a b s t r a c t

Objective: To assess the QTc interval variation after low-dose droperidol in a population of undifferentiated, sta- ble, 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 admin- istration, defined as the maximum delta (change) of QTc interval. Other outcomes included proportion of pa- tients 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.

(C) 2021

1. Introduction

Droperidol is an antipsychotic drug with anti-dopaminergic (D2 re- ceptor antagonist) activity that has been extensively used in emergency departments (EDs) for indications such as acute agitation, headache, nausea, vomiting, and abdominal pain [1]. The United States Food and Drug Administration , however, has only post-operative nausea and vomiting in their indications for droperidol. In 2001, the FDA issued a black box warning on droperidol due to case reports of QT prolonga- tion and Torsades de pointes (TdP), a Life-threatening arrhythmia [2,3]. Its use decreased significantly following the warning even though

* Corresponding author at: Department of Emergency Medicine, Mayo Clinic, United States.

E-mail address: [email protected] (L. Oliveira J. e Silva).

many clinicians remained skeptical of the reasons for such restrictions and believed that there were few or no alternative drugs with an im- proved Adverse effect profile [4].

QT prolonging effect of droperidol is presumably dose-dependent

[5]. The FDA black box warning was based on case reports and studies using droperidol doses 50 to 100 times higher than those commonly given in EDs in the United States [3,6]. All the reported deaths associated with droperidol were in patients whose dosage exceeds common med- ical practice, with at least 3 cases with intravenous doses of 600 mg [7]. Several ED-based studies have been published after such warning for a variety of indications and, to date, none have reported high incidence of clinically significant arrhythmias [8-29]. TdP is very rare in patients receiving droperidol in the ED with estimate rates at approximately 6 per 100,000 administrations [8,9]. Given the consistent evidence of safety in the literature, the American Academy of Emergency Medicine

https://doi.org/10.1016/j.ajem.2021.12.039

0735-6757/(C) 2021

performed a comprehensive literature review and concluded that “droperidol is a safe medication in the treatment of nausea, headache, and agitation” and that electrocardiogram or Telemetry monitoring for doses <2.5 mg were not indicated [30]. Despite the relatively large body of evidence supporting the safety of low-dose droperidol, there are no published studies prospectively evaluating the real-time QTc var- iation during cardiac monitoring after low-dose droperidol administra- tion in the ED.

In this prospective observational study, we aimed to evaluate in real- time the immediate effect of low-dose droperidol (<= 2.5 mg) on the QTc interval of non-agitated patients in the ED. Specifically, we sought to as- sess the QTc variation after low-dose droperidol and to understand its safety by evaluating the incidence of serious arrhythmias in a popula- tion of undifferentiated, stable and non-agitated patients receiving droperidol in the ED.

1. Methods

This manuscript adheres to the Strengthening the Reporting of Ob- servational Studies in Epidemiology (STROBE) guidelines for reporting observational studies [31]. Ethical approval was secured through the in- stitutional review board and informed consent was obtained from pa- tients prior to administering droperidol and monitoring of their QTc.

• 1. Study design, setting, and participants

This prospective cohort study was carried out in an academic quater- nary ED in Minnesota with approximately 80,000 patient visits per year. Patients aged 12 years of age or older who received low-dose droperidol (<= 2.5 mg) for indications other than acute behavioral disturbances be- tween June 20, 2019, and July 16, 2021, were included. Eligible indications of droperidol for this study included the treatment of headache, pain other than headache, nausea, and vomiting. Exclusion criteria consisted of critically ill patients, those with an Altered level of consciousness or ag- itation, and pregnant patients. The decision of giving or not droperidol was at the discretion of ED attendings, and we did not restrict the inclu- sion of patients based on age. The lowest age among patients receiving droperidol during the study period was 12 years and for this reason our sample included patients of that age or older.

Potentially eligible patients for which the ED provider placed an order for droperidol were identified through the electronic health re-

discretion of changing the method as an infusion based on workload as well as preconceptions of the likelihood of adverse effects such as akathisia. This allowed two different methods of administration, and we were able to compare the pharmacological effects of both infusion and bolus, which enriches the quality of the observations in terms of peak effect, duration, and QT prolongation.

