Comparative study between S-(+)-ketamine­midazolam and fentanyl­droperidol in black-tufted marmosets (Callithrix penicillata) / Estudo comparativo entre S-(+)cetamina-midazolam e fentanil-droperidol em saguis-de-tufo-preto (Callithrix penicillata)

Sedative and antinociceptive effects of two anesthetic protocols in black-tufted marmosets were compared in this study. Twenty-six marmosets underwent chemical immobilization for physical examination, blood sampling, tattooing, and microchipping. Animals were randomly treated with S-(+)-ketamine (10 mg/kg) and midazolam (1 mg/kg) (KM) or fentanyl (12.5 µg/kg) and droperidol (625 µg/kg) (FD) given by intramuscular injection. Heart and respiratory rates were recorded. Sedation, antinociception, muscle relaxation, posture, auditory, and visual responses were evaluated using a scoring system. Sedation in KM was achieved faster (p < 0.001) and lasted for a shorter period of time (p = 0.0009). KM was similar to FD in its cardiorespiratory effects, auditory and visual responses. Both protocols promoted adequate sedation to allow manipulation. Animals in KM assumed lateral recumbency while animals in FD maintained a quadrupedal posture during evaluation. FD produced less intense sedation and muscle relaxation but a higher degree of antinociception compared to KM and is suitable for procedures that require analgesia in black-tufted marmosets.(AU)

O presente estudo comparou os efeitos cardiorrespiratórios, sedativos e antinociceptivos de dois protocolos anestésicos em saguis-de-tufo-preto (Callithrix penicillata). Vinte e seis saguis foram submetidos à contenção química para exame físico, coleta de sangue, tatuagem de identificação e microchip. Os animais foram tratados aleatoriamente com a associação de S-(+)-cetamina (10 mg/kg) e midazolam (1 mg/kg) (KM) ou fentanil (12,5 µg/kg) e droperidol (625 µg/kg) (FD), administrados por injeção intramuscular. Foram avaliadas frequência cardíaca, frequência respiratória, sedação, antinocicepção, relaxamento muscular, postura e resposta ao estímulo auditivo e visual. A sedação em KM foi alcançada mais rapidamente (p <0,001) e teve um tempo hábil mais curto (p = 0,0009). KM foi semelhante a FD nos efeitos cardiorrespiratórios, respostas auditivas e visuais. Os dois protocolos promoveram sedação adequada para manipulação. Os animais do grupo KM permaneceram em decúbito lateral durante a avaliação, enquanto os animais em FD mantiveram postura quadrupedal. FD resultou em sedação e relaxamento muscular de menor intensidade, porém com maior escore de antinocicepção em comparação com KM, sendo adequada para procedimentos que requerem analgesia em saguis-de-tufo-preto.(AU)

Prospective real-time evaluation of the QTc interval variation after low-dose droperidol among emergency department patients.

OBJECTIVE: To assess the QTc interval variation after low-dose droperidol in a population of undifferentiated, stable, and non-agitated patients receiving droperidol in the emergency department. METHODS: Prospective cohort study of patients aged ≥12 years of age who received low-dose droperidol (≤ 2.5 mg) for indications other than acute behavioral disturbances. QTc intervals were monitored in real-time during pre-specified observation periods in the ED. Primary outcome was variation of QTc interval after droperidol administration, defined as the maximum delta (change) of QTc interval. Other outcomes included proportion of patients with a QTc ≥ 500 ms after droperidol, delta ≥ +60 ms, and incidence of clinical adverse events. Patients were monitored up to 30 min after IV bolus and up to 46 min after infusion. RESULTS: A total of 68 patients were included (mean age 42.1 years, 66.2% females). The median dose of droperidol was 1.875 mg (range 0.625 mg, 2.5 mg) and 94.1% received droperidol for headache management. Most patients received droperidol as a 2-min bolus (n = 41, 60.3%). The mean maximum delta of QTc interval after droperidol across all 68 patients was +29.9 ms (SD 15). A total of 12 patients (17.6%) experienced a QTc interval ≥ 500 ms during the observation period after droperidol, and 3 patients (4.4%) had a delta QTc ≥ +60 ms. There were no serious arrhythmias, such as TdP, or deaths among the 68 participants in this study (0/68). However, 13.2% (n = 9) had at least one non-serious adverse event including restlessness and/or anxiety. CONCLUSION: The QTc interval slightly increased after droperidol administration, but these prolongations were brief, mostly below 500 msec and did not lead to serious arrhythmias. The yield of continuous cardiac monitoring in patients receiving low doses of droperidol is likely low.

A Prospective Study of Intramuscular Droperidol or Olanzapine for Acute Agitation in the Emergency Department: A Natural Experiment Owing to Drug Shortages.

