TRANSLATING RESEARCH INTO PRACTICE
Rajesh R. Tampi, MD, MS, DFAPA, DFAAGP, Column Editor
A month-to-month column devoted to reviewing the literature and sharing medical implications.
Delirium is a standard neuropsychiatric situation in sufferers with vital sickness that’s characterised by acute cognitive and attentional disturbances. It’s related to poor outcomes, together with extended hospitalization, elevated mortality, and long-term cognitive impairment. Administration primarily focuses on figuring out and addressing underlying causes. Antipsychotics are ceaselessly used to handle the agitation and psychosis seen in sufferers with delirium. Nevertheless, antipsychotic use just isn’t with out its dangers. One of many extra regarding opposed results is cardiac arrhythmia together with QTc prolongation. This secondary evaluation of a randomized managed trial assesses the cardiac security of utilizing antipsychotics in sufferers with vital sickness.
The Examine
Stollings JL, Boncyk CS, Birdrow CI, et al. Antipsychotics and the QTc interval throughout delirium within the intensive care unit: a secondary evaluation of a randomized medical trial. JAMA Netw Open. 2024;7(1):e2352034.
Examine Funding
This research was funded by the Nationwide Institutes of Well being grants and the Veterans Affairs Geriatric Analysis Training and Clinic Heart.
Examine Aims
To guage whether or not the administration of intravenous (IV) haloperidol and ziprasidone is related to QTc interval prolongation in sufferers with vital sickness and delirium.
Methodology
This research was a secondary evaluation of a randomized, double-blind, placebo-controlled, part 3 intention-to-treat trial (MIND-USA) performed at 16 medical facilities in america. The affected person inhabitants included intensive care unit (ICU) sufferers aged 18 years or older with a analysis of delirium, confirmed utilizing the Confusion Evaluation Technique for the ICU. Individuals had been random 1:1:1 to obtain placebo, IV haloperidol, or IV ziprasidone. Doses had been administered each 12 hours and both doubled or halved based mostly on the presence or absence of delirium.
Examine Strengths
1. This research is a big, multicenter, randomized, double-blind, placebo-controlled trial.
2. The research investigated antipsychotic use at a better QTc threshold (550 ms) than is commonly utilized in medical follow.
3. Frequent QTc monitoring (at the very least twice day by day) and extended QTc measurements with bedside telemetry had been carried out, which had been validated with 12-lead ECG.
4. The research inhabitants concerned sufferers within the ICU with acute and extreme comorbid sickness.
5. A excessive most dosing vary (as much as 20 mg/day of haloperidol and 40 mg/day of ziprasidone) was used.
Examine Weaknesses
1. There isn’t any file of concomitant drugs, electrolyte abnormalities, or arrhythmias (ie, atrial fibrillation, bundle department block).
2. IV ziprasidone was used to keep up blinding. This route is never utilized in medical follow.
3. There was no standardization of ECG gear throughout websites.
4. The Bazett formulation was used, which overestimates QTc at excessive coronary heart charges and underestimates QTc at low coronary heart charges.
5. The research used a variety of antipsychotic dosing (minimal of 1.25 mg and a pair of.5 mg twice day by day of haloperidol and ziprasidone, respectively), and prior proof suggests there might be a dose-dependent impact of antipsychotics on QTc prolongation.
For this secondary evaluation of the MIND-USA trial, the first end result was the median change in QTc interval between days 1 and a pair of. Secondary outcomes included impact of remedy group on submit randomization day 2 most predose QTc interval, correlation between bedside telemetry and electrocardiogram (ECG) measurements, incidence of ventricular arrhythmias, and affiliation of intercourse and QTc interval on day 2 of remedy. The authors additionally checked out day by day predose and postdose QTc intervals, in addition to affected person elements that will affect the preliminary postdose QTc interval.
Examine Outcomes
A complete of 566 sufferers had been included within the research, with 192 randomly assigned to IV haloperidol, 190 randomly assigned to IV ziprasidone, and 184 randomly assigned to placebo. Baseline demographic traits had been related throughout teams. The median age was 60.1 years (IQR, 51.4-68.7), and 323 of the contributors had been males (57%). Prerandomization QTc intervals had been related within the 3 remedy teams: haloperidol, 458.0 ms (IQR, 432.0-479.0); ziprasidone, 451.0 ms (IQR, 424.0-472.0); and placebo, 452.0 ms (IQR, 432.0-472.0). Throughout all teams, 8% of the sufferers had the drug held due to QTc prolongation, with this occasion occurring extra generally within the teams receiving an antipsychotic (placebo, 5%; haloperidol, 7%; and ziprasidone, 11%).
