Long‐term patient‐important outcomes after septic shock: A protocol for 1‐year follow‐up of the CLASSIC trial

Abstract

Background In patients with septic shock, mortality is high, and survivors experience long‐term physical, mental and social impairments. The ongoing Conservative vs Liberal Approach to fluid therapy of Septic Shock in Intensive Care (CLASSIC) trial assesses the benefits and harms of a restrictive vs standard‐care intravenous (IV) fluid therapy. The hypothesis is that IV fluid restriction improves patient‐important long‐term outcomes. Aim To assess the predefined patient‐important long‐term outcomes in patients randomised into the CLASSIC trial. Methods In this pre‐planned follow‐up study of the CLASSIC trial, we will assess all‐cause mortality, health‐related quality of life (HRQoL) and cognitive function 1 year after randomisation in the two intervention groups. The 1‐year mortality will be collected from electronic patient records or central national registries in most participating countries. We will contact survivors and assess EuroQol 5‐Dimension, ‐5‐Level (EQ‐5D‐5L) and EuroQol‐Visual Analogue Scale and Montreal Cognitive Assessment 5‐minute protocol score. We will analyse mortality by logistic regression and use general linear models to assess HRQoL and cognitive function. Discussion With this pre‐planned follow‐up study of the CLASSIC trial, we will provide patient‐important data on long‐term survival, HRQoL and cognitive function of restrictive vs standard‐care IV fluid therapy in patients with septic shock.

Long-term effects of restriction of intravenous fluid in adult ICU patients with septic shock

“…The pre-speci ed secondary outcomes assessed 1 year after randomisation were all-cause mortality, HRQoL, and cognitive function [11]. To increase follow-up rate and uniform data collection, we made a standard operating procedure (in the ESM1) for all patients [14].…”

“…The trial protocol was approved by the relevant medicine agencies and ethics committees [6]. The trial protocol, statistical analysis plan and primary results have been published elsewhere [6,12]; so has the statistical analysis plan for the 1-year outcomes [11]. Some deviations from the protocol and analysis plan were necessary; these are outlined with rationales in the Electronic Supplementary Material (ESM1).…”

“…We deviated from the prede ned analysis plan in the following ways [11]: 1) HRQoL and Mini MoCA were non-normally distributed, hence why we used Kryger Jensen and Lange test only [27], 2) statistical handling of mortality was not clearly speci ed; we primarily used adjusted logistic regression models with G-computation and non-parametric bootstrapping, 3) we added secondary analyses in survivors only, 4) we added best-worst and worst-best case scenario sensitivity analyses for missing data despite Little's test rejected data being missing completely at random (described in detail, with reasoning, in ESM1).…”

“…Analyses were performed using R (R Core Team, Foundation for Statical Computing, Vienna, Austria), versions 4.2.0 and 4.2.1. P-values below 0.01 were considered statistically signi cant due to multiple testing [11].…”

“…The Conservative vs. Liberal Approach to Fluid Therapy of Septic Shock in Intensive Care (CLASSIC) trial assessed IV uid restriction vs. standard IV uid therapy and found similar mortality and other outcomes in the two intervention groups at 90 days [6]. In this report, we present the results of the pre-planned assessment of mortality, HRQoL and cognitive function at 1 year in the CLASSIC trial [11]. We hypothesised that uid restriction would improve long-term outcomes.…”