STUDY OBJECTIVE: Intramuscular medications are commonly used to treat agitation in the emergency department (ED). The purpose of this study is to compare intramuscular droperidol and olanzapine for treating agitation. METHODS: This was a prospective observational study of ED patients receiving intramuscular droperidol or olanzapine for acute agitation. The treating physician determined the medication and dose; however, over time drug shortages made either olanzapine (July to September 2019) or droperidol (November 2019 to March 2020) unavailable, creating a natural experiment. The primary outcome was time to adequate sedation, assessed by the Altered Mental Status Scale (AMSS), defined as time to AMSS score less than or equal to 0. RESULTS: We analyzed 1,257 patients (median age 42 years; 73% men); 538 received droperidol (median dose 5 mg) and 719 received olanzapine (median dose 10 mg). The majority of patients (1,086; 86%) had agitation owing to alcohol intoxication. Time to adequate sedation was 16 minutes (interquartile range 10 to 30 minutes) for droperidol and 17.5 minutes (interquartile range 10 to 30 minutes) for olanzapine (absolute difference -0.7 minutes; 95% confidence interval -2.1 to 0.5 minutes). Adjusted Cox proportional hazard model analysis revealed no difference between groups in time to sedation (hazard ratio for adequate sedation for droperidol compared with olanzapine 1.12; 95% confidence interval 1.00 to 1.25). Patients receiving olanzapine were more likely to receive additional medications for sedation (droperidol 17%; olanzapine 24%; absolute difference -8% [95% confidence interval -12% to -3%]). We observed no difference between drugs regarding adverse effects except for extrapyramidal adverse effects, which were more common with droperidol (n=6; 1%) than olanzapine (n=1; 0.1%). CONCLUSION: We found no difference in time to adequate sedation between intramuscular droperidol and olanzapine.

Reintegrating droperidol into emergency medicine practice.

PURPOSE: After a long period of low utilization, droperidol has become easier to obtain in the US market. This comprehensive review discusses the safety, indications, clinical efficacy, and dosing of droperidol for use in the emergency department (ED) setting. SUMMARY: In 2001 the US Food and Drug Administration (FDA) mandated a boxed warning in the labeling of droperidol after reports of QT interval prolongation associated with droperidol use. Since that time, it has been difficult to access droperidol in the United States; as a result, many practicing clinicians lack experience in its clinical use. Multiple studies have been conducted to assess the clinical efficacy and safety of droperidol use in ED patients. Results consistently show the safety of droperidol and its clinical efficacy when used as an analgesic, antiemetic, and sedative. Now that droperidol is more widely available for use in the US market, pharmacists and prescribers need to reliably translate safety and efficacy data compiled since 2001 to help ensure appropriate and effective use of the medication. CONCLUSION: Droperidol is an effective and safe option for the treatment of acute agitation, migraine, nausea, and pain for patients in the ED setting. Healthcare professionals can adopt droperidol for use in clinical practice, and they should become familiar with how to dose and monitor droperidol for safe and effective use.

The Incidence of QT Prolongation and Torsades des Pointes in Patients Receiving Droperidol in an Urban Emergency Department.

INTRODUCTION: Droperidol carries a boxed warning from the United States Food and Drug Administration for QT prolongation and torsades des pointes (TdP). After a six-year hiatus, droperidol again became widely available in the US in early 2019. With its return, clinicians must again make decisions regarding the boxed warning. Thus, the objective of this study was to report the incidence of QT prolongation or TdP in patients receiving droperidol in the ED. METHODS: Patients receiving droperidol at an urban Level I trauma center from 1997-2001 were identified via electronic health record query. All patients were reviewed for cardiac arrest. We reviewed electrocardiogram (ECG) data for both critically-ill and noncritical patients and recorded Bazett's corrected QT intervals (QTc). ECGs from critically-ill patients undergoing resuscitation were further risk-stratified using the QT nomogram. RESULTS: Of noncritical patients, 15,374 received 18,020 doses of droperidol; 2,431 had an ECG. In patients with ECGs before and after droperidol, the mean QTc was 424.3 milliseconds (ms) (95% confidence interval [CI], 419.7-428.9) before and 427.6 ms (95% CI, 424.3-430.9), after droperidol (n = 170). Regarding critically-ill patients, 1,172 received droperidol and 396 had an ECG. In the critically-ill group with ECGs before and after droperidol mean QTc was 435.7 ms (95% CI, 426.7-444.7) before and 435.8 ms (95% CI, 427.5-444.1) after droperidol (n = 114). Of 337 ECGs suitable for plotting on the QT nomogram, 13 (3.8%) were above the "at-risk" line; 3/136 (2.2%; 95% CI, 0.05-6.3%) in the before group, and 10/202 (4.9%; 95% CI, 2.4%-8.9%) in the after group. A single case of TdP occurred in a patient with multiple risk factors that did not reoccur after a droperidol rechallenge. Thus, the incidence of TdP was 1/16,546 (0.006%; 95% CI, 0.00015 - 0.03367%). CONCLUSION: We found the incidence of QTc prolongation and TdP in ED patients receiving droperidol to be extremely rare. Our data suggest the FDA "black box warning" is overstated, and that close ECG monitoring is useful only in high-risk patients.