The median QTc interval modifications from day 1 to day 2 had been as follows: haloperidol, −1.0 ms (IQR, −28.0 to fifteen.0); ziprasidone, 0 ms (IQR, −23.0 to twenty.0); and placebo, −3.5 ms (IQR, −24.8 to 17.0).
The median publicity days to the research drug throughout teams was 4.0 (IQR, 3.0-7.0), with related delirium period throughout teams: haloperidol, 4.0 days (IQR, 2.0-7.0); ziprasidone, 4.0 days (IQR, 2.0-6.0); and placebo, 4.0 days (IQR, 2.0-8.0). After controlling for baseline covariates, neither haloperidol (OR, 0.95; 95% CI, 0.66-1.37; P = .78) nor ziprasidone (OR, 1.09; 95% CI, 0.75-1.57; P = .78) had a major distinction in most predose QTc interval on research day 2 in comparison with placebo.
Among the many subset of sufferers who had a predose and postdose QTc measured, there was no vital distinction in preliminary postdose QTc interval between the three teams and no change in QTc interval for haloperidol (OR, 1.26; 95% CI, 0.74-2.15; P = .58) or ziprasidone (OR, 1.30; 95% CI, 0.76-2.23; P = .58) in comparison with placebo.
The impact of remedy on day 2 most QTc interval was not modified by intercourse (P = .41 for interplay). The median of the imply predose QTc interval for all days throughout the intervention interval was 444.0 ms (IQR, 420.5-470.0) within the haloperidol group, 445.0 ms (IQR, 419.5-465.0) within the ziprasidone group, and 442.5 ms (IQR, 421.4-469.4) within the placebo group.
There was a reasonable correlation (Spearman correlation coefficient of 0.53; P < .001) between paired measurements of bedside telemetry and ECG QTc interval values. After they differed, telemetry-measured QTc was extra typically longer, particularly with QTc intervals larger than 550 ms.
Torsade de pointes occurred twice throughout the research, each occasions within the haloperidol group. Neither occasion occurred inside 4 days of haloperidol receipt, in order that they had been deemed unrelated to the research drug. Ventricular tachycardia occurred 5 occasions on the identical day as research drug receipt (2 haloperidol recipients, 3 ziprasidone recipients) and in 1 affected person (haloperidol recipient) 1 day after research drug receipt. Ventricular tachycardia and ventricular fibrillation occurred 1 day after research drug receipt (1 ziprasidone recipient), and ventricular fibrillation occurred 2 days after research drug receipt (1 ziprasidone recipient). Nevertheless, the research drug was not discontinued on account of any of those occasions as a result of the medical group didn’t decide these occasions to be related to research drug administration.
Conclusions
Acute agitation and psychosis can happen in delirium, resulting in pharmacologic intervention, together with antipsychotic use. This research suggests the usage of IV haloperidol and ziprasidone in sufferers with extreme medical sickness and QTc intervals as much as 550 ms could also be protected and effectively tolerated.
Sensible Purposes
When managing neuropsychiatric disturbances of delirium pharmacologically, clinicians might use IV antipsychotics. This research offers proof that IV haloperidol or ziprasidone could be safely administered to hospitalized sufferers with QTc intervals as much as 550 ms with a low baseline danger of QTc prolongation.
Backside Line
This secondary evaluation of a randomized, double-blind, placebo-controlled medical trial discovered no proof that haloperidol or ziprasidone brought on clinically related QTc interval modifications or ventricular arrhythmias in sufferers with vital sickness and delirium, and comparatively low baseline danger for QTc prolongation.
Dr Robak is a third-year psychiatry resident at Creighton College in Omaha, Nebraska. Dr Modi is a first-year psychiatry resident at Creighton College.
Dr Schuster is a fourth-year psychiatry resident at Creighton College. Dr Mullen is an assistant professor of psychiatry at Saint Louis College Faculty of Drugs in Missouri. Dr Tampi is professor and chair of the Division of Psychiatry at Creighton College Faculty of Drugs and Catholic Well being Initiatives Well being Behavioral Well being Providers. He’s additionally an adjunct professor of psychiatry at Yale Faculty of Drugs in New Haven, Connecticut, and a member of the Psychiatric Instances editorial board.
Reference
Stollings JL, Boncyk CS, Birdrow CI, et al. Antipsychotics and the QTc interval throughout delirium within the intensive care unit: a secondary evaluation of a randomized medical trial. JAMA Netw Open. 2024;7(1):e2352034.
