Article, Emergency Medicine

Effectiveness and safety of droperidol in a United States emergency department

a b s t r a c t

Background: Droperidol is a dopamine receptor antagonist that functions as an analgesic, sedative, and anti- emetic. In 2001, the U.S. Food and Drug Administration required a black box warning in response to case reports of QT prolongation and potential fatal arrhythmias. The aim of this study was to evaluate the effectiveness and safety of droperidol in patients presenting to a United States Emergency Department (ED).

Methods: Observational cohort study of all droperidol administrations from 1/1/2012 through 4/19/2018 at an ac- ademic ED. The primary endpoint was mortality within 24 h of droperidol administration. Secondary endpoint included use of rescue analgesics.

Results: A total of 6,881 visits by 5,784 patients received droperidol of whom 6,353 visits authorized use of their records for research, including 5.4% administrations in children and 8.2% in older adults (>=65). Droperidol was used as an analgesic for pain (N = 1,387, 21.8%) and headache (N = 3,622, 57.0%), as a sedative (N = 550, 8.7%), and as an antiemetic (N = 794, 12.5%). No deaths secondary to droperidol administration were recorded within 24 h. Need for Rescue analgesia occurred in 5.2% of patients with headache (N = 188) and 7.4% of patients with pain (N = 102); 1.1% of patients with headache received rescue opioids (N = 38) after droperidol, as did 5.4% of patients with pain other than headache (N = 75). No patients had fatal arrhythmias. Akathisia occurred in 2.9%.

Conclusion: No fatalities were seen among this large cohort of patients who received droperidol in the ED. Our findings suggest droperidol’s effectiveness and safety when used as an analgesic, antiemetic and/or sedative.

(C) 2019

Introduction

Droperidol is an anti-dopaminergic (D2 receptor antagonist) an- tipsychotic in the same class as haloperidol, with histamine and se- rotonin antagonist properties. It is an inexpensive and rapid-acting medication with a short half-life. From the time that it came to

Abbreviations: ED, Emergency Medicine; FDA, Food and Drug Administration; ECG, electrocardiogram; ICD, International Classification of Disease; APAP, acetaminophen; IQRs, interquartile ranges.

* Corresponding author at: 200 First Street SW, Generose Building, G-410, Department of Emergency Medicine, Mayo Clinic, Rochester, MN 55905, United States.

E-mail address: [email protected] (F. Bellolio).

market in 1967, it was used extensively by emergency physicians, psychiatrists and anesthesiologists around the world for the treat- ment of headache, nausea, agitation, acute pain, chronic pain, pain in the context of opioid-tolerance and refractory abdominal pain [1]. In December 2001, the United States Food and Drug Administra- tion (FDA) required a black box warning on droperidol due to con- cerns of QT prolongation and potential fatal arrhythmias [2]. The warning was based on two studies of high-dose droperidol that de- tected QT prolongation and 65 cases reported through the FDA MedWatch system over a five-year period; like the clinical studies, many of the case reports were associated with very high doses of droperidol, ranging from 50 to 100 mgs [3-5]. The evidence for the warning was based on surveillance data rather than from the peer- reviewed literature, despite the existence of several peer-reviewed

https://doi.org/10.1016/j.ajem.2019.09.007

0735-6757/(C) 2019

studies analyzing the risk of QT prolongation with droperidol. The authors of these studies stated that they did not find evidence suffi- cient to warrant the severity and consequences of a black box warn- ing [3-6]. Among both emergency physicians and anesthesiologists, the use of droperidol decreased dramatically following the FDA warming. Since then, droperidol has almost disappeared from the clinical armamentarium, resulting in an entire generation of physi- cians unaware of its pharmacological properties and indications [7-9]. At the same time there have been significant increases in alter- native, and generally more expensive, medications for nausea, agita- tion, and treatment of headache.