An overview of intravenous amisulpride as a new therapeutic option for the prophylaxis and treatment of postoperative nausea and vomiting.

Introduction: Current therapies of postoperative nausea and vomiting (PONV) are based on a combination of antiemetics from different pharmacological classes. Dopamine receptor antagonists are one of the cornerstones of such multimodal antiemetic approach, with droperidol being the best studied representative of this group. Droperidol's use has significantly declined after the FDA's black-box warning in 2001 due to its QT-prolonging properties. Amisulpride is a promising antiemetic agent which could fill this gap.Areas covered: In this review, the authors discuss the pharmacological profile as well as clinical safety and efficacy of intravenous amisulpride and its relevance in the management of PONV. The article is based on a Medline, ClinicalTrials.gov, and Cochrane Library search for studies on amisulpride conducted so far.Expert opinion: Promising clinical results on Barhemsys®, an intravenous formulation of amisulpride, make it a potential future drug of choice from the dopamine receptor antagonist group, replacing droperidol after its safety concerns. Amisulpride's success on the market will mostly be determined by its cost-effectiveness and it will likely find a brighter use on the US-market, where the black-box warning led to droperidol's withdrawal, while in many European countries, droperidol is still being used as an antiemetic.

Randomized Placebo-controlled Trial of Droperidol and Ondansetron for Adult Emergency Department Patients With Nausea.

OBJECTIVE: The objective was to separately compare effectiveness of 1.25 mg of intravenous (IV) droperidol and 8 mg of IV ondansetron with 0.9% saline placebo for adult emergency department (ED) patients with nausea. A novel primary outcome measure, expected to aid clinical interpretation of reported results, was employed. METHODS: A randomized controlled trial was conducted at the three EDs of Monash Health, Melbourne, Australia. The design was to demonstrate superiority of the active drugs over placebo. The primary outcome measure of symptom improvement was defined as a visual analog scale (VAS) rating change of -8 mm or more from baseline at 30 minutes posttreatment. Mean VAS changes per group and percentages experiencing the desired treatment effect were also compared. The study was concluded after recruitment of 215 of the planned 378 patients, as interim analysis confirmed that continuation could not result in a finding of superiority. RESULTS: Of 215 patients, 73 (34%), 71 (33%), and 71 (33%) received droperidol, ondansetron, and placebo. Symptom improvement occurred in 75% (95% confidence interval [CI] = 64% to 85%), 80% (95% CI = 69% to 89%), and 76% (95% CI = 64% to 85%), respectively. Mean VAS changes were -29 mm (95% CI = -36 to -23 mm), -34 mm (95% CI = -41 to -28 mm), and -24 mm (95% CI = -29 to -19 mm), respectively. Desired treatment effects were experienced by 77% (95% CI = 65% to 86%), 73% (95% CI = 61% to 83%), and 59% (95% CI = 47% to 71%), respectively. CONCLUSION: For adult ED patients with nausea, superiority was not demonstrated for droperidol or ondansetron over placebo.

Parenteral Antipsychotic Choice and Its Association With Emergency Department Length of Stay for Acute Agitation Secondary to Alcohol Intoxication.

BACKGROUND: Acute agitation secondary to alcohol intoxication frequently requires parenteral sedatives for patient and caregiver safety. Antipsychotics play a prominent role; however, no consensus exists regarding the ideal agent. One important consideration when evaluating the choice of antipsychotic is its association with emergency department (ED) length of stay (LOS). OBJECTIVES: We sought to determine the median ED LOS for patients receiving a single parenteral dose of an antipsychotic for acute agitation secondary to alcohol intoxication in an urban Level I trauma center. METHODS: This was a retrospective review of patients receiving a single parenteral dose of droperidol, haloperidol, or olanzapine who were acutely intoxicated on alcohol from 2011 to 2016. Patients needing psychiatric assessment in our ED are discharged to a geographically separate department; thus, ED LOS is minimally impacted by waits for psychiatric assessment. Data were abstracted from the electronic medical record and are presented descriptively. RESULTS: A total of 40,601 patients were identified and screened; 24,319 patients were intoxicated but received no sedation. Of those remaining 4,495 received multiple drugs and/or benzodiazepines leaving 11,787 for analysis. Median age was 42 years, 76% were male, and 5% of patients were admitted. Mean breath ethanol concentration was 227 mg/dL. Antipsychotics administered were as follows: droperidol (n = 3,790), haloperidol (n = 1,449), and olanzapine (n = 6,548). Median ED LOS was shortest for droperidol (499 minutes, 95% confidence interval [CI] = 493-506 minutes), which was significantly shorter than both haloperidol (524 minutes, 95% CI = 515-537 minutes) and olanzapine (533 minutes, 95% CI = 528-539 minutes). No cases of sudden cardiac death occurred. CONCLUSION: Droperidol, when given as monotherapy for sedation of acute agitation secondary to alcohol intoxication, was associated with significantly shorter ED LOS than either parenteral haloperidol or parenteral olanzapine. No difference in ED LOS was observed between haloperidol and olanzapine.

