstrated high responsiveness between ICU discharge and at 6 months and was predictive of a persistent impairment trajectory (AUROC 0.859 (95%CI 0.804–0.914), p < 0.001). Conclusions Within sepsis survivors, two distinct recovery trajectories of physical recovery were demonstrated. Older patients with more co-morbidities and lower educational achievements were more likely to have a persistent physical impairment trajectory. In regard to trajectory prediction, the PF score of the SF-36 was more responsive than the PCS and could be considered for primary outcomes. Future trials should consider adaptive trial designs that can deal with non-responders or sub-cohort specific outcome measures more effectively.

Prevalence of post-intensive care syndrome among Japanese intensive care unit patients: a prospective, multicenter, observational J-PICS study

“…In our study, population with only mandatory education was an independent predictor for the occurrence of PICS. This observation is consistent with that of the previous studies, which demonstrated that population with only mandatory education was associated with physical impairment [ 49 ], mental impairment [ 55 ] and PICS [ 7 ]. Socioeconomic position is a broad term which assesses the socioeconomic status, including education level, occupation and income.…”

“…The underprivileged persons often have high rates of cardiovascular disease and mortality due to tobacco smoking and less physical activity [ 55 ]. Furthermore, those who received less formal education is associated with low income, small social network to use resources for recovery, less coping ability for the rehabilitation process and less accurate recall [ 7 , 49 , 55 , 56 ]. Additionally, financial distress has a direct effect on mental status [ 57 ].…”

“…Responsiveness is the instrument’s ability to detect change over time in the construct to be measured [ 47 , 48 ]. Responsiveness of SF-36 PCS and MCS scores to negative change or no change in Global Assessment Rating at 6 months was calculated using the effect size index [ 49 , 50 ]. Cohen’s d effect size was used to evaluate the changes as small (0.2–0.49), moderate (0.5–0.79) and large (> 0.80) [ 47 , 51 ].…”

Prevalence of post intensive care syndrome among Japanese intensive care unit patients: A prospective, multicenter, observational J-PICS study

“…In our study, population with only mandatory education was an independent predictor for the occurrence of PICS. This observation is consistent with that of the previous studies, which demonstrated that population with only mandatory education was associated with physical impairment [49], mental impairment [55], and PICS [7]. Socioeconomic position is a broad term which assesses the socioeconomic status, including education level, occupation, and income.…”

“…Responsiveness is the instrument's ability to detect change over time in the construct to be measured [47,48]. Responsiveness of SF-36 PCS and MCS scores to negative change or no change in Global Assessment Rating at 6 months was calculated using the effect size index [49,50]. Cohen's d effect size was used to evaluate the changes as small (0.2-0.49), moderate (0.5-0.79), and large (> 0.80) [47,51].…”