To evaluate QTc prolongation and variation over time, the QTc inter- val of patients who received droperidol as a 2-min IV bolus were mon- itored every 2 min up to 30 min or until other patient care priorities precluded the continuity of monitoring (e.g., patient had to go to radiol- ogy for imaging). Similarly, those who received a 15-min infusion had their QTc intervals recorded every 2 min from the start of infusion up to 46 min or until other care priorities precluded the continuity of monitor- ing. time zero was defined as the moment in which either the bolus or in- fusion were started. The 46-min time stamp for those who received the infusion marked approximately 30 min after the end of their infusion.

As for droperidol pharmacokinetics, its onset of action is approxi- mately 3 to 10 min, with peak concentrations reported around 30 to 60 min and a short half-life of 2 h [1]. There is likely a lower, and pro- longed peak for an infusion versus a bolus dose [1].

• 1. Baseline characteristics

Baseline characteristics of our cohort were obtained including age, sex, dose of droperidol, indication for which droperidol was given, his- tory of prior long QT interval, use of outpatient medications known to prolong the QT interval, and use of ED medications known to prolong the QT interval. The full list of these drug medications is available in Appendix S1.

Table 1

Description of study cohort and incidence of adverse events.

Patients Receiving Droperidol in

the ED (N = 68)

Demographics, medications, prior history of long QT

Age (years), mean (SD) 42.1 (15.8)

Age < 18 years, n (%) 2 (2.9%)

Age 18-65 years, n (%) 60 (88.2%)

Age > 65 years, n (%) 6 (8.8%)

Female, n (%) 45 (66.2%)

cord system. Eligible patients were consented by on-call research coor-

dinators who subsequently monitored patients’ QTc intervals in real- time during pre-specified observation periods in the ED.

Any home medication known to prolong the QTc

interval, n (%)

Any ED medication known to prolong the QTc interval, n (%)

32 (47.1%)

6 (8.8%)

• 1. QTc interval monitoring

Consented participants were placed in a cardiac monitor (IntelliVue Phillips MX 700) prior to the administration of droperidol and the QTc in- terval was recorded before (baseline QTc), at the time of droperidol ad- ministration, and every 2 min thereafter. The QT interval is an estimation of ventricular repolarization, therefore is dependent of the heart rate. Given the inherent variability of heart rate in different physio- logical states across time, it is recommended that for a proper interpreta- tion and risk stratification of the QT interval, its length should be corrected by the associated heart rate at the moment of measurement. The corrected interval is denominated “QTc” throughout this manuscript. For the calcu- lation of the QTc interval, the cardiac monitors in our ED used the Bazett correction formula (QTc = interval QT/interval RR^1/2) by default [32,33]. The decision to use measurements from cardiac monitor was based on fea-

sibility and because the guideline at our facility does not require a 12-lead

History of Long QT, n (%) 2 (2.9%)

Droperidol details

Headache? 64 (94.1%)

Abdominal Pain 1 (1.5%)

Nausea/Vomiting 5 (7.4%)

Other 3 (4.4%)

Mean dose (SD) 1.681 mg (0.421)

Median dose (range) 1.875 mg (0.625-2.5)

0.625 mg, n (%) 7 (10.3%)

1.25 mg, n (%) 8 (11.8%)

1.875 mg, n (%) 52 (76.5%)

2.5 mg, n (%) 1 (1.5%)

Bolus, n (%) 41 (60.3%)

Infusion, n (%) 27 (39.7%)

QTc prolongation after droperidol

QTc interval >= 500 ms 12 (17.6%)

Delta of QTc >= +60 ms 3 (4.4%)

Adverse events

Any serious adverse event, n (%) 0 (0.0%)

Serious arrhythmia, n (%) 0 (0.0%)

ECG prior or during droperidol administration for doses <=2.5 mg.

Death, n (%)

+

0 (0.0%)

Patients were administered droperidol as either an IV bolus over 2 min or as an IV infusion over 15 min. The mode of administration of droperidol is IV push by default in our system, as the medication is safe and effective using that route. Nursing staff, however, had the

Any non-serious adverse event , n (%) 9 (13.2%)

Restlessness, n (%) 5 (7.4%)

Anxiety, n (%) 5 (7.4%)

* Patients may have had more than one indication documented.