Incidence of akathisia after postoperative nausea and vomiting prophylaxis with droperidol and ondansetron in outpatient surgery: A multicentre controlled randomised trial.

BACKGROUND: Akathisia, a distressing movement disorder induced by butyrophenones, has been described with low doses of droperidol used for postoperative nausea and vomiting (PONV) prophylaxis, but the incidence remains unclear. OBJECTIVES: To determine the incidence of akathisia after PONV prophylaxis with two doses of droperidol in comparison with ondansetron, in patients undergoing ambulatory surgery. We hypothesised that the incidence of akathisia is higher with droperidol than that with ondansetron. DESIGN: Randomised controlled double blind trial. SETTING: Two University Hospital Centres and two private Clinics from January to September 2014. PATIENTS: Patients (n=297) undergoing general anaesthesia for ambulatory surgery were randomly allocated to receive PONV prophylaxis with droperidol (0.625 or 1.25 mg) or ondansetron 4 mg; patients of the three groups also received 4 mg of dexamethasone. Exclusion criteria were contraindication to droperidol and ondansetron, use of psychotropic medications or benzodiazepines or history of psychotic illness. INTERVENTIONS: Participants received droperidol (0.625 or 1.25 mg) or ondansetron 4 mg during general anaesthesia. After discharge from the postanaesthesia care unit presence and severity of akathisia were assessed using the Barnes Akathisia Rating Scale at 4 h postoperatively. MAIN OUTCOME MEASURES: Score of the Global Clinical Assessment of Akathisia of Barnes Akathisia Rating Scale. RESULTS: The number of akathisia observed was 1/118 (0.8%) in the ondansetron group, 1/84 (1.2%) in droperidol 0.625 mg group, and 3/87 (3.4%) in droperidol 1.25 mg group. The akathisia rate difference among the three groups was not significant (P = 0.52). We could not demonstrate significant differences in the incidence of akathisia between the two doses of droperidol. The only case of marked akathisia treated with benzodiazepines was observed after droperidol 1.25 mg. CONCLUSION: The use of droperidol or ondansetron for PONV prophylaxis is associated to a low incidence of akathisia (0.8 to 3.4%) after general anaesthesia for ambulatory surgery. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01942343.

A Prospective Before and After Study of Droperidol for Prehospital Acute Behavioral Disturbance.

STUDY OBJECTIVE: Acute behavioral disturbance is a common problem for emergency medical services. We aimed to investigate the safety and effectiveness of droperidol compared to midazolam in the prehospital setting. METHODS: This was a prospective before and after study comparing droperidol to midazolam for prehospital acute behavioral disturbance, when the state ambulance service changed medications. The primary outcome was the proportion of adverse effects (airway intervention, oxygen saturation < 90%, respiratory rate < 12, systolic blood pressure < 90 mmHg, sedation assessment tool score -3 and dystonic reactions) in patients receiving sedation. Secondary outcomes included time to sedation, requirement for additional sedation, staff and patient injuries, and prehospital time. RESULTS: There were 141 patients administered midazolam and 149 patients administered droperidol in the study. Alcohol was the most common cause of acute behavioral disturbance. Fewer patient adverse events occurred with droperidol (11/149) compared to midazolam (33/141) (7% vs. 23%; absolute difference 16%; 95% confidence interval [CI]: 8% to 24%; p = 0.0001). Median time to sedation was 22 min (interquartile range [IQR]:18 to 35 min) for droperidol compared to 30 min (IQR:20 to 45 min) for midazolam. Additional prehospital sedation was required in 6/149 (4%) droperidol patients and 20/141 (14%) midazolam patients, and 11 (7%) droperidol and 59 (42%) midazolam patients required further sedation in the emergency department. There were no differences in patient or staff injuries, or prehospital time. CONCLUSIONS: The use of droperidol for acute behavioral disturbance in the prehospital setting is associated with fewer adverse events, a shorter time to sedation, and fewer requirements for additional sedation.

Dopamine D2-receptor Antagonist Droperidol Deepens Sevoflurane Anesthesia.

