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The New England Journal of Medicine Dec 2018There are conflicting data on the effects of antipsychotic medications on delirium in patients in the intensive care unit (ICU). (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
There are conflicting data on the effects of antipsychotic medications on delirium in patients in the intensive care unit (ICU).
METHODS
In a randomized, double-blind, placebo-controlled trial, we assigned patients with acute respiratory failure or shock and hypoactive or hyperactive delirium to receive intravenous boluses of haloperidol (maximum dose, 20 mg daily), ziprasidone (maximum dose, 40 mg daily), or placebo. The volume and dose of a trial drug or placebo was halved or doubled at 12-hour intervals on the basis of the presence or absence of delirium, as detected with the use of the Confusion Assessment Method for the ICU, and of side effects of the intervention. The primary end point was the number of days alive without delirium or coma during the 14-day intervention period. Secondary end points included 30-day and 90-day survival, time to freedom from mechanical ventilation, and time to ICU and hospital discharge. Safety end points included extrapyramidal symptoms and excessive sedation.
RESULTS
Written informed consent was obtained from 1183 patients or their authorized representatives. Delirium developed in 566 patients (48%), of whom 89% had hypoactive delirium and 11% had hyperactive delirium. Of the 566 patients, 184 were randomly assigned to receive placebo, 192 to receive haloperidol, and 190 to receive ziprasidone. The median duration of exposure to a trial drug or placebo was 4 days (interquartile range, 3 to 7). The median number of days alive without delirium or coma was 8.5 (95% confidence interval [CI], 5.6 to 9.9) in the placebo group, 7.9 (95% CI, 4.4 to 9.6) in the haloperidol group, and 8.7 (95% CI, 5.9 to 10.0) in the ziprasidone group (P=0.26 for overall effect across trial groups). The use of haloperidol or ziprasidone, as compared with placebo, had no significant effect on the primary end point (odds ratios, 0.88 [95% CI, 0.64 to 1.21] and 1.04 [95% CI, 0.73 to 1.48], respectively). There were no significant between-group differences with respect to the secondary end points or the frequency of extrapyramidal symptoms.
CONCLUSIONS
The use of haloperidol or ziprasidone, as compared with placebo, in patients with acute respiratory failure or shock and hypoactive or hyperactive delirium in the ICU did not significantly alter the duration of delirium. (Funded by the National Institutes of Health and the VA Geriatric Research Education and Clinical Center; MIND-USA ClinicalTrials.gov number, NCT01211522 .).
Topics: Aged; Antipsychotic Agents; Critical Illness; Delirium; Dopamine Antagonists; Double-Blind Method; Female; Haloperidol; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Piperazines; Respiratory Insufficiency; Shock; Thiazoles; Treatment Failure
PubMed: 30346242
DOI: 10.1056/NEJMoa1808217 -
Palliative & Supportive Care Aug 2015The aim of this study was to compare the efficacy and side-effect profile of the typical antipsychotic haloperidol with that of the atypical antipsychotics risperidone,... (Comparative Study)
Comparative Study
OBJECTIVE
The aim of this study was to compare the efficacy and side-effect profile of the typical antipsychotic haloperidol with that of the atypical antipsychotics risperidone, olanzapine, and aripiprazole in the management of delirium.
METHOD
The Memorial Delirium Assessment Scale (MDAS), the Karnofsky Performance Status (KPS) scale, and a side-effect rating were recorded at baseline (T1), after 2-3 days (T2), and after 4-7 days (T3). Some 21 cases were case-matched by age, preexisting dementia, and baseline MDAS scores, and subsequently analyzed.
RESULTS
The baseline characteristics of the medication groups were not different: The mean age of the patients ranged from 64.0 to 69.6 years, dementia was present in between 23.8 and 28.6%, and baseline MDAS scores were 19.9 (haloperidol), 18.6 (risperidone), 19.4 (olanzapine), and 18.0 (aripiprazole). The doses of medication at T3 were 5.5 mg haloperidol, 1.3 mg risperidone, 7.1 mg olanzapine, and 18.3 mg aripiprazole. Over one week, the decline in MDAS scores between medications was equal, and no differences between individual MDAS scores existed at T2 or T3. After one week, the MDAS scores were 6.8 (haloperidol), 7.1 (risperidone), 11.7 (olanzapine), and 8.3 (aripiprazole). At T2, delirium resolution occurred in 42.9-52.4% of cases and at T3 in 61.9-85.7%; no differences in assessments between medications existed. Recorded side effects were extrapyramidal symptoms (EPSs) in haloperidol- and risperidone-managed patients (19 and 4.8%, respectively) and sedation with olanzapine (28.6%).