Many clinicians keept using droperidol in their daily practice, without observing significant safety issues, as Droperidol has the po- tential to be an opiate sparing analgesic. Nuttal and colleagues pub- lished a study with a cohort of more than 20,000 patients, finding no cases of Polymorphic ventricular tachycardia and overall a very high safety profile for the administration of low doses of droperidol [10]. Furthermore, surveys have found that physicians across spe- cialties believe that there are few or no alternative antiemetic drugs with better Adverse effect profiles and do not believe the black box warning was justified [7-9].

The Clinical Guidelines Committee of the American Academy of Emergency Medicine reviewed the literature in 2014 and found no evidence that low-dose droperidol (under 2.5 mg) was unsafe for use in the Emergency Department (ED) [11]. In this setting, droperidol has been proven to be effective in treating acute migraine headaches [12]. Droperidol used in monotherapy is at least as effec- tive as benzodiazepines alone or in combination for agitation, with- out risk of respiratory depression [1,13]. A randomized clinical trial found midazolam-droperidol Combination therapy to be superior to either droperidol or olanzapine monotherapy for intravenous seda- tion of the acutely agitated ED patient [14]. An observational study in 6 EDs looked at Electrocardiograms of 1,009 patients after droperidol administration at high-dose for sedation of acute be- havioral disturbance; this study found no evidence of increased risk for QT prolongation [15]. Several studies, including a subgroup of the analysis in this investigation, also demonstrated the safety of droperidol in Geriatric population [16,17].

The objectives of this study were to evaluate the safety and effective- ness of droperidol as an analgesic, antiemetic and sedative for patients presenting to the ED.

Methods

Study design and setting

This was a retrospective cohort study of all droperidol administra- tions from January 1, 2012 through April 19, 2018 at an academic adult and pediatric emergency department with 77,000 annual visits. The study was approved by the institution’s IRB (study number 18- 003909).

This study adheres to the STROBE (STrengthening the reporting of OBservational studies in Epidemiology) guidelines for reporting obser- vational studies [18].

Selection of participants

Patients were identified by searching a clinical data repository for all droperidol administrations in the ED, and all information from the ED visit was retrieved. For patients who consented to research use of their records, ECG data and medical record reports of comorbidities and past medical history were pulled. The analysis of mortality included all adults and children who received droperidol in the ED during the study time period; all other reports and analyses included only patients with research consent.

Variables

We collected data on each patient’s date of visit, age, current medi- cations, date and time of droperidol administration, any other medica- tions administered in the same ED visit, chief complaint and final diagnosis. Reasons for droperidol administration were assigned based on chief complaint and final diagnosis, and classified into 4 categories: pain (different from headache), headache, sedative, and anti-emetic. The study period was selected based on information retrieved from a consistent database, as prior to 2012 and after May 2018 we had changed to a different medical record system, and all the variables in- cluded in the study did not change during the study period.

Measurements

A random sample of 10% of the patients who authorized medical re- cord review was created. These records were manually reviewed by one investigator, who was not blinded to the study hypothesis, and ques- tions were resolved by consensus by all other investigators. The re- viewer was trained following explicit protocols, precisely defined variables, and standardized abstraction instruments. The following data were extracted: indication for droperidol (pain, headache, sedative, anti-emetic), extrapyramidal symptoms, arrhythmias, symptom resolu- tion, any other adverse medication effects, other medications adminis- tered simultaneously, any rescue analgesia, and disposition. Interrater agreement between the electronic data review and independent review was assessed and found to be good (results below).

Adverse events were identified in two ways: through medical coding for the entire research-authorized cohort, and through chart review for a random subset of 796 visits. We used the International Classification of Diseases, Ninth and Tenth Revisions (ICD-9, ICD-10) codes for ventricu- lar tachycardia (ICD-9 427.1, ICD-10, I49.01, I49.02), ventricular fibrilla- tion (ICD-9 427.41, ICD-10 I47.2), asystole (ICD-9 427.5, ICD-10 I46.9), and dystonia (ICD-9 333.79, ICD-10 G24.9).

Outcomes

The primary endpoint was mortality within 24 h of droperidol ad- ministration. This outcome was measured in all patients who received droperidol, as this was important for determining the safety of clinical use of droperidol and was part of an internal quality improvement eval- uation for droperidol’s safety.