BACKGROUND: Although midbrain dopaminergic pathways are known to contribute to arousal and emergence from anesthesia, few reports exist regarding the anesthetic effects of dopamine D2 receptor antagonism in humans. This study examined the effect of the D2 receptor antagonist droperidol on sevoflurane anesthesia by examining α and slow wave electroencephalogram oscillations. METHODS: Forty-five patients, age 20 to 60 yr, were enrolled. Frontal electroencephalograms were continuously collected for offline analysis via Bispectral Index monitoring. After induction of anesthesia, end-tidal sevoflurane concentration was deliberately maintained at 1%, and intravenous droperidol (0.05 mg/kg bolus) was administered. Electroencephalogram changes were examined in power spectrum and bicoherence, before and 10 min after droperidol injection, then compared using the Wilcoxon signed-ranks test and/or paired t test. RESULTS: Droperidol significantly augmented the α-bicoherence peak induced by sevoflurane from 30.3% (24.2%, 42.4%) to 50.8% (41.7%, 55.2%) (median [25th, 75th percentiles]; P < 0.0001), Hodges-Lehman median difference, 15.8% (11.3 to 21.4%) (95% CI). The frequency of the α-bicoherence peak was simultaneously shifted to the lower frequency; from 11.5 (11.0, 13.0) to 10.5 (10.0, 11.0) Hz (median [25th, 75th percentiles], P < 0.0001). Averaged bicoherence in the δ-θ area increased conspicuously from 17.2% (15.6 to 18.7%) to 25.1% (23.0 to 27.3%) (mean [95% CI]; P < 0.0001), difference, 8.0% (6.0 to 9.9%). CONCLUSIONS: Droperidol augments both α and δ-θ bicoherences while shifting the α-bicoherence peaks to lower frequencies, and enhances the effect of sevoflurane anesthesia on the electroencephalogram via γ-aminobutyric acid-mediated oscillatory network regulation.

Higher dose of palonosetron versus lower dose of palonosetron plus droperidol to prevent postoperative nausea and vomiting after eye enucleation and orbital hydroxyapatite implant surgery: a randomized, double-blind trial.

OBJECTIVE: Postoperative nausea and vomiting (PONV) is commonly observed after eye enucleation and orbital hydroxyapatite implant surgery. This prospective, randomized, double-blind trial was conducted to investigate the hypothesis that compared with monotherapy using a higher dose of palonosetron, using a lower dose of palonosetron in combination with droperidol could reduce the incidence of PONV and achieve similar prophylaxis against PONV after the aforementioned surgery. PATIENTS AND METHODS: A total of 129 patients who were in the American Society of Anesthesiologists Classes I and II, aged between 18 and 70 years, and scheduled for eye enucleation and orbital hydroxyapatite implant surgery, were enrolled in this study. They were randomized into three groups: Group P2.5 (2.5 µg/kg palonosetron), Group P7.5 (7.5 µg/kg palonosetron), and Group P+D (2.5 µg/kg palonosetron and 15 µg/kg droperidol). Patients received the different antiemetic regimens intravenously 5 min before surgery. The severity of nausea and vomiting and the complete response (CR) rate during a 72-h postoperative period were assessed. RESULTS: All patients completed the trial. The nausea score of Group P2.5 was significantly higher than those of the other two groups at 0-4 h and 24-48 h (P<0.05). Vomiting scores among all groups were similar during all intervals (P>0.05). Compared with Group P2.5, the CR rate was significantly improved at all intervals in Group P+D, except at 4-72 h, and was also elevated at 24-72 h in Group P7.5 (P<0.05). Fewer patients in Group P2.5 did not experience any nausea or vomiting throughout the study (49%) compared with those in Group P7.5 (67%) and Group P+D (81%; P<0.01). CONCLUSION: Combining low-dose palonosetron with droperidol potentiated prophylaxis for PONV and achieved a similar prophylactic effect as that with a higher dose of palonosetron.

Intravenous midazolam-droperidol combination, droperidol or olanzapine monotherapy for methamphetamine-related acute agitation: subgroup analysis of a randomized controlled trial.