SIGNIFICANCE OF RESULTS
Haloperidol, risperidone, aripiprazole, and olanzapine were equally effective in the management of delirium; however, they differed in terms of their side-effect profile. Extrapyramidal symptoms were most frequently recorded with haloperidol, and sedation occurred most frequently with olanzapine.
Topics: Aged; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Delirium; Dementia; Female; Haloperidol; Humans; Male; Middle Aged; Olanzapine; Risperidone
PubMed: 25191793
DOI: 10.1017/S1478951514001059 -
Annals of Emergency Medicine Dec 2021We hypothesized that the use of intramuscular ketamine would result in a clinically relevant shorter time to target sedation. (Randomized Controlled Trial)
Randomized Controlled Trial
STUDY OBJECTIVE
We hypothesized that the use of intramuscular ketamine would result in a clinically relevant shorter time to target sedation.
METHODS
We conducted a randomized clinical trial comparing the rapidity of onset, level of sedation, and adverse effect profile of ketamine compared to a combination of midazolam and haloperidol for behavioral control of emergency department patients with severe psychomotor agitation. We included patients with severe psychomotor agitation measured by a Richmond Agitation Score (RASS) ≥+3. Patients in the ketamine group were treated with a 5 mg/kg intramuscular injection. Patients in the midazolam and haloperidol group were treated with a single intramuscular injection of 5 mg midazolam and 5 mg haloperidol. The primary outcome was the time, in minutes, from study medication administration to adequate sedation, defined as RASS ≤-1. Secondary outcomes included the need for rescue medications and serious adverse events.
RESULTS
Between June 30, 2018, and March 13, 2020, we screened 308 patients and enrolled 80. The median time to sedation was 14.7 minutes for midazolam and haloperidol versus 5.8 minutes for ketamine (difference 8.8 minutes [95% confidence interval (CI) 3.0 to 14.5]). Adjusted Cox proportional model analysis favored the ketamine arm (hazard ratio 2.43, 95% CI 1.43 to 4.12). Five (12.5%) patients in the ketamine arm and 2 (5.0%) patients in the midazolam and haloperidol arm experienced serious adverse events (difference 7.5% [95% CI -4.8% to 19.8%]).
CONCLUSION
In ED patients with severe agitation, intramuscular ketamine provided significantly shorter time to adequate sedation than a combination of intramuscular midazolam and haloperidol.
Topics: Adult; Anesthetics, Dissociative; Canada; Female; Haloperidol; Humans; Hypnotics and Sedatives; Injections, Intramuscular; Ketamine; Male; Midazolam; Middle Aged; Psychomotor Agitation
PubMed: 34353650
DOI: 10.1016/j.annemergmed.2021.05.023 -
Journal of Clinical Anesthesia Feb 2021Delirium is frequently observed in the postoperative and intensive care unit (ICU) population. Due to the multifactorial origin of delirium and according to... (Randomized Controlled Trial)
Randomized Controlled Trial
Ketamine vs. haloperidol for prevention of cognitive dysfunction and postoperative delirium: A phase IV multicentre randomised placebo-controlled double-blind clinical trial.
STUDY OBJECTIVE
Delirium is frequently observed in the postoperative and intensive care unit (ICU) population. Due to the multifactorial origin of delirium and according to international guidelines (e.g., American Geriatrics Society; Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption (PADIS) guideline), there are several but no incontestable options for prevention and symptomatic treatment. The purpose of the Baden PRIDe (Prevention and Reduction of Incidence of postoperative Delirium) trial was to determine whether postoperative cognitive dysfunction and delirium could be prevented by the combination of possible preventive agents such as haloperidol and ketamine. In addition, pre- and postoperative levels of the biomarkers cortisol, neuron specific enolase (NSE) and S100β were measured to investigate their dynamics in delirious and non-delirious patients after surgery.
DESIGN
The Baden PRIDe Trial was an investigator-initiated, phase IV, two-centre, randomised, placebo-controlled, double-blind clinical trial.
SETTING
Perioperative care.
PATIENTS
182 adult patients that underwent elective or emergency surgery under general or combined (i.e., general and regional) anaesthesia.
INTERVENTIONS
Pre-anaesthetic, pharmacologic prevention of postoperative brain dysfunction with haloperidol, ketamine, and the combination of both vs. placebo.