Secondary endpoints included extrapyramidal symptoms and res- cue analgesic use, defined as requiring another medication for pain or headache in the 30 to 60 min after the first administration of droperidol. We considered that medications with administration times within 30 min of each other were given at the same time. Medications consid- ered as Rescue analgesics were another dose of droperidol, NSAIDs (celecoxib, ibuprofen, ketorolac), acetaminophen (APAP), opioids (co- deine/APAP, fentanyl, hydrocodone/APAP, hydromorphone, morphine, oxycodone, oxycodone/APAP, tramadol), antidopaminergic drugs (metoclopramide, prochlorperazine, promethazine), triptans (dihydro- ergotamine, naratriptan, rizatriptan, sumatriptan), anti-Neuropathic pain medications (gabapentin, pregabalin), antiepileptics (carbamaze- pine, fosphenytoin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, phenytoin, topiramate, Valproic acid), corticosteroids (dexamethasone, hydrocortisone, methylprednisolone, prednisone), anti-psychotics/leptoanalgesics (haloperidol, chlorpromazine, olanzapine, ziprasidone), butalbital/APAP/caffeine, magnesium sulfate, propofol, and caffeine.

Statistical Methods

Continuous features were summarized with medians and interquar- tile ranges (IQRs), and categorical features were summarized with fre- quency counts and percentages. Statistical analyses were

Table 1

Demographics and indication for Droperidol administration.

N = 6,353 Visits

Table 2

resolution of symptoms.

N = 796 Charts

Feature Median (25th, 75th percentiles)

Age at visit date (years) 38 (28, 51)

Length of stay (hours) 3.8 (2.7, 5.4)

n (%)

Sex

Female 4,441 (69.9)

Male 1,912 (30.1)

Indication for droperidol

Pain 1,387 (21.8)

Headache 3,622 (57.0)

Nausea/vomiting 794 (12.5)

Sedation 550 (8.7)

Rescue analgesic (All indications)

Any 373 (5.9)

Opioid 142 (2.2)

Rescue analgesic (Pain)

Any 102 (7.4)

Opioid 75 (5.4)

Rescue analgesic (Headache)

Any 188 (5.2)

Opioid 38 (1.1)

Rescue analgesic (Nausea/vomiting)

Any 52 (6.6)

Opioid 21 (2.6)

Rescue analgesic (Sedation)

Any 31 (5.6)

Opioid 8 (1.5)

Admitted to hospital from ED 1,222 (19.2)

performed using version 9.4 of the SAS software package (SAS Insti- tute, Cary, NC).

Results

A total of 6,881 visits by 5,784 distinct patients included administra- tion of droperidol between January 1, 2012 and April 19, 2018. Of these, 6,353 visits among 5,334 distinct patients authorized use of their med- ical records for research. A total of 69.9% of the administrations were in female patients, median age of 38 years (IQR 28-51), and 343 (5.4%) were children under the age of 18. Approximately 19.2% of the visits re- sulted in hospital admission. Demographics, indications for droperidol, use of Rescue medications, and admission rates are summarized in Table 1. Among the 6,353 visits, 21.8% received droperidol for pain (N = 1,387), 57.0% for headache (N = 3,622), 8.7% as sedative (N = 550), and 12.5% as anti-emetic (N = 794).

Primary outcome

Zero deaths attributable to droperidol administration were re- corded within 24 h among the 5,784 patients (n = 6,881 visits). One patient died within 24 h of droperidol administration from re- spiratory failure unrelated to the droperidol administration. This pa- tient was terminally ill from metastatic cancer, had a normal ECG in the ED, and was admitted to a critical care unit where no fatal ar- rhythmias or QTc prolongation were noted; patient’s cause of death was respiratory failure.