AIM: To examine the efficacy and safety of (1) midazolam-droperidol versus droperidol and (2) midazolam-droperidol versus olanzapine for methamphetamine-related acute agitation. DESIGN AND SETTING: A multi-centre, randomized, double-blind, controlled, clinical trial was conducted in two Australian emergency departments, between October 2014 and September 2015. PARTICIPANTS: Three hundred and sixty-one patients, aged 18-65 years, requiring intravenous medication sedation for acute agitation, were enrolled into this study. We report the results of a subgroup of 92 methamphetamine-affected patients. INTERVENTION AND COMPARATOR: Patients were assigned randomly to receive either an intravenous bolus of midazolam 5 mg-droperidol 5 mg combined, droperidol 10 mg or olanzapine 10 mg. Two additional doses were administered, if required: midazolam 5 mg, droperidol 5 mg or olanzapine 5 mg, respectively. MEASUREMENTS: The primary outcome was the proportion of patients sedated adequately at 10 minutes. Odds ratios with 95% confidence intervals (ORs, 95% CI) were estimated. FINDINGS: The baseline characteristics of patients in the three groups were similar. At 10 minutes, significantly more patients in the midazolam-droperidol group [29 of 34 (85.3%)] were sedated adequately compared with the droperidol group [14 of 30 (46.7%), OR = 6.63, 95% CI = 2.02-21.78] or with the olanzapine group [14 of 28 (50.0%), OR 5.80, 95% CI = 1.74-19.33]. The number of patients who experienced an adverse event (AE) in the midazolam-droperidol, droperidol and olanzapine groups was seven of 34, two of 30 and six of 28, respectively. The most common AE was oxygen desaturation. CONCLUSION: A midazolam-droperidol combination appears to provide more rapid sedation of patients with methamphetamine-related acute agitation than droperidol or olanzapine alone.

Midazolam-Droperidol, Droperidol, or Olanzapine for Acute Agitation: A Randomized Clinical Trial.

STUDY OBJECTIVE: We aim to determine the most efficacious of 3 common medication regimens for the sedation of acutely agitated emergency department (ED) patients. METHODS: We undertook a randomized, controlled, double-blind, triple-dummy, clinical trial in 2 metropolitan EDs between October 2014 and August 2015. Patients aged 18 to 65 years and requiring intravenous medication sedation for acute agitation were enrolled and randomized to an intravenous bolus of midazolam 5 mg-droperidol 5 mg, droperidol 10 mg, or olanzapine 10 mg. Two additional doses were administered, if required: midazolam 5 mg, droperidol 5 mg, or olanzapine 5 mg. The primary outcome was the proportion of patients adequately sedated at 10 minutes. RESULTS: Three hundred forty-nine patients were randomized to the 3 groups. Baseline characteristics were similar across the groups. Ten minutes after the first dose, significantly more patients in the midazolam-droperidol group were adequately sedated compared with the droperidol and olanzapine groups: differences in proportions 25.0% (95% confidence interval [CI] 12.0% to 38.1%) and 25.4% (95% CI 12.7% to 38.3%), respectively. For times to sedation, the differences in medians between the midazolam-droperidol group and the droperidol and olanzapine groups were 6 (95% CI 3 to 8) and 6 (95% CI 3 to 7) minutes, respectively. Patients in the midazolam-droperidol group required fewer additional doses or alternative drugs to achieve adequate sedation. The 3 groups' adverse event rates and lengths of stay did not differ. CONCLUSION: Midazolam-droperidol combination therapy is superior, in the doses studied, to either droperidol or olanzapine monotherapy for intravenous sedation of the acutely agitated ED patient.

Physicochemical stability of ternary admixtures of butorphanol, ketamine, and droperidol in polyolefin bags for patient-controlled analgesia use.

BACKGROUND: Delivery of drug admixtures by intravenous patient-controlled analgesia is a common practice for the management of postoperative pain; however, analytical confirmation of the compatibility and stability of butorphanol tartrate, ketamine hydrochloride, and droperidol combined in ternary admixtures is not available. METHODS: Butorphanol tartrate, ketamine hydrochloride, and droperidol have been examined for compatibility and stability when combined with 0.9% sodium chloride injection stored at 4°C and 25°C with light protection for a total of 14 days. Concentrations were 0.067 mg/mL, 1.33 mg/mL, and 0.033 mg/mL for butorphanol tartrate, ketamine hydrochloride, and droperidol, respectively. Drug concentrations were determined using high-performance liquid chromatographic analysis. RESULTS: All three drugs were very stable (>97%) at 4°C and 25°C for 14 days. The ternary admixtures were initially clear and colorless throughout the observation period, and the pH value did not change significantly. CONCLUSION: The results confirm that the ternary admixture of butorphanol tartrate 0.067 mg/mL, ketamine hydrochloride 1.33 mg/mL, and droperidol 0.033 mg/mL in 0.9% sodium chloride injection were stable for 14 days when stored in polyolefin bags at 4°C and 25°C and protected from light.

Polysubstance-induced relapse of schizoaffective disorder refractory to high-dose antipsychotic medications: a case report.

