Quetiapine Versus Haloperidol in the Management of Hyperactive Delirium: Randomized Controlled Trial

Zakhary et al. Neurocritical Care; Oct;41(2):550-557. doi:10.1007/s12028-024-01948-w

Clinical Question

• In critically ill patients with delirium, does quetiapine in comparison to haloperidol, reduce the severity of delirium?

Background

• Delirium affects 30-50% of adult ICU patients
• Haloperidol is licensed for the treatment of acute delirium in the UK 
  • Previous RCTs have compared haloperidol with placebo for delirium prophylaxis in ICU patients, with negative results:
    • HOPE-ICU (2013, n=142) found no improvement in delirium-free days
    • REDUCE (2018, n=1789) found no improvement in survival or delirium
  • There is more mixed evidence of possible benefit in treatment of patients with established delirium:
    • MIND-USA (2018, n=566) found no difference in the duration of delirium in a mixed cohort of hyperactive and hypoactive delirium
    • AID-ICU (2022, n=963) found no improvement in their primary composite outcome of number of days alive and out of hospital by day 90, but did note an significant mortality benefit. The same group published a pre-planned secondary Bayesian analysis on this trial that concluded that there was a high probability of benefits in both their primary outcome and mortality, as well as a (frequentist) meta-analysis of 11 RCTs comparing haloperidol with placebo, concluding that there was a likely benefit without statistical significance 
• Quetiapine is an atypical antipsychotic with a lower risk of extrapyramidal symptoms, and is used off-label for delirium 
  • Two small RCTs (Devlin et al. 2010, Kim et al. 2019) demonstrated possible benefits of giving quetiapine to ICU patients compared with placebo
• Previous RCTs comparing haloperidol and quetiapine in patients who are not on critical care have shown no differences in delirium scores or other outcomes

Design

• Single-centre double-blind randomised controlled trial
  • Double-blindness using over-encapsulation
  • 1:1 randomisation, intention-to-treat analysis
• Delirium diagnosed with Confusion Assessment Method for the ICU (CAM-ICU) and Richmond Agitation Sedation Scale (RASS). These were used for enrolment only   
• Sample size was calculated based on a pilot-trial effect of 0.653, an alpha error of 5%, and an expected power of 95% 
• The DRS-R-98 severity score was used to quantify delirium severity for the primary outcome
  • This has 13 components, each rated 0-3, leading to an overall score out of 39 (higher is worse)
  • Although this has demonstrated good reliability and validity outside of the ICU context, is a much more lengthy assessment and several of the components can be difficult to assess or affected by mechanical ventilation 
  • Unlike CAM-ICU, it gives a continuous (ordinal) score 
  • The DRS-R-98 severity score was calculated on the day of delirium diagnosis / enrolment, as well as day 3 and 7 

Setting

• Alexandria University Hospitals in Egypt 
• April to July 2023

Population

• Inclusion: Adult ICU patients admitted for any reason diagnosed with hyperactive delirium using RASS and CAM-ICU scores
• Exclusions: Lack of consent from “the patient’s legal guardian”. Substance-induced delirium. Previous use of antipsychotics. Known allergies or intolerances to study drugs. Pregnancy or breastfeeding. Acute renal injury. Hepatic failure. Any condition hindering oral medication intake. Recent central nervous system haemorrhagic or ischaemic stroke. Head trauma.
• 344 patients screened, 100 randomised 
  • 244 excluded; 74 guardians refused consent to participate, 66 “not meeting inclusion criteria”, 32 could not take oral medications, 30 had acute kidney injury, 22 were on antispychotics, 12 had hepatic failure, and 8 had substance-induced delirium
  • 100 (29%) met criteria for randomisation; 50 to the quetiapine group and 50 to the haloperidol group
• Baseline characteristics were non-significantly different between groups (quetiapine v haloperidol):
  • Age 68 vs 69
  • APACHE II 24.2 vs 24.2
  • Female sex 72% vs 48%
  • Infections: 56% vs 44%
  • CNS pathology 24% vs 12%
  • Day 1 DRS-R-98 28.0 vs 30.0
  • APACHE scores averaged 24.7 
• Overall, 60% of patients were admitted with cardiac disease, 30% had infections, 24% trauma, and 18% chest disease.  
• Unclear how many patients in each group were mechanically ventilated 

Intervention

• Quetiapine
  • Oral or nasogastric quetiapine (25-50 mg/day) titrated based on agitation symptoms

Control

• Haloperidol
  • Oral or nasogastric haloperidol (1-2 mg/day) titrated based on agitation symptoms

Management common to both groups

• All patients received a complete history, demographic data collection, physical examination, hormonal profile, and brain CT scan. Risk factors were assessed “using mnemonics”
• DRS-R-98 severity scores were calculated at days 1, 3, and 7 
• All patients “received their standard care during their hospital stay”