⁺ One patient reported both restlessness and anxiety.

• 1. Outcome measures

Primary outcome included the variation of QTc interval after droperidol administration, defined as the maximum delta (i.e., change) of QTc interval. This was calculated by subtracting the QTc interval at baseline (before droperidol administration) from the longest/highest value of QTc interval recorded at any time after droperidol for each pa- tient. We also evaluated the differences between the baseline QTc and the QTc interval at 10, 20, 30, 40 (only for infusion group), and 46 min (only for infusion group) after droperidol initiation. Furthermore, we evaluated the proportion of patients who reached a QTc >= 500 ms at any time after droperidol administration, and the proportion of patients who had a delta >=60 ms. The change of >= +60 ms in the QTc interval has been reported as concerning by prior literature [34].

Secondary outcomes included clinical adverse events, which were classified as serious or non-serious. serious adverse events were defined as death or any serious arrhythmias including ventricular dysrhythmias such as TdP, ventricular fibrillation, or ventricular tachycardia. Non- serious adverse events were defined as the presence of akathisia (rest- lessness), anxiety, dyskinesia, dystonia, or any other extra-pyramidal symptom after the administration of droperidol. Patients were directly asked about adverse events at the end of the monitoring period.

• 1. Data analysis

Statistical analyses were conducted using BlueSky Statistics (Version 7.0.746.34007) GUI for R. For descriptive statistics, continuous features were summarized as means and standard deviations (SD) or median and ranges (minimum, maximum) according to data distribution, while categorical features were summarized as counts and percentages. For the before and after analyses, mean differences (MDs) with 95%

confidence intervals were calculated and p-values were obtained through a paired t-test. When comparing means between independent samples (e.g., comparison of maximum delta of QTc between those who received bolus and those who received infusion), t-tests without assum- ing equal variances were used. When comparing proportions of a cer- tain binary outcome (e.g., proportion of patients with QTc >= 500 ms) between independent samples, Fisher exact tests were used. Analyses were stratified by form of droperidol administration (bolus or infusion). All tests were 2-sided, and statistical significance was set at alpha less than 0.05.

1. Results

A total of 68 patients receiving droperidol in the ED for analgesia or as an antiemetic were included in the analysis. Their mean age was

42.1 years (SD 15.8) and 45 (66.2%) were female. Most patients received droperidol as a 2-min bolus (n = 41, 60.3%). Overall, the median dose of droperidol was 1.875 mg (range 0.625 mg, 2.5 mg) and 94.1% received droperidol for headache management. Two patients had a history of long QT (2.9%), 32 patients (47.1%) were taking at least one home med- ication known to prolong the QT interval, and 6 patients (8.8%) received at least one ED medication (other than droperidol) known to prolong the QT interval. (Table 1)

• 1. QTc variation

Among those who received a bolus of droperidol, the mean QTc in- terval at baseline was 449 ms (SD 28) and the median was 444 ms (range 376, 505). Those who received an infusion had a mean baseline QTc interval of 449 ms (SD 22) and a median of 449 ms (range 400, 493). (Table 2) Fig. 1 illustrates QTc interval changes over time for

Table 2

QTc intervals (ms) stratified by form of droperidol administration.

