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If you were called to help with a patient in the intensive care unit who was agitated and out of it, what would you recommend? Well, of course, first you’d try to determine the basis of those symptoms, and at some point you’d assess for delirium using standard screening tools, like the Confusion Assessment Method for the ICU or the Intensive Care Delirium Screening Checklist. If you were to conclude that delirium was indeed present and clearly problematic, then what? Well, if you’d recommend an antipsychotic, you’d not be alone. Haloperidol is used in about half of all intensive care unit patients with delirium, according to an international cohort study in 2018. And yet, did you know that there’s actually only 1 placebo-controlled trial of haloperidol for this purpose?
Hi! Jim Phelps here for the Psychopharmacology Institute. Let’s look at a new randomized trial from the New England Journal of Medicine comparing haloperidol and placebo for ICU delirium. If the answer was yes, sure enough, it is better than placebo, well, that would be kind of boring, wouldn’t it? Just affirming what you perhaps would have recommended? Well, that’s not what was found. So, we’d better look at dosages used and outcome measures. In that order, the dosage was 2.5 mg of haloperidol intravenously once daily with an option to repeat the dose up to a total of 20 mg of haloperidol daily. Placebo was given in the same volume—0.5 mL with a parallel maximum of 4 mL total per day. Remarkably, the median daily dose of haloperidol was 8 mg, 3–4 doses in 24 hours for a median of 3 days while in the ICU, with virtually identical dosing of placebo, 3–4 doses per 24 hours for a median of 3 days.
The primary outcome measure was “days alive and out of hospital in the following 90 days.” Did haloperidol get people out of the hospital faster? Well, a little. Patients receiving haloperidol had 36 days out of hospital and alive in the following 90 days vs 33 days in the patients who got placebo instead of haloperidol in the ICU. This is a slight advantage for haloperidol, but this was not statistically significant in this sample of roughly 1,000 patients. And yes, it is notable that the investigators were able to randomize 1,000 patients. The study was conducted in 16 intensive care units across different Scandinavian and European countries.
How about mortality? Was the outcome worse for patients receiving haloperidol? No, as 36% percent of patients who received haloperidol died vs 43% of those receiving placebo. The length of stay in the intensive care unit was a tad longer for haloperidol patients, 29 days vs 26.5 days. Obviously, these patients were quite ill and vulnerable. Roughly half had hypoactive delirium and half hyperactive. Interestingly, there was no statistical advantage for haloperidol even in the hyperactive subset.
In the bigger picture, recent guidelines for management of delirium in the intensive care unit based on a 2018 consensus of opinion from specialists in critical care medicine discourage the routine use of antipsychotics in the treatment of delirium. However, they note that patients who experience significant distress due to anxiety, fearfulness, hallucinations, or delusions or patients who are agitated and might be physically harmful to themselves or others might benefit from short-term use of haloperidol or an atypical antipsychotic until those distressing symptoms resolve. However, the critical care guidelines specifically warn against the risk of the antipsychotic being continued after discharge from the intensive care unit, which was a reason for avoiding these medications in the first place. Which brings us then to an important detail in this New England Journal study: What was the duration of use, not just the dosing? And the answer: Patients were screened for delirium twice daily by a clinical staff and haloperidol or placebo was stopped when delirium was no longer present.
So, the key difference then versus the critical care guidelines? In this trial, the indication for haloperidol was delirium vs distress due to anxiety or fearfulness or delusions. Well, translating all this, haloperidol will not help resolve delirium. It should be used only for distressing or concerning symptoms of delirium and only until those symptoms resolve. Beyond that, it adds risk without improving course, and that’s the same as the recommendations in the earlier critical care consensus guidelines. So, why bother even looking at these new data? Well, remember, haloperidol is still used in about half of all cases of delirium in the intensive care unit. The strong implication from this new study is that we should be more judicious about when to use it or recommend it and more aggressive in stopping it.
For more on management of ICU patients, those 2018 critical care guidelines in the related references offer suggestions for management of pain, agitation and sleep disturbance as well.