Secondary outcomes

Rescue analgesia and opioid use

Need for rescue analgesia occurred in 5.2% of patients with head- ache (N = 188) and 7.4% of patients with pain other than headache (N = 102); 1.1% of patients with headache received rescue opioids (N = 38) after droperidol, as did 5.4% of patients with pain other than headache (N = 75). (Table 1) From the independent chart

Indication for Droperidol n (%)

Pain

Resolution 56 (50.0)

Total 112

Headache

Resolution 406 (79.5)

Total 511

Nausea/vomiting

Resolution 65 (56.5)

Total 115

Sedation

Resolution 28 (48.3)

Total 58

review of 796 patients, complete symptom resolution was docu- mented in 79.5% of the patients with headache (N = 406) after ad- ministration of droperidol. Symptom resolution was documented in 50.0% of patients with pain other than headache (N = 56). Nau- sea/vomiting was reported as relieved in 56.5% of patients (N = 65), and behavioral sedation was documented as achieved in 48.3% of patients (N = 28). (Table 2).

A total of 1,204 visits (19.0%) included the administration of any opioid at some time during the visit (i.e., including administrations not considered rescue analgesia). Patients in each of the four indica- tion categories received opioids, including 46.7% of pain other than headache (N = 648), 9.6% of headache (N = 346), 20.7% of nausea/ vomiting (N = 164), and 8.4% of sedation patients (N = 46). The most commonly administered drug/route was IV fentanyl (50.2% [N = 604] of those receiving any opioids received at least one dose of IV fentanyl), followed by IV hydromorphone (26.9%, N = 324), IV morphine (26.1%, N = 314), PO oxycodone (10.9%, N = 131), and PO tramadol (1.5%, N = 18). All other medications were given to less than 1% of those receiving opioids. The highest rate of any opi- oid administration was among those aged 65 and older (26.4%, N = 137), followed by people aged 18 to b 65 (19.0%, N = 1051); opioid administration was less common among people under age 18 (5.1%, N = 16).

Extrapyramidal symptoms.

We did not find any acute events of akathisia or dystonia coded in the electronic dataset. Among the 796 independently charts reviewed, 2.9% (N = 23) of cases had akathisia were noted and it was resolved in every case with diphenhydramine. None of these pa- tients had akathisia documented on their dismissal diagnosis, so this would have been missed if using Claims data only.

Arrhythmias and QTc prolongation

We retrieved all ECGs administered during the study time period (January 1, 2012 and April 19, 2018). We identified ECGs for the

Table 3

Summary of ECGs.

N = 6,353 Visits

ECGs n (%)

Up to 6 months before droperidol

No

4,196 (66.1)

Yes, with QTc b 500

2,080 (32.7)

Yes, with QTc >= 500

Within 24 h after droperidol

77 (1.2)

No

4,679 (73.7)

Yes, with QTc b 500

1,631 (25.7)

Yes, with QTc >= 500

43 (0.7)

Medical records reviewed”>droperidol cohort that were dated from 6 months before droperidol administration to 24 h after. QTc >= 500 was considered prolonged in both Males and females. ECG results are summarized in Table 3. Among 6,353 patient visits, 2,157 (34.0%) had ECG within 6 months including 3.6% (n = 77) with QTc >= 500 prior to the ED visit. There were 1,674 ECGs within 24 h after droperidol administration, includ- ing 43 (2.6%) with a QTc >= 500. Of the 43 patients with prolonged QT after droperidol, 25 had an ECG within 6 months before droperidol administration; the prior ECG showed long QT in 8 patients and no long QT in 17.

Sample of medical records reviewed

A random sample of 796 visits from patients who authorized use of their medical records for research was reviewed in detail to assess the accuracy of the electronic data retrieval. A compari- son of indication for droperidol, use of rescue analgesics, and ad- mission rates identified by the electronic data retrieval versus the independent chart review is available in the appendix. Overall, 653 (82%) of the visits demonstrated agreement with regard to indication for droperidol. The differences in indication were in patients who presented with multiple symptoms. After further discussion of the medical records versus claims data, the accuracy of the electronic data retrieval resulted in agreement greater than 99%.