	Bolus				Infusion
	N	Mean (SD)	Median (Range)		N	Mean (SD)	Median (Range)
Time (minutes) at which QTc intervals Before? 41		were measured 448.7 (27.9)	444 (376, 505)	27		448.7 (22.4)	449 (400, 493)
0?? min	41	452.4 (26.2)	447 (390, 505)	27		447.4 (26.9)	448 (387, 499)
2??? min	41	453.3 (30.9)	450 (383, 522)	25		451.4 (24.2)	452 (403, 508)
4 min	41	457.7 (25.7)	459 (392, 506)	25		444.1 (22.9)	442 (405, 488)
6 min	40	458.9 (28.4)	452 (405, 523)	25		446.3 (28.3)	439 (387, 532)
8 min	39	456.5 (25.8)	455 (398, 511)	25		450.7 (23.1)	447 (420, 496)
10 min	40	457.8 (27.5)	455 (388, 521)	25		450.6 (24.4)	454 (391, 492)
12 min	39	462.3 (26.4)	461 (390, 537)	24		447.0 (23.7)	447 (405, 487)
14 min	39	459.4 (28.0)	458 (379, 519)	23		457.3 (24.6)	465 (402, 496)
16? min	39	457.2 (29.3)	458 (395, 529)	24		451.4 (20.2)	452.5 (418, 499)
18 min	36	460.5 (27.2)	456.5 (393, 534)	25		449.8 (23.1)	448 (415, 485)
20 min	34	453.1 (25.6)	456 (400, 499)	23		451.3 (20.5)	453 (405, 483)
22 min	34	455.5 (33.8)	453 (381, 547)	22		449.5 (17.5)	451 (408, 479)
24 min	35	456.3 (29.1)	453 (390, 522)	23		454.6 (21.6)	452 (413, 493)
26 min	34	459.4 (29.8)	457.5 (399, 517)	22		452.9 (23.7)	453 (390, 493)
28 min	35	456.0 (26.7)	455 (395, 524)	21		455.7 (27.1)	455 (413, 529)
30 min	35	454.2 (29.9)	453 (389, 532)	21		457.3 (29.0)	452.5 (416, 526)
32 min	-	-	-	20		454.1 (21.1)	453.5 (421, 495)
34 min	-	-	-	21		455.5 (21.8)	459 (410, 491)
36 min	-	-	-	22		450.4 (20.9)	445 (420, 487)
38 min	-	-	-	21		449.3 (28.3)	449 (386, 505)
40 min	-	-	-	22		453.8 (20.8)	454 (420, 480)
42 min	-	-	-	22		454.9 (23.1)	453 (401, 487)
44 min	-	-	-	22		455.4 (26.0)	463 (413, 505)
46 min	-	-	-	22		454.1 (23.9)	458 (397, 499)
Doses
Dose (mg)	41	1.630 (0.481)	1.875 (0.625, 2.500)	27		1.875 (0.302)	1.875 (0.625, 1.875)
Longest QTc	41	481.4 (27.3)	481 (419, 547)	27		474.2 (25.4)	474 (432, 532)
Delta+ QTc	41	32.7 (12.0)	33 (10, 62)	27		25.5 (18.1)	23 (-12, 62)

* Right before the administration of droperidol (baseline QTc).

?? Start of 2-min bolus or 15-min infusion.

??? End of the 2-min bolus.

^? 1 min after the end of the 15-min infusion.

⁺ Maximum delta of QTc calculated as the maximum QTc interval recorded after droperidol administration minus the QTc interval before administration (baseline).

both bolus and infusion (Fig. 1) Females had longer QTc intervals than males (mean QTc at baseline 456 ms vs 434 ms, p = 0.001), and both sexes had similar variation over time. (Fig. 2)

The mean maximum delta of QTc interval after droperidol across all 68 patients was +29.9 ms (SD 15). The smallest delta was -12 ms while the largest was +62 ms. Only 2 patients had a negative delta (i.e., longest value of QTc interval after droperidol was lower than their baseline QTc). The mean longest value of QTc after droperidol was 478.6 ms (SD 26.6). The longest QTc interval after droperidol ad- ministration was 547 ms for one patient. The maximum delta of QTc for those who received a 2-min bolus was not statistically different than those who received a 15-min infusion (mean + 32.7 ms with bolus vs +25.5 ms with infusion, p = 0.075). Males and females also had similar deltas (mean + 32.9 ms in males vs +28.3 ms in females, p = 0.266), along with patients who were taking at least one home medication known to prolong the QT when compared to those not (mean + 30.5 ms vs + 29.3 ms, p = 0.746). Those receiving at least one other medication during their ED visit known to prolong the QT also had similar variation compared to those not receiving it (mean + 29.8 ms vs +29.9 ms, p = 0.996). Delta QTc’s across different droperidol doses were also similar with an average of approximately

+30 ms. The one patient who received 2.5 mg had a maximum delta

of +43 ms, and the longest measured QTc was 491 ms. (Table 3).

