Mediators of neutrophil-lymphocyte ratio in the relationship between ondansetron pre-treatment and the mortality of ICU patients on mechanical ventilation: Causal mediation analysis from the MIMIC-IV database

Aims The mortality of critically ill patients undergoing mechanical ventilation (MV) is high and few strategies are available. We explored the relationship between ondansetron pre-treatment, the neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR), and mortality of ventilated patients in the intensive care unit. Methods We developed a retrospective cohort study that involved patients undergoing MV in the Multiparameter Intelligent Monitoring in Intensive Care IV (MIMIC-IV) database. Causal mediation analysis was conducted to assess the relationship of ondansetron use and mortality and to explore the potential causal pathway mediated by the NLR or PLR. The primary outcome was 28-day mortality. Results A total of 17 927 eligible patients took part in the study (5665 had taken ondansetron before MV initiation and 12 262 patients had not). The odds ratio (OR) for 28-day mortality for ondansetron use uncorrelated with the mediator (NLR, PLR) was 0.72 (95% confidence interval [CI] = 0.64-0.81, P < .001). Ondansetron was also associated with a reduction in 28-day mortality after controlling for the mediator of NLR (OR = 0.98, 95% CI = 0.97-0.99, P < .01). For the indirect effect, the NLR could explain 13.47% (95% CI = 8.59-20.54%, P < .01) of the impact of ondansetron use on 28-day mortality. The proportion mediated increased to 21.50% (95% CI = 12.36-47.44%, P < .01) for 90-day mortality. Adjusted mediation analysis revealed no suggestion of a causal mediation pathway for this effect by the PLR (P = .12). Conclusions NLR may play substantial roles in the relationship between ondansetron pre-treatment before initiation of mechanical ventilation and the reduction of death risk in ventilated patients.