BACKGROUND: The high prevalence of comorbid illicit drug use in persons with chronic psychotic illness represents a strong determinant of psychotic relapse and rehospitalization. Epidemiological studies indicate changing patterns of illicit drug use in Australia, which are concerning because of increased use of crystal methamphetamine, also known as "ice." An important complication of habitual use of crystal methamphetamine is the development of a dose-dependent acute psychotic reaction. We report a case of an acute psychotic relapse in response to polydrug use most notable for multiple recent binges of crystal methamphetamine. Unlike previously described case reports, our patient's acute psychosis was refractory to ultra-high doses of multiple antipsychotic medications. This presented safety challenges due to the risk of serious side effects with high-dose antipsychotic medications. CASE PRESENTATION: A 30-year-old white man with a past history of schizoaffective disorder was brought to our emergency department by the police in a state of extreme agitation, combativeness, and paranoia after use of cannabis and crystal methamphetamine. Despite existing compliance with zuclopenthixol decanoate depot medication, he required multiple emergency injections of zuclopenthixol acetate, and regular high-dose droperidol, chlorpromazine, and lorazepam. However, he remained severely agitated and psychotic with continuous threats of harm to others. A test of antipsychotic drug metabolism by cytochrome P450 enzymes did not reveal a pharmacogenetic cause for the poor therapeutic efficacy of antipsychotic medications. His psychosis did not appear to be modified by psychoactive medications but was instead self-limited to the presence of endogenous methamphetamine within his system. He fully recovered 96 to 120 hours post-presentation and was discharged home with out-patient clinic follow-up. CONCLUSIONS: The current case highlights the challenging nature of a severe psychotic relapse precipitated by illicit substances that is resistant to medical management. High doses of multiple antipsychotic medications may be required to manage dangerous behaviors associated with these acute psychotic relapses. These patients require close monitoring for adverse effects with adjustment of dosing to ensure the optimal balance of risk versus benefit while the patient is acutely psychotic. The results are of relevance for the management of psychiatric emergencies in emergency departments and acute mental health settings.

Population pharmacokinetics of intramuscular droperidol in acutely agitated patients.

BACKGROUND: Intramuscular droperidol is used increasingly for sedation of aggressive and violent patients. This study aimed to characterise the pharmacokinetics of intramuscular droperidol in these patients to determine how rapidly it is absorbed and the expected duration of measurable drug concentrations. METHODS: We undertook a population pharmacokinetic analysis of a subgroup of patients from a clinical trial comparing droperidol and midazolam: 17 receiving 5 mg and 24 receiving 10 mg droperidol. Droperidol was measured using high-performance liquid chromatography. Pharmacokinetic modelling was performed under a nonlinear mixed effects modelling framework (NONMEM v7.2). The model was used to simulate concentration time profiles of three typical doses, 5 mg, 10 mg and 10 mg + 10 mg repeated at 15 min. RESULTS: A two-compartment first-order input with first-order output model fitted the data best. The absorption rate constant was poorly characterised by the data and an estimate of the first order rate constant of absorption when fixed to 10 h-1 provided a stable model and lowest objective function. This represents extremely rapid absorption with a half-life of 5 min. The final model had a clearance of 41.9 l h-1 and volume of distribution of the central compartment of, 73.6 l. Median and interquartile range of initial (alpha) half-life was 0.32 h (0.26-0.37 h) and second (beta) half-life was 3.0 h (2.5-3.6 h). Simulations indicate that 10 mg alone provides an 80% probability of being above the lower limit of quantification (5 µg l-1 ) for 7 h, 2 h longer than for 5 mg. Giving two 10 mg doses increased this duration to 10 h. CONCLUSIONS: Intramuscular droperidol is rapidly absorbed with high therapeutic concentrations after 5 and 10 mg doses, and supports clinical data in which droperidol sedates rapidly for up to 6 h.

[The Effectiveness of Epidural Droperidol for Prophylaxis of Postoperative Nausea and Vomiting: A Comparative Study of Droperidol and Adrenaline].

BACKGROUND: Intravenous droperidol has strong evidence for antiemetic efficacy in high risk patients for prevention of postoperative nausea and vomiting (PONV). However it is not clear whether continuous epidural administration of doroperidol prevent PONV. It has been reported that epidural adrenaline decreases PONV; therefore we prospectively compared the effectiveness of epidural droperidol and adrenaline for prophylaxis of PONV. METHODS: Eighty-six patients were scheduled for abdominal gynecological surgery under general-epidural anesthesia in the study. Patients were randomly assigned to droperidol group or adrenaline group. We investigated the incidences of PONV, the frequency of using the antiemetics. RESULTS: There was no statistical difference between the groups. The incidences of PONV were 27.9% (doropeidol group) and 58.1% (adrenaline group), respectively (P = 0.0046). The frequency of the anti-emetics use were 18.6% and 41.9%, respectively (P = 0.0189). There was one patient who needed cancellation of continuous epidural administration for vomiting in adrenaline group, but no patient in doropeidol group. CONCLUSIONS: The results suggest that epidural droperidol effectively decreases PONV in high risk patients. However epidural adrenaline might be ineffective.