A total of 12 patients (17.6%) experienced a QTc interval >= 500 ms during the observation period after droperidol administration, and 3 pa- tients (4.4%) had a delta QTc >= +60 ms. (Table 1) Importantly, two pa- tients (2.9%) had a prolonged QTc >= 500 ms at baseline, prior to

administration of droperidol. Patients who received droperidol as a bolus dose had a higher proportion of QTc >= 500 ms after droperidol ad- ministration than those who received it as an infusion; this difference was not statistically significant (22.0% vs 11.1%, p = 0.338). Similarly, there was no difference in the proportion of patients with delta >= +60 ms between groups (4.9% vs 3.7%, p = 1.0).

• 1. QTc changes at different times

At 10 min, the QTc interval of patients who received droperidol as a bolus was significantly higher compared to their baseline (mean differ- ence + 10.5 ms, 95% CI +5.2 ms to +15.9 ms). At 20 and 30 min, point estimates were also positive but the differences were not statistically significant. For those who were administered droperidol as an infusion, mean differences ranged from +3.0 ms (at 10 min) to +10.3 ms (at 30 min), but only the difference between the 30-min mark and baseline was statistically significant. (Table 4)

• 1. Clinical adverse events

There were no serious arrhythmias, such as TdP, or deaths among the 68 participants in this study. However, 13.2% (n = 9) had at least one non-serious adverse event including restlessness and/or anxiety. (Table 1) Among the bolus group, 6 of 41 (14.6%) patients experienced a non-serious adverse event, while 3 of 27 (11.1%) experienced non- serious adverse events when receiving a droperidol infusion. Patients who had a non-serious adverse event had higher maximum delta of

Fig. 1. Mean QTc interval (ms) at baseline (before) and every 2 min after droperidol stratified by the form of administration (bolus or infusion). The circle represents the mean QTc interval, and the lines represent 1 standard deviation above and below the mean.

Fig. 2. Mean QTc interval (ms) at baseline (before) and every 2 min after droperidol stratified by the form of administration (bolus or infusion) and sex (female or male). The circle represents the mean QTc interval, and the lines represent 1 standard deviation above and below the mean.

QTcafter droperidol than those without an adverse event (mean + 42.4 ms vs +27.9 ms, mean difference + 14.5 ms, 95% CI +4.29 ms to +24.70 ms, p = 0.009).

1. Discussion

In this prospective observational study, we found that, on average, the maximum delta of QTc interval was 30 ms longer, with only 4.4% of patients reaching a delta >= +60 ms immediately after the administra- tion of low-dose droperidol in the ED. Although 17.6% had a QTc >= 500 ms at some point after droperidol, none of them had a serious arrhythmia. Given the lack of a control group, it is uncertain if such changes would similarly occur in the absence of droperidol or with other drugs. Non- serious adverse events including restlessness and anxiety occurred ap- proximately in 1 in 10 patients receiving droperidol, and those who had at least one non-serious adverse event had higher deltas of QTc than those without adverse events.

For those receiving droperidol as a bolus, the QTc interval peaked 10 min after the administration of the 2-min bolus and decreased thereafter. For those receiving an infusion, it peaked at 30 min (i.e., approximately 15 min after the end of the 15-min infusion) and de- creased thereafter. A potential corollary of the timing of QTc variation in our data set is that by the time the ED encounter is done, the effects of droperidol on QTc have largely worn off and it is safe to discharge these patients from a cardiac monitoring perspective.