Abstract
Haloperidol for the Treatment of Delirium in ICU Patients
Nina C Andersen-Ranberg, Lone M Poulsen, Anders Perner, Jørn Wetterslev, Stine Estrup, Johanna Hästbacka, Matt Morgan, Giuseppe Citerio, Jesus Caballero, Theis Lange, Maj-Brit N Kjær, Bjørn H Ebdrup, Janus Engstrøm, Markus H Olsen, Marie Oxenbøll Collet, Camilla B Mortensen, Sven-Olaf Weber, A Sofie Andreasen, Morten H Bestle, Bülent Uslu , Helle Scharling Pedersen , Louise Gramstrup Nielsen , Hans C Toft Boesen , Jacob V Jensen , Lars Nebrich , Kirstine La Cour , Jens Laigaard , Cecilie Haurum , Marie W Olesen , Christian Overgaard-Steensen , Bo Westergaard , Björn Brand , Gitte Kingo Vesterlund 1 Pernille Thornberg Kyhnauv 1 Vibe S Mikkelsen 1 Simon Hyttel-Sørensen 1 Inge de Haas 1 Søren R Aagaard 1 Line O Nielsen 1 Anne S Eriksen 1 Bodil S Rasmussen 1 Helene Brix 1 Thomas Hildebrandt 1 Martin Schønemann-Lund 1 Hans Fjeldsøe-Nielsen 1 Anna-Maria Kuivalainen Ole Mathiesen; AID-ICU Trial Group
Background: Haloperidol is frequently used to treat delirium in patients in the intensive care unit (ICU), but evidence of its effect is limited.
Methods: In this multicenter, blinded, placebo-controlled trial, we randomly assigned adult patients with delirium who had been admitted to the ICU for an acute condition to receive intravenous haloperidol (2.5 mg 3 times daily plus 2.5 mg as needed up to a total maximum daily dose of 20 mg) or placebo. Haloperidol or placebo was administered in the ICU for as long as delirium continued and as needed for recurrences. The primary outcome was the number of days alive and out of the hospital at 90 days after randomization.
Results: A total of 1000 patients underwent randomization; 510 were assigned to the haloperidol group and 490 to the placebo group. Among these patients, 987 (98.7%) were included in the final analyses (501 in the haloperidol group and 486 in the placebo group). Primary outcome data were available for 963 patients (97.6%). At 90 days, the mean number of days alive and out of the hospital was 35.8 (95% confidence interval [CI], 32.9 to 38.6) in the haloperidol group and 32.9 (95% CI, 29.9 to 35.8) in the placebo group, with an adjusted mean difference of 2.9 days (95% CI, -1.2 to 7.0) (P = 0.22). Mortality at 90 days was 36.3% in the haloperidol group and 43.3% in the placebo group (adjusted absolute difference, -6.9 percentage points [95% CI, -13.0 to -0.6]). Serious adverse reactions occurred in 11 patients in the haloperidol group and in 9 patients in the placebo group.
Conclusions: Among patients in the ICU with delirium, treatment with haloperidol did not lead to a significantly greater number of days alive and out of the hospital at 90 days than placebo. (Funded by Innovation Fund Denmark and others; AID-ICU ClinicalTrials.gov number, NCT03392376; EudraCT number, 2017-003829-15.).
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Reference
Andersen-Ranberg, N. C., Poulsen, L. M., Perner, A., Wetterslev, J., Estrup, S., Hästbacka, J., Morgan, M., Citerio, G., Caballero, J., Lange, T., Kjær, M. N., Ebdrup, B. H., Engstrøm, J., Olsen, M. H., Oxenbøll Collet, M., Mortensen, C. B., Weber, S. O., Andreasen, A. S., Bestle, M. H., Uslu, B., … AID-ICU Trial Group (2022). Haloperidol for the treatment of delirium in ICU patients. New England Journal of Medicine, 387(26), 2425-2435.
Related References
Devlin, J. W., Skrobik, Y., Gélinas, C., Needham, D. M., Slooter, A. J. C., Pandharipande, P. P., Watson, P. L., Weinhouse, G. L., Nunnally, M. E., Rochwerg, B., Balas, M. C., van den Boogaard, M., Bosma, K. J., Brummel, N. E., Chanques, G., Denehy, L., Drouot, X., Fraser, G. L., Harris, J. E., Joffe, A. M., … Alhazzani, W. (2018). Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Critical Care Medicine, 46(9), e825–e873.