MEASUREMENTS
Assessment of cognitive performance pre- and postoperatively with the MMSE, the DOS, the Nursing Delirium Screening Scale (Nu-DESC) or the Intensive Care Delirium Screening Checklist (ICDSC) during ICU stay.
MAIN RESULTS
None of the three study arms - haloperidol, ketamine, or both drugs combined - was significantly superior to placebo for prevention of postoperative brain dysfunction and delirium (P = 0.39). Measured levels of postoperative cortisol were significantly higher in delirious patients. S-100β levels were significantly higher in all postoperative outcome groups (cognitive impairment, delirium, no cognitive decline), whereas postoperative NSE levels declined in all groups.
CONCLUSIONS
The study results offer no possibility for a novel recommendation for prevention of postoperative cognitive decline including delirium. Perioperative S-100β trajectories in patients with cognitive deterioration suggest affection of glial cells in particular.
TRIAL REGISTRATION
ClinicalTrials.govNCT02433041; registered on April 7, 2015.
Topics: Adult; Cognitive Dysfunction; Delirium; Double-Blind Method; Haloperidol; Humans; Ketamine
PubMed: 33120302
DOI: 10.1016/j.jclinane.2020.110099 -
Pharmacopsychiatry Mar 2023Thyrotropin-releasing hormone (TRH), at doses lower than those needed to stimulate prolactin secretion directly, can almost completely antagonize dopamine inhibition of... (Review)
Review
Thyrotropin-releasing hormone (TRH), at doses lower than those needed to stimulate prolactin secretion directly, can almost completely antagonize dopamine inhibition of prolactin release. In normal men, prolactin increases 15 min following an i. v. bolus of 12.5 µg TRH (the mini-TRH test), but not the maximal prolactin response to TRH or basal prolactin, positively correlated with prolactin response to haloperidol and negatively with 24-h urinary excretion of homovanillic acid (HVA). These results suggest that the mini-TRH test is a better estimate of dopamine inhibition of prolactin release than the maximal prolactin response or basal prolactin level. A recent neuroimaging study suggested that in schizophrenia, there is a widely distributed defect in extrastriatal dopamine release, but the patients were not in the most acute phase of psychosis. The evidence is reviewed that this defect extends to tuberoinfundibular dopamine (TIDA) and which symptoms are associated with the test. In patients with acute nonaffective psychosis, the mini-TRH test positively correlated with nonparanoid delusions and memory dysfunction, indicating decreased dopamine transmission in association with these symptoms. In patients with acute drug-naïve first-episode schizophrenia, the mini-TRH test negatively correlated with negative disorganization symptoms and with basal prolactin. The latter correlation suggests the contribution of factors related to maximal prolactin stimulation by TRH; therefore, an alternative dose of 6.25 μg TRH could be used for the mini-TRH test in first-episode patients, allowed by increased sensitivity of the present prolactin tests. Future studies are needed to investigate whether the mini-TRH test could help in finding the optimal antipsychotic medication.
Topics: Male; Humans; Dopamine; Prolactin; Thyrotropin-Releasing Hormone; Haloperidol; Schizophrenia
PubMed: 36495238
DOI: 10.1055/a-1978-8348 -
JAMA Psychiatry May 2019Although several pharmacological interventions for delirium have been investigated, their overall benefit and safety remain unclear. (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Although several pharmacological interventions for delirium have been investigated, their overall benefit and safety remain unclear.
OBJECTIVE
To evaluate evidence regarding pharmacological interventions for delirium treatment and prevention.
DATA SOURCES
PubMed, Embase, ProQuest, ScienceDirect, Cochrane Central, Web of Science, ClinicalKey, and ClinicalTrials.gov from inception to May 17, 2018.
STUDY SELECTION
Randomized clinical trials (RCTs) examining pharmacological interventions for delirium treatment and prevention.
DATA EXTRACTION AND SYNTHESIS
To extract data according to a predetermined list of interests, the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines were applied, and all meta-analytic procedures were conducted using a random-effects model.
MAIN OUTCOMES AND MEASURES
The primary outcomes were treatment response in patients with delirium and the incidence of delirium in patients at risk of delirium.