On average, the maximum QTc interval change after droperidol was approximately +30 ms in our study. This is lower than what previous authors have reported as concerning (change >= +60 ms) [34]. There

were a few patients in our cohort who experienced a delta QTc >= +60 ms (4.4%) or a QTc interval >= 500 ms at some point after droperidol admin- istration (17.6%) but none of these patients developed serious arrhyth- mias. These findings reflect prior evidence showing droperidol can transiently increase the QTc interval, but it does not necessarily trans- late into an increased risk of serious arrhythmias, even at higher doses [28,35]. Given the lack of a control group, it is uncertain how much of the increase seen in our study is due to the independent effect of droperidol on the QTc interval. This might have occurred due to the pre- dominance of females in our cohort (longer baseline QTc intervals) and other factors such as a significant proportion of patients already using medications with potential QT-prolonging effects prior to the ED visit. However, deltas were similar when we stratified by these variables. Prior controlled experiments have challenged the association between low-dose droperidol and QTc prolongation. For example, in a random- ized study in the operating room setting, White and colleagues com- pared the outcome of QTc prolongation between low doses of droperidol (0.625 to 1.25 mg) and saline (placebo), and there were no significant differences [36]. Other operating room-based randomized controlled studies have shown similar QTc prolongations between ondansetron and low-dose droperidol [37,38]. Moreover, one ED- based study (the DORM trial) evaluating a dose of 10 mg of droperidol for acute agitation found similar proportions of abnormal QTc between droperidol and midazolam [12].

No patients receiving low-dose droperidol had a serious adverse

event in our study. These findings are largely consistent with prior liter- ature that indicates that droperidol is safe to be used in the ED, espe- cially at low doses (<= 2.5 mg) [8,9,30,34,39,40]. A recent Cochrane

Table 3

Maximum delta and longest values of QTc interval (ms) after droperidol stratified by different variables of interest.

incidence of TdP in patients receiving droperidol in the ED to be 1/16,546 (0.006%, or 6 per 100,000) [9]. Average doses of droperidol in this study, however, were mostly greater than 2.5 mg. Other factors

Maximum Delta⁺ of QTc interval (ms)

Longest Value? of QTc interval (ms)

to consider to completely understand the occurrence of TdP are the association of droperidol and other QTc prolonging drugs, the use of Cumulative doses, presence of structural heart disease and most impor- tantly acute electrolyte abnormalities around the administration of the drug.

Lastly, approximately 13% of our cohort had non-serious adverse events such as anxiety and restlessness after receiving droperidol. The proportion of patients reporting restlessness (i.e., akathisia) was similar to other prospective studies including a randomized blinded ED-based study in which patients received 2.5 mg of droperidol for acute migraine headaches, and akathisia was reported in 13.3% of patients [19]. As previously mentioned, given the lack of a control group in our study, we cannot evaluate causality between droperidol administration and subse- quent extrapyramidal symptoms. Nevertheless, the Cochrane systematic review by Weibel and colleagues found 23 randomized controlled trials comparing the incidence of extrapyramidal symptoms between droperidol and placebo in the context of postoperative nausea and vomiting prevention, and they found that those receiving droperidol had a higher incidence of these symptoms (60/1726 [3.5%]) than those receiv- ing placebo (23/1544 [1.5%]), but the pooled effect estimate yielded a wide confidence interval (pooled risk ratio 1.43, 95% CI 0.87 to 2.35) [41]. Most importantly in our cohort, patients who had at least one non- serious adverse event had greater delta QTc’s compared to those without adverse events (mean + 42.4 ms vs +27.9 ms). This data suggests that non-serious adverse events after low-dose droperidol might assist on the identification of patients at higher risk of having greater QTc changes.

