Clinical Outcomes of Dantrolene in Neuroleptic Malignant Syndrome: A Nationwide Retrospective Study

Neuroleptic malignant syndrome (NMS) is a life-threatening adverse reaction to antipsychotic medications. Dantrolene is commonly used to manage NMS; however, supportive evidence from large-scale clinical studies remains limited. This study aimed to evaluate the clinical impact of early dantrolene administration in intensive care unit (ICU)-admitted patients with NMS using a nationwide inpatient database in Japan.

A retrospective cohort study was conducted using the Japanese Diagnosis Procedure Combination database from April 2010 to March 2023. Patients aged ≥ 16 years diagnosed with NMS and admitted to the ICU were included. The exposure of interest was dantrolene administration within the first 2 days of admission. The primary outcome was in-hospital mortality; secondary outcomes included ICU and hospital length of stay. Baseline adjustment between the dantrolene-treated and untreated groups was performed using two methods: propensity score matching (PSM) and generalized linear mixed models (GLMMs).

A total of 2234 patients met the inclusion criteria, including 1475 treated with dantrolene and 759 without. In both analyses, dantrolene use was associated with an increase in in-hospital mortality (adjusted OR: 2.03, 95% CI: 1.16-3.54; p = 0.01 in GLMM, adjusted OR: 1.92, 95% CI: 1.17-3.24; p = 0.01 in PSM). Dantrolene was also associated with prolonged ICU stay (mean difference: 1.66, 95% CI: 1.05-2.26; p < 0.001 in GLMM and 2.03, 95% CI: 1.31-2.76; p < 0.001 in PSM) and hospital stay (mean difference: 6.85, 95% CI: 3.48-10.21; p < 0.001 in GLMM and 6.81 days, 95% CI: 3.46-10.16; p < 0.001 in PSM). Subgroup analyses stratified by age (< 65 vs. ≥ 65 years) yielded similar trends.

In the largest study of NMS to date, early initiation of dantrolene was associated with higher in-hospital mortality and prolonged ICU/hospital stay. These findings suggest that routine use of dantrolene in NMS should be reevaluated.