RESULTS
A total of 58 RCTs were included, in which 20 RCTs with 1435 participants (mean age, 63.5 years; 65.1% male) compared the outcomes of treatment and 38 RCTs with 8168 participants (mean age, 70.2 years; 53.4% male) examined the prevention of delirium. A network meta-analysis demonstrated that haloperidol plus lorazepam provided the best response rate for delirium treatment (odds ratio [OR], 28.13; 95% CI, 2.38-333.08) compared with placebo/control. For delirium prevention, the ramelteon, olanzapine, risperidone, and dexmedetomidine hydrochloride groups had significantly lower delirium occurrence rates than placebo/control (OR, 0.07; 95% CI, 0.01-0.66 for ramelteon; OR, 0.25; 95% CI, 0.09-0.69 for olanzapine; OR, 0.27; 95% CI, 0.07-0.99 for risperidone; and OR, 0.50; 95% CI, 0.31-0.80 for dexmedetomidine hydrochloride). None of the pharmacological treatments were significantly associated with a higher risk of all-cause mortality compared with placebo/control.
CONCLUSIONS AND RELEVANCE
This network meta-analysis demonstrated that haloperidol plus lorazepam might be the best treatment and ramelteon the best preventive medicine for delirium. None of the pharmacological interventions for treatment or prophylaxis increased the all-cause mortality.
Topics: Antipsychotic Agents; Delirium; Drug Therapy, Combination; Haloperidol; Humans; Indenes; Lorazepam; Network Meta-Analysis; Treatment Outcome
PubMed: 30810723
DOI: 10.1001/jamapsychiatry.2018.4365 -
Ugeskrift For Laeger Apr 2017
Topics: Aggression; Antipsychotic Agents; Drug Therapy, Combination; Haloperidol; Humans; Promethazine; Psychotic Disorders
PubMed: 28416057
DOI: No ID Found -
Molecular Psychiatry Aug 2023Antipsychotic drugs differ in their propensity to cause extrapyramidal side-effects (EPS), but their dose-effects are unclear. Therefore, we conducted a systematic... (Meta-Analysis)
Meta-Analysis
Antipsychotic drugs differ in their propensity to cause extrapyramidal side-effects (EPS), but their dose-effects are unclear. Therefore, we conducted a systematic review and dose-response meta-analysis. We searched multiple electronic databases up to 20.02.2023 for fixed-dose studies investigating 16 second-generation antipsychotics and haloperidol (all formulations and administration routes) in adults with acute exacerbations of schizophrenia. The primary outcome was the number of participants receiving antiparkinsonian medication, and if not available, the number of participants with extrapyramidal side-effects (EPS) and the mean scores of EPS rating scales were used as proxies. The effect-size was odds ratio (ORs) compared with placebo. One-stage random-effects dose-response meta-analyses with restricted cubic splines were conducted to estimate the dose-response curves. We also examined the relationship between dopamine D receptor (DR) occupancy and ORs by estimating occupancies from administrated doses. We included data from 110 studies with 382 dose arms (37193 participants). Most studies were short-term with median duration of 6 weeks (range 3-26 weeks). Almost all antipsychotics were associated with dose-dependent EPS with varied degrees and the maximum ORs ranged from OR = 1.57 95%CI [0.97, 2.56] for aripiprazole to OR = 7.56 95%CI [3.16, 18.08] for haloperidol at 30 mg/d. Exceptions were quetiapine and sertindole with negligible risks across all doses. There was very low quality of findings for cariprazine, iloperidone, and zotepine, and no data for clozapine. The DR occupancy curves showed that the risk increased substantially when DR occupancy exceeded 75-85%, except for DR partial agonists that had smaller ORs albeit high DR occupancies. In conclusion, we found that the risk of EPS increases with rising doses and differs substantially in magnitude among antipsychotics, yet exceptions were quetiapine and sertindole with negligible risks. Our data provided additional insights into the current DR therapeutic window for EPS.
Topics: Adult; Humans; Antipsychotic Agents; Quetiapine Fumarate; Haloperidol; Clozapine; Receptors, Dopamine D2; Drug-Related Side Effects and Adverse Reactions
PubMed: 37537284
DOI: 10.1038/s41380-023-02203-y -
Medical Principles and Practice :... 2018The aim of this systematic review and meta-analysis was to investigate whether or not the use of haloperidol could reduce the incidence of delirium in adult patients. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
The aim of this systematic review and meta-analysis was to investigate whether or not the use of haloperidol could reduce the incidence of delirium in adult patients.
