Restrictive versus standard IV fluid therapy in adult ICU patients with septic shock—Bayesian analyses of the CLASSIC trial

Abstract

BackgroundThe CLASSIC trial assessed the effects of restrictive versus standard intravenous (IV) fluid therapy in adult intensive care unit (ICU) patients with septic shock. This pre‐planned study provides a probabilistic interpretation and evaluates heterogeneity in treatment effects (HTE).MethodsWe analysed mortality, serious adverse events (SAEs), serious adverse reactions (SARs) and days alive without life‐support within 90 days using Bayesian models with weakly informative priors. HTE on mortality was assessed according to five baseline variables: disease severity, vasopressor dose, lactate levels, creatinine values and IV fluid volumes given before randomisation.ResultsThe absolute difference in mortality was 0.2%‐points (95% credible interval: −5.0 to 5.4; 47% posterior probability of benefit [risk difference <0.0%‐points]) with restrictive IV fluid. The posterior probabilities of benefits with restrictive IV fluid were 72% for SAEs, 52% for SARs and 61% for days alive without life‐support. The posterior probabilities of no clinically important differences (absolute risk difference ≤2%‐points) between the groups were 56% for mortality, 49% for SAEs, 90% for SARs and 38% for days alive without life‐support. There was 97% probability of HTE for previous IV fluid volumes analysed continuously, that is, potentially relatively lower mortality of restrictive IV fluids with higher previous IV fluids. No substantial evidence of HTE was found in the other analyses.ConclusionWe could not rule out clinically important effects of restrictive IV fluid therapy on mortality, SAEs or days alive without life‐support, but substantial effects on SARs were unlikely. IV fluids given before randomisation might interact with IV fluid strategy.

Effects of IV fluid restriction according to site‐specific intensity of standard fluid treatment—protocol

“…Finally, the chosen priors may be challenged, but we deliberately chose weakly informative priors to minimise their influence consistent with previous analyses. 5,6,19,20 We have not planned sensitivity analyses with alternative priors due to the post hoc nature of the study. Notably, previous Bayesian analyses of the CLASSIC trial were robust to the selection of priors, likely due to the relatively large number of patients.…”

“…Notably, previous Bayesian analyses of the CLASSIC trial were robust to the selection of priors, likely due to the relatively large number of patients. 5 In conclusion, the outlined study will provide data on the effects of heterogeneity in treatment intensity while considering patient characteristics in critically ill adult patients with septic shock in the CLAS-SIC trial.…”

“…The outlined post hoc analyses are inspired by the Protocolized Resuscitation In Sepsis Meta-Analysis of early-goal directed therapy in sepsis 4 and previous heterogeneity of treatment effects analyses. [5][6][7] The analyses will be conducted once the protocol is accepted for publication in a peer-reviewed journal. The manuscript will be reported according to the Strengthening the Reporting of Observational Studies in Epidemiology statement 8 and the Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis statement 9 (completed checklists are included in Supporting Information S1).…”

“…We will use neutral weakly informative priors (i.e., centred on no difference between the groups) having minimal influence following the approach in previous analyses (detailed provided in the ESM). [5][6][7] Model diagnostics will be aligned with methods previously described in similar analyses. 5-7…”