Can Droperidol Be Given with Ativan 2mg and Benadryl 50mg?
Yes, droperidol can be safely combined with lorazepam (Ativan) 2mg, but adding diphenhydramine (Benadryl) 50mg to this combination is not evidence-based and may increase sedation and anticholinergic side effects without additional benefit for acute agitation.
Evidence-Based Combination Therapy
The American College of Emergency Physicians provides Level B guideline recommendations supporting combination therapy for acute agitation, but the evidence specifically addresses antipsychotic-benzodiazepine combinations, not triple-drug regimens including antihistamines 1.
Droperidol Plus Lorazepam: Supported Combination
Droperidol 5mg combined with a benzodiazepine is an established approach for acute agitation, with multiple studies demonstrating safety and efficacy 1, 2.
The combination of droperidol/midazolam achieved adequate sedation in 51.2% of patients at 10 minutes versus only 7% with haloperidol/lorazepam, demonstrating that droperidol-benzodiazepine combinations work rapidly 3.
In a large randomized trial, midazolam 5mg-droperidol 5mg was superior to droperidol 10mg or olanzapine 10mg monotherapy, with 25% more patients adequately sedated at 10 minutes 4.
The Benadryl Question: Not Evidence-Based
There is no guideline or research evidence supporting the addition of diphenhydramine to droperidol-lorazepam combinations for acute agitation 1, 5, 2.
Diphenhydramine is traditionally added to antipsychotic regimens to prevent extrapyramidal symptoms (EPS), but droperidol at 5mg doses has minimal EPS risk—only one case of dystonia was reported in the largest prospective study of 2,468 ED patients 1.
Adding diphenhydramine increases anticholinergic burden, sedation, and delirium risk without addressing the primary goal of controlling agitation 1.
Recommended Approach
For Acute Undifferentiated Agitation
Use droperidol 5mg IM/IV plus lorazepam 2mg IM/IV without diphenhydramine 1, 2.
This combination provides rapid sedation (median time 10 minutes) with complementary mechanisms of action 3.
Droperidol works faster than haloperidol when rapid sedation is required, making it preferable for severe agitation 1.
The benzodiazepine component (lorazepam 2mg) is particularly advantageous when the etiology might involve alcohol withdrawal or seizures 2.
Alternative Superior Combination
Consider droperidol 5mg plus midazolam 5mg instead of lorazepam if available 4, 3.
This combination achieved adequate sedation at 10 minutes in 64% of patients versus 29% with lorazepam alone 6.
Midazolam-droperidol required fewer additional doses and had faster time to sedation (6 minutes faster than droperidol alone) 4.
Respiratory depression was numerically lower with droperidol (12%) compared to lorazepam (48%) in one randomized trial 6.
Safety Monitoring
Cardiac Considerations
While droperidol carries an FDA black box warning for QT prolongation, large patient series (12,000+ patients) have demonstrated safety in the ED setting with no documented dysrhythmic events in patients without serious comorbidities 1.
Obtain a baseline ECG if cardiac risk factors are present, though routine ECG monitoring is not required for all patients 1.
Respiratory Monitoring
Monitor for respiratory depression, particularly with benzodiazepine combinations, though droperidol appears to cause less respiratory depression than benzodiazepines alone 6.
Patients in the droperidol/midazolam group may require oxygen supplementation (25.6% vs 9.3% with haloperidol/lorazepam), though no patients required intubation 3.
Common Pitfalls to Avoid
Do not add diphenhydramine prophylactically to prevent EPS with droperidol—the risk is minimal at standard doses and the anticholinergic burden outweighs any theoretical benefit 1.
Avoid using droperidol 10mg as initial dose—patients receiving 5mg required less rescue sedation (9.6%) than those receiving 10mg (14.8%) 7.
Do not use this combination if anticholinergic or sympathomimetic toxicity is suspected, as antipsychotics can worsen agitation in these scenarios 2.