Frequently Asked Questions

Intravenous hydroxyzine was associated with a higher delirium improvement rate than intravenous haloperidol, while time to improvement did not significantly differ in the primary analysis. In the main cohort, delirium improvement occurred in 23.9% of patients treated with hydroxyzine (17 of 71) versus 8.5% treated with haloperidol (7 of 82), with P = .009. Mean time to delirium improvement was 7.0 days (95% CI, 5.7 38.3) with hydroxyzine and 8.2 days (95% CI, 7.6 38.8) with haloperidol, which was not statistically significant by log-rank test (P = .059) or age- and sex-adjusted Cox regression (hazard ratio 0.45, 95% CI, 0.18 31.11; P = .081).

No significant difference was shown in the primary analysis, although the results numerically favored hydroxyzine. Mean time to delirium improvement was 7.0 days with intravenous hydroxyzine versus 8.2 days with intravenous haloperidol, with a log-rank P value of .059. In Cox regression adjusted for age and sex, the hazard ratio was 0.45 (95% CI, 0.18 31.11; P = .081), so the study did not demonstrate a statistically significant difference in time to improvement.

Yes. After excluding those route-switch cases, hydroxyzine still had a higher delirium improvement rate, and the time-to-improvement comparison continued to numerically favor hydroxyzine. In that additional analysis, delirium improvement occurred in 33.3% of hydroxyzine-treated patients (17 of 51) versus 10.0% of haloperidol-treated patients (7 of 70), with P = .001. Mean time to improvement was 6.5 days (95% CI, 5.2 37.8) with hydroxyzine and 8.1 days (95% CI, 7.4 38.8) with haloperidol, with P = .055.

Delirium was defined as a positive result on the Confusion Assessment Method (CAM) or the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Nurses assessed CAM or CAM-ICU twice daily, in the morning and evening, for high-risk patients and for those with direct risk factors or suspected delirium. Improvement of delirium was defined as a negative CAM or CAM-ICU result for 3 consecutive days.

The study included hospitalized patients at Keio University Hospital from April 1, 2017, to September 30, 2022, who received intravenous hydroxyzine or intravenous haloperidol as monotherapy for treatment of delirium. Out of 5,555 patients who developed delirium during the study period, only 71 patients in the hydroxyzine group (1.3%) and 82 in the haloperidol group (1.5%) met eligibility criteria. Patients were excluded if they received concomitant delirium drugs, simultaneous intravenous hydroxyzine and haloperidol, oral hydroxyzine or haloperidol, treatment before delirium onset, treatment for reasons other than delirium, benzodiazepine withdrawal delirium, high risk of alcohol withdrawal delirium, or only 1 day of treatment.

The mean first-day dose was 29.9 mg/day for intravenous hydroxyzine and 3.3 mg/day for intravenous haloperidol. The mean maximum dose during treatment was 36.1 mg/day for hydroxyzine and 4.1 mg/day for haloperidol. These values describe how monotherapy was used in this retrospective inpatient cohort.

The authors concluded that intravenous hydroxyzine could be a promising alternative to antipsychotics for treating delirium, based on a higher improvement rate than haloperidol in this retrospective monotherapy cohort. They also stated that hydroxyzine was not inferior for time to delirium improvement and was superior for the rate of delirium improvement. However, the findings were described as preliminary, and the authors said prospective studies are needed to examine efficacy and safety.

No. The study discusses that hydroxyzine may be relatively safe and notes concern about adverse effects with haloperidol, but this study did not examine adverse events. The authors specifically stated that investigation is needed to assess the safety of hydroxyzine in patients with delirium and advised caution about drowsiness in elderly patients.

The authors proposed that hydroxyzine's sedative and anxiolytic effects may contribute to delirium improvement, although they stated that the exact mechanism is unknown. They noted that hydroxyzine crosses the blood-brain barrier, affects the tuberomammillary nucleus, and that a prior positron emission tomography study found hydroxyzine 30 mg occupied approximately 70% of histamine H1 receptors. The paper argues that histamine H1 receptor blockade may be important in the pharmacologic treatment of delirium.

The main limitations were its retrospective design, the possibility of confounding and treatment-selection bias, the lack of adjustment for the type and severity of physical illness, the very small and highly selected monotherapy sample, and the absence of adverse-event assessment. Only 71 hydroxyzine-treated patients and 82 haloperidol-treated patients were included out of 5,555 patients who developed delirium. The authors also noted an era effect, with haloperidol used in approximately 90% of cases before 2021 and hydroxyzine used in approximately 90% of cases after 2021 following introduction of an institutional delirium algorithm.