Outcome

• Primary outcome: “Response rate”, defined as a reduction of DRS-R-98 score by 50% or more from baseline, and DRS-R-98 severity score of 12 or less without relapse 
  • No statistically significant difference in response rate between groups (quetiapine vs haloperidol 96% v 88%, p=0.609)
• Secondary outcomes, comparing quetiapine and haloperidol:
  • Reported as significantly better in quetiapine group:
    • Length of ICU stay (10.1 days vs 11.7 days, p=0.018)
    • DRS-R-98 on day 7 (5.0 vs 9.0, p<0.001)
    • “Sleeping hours” on day 3 (3.4 hours vs 2.7 hours, p=0.038) and day 7 (6.0 hours vs 3.5 hours, p<0.001). This was measured by nurses “using a subjective method”, taking into account “periods of quiet” and “disruptions”, and rounded into hourly buckets at the patient-level
  • No significant difference in:
    • Length of hospital stay (14.3 days vs 15.4 days)
    • DRS-R-98 on day 3 (13.0 v 13.0)
    • Need for mechanical ventilation (36% vs 40%)
    • ICU mortality (16% vs 28%)
    • In-hospital mortality (16% vs 32%) 
• Safety outcomes reported were QT prolongation (1 in haloperidol group, 3 in quetiapine group) and extrapyramidal side effects (3 in haloperidol group, unclear if any in quetiapine group)

Authors’ Conclusions

• “Quetiapine may be equally as effective as haloperidol in treating the symptoms of hyperactive delirium in critically ill patients, with no mortality benefit.”

Strengths

• Randomised controlled trial
• Double-blinded
• Intention-to-treat analysis 
• Focus on the hyperactive delirium cohort, with external validity relevant to most ICU populations
• Important question given the common usage of quetiapine and haloperidol in the adult ICU setting
• Mortality, length of stay, and requirement of mechanical ventilation are meaningful and important measures

Weaknesses

• No placebo arm in a trial with a group of patients that had a very high rate of their primary outcome in both groups (88% vs 96%), and used quite low doses of antipsychotic medication
  • Haloperidol dosing was a maximum of 1-2mg orally per day in this trial, which is less than what UK guidelines in the BNF allow, and much less than the AID-ICU trial (which randomised patients to receive 2.5mg IV three times per day plus extra as needed up to 20mg per day; patients received a median of 8.3mg per day) 
  • From published dose conversion tables for psychiatric indications, the 1-2mg haloperidol dose is approximately in line with the quetiapine dosing (25-50mg) used in this trial
  • However – how well would this cohort of patients done without any antipsychotic medication?
• The authors state a sample size calculation was made based on an uncited pilot study effect size of 0.653, an alpha error of 5%, expected power of 95% 
  • The study appears designed to detect a very large improvement in response rate with quetiapine compared with haloperidol. A negative finding in this context should not generally be used as a positive statement of equivalence, as the trial may have just been underpowered to detect a smaller effect
  • It is not stated what final sample size figure was reached, nor what “effect size” means in this context of a binomial outcome (I assume relative risk)
• Unclear treatment of mechanically ventilated patients. Although 38% of patients in this trial needed mechanically ventilated at some point, it is unclear to me:
  1. How many patients in each arm were mechanically ventilated on enrolment, if any?
  2. If patients progressed to needing mechanical ventilation during the trial, was the intervention continued or discontinued? 
  3. How was the DRS-R-98 scoring amended for these patients?
  4. Has the DRS-R-98 score been validated in mechanically ventilated patients?
• The primary outcome was based on DRS-R-98 scores in just two snapshots on days 3 and 7, presumably because of how long the assessment takes. Patients’ clinical courses could easily have fluctuated significantly in this time
  • Given how infrequently we use this score in clinical practice and how difficult it is to quantitatively explain in patient-centred terms, I may have preferred CAM-ICU or other scoring that could have been done more frequently
• Excluded all patients with AKI or liver failure, which have high incidences and in whom outcomes from this study may have been useful 
• Unclear reporting of side effects, adverse effects, and reasons for discontinuation of therapy 
• Single-centre study with a fairly small sample size (100) carried out over a short period of time (April to July 2023) 

The Bottom Line

• This trial supports the use of either quetiapine or haloperidol as safe and effective options for treating hyperactive delirium in the critical care unit
• I would not personally change practice to prescribe quetiapine based on the reported reduction in secondary outcomes of ICU length of stay and hours asleep in this trial
• Given the pre-existing RCT evidence on likely mortality and morbidity benefits of haloperidol compared with placebo, I will continue to use haloperidol as first line for hyperactive delirium
• I will generally consider quetiapine in patients with contraindications to haloperidol (eg. parkinsonism), and feel reassured that on balance it probably confers similar benefits 

External Links

• article: Quetiapine Versus Haloperidol in the Management of Hyperactive Delirium: Randomized Controlled Trial
• further reading: Haloperidol for the treatment of delirium in critically ill patients: an updated systematic review with meta-analysis and trial sequential analysis
• further reading: Deranged Physiology’s Trials and Guidelines section on Antispychotics for Delrium

Metadata

Summary author: Hrisheekesh Vaidya – @hqva
Summary date: 01/11/2024
Peer-review editor: David Slessor

Picture by: Brett Sayles – Pexels.com