The median droperidol dose among the 796 visits that were inde- pendently reviewed was 0.625 mg, reflecting 415 (52.1%) visits with this dose, 40.5% (N = 322) receiving N=2.5 mg, and 2.4% (N = 19) receiving 5 mg of droperidol. Overall, 69.5% (N = 553) of symptoms were resolved after droperidol administration, as noted in the med- ical records. By indication, symptom resolution was observed in 73.8% (N = 460) of droperidol administrations for analgesia, 56.5% (N = 65) of droperidol for nausea/vomiting, and 48.3% (N = 28) of droperidol administered for sedation.

Droperidol in older adults

There were 519 visits including droperidol administration among patients age N=65 (8.2%). Indications were: pain (N = 105, 20.2%), headache (N = 251, 48.4%), sedation (N = 57, 11.0%), and nausea/

vomiting (N = 106, 20.4%). Among older adults, 10.5% (N = 11) with pain and 5.6% (N = 14) with headache received one or more rescue analgesics 30 to 60 min after droperidol. Overall, opioids were used in 60.0% (N = 63) of older adults receiving droperidol for pain and 17.1% (N = 43) for headache. Among pain patients re- ceiving any opioids, 49.2% (N = 31) received opioids before the first droperidol administration. For headache patients receiving any opioids, 39.5% (N = 17) received opioids before droperidol.

Droperidol in children

There were 343 visits with droperidol administrations among pa- tients age b 18 years. Indications were pain (N = 33, 10.6%), head- ache (N = 231, 74.0%), sedation (N = 27, 8.7%), and nausea/ vomiting (N = 21, 6.7%). The need for a rescue analgesic after droperidol was administered was infrequent. No children with pain received rescue analgesics after droperidol, and 3.0% (N = 7) of chil- dren with headache received rescue analgesics after droperidol. Overall, opioids were used in 24.2% (N = 8) of the children receiving droperidol for pain and 3.0% (N = 7) for headache. Opioids were given before droperidol in 50.0% (N = 4) of children with pain re- ceiving any opioids and 71.4% (N = 5) of children with headache re- ceiving any opioids.

Discussion

Our study suggest that QT prolongation was rare among more than 6,000 ED visits that received droperidol. Among the 1,674 pa- tients whose ECG was obtained within 24 h, QT >= 500 was noted in more than 3.6% prior to the ED visit. Importantly, there were no clinically significant arrhythmias or deaths attributable to droperidol. The only death within 24 h after droperidol was deemed secondary to respiratory failure, unrelated to droperidol administration. The only adverse effect noted thought claims data and chart review was akathisia. Akathisia was infrequent and tran- sient, occurring in 2.9% of patients whose charts were reviewed, and were all resolved by diphenhydramine. This is consistent with previous studies finding insufficient evidence to warrant the severity and consequences of a black box warning for QT prolonga- tion associated with droperidol [3-6].

This study supports the findings the Clinical Guidelines Com- mittee of the American Academy of Emergency Medicine which found no evidence that low-dose droperidol (under 2.5 mg) was unsafe for use in the ED [11]. Indeed, a prospective study published in 2015 showed no increase in risk for abnormal QT interval and 0 cases of Torsades de pointes in a large cohort of patients given high-dose droperidol (median dosage of 10 mg) for behavioral se- dation [15]. Our study found no documented cases of torsades de points in a large cohort of cases.

Additionally, our study supports the effectiveness of droperidol for treating headache in the ED with only 5.2% requiring additional medications. At the same time, 7.4% of the pain (non headache) co- hort required rescue analgesia after administration of droperidol. Additionally, chart review showed that droperidol effectively re- solved patient headache complaints in nearly 4 out of 5 cases, and completely resolved non headache pain in half of cases. Our study is consistent with previous studies that support effectiveness of droperidol for acute migraine headaches and sedation in the ED [1,13]. We believe these findings support the use of droperidol as a non-opiate, non-NSAID analgesic with the potential to serve as an alternative when considering high risk population for complica- tions related to the other classes of analgesics. Droperidol was ef- fective for 56.5% of cases of nausea/vomiting; this is similar to the effects of other antiemetics [19]. Finally, droperidol was found ef- fective in 48.3% of behavioral cases where sedation was necessary. A prospective trial of droperidol for sedation found significantly fewer adverse events, a shorter time to sedation, and fewer re- quirements for additional sedation compared to midazolam for acute behavioral disturbances in the prehospital setting [20]. It should be noted that these findings were from the independent chart review and were only counted as symptom resolution if med- ical notes specifically mentioned symptom relief post droperidol administration. Therefore, symptom resolution is likely higher than the reported rates, as oftentimes the resolution is not men- tioned in the medical chart.

