Discussion
delirium, psychotic, extrapyramidal symptoms, agitation, psychotic symptoms
TORSADE DE POINTES, SECONDARY
This multi-center randomized double-blind, placebo-controlled trial aiming to assess the effect of haloperidol on DCFDs within 14 days after randomization was preliminarily halted, per DSMB advice upon planned interim analysis because of futility of reaching the predefined difference of one day in DCFDs.Our primary findings are in line with the MIND-USA and AID-ICU trial [Our findings, combined with those of Hope-ICU, encourage further research, focusing on delirium-associated symptoms, specifically those related to agitation, and the possible rescue medication-sparing effect of haloperidol rather than on delirium as a the main outcome of interest. More importantly, we feel that our results indicate that abandoning haloperidol from clinical practice to manage delirium symptoms at the ICU may not currently be warranted before further studies have definitely excluded such effects. Our findings and those from the Hope-ICU trial appear in line with current clinical experience, indicating that haloperidol might help reduce agitation in ICU patients with delirium.Interestingly, no differences were observed regarding psychotic symptoms. It is unclear whether this points to haloperidol’s intrinsic lack of effect on psychotic features in ICU delirium, or the fact that more rescue atypical antipsychotics were administered in the control group. Another explanation may be the trial’s lack of statistical power.Safety issues such as extrapyramidal symptoms, prolonged QTc interval and torsade de pointes occurred infrequently and did not differ between the two groups, consistent with the previous trials [A strength of this trial is that delirium assessments were performed three times daily. This may better facilitate the assessment of any response of fluctuating delirium symptoms to haloperidol compared with other studies [Our study has several limitations. First, this trial was prematurely terminated as advised by the DSMB partly because of randomization challenges due to the informed consent requirement (as compared to deferred consent in the AID-ICU trial), and therefore, in general all findings related to secondary outcomes should be viewed as hypothesis generating. Second, approximately 75% of all screened patients were deemed ineligible according to our exclusion criteria, which may limit external validity. Third, we did not assess actual adherence to the ABCDEF bundle during the intervention periods but only assessed estimates on adherence by the local PI’s [