Ketamine as Rescue Treatment for Difficult-to-Sedate Severe Acute Behavioral Disturbance in the Emergency Department.

STUDY OBJECTIVE: We investigate the effectiveness and safety of ketamine to sedate patients with severe acute behavioral disturbance who have failed previous attempts at sedation. METHODS: This was a prospective study of patients given ketamine for sedation who had failed previous sedation attempts. Patients with severe acute behavioral disturbance requiring parenteral sedation were treated with a standardized sedation protocol including droperidol. Demographics, drug dose, observations, and adverse effects were recorded. The primary outcome was the number of patients who failed to sedate within 120 minutes of ketamine administration or requiring further sedation within 1 hour. RESULTS: Forty-nine patients from 2 hospitals were administered rescue ketamine during 27 months; median age was 37 years (range 20-82 years); 28 were men. Police were involved with 20 patients. Previous sedation included droperidol (10 mg; 1), droperidol (10+10 mg; 33), droperidol (10+10+5 mg; 1), droperidol (10+10+10 mg; 11), and combinations of droperidol and benzodiazepines (2) and midazolam alone (1). The median dose of ketamine was 300 mg (range 50 to 500 mg). Five patients (10%; 95% confidence interval 4% to 23%) were not sedated within 120 minutes or required additional sedation within 1 hour. Four of 5 patients received 200 mg or less. Median time to sedation postketamine was 20 minutes (interquartile range 10 to 30 minutes; 2 to 500 minutes). Three patients (6%) had adverse effects, 2 had vomiting, and a third had a transient oxygen desaturation to 90% after ketamine that responded to oxygen. CONCLUSION: Ketamine appeared effective and did not cause obvious harm in this small sample and is a potential option for patients who have failed previous attempts at sedation. A dose of 4 to 5 mg/kg is suggested, and doses less than 200 mg are associated with treatment failure.

A Large Retrospective Cohort of Patients Receiving Intravenous Olanzapine in the Emergency Department.

BACKGROUND: Olanzapine is an atypical antipsychotic with similar pharmacologic properties to droperidol. Due to the current droperidol shortage, the authors' clinical practice has been to substitute olanzapine for droperidol in many situations. At this time, olanzapine is U.S. Food and Drug Administration approved for oral and intramuscular (IM) use only, but due to its increased utility, intravenous (IV) olanzapine was recently approved for use in the study emergency department (ED). OBJECTIVES: The authors sought to review the use and safety of IV olanzapine in the ED patient population. METHODS: A retrospective review of consecutive patients receiving IV olanzapine between January 1, 2014, and July 1, 2014, was conducted. Data were collected via an electronic medical record review. The study was deemed exempt from informed consent by our institutional review board. RESULTS: A total of 713 patients received IV olanzapine during the study period. The median age was 38 years (range = 18 to 85 years), and 313 patients were male (43.9%). Primary indications for IV olanzapine administration included acute agitation (n = 245, 34.4%), abdominal pain (n = 165, 23.1%), headache (n = 121, 17.0%), nausea and vomiting (n = 107, 15.0%), pain (other; n = 60, 8.4%), and unknown (n = 15, 2.1%). IV dosing varied: 1.25 mg (n = 20, 2.8%), 2.5 mg (n = 185, 25.9%), 5 mg (n = 507, 71.1%), and 10 mg (n = 1, 0.1%). Forty-nine patients required a second dose of olanzapine (22 IV, 26 IM, one oral). The maximum total dose of olanzapine was 20 mg. Ninety-eight patients required a total of 146 doses of additional sedatives during their ED course. Other sedative medications included ketamine (n = 17, 2.4%), haloperidol (n = 48, 6.7%), and benzodiazepines (n = 81, 11.4%). Hypoxia was noted in 74 patients (10.4%). Major respiratory complications, including airway stimulation or repositioning maneuvers and intubation, occurred in 15 patients (2.1%). After consensus review, one intubation was classified as "likely related" to olanzapine administration, and two were classified as "possibly related" to olanzapine. Akathisia likely occurred in four patients (0.6%), and no allergic reactions were identified. Electrocardiograms (ECGs) were performed in 322 patients. A total of 251 patients had an ECG performed before olanzapine administration (median QTc = 404 ms), and 88 patients had an ECG performed after olanzapine administration (median QTc = 415 ms). Acute alcohol and drug intoxication was common, 118 (16.5%) patients were positive for ethanol, and seven of 23 drug screens were positive for sympathomimetics. Thirty-four of 284 admissions (4.5%) were to intermediate or intensive care unit beds. No patients died while in the ED and no cases of sudden cardiac death were noted. CONCLUSIONS: In this large retrospective review, IV olanzapine appears to be a safe in the management of a variety of ED indications. Hypoxia was common, but serious airway compromise was rare.