Limitations

This study was conducted at a single site; however, due to lim- ited access to droperidol across the nation since the black box warning issued by the FDA [7-9], multicenter studies could have been difficult. Because of the retrospective nature of the data col- lection, we depend on the accuracy and availability of data in the medical record and billing data. Further, while this retrospective study suggests the effectiveness of droperidol as an analgesic, anti- emetic, and sedative, it does not prove its Analgesic efficacy. Stan- dardization of the doses, indications, as well as documentation of an ECG for every patient was not possible, however our results re- flect the practice of emergency care as well as the historical and po- tential uses of droperidol. Indeed, the black box recommends

cardiac monitoring before, during and after administration of droperidol. Though this did not occur in practice, acute QT prolon- gation is short-lived (peaks at 10 min and disappears at 15 min), thus patients are often in no risk of medication induced QT prolon- gation when they leave the ED [21]. The outcomes were extracted by a single abstractor not blinded to the study hypothesis. To min- imize risk of bias we followed Standardized reporting guidelines, had a clear data abstraction form, and we further calculated interrater agreement with the electronic chart review (Appendix Table A1).

The adverse events of akathisia and dystonia were not recorded as a final diagnosis in any of the patients identified through medical record review as having an adverse effect. The rate of adverse effects may be underreported in the medical record, as it appears that in all recorded cases the effects were transient and resolved with diphen- hydramine or benztropine. Also, the symptoms resolution might be over estimated because is usually underreported in the ED visit, and it is possible that patients did not receive rescue analgesia de- spite of still being in pain.

Mortality data was obtained for all patients through an internal da- tabase that gets updated regularly when a notice of death is received even from other states, however this does not represent a national data- base of mortality, and out-of-state patients could be missed. Finally, 7.7% of the patients did not allow their medical records to be used for re- search; however, there was no difference in age or gender between those included and excluded.

Conclusion

There were no fatalities attributable to droperidol among this large cohort of patients who received droperidol in the ED. Less than 8% of the patients with headache or pain needed a rescue anal- gesic after droperidol administration. Our findings suggest droperidol’s effectiveness and safety when used as an analgesic, an- tiemetic and/or sedative.

The development of novel pain management strategies is a national priority due to the opioid epidemic [22]. Droperidol is an alternative to opioid use in acute pain management and those at high-risk of compli- cations for NSAID use, treatment of nausea and vomiting and well as emergency sedation.

Author contributions

CMG, DC, MFB, and MMJ conceived the study. CMG, AEM, MFB, CL, MMJ, and DC developed the dataset. CL and MMJ had complete access to the data and performed the analyses. CMG drafted the manuscript, and all authors contributed substantially to its revi- sion. MFB takes responsibility for the paper as a whole.

Declaration of Conflict of Interest

None of the authors have conflict of interest to disclose.

Acknowledgement

This publication was made possible by CCaTS Small grant pro- gram, CTSA Grant Number UL1 TR000135 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH). Its contents are solely the re- sponsibility of the authors and do not necessarily represent the offi- cial view of NIH.

Appendix

See Table A1

Table A1

Comparison between electronic data retrieval and independent chart review, N = 796.

Indication for Droperidol Chart Review

Electronic Data Retrieval

Pain

Headache

Nausea/vomiting

Sedation

Pain

97

43

32

5

Headache

2

433

7

0

Nausea/vomiting

8

19

73

3

Sedation Rescue Analgesics

5

16

3

Chart Review

50

Electronic Data Retrieval

No

Yes

No

746

22

Yes Admitted

8

Chart Review

20

Electronic Data Retrieval

No

Yes

No

626

10

Yes

6

154

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