SUBJECTS AND METHODS
PubMed, Embase, the Cochrane Library, Elsevier, Wiley, and Ovid were searched for randomized controlled trials and prospective interventional cohort studies that compared haloperidol with placebo for delirium prophylaxis or with second generation antipsychotics for delirium treatment. The primary end point was the incidence and severity of delirium. After reviewing 272 relevant articles, 10 studies with 1,861 patients were finally included (haloperidol vs. placebo in 8 studies [n = 1,734], and haloperidol vs. second-generation antipsychotics in 2 studies [n = 127]). Revman 5.3 was used for the data analysis.
RESULTS
Compared with placebo, a high dose of prophylactic haloperidol (≥5 mg/day) may help reduce the incidence of delirium in surgical patients (risk ratio 0.50, 95% CI 0.32, 0.79). There were no differences in the duration of delirium, QTc interval prolongation, extrapyramidal symptoms, intensive care unit stay, hospital stay, or mortality between the haloperidol and placebo groups. For delirium treatment, haloperidol exhibited similar effects as the second-generation antipsychotics.
CONCLUSIONS
In this study, the limited available data revealed that prophylaxis haloperidol at a dose of ≥5 mg/day might help reduce delirium in adult surgical patients. Further outcome studies with larger sample sizes are required to confirm these findings.
Topics: Adult; Antipsychotic Agents; Delirium; Female; Haloperidol; Humans; Male; Postoperative Complications
PubMed: 29518791
DOI: 10.1159/000488243 -
The Cochrane Database of Systematic... Jan 2009Chronic amphetamine users may have experience of paranoia and hallucination. It has long been believed that dopamine antagonists, such as chlorpromazine, haloperidol,... (Review)
Review
BACKGROUND
Chronic amphetamine users may have experience of paranoia and hallucination. It has long been believed that dopamine antagonists, such as chlorpromazine, haloperidol, and thioridazine, are effective for the treatment of amphetamine psychosis.
OBJECTIVES
To evaluate risks, benefits, costs of treatments for amphetamine psychosis.
SEARCH STRATEGY
MEDLINE (1966-2007), EMBASE (1980-2007), CINAHL (1982-2007), PsychINFO (1806-2007), CENTRAL (Cochrane Library 2008 issue 1), references of obtained articles.
SELECTION CRITERIA
All randomised controlled and clinical trials (RCTs, CCTs) evaluating treatments (alone or combined) for people with amphetamine psychosis
DATA COLLECTION AND ANALYSIS
Two authors evaluated and extracted the data independently. Dichotomous data were extracted on an intention-to-treat basis in which the dropouts were assigned as participants with the worst outcomes. The Relative Risk (RR) with the 95% confidence interval (95% CI) was used to assess the dichotomous data. The Weighted Mean Difference (WMD) with 95% CI was used to assess the continuous data.
MAIN RESULTS
The comprehensive searches found one randomised controlled trial of treatment for amphetamine psychosis meeting the criteria for considering studies. The study involved 58 participants and compared the efficacy and tolerability of two antipsychotic drugs, olanzapine (a newer antipsychotic) and haloperidol (a commonly used antipsychotic medication used as a control condition), in treating amphetamine-induced psychosis. The results show that both olanzapine and haloperidol at clinically relevant doses were efficacious in resolving psychotic symptoms, with the olanzapine condition showing significantly greater safety and tolerability than the haloperidol control as measured by frequency and severity of extrapyramidal symptoms.
AUTHORS' CONCLUSIONS
Only one RCT of treatment for amphetamine psychosis has been published. Outcomes from this trial indicate that antipsychotic medications effectively reduce symptoms of amphetamine psychosis, the newer generation and more expensive antipsychotic medication, olanzapine, demonstrates significantly better tolerability than the more affordable and commonly used medication, haloperidol.There are other two studies that did not meet the inclusion criteria for this review. The results of these two studies show that agitation and some psychotic symptoms may be abated within an hour after antipsychotic injection.Whether this limited evidence can be applied for amphetamine psychotic patients is not yet known.The medications that should be further investigate are conventional antipsychotics, newer antipsychotics and benzodiazepines. However, naturalistic studies of amphetamine psychotic symptoms and the prevalence of relapse to psychosis in the presence of amphetamine, are also crucial for advising the development of study designs appropriate for further treatment studies of amphetamine psychosis.
Topics: Amphetamine-Related Disorders; Antipsychotic Agents; Benzodiazepines; Haloperidol; Humans; Olanzapine; Psychoses, Substance-Induced
PubMed: 19160215
DOI: 10.1002/14651858.CD003026.pub3