All (n = 68)
Mean (SD)	+29.9 (15.0)	478.6 (26.6)
Median (range)	+31.5 (-12, +62)	476.5 (419, 547)
2-min bolus (n = 41) Mean (SD)	+32.7 (12.0)	481.4 (27.3)
Median (range)	+33 (+10, +62)	481 (419, 547)
15-min infusion (n = Mean (SD)	27) +25.5 (18.1)	474.2 (25.4)
Median (range)	+23 (-12, +62)	474 (432, 532)
Female (n = 45)
Mean (SD)	+28.3 (14.0)	484.6 (25.1)
Median (range)	+29 (-5, +62)	483 (440, 547)
Male (n = 23)
Mean (SD)	+32.9 (16.8)	466.8 (26.1)
Median (range)	+33 (-12, +62)	467 (419, 523)
History of Long QT (n = 2)
Mean (SD)	+31.5 (12.0)	485 (1.4)
Median (range)	+31.5 (+23, +40)	485 (484, 486)
Without History of Long QT (n = 66)
Mean (SD)	+29.8 (15.2)	478.4 (27.0)
Median (range)	+31.5 (-12, +62)	476 (419, 547)
Any other ED medication known to prolong QT (n = 6)
Mean (SD)	+29.8 (18.0)	482.3 (34.5)
Median (range)	+25 (+13, +62)	485.5 (441, 532)
Without other ED medications known to prolong QT (n = 62)
Mean (SD)	+29.9 (14.9)	478.2 (26.1)
Median (range)	+32.5 (-12, +62)	476 (419, 547)
Any home medication known to prolong QT (n = 32)
Mean (SD)	+30.5 (15.1)	482.6 (28.1)
Median (range)	+33 (-12, +62)	480.5 (432, 547)
No Home medications known to prolong QT (n = 36)
Mean (SD)	+29.3 (15.1)	475.0 (25.2)
Median (range)	+30.5 (-5, +62)	474.5 (419, 532)
0.625 mg (n = 7)
Mean (SD)	+31.6 (11.1)	474.7 (39.3)
Median (range)	+31 (+13, +44)	462 (440, 547)
1.25 mg (n = 8)
Mean (SD)	+28.3 (9.5)	479.0 (28.2)
Median (range)	+31 (+13, +40)	473 (443, 526)
1.875 mg (n = 52)
Mean (SD)	+29.6 (16.3)	478.8 (25.2)
Median (range)	+31 (-12, +62)	476.5 (419, 534)
2.5 mg (n = 1) Mean (SD)	+43 (NA)	491 (NA)
Median (range)	+43 (NA)	491 (NA)
Any adverse events (n = 9)
Mean (SD)	+42.4 (12.7)	471.2 (28.1)
Median (range)	+37 (+29, +62)	467 (436, 526)
Without adverse events (n = 59)
Mean (SD)	+27.9 (14.5)	479.7 (26.5)
Median (range)	+29 (-12, +62)	478 (419, 547)

1. Limitations

NA, not applicable.

* Defined as the longest QTc interval recorded for each patient after the initiation of droperidol.

⁺ Defined as the longest value of QTc interval at any time after droperidol minus the QTc interval at baseline (before droperidol administration).

systematic review supports the findings of very low incidence of life- threatening cardiac events related to droperidol administration [41], with benefits probably outweighing the risks. Weibel and colleagues evaluated 95 randomized trials that assessed droperidol as an agent for postoperative nausea and vomiting in adults undergoing general an- esthesia and there were zero studies reporting a serious adverse event secondary to droperidol administration (doses of droperidol in these studies ranged from 0.25 mg to 7.5 mg) [41]. When the authors evalu- ated studies reporting the incidence of any arrhythmia between droperidol and placebo, they found a lower Incidence of arrhythmias with droperidol as compared to placebo across 7 studies (2/336 [0.6%] vs 3/323 [0.9%]) [41]. Most recently, Cole and colleagues estimated the

There are several limitations requiring acknowledgment. First, this was a single-center study at an academic institution with a relatively small sample of patients enrolled. However, the QTc interval was mea- sured before and at several time points after droperidol administration which provided us more than 2000 QTc intervals recorded. Second, we used measurements of Bazett-Corrected QT interval automatically cal- culated from a portable cardiac monitor. Although widely used in the droperidol literature, there is overcorrection at high heart rates and under correction at lower heart rates with the Bazett’s QT correction [42]. Third, there is likely selection bias in our sample because this was a convenience sample at the times when a research coordinator was available, and we had to pause the enrollment for several months due to COVID-19. Moreover, as droperidol was given at the discretion of ED providers, there is certainly some additional selection bias that could be present due to providers avoiding droperidol in patients at higher risk of having cardiac arrhythmias (e.g., those with electrolyte disturbances or underlying cardiac disease). Fourth, some data points were missing due to interruptions in the context of usual ED care (e.g., patient needed to go to radiology for CT imaging). However, none of the patients who had at least one QTc interval missing at some point (n = 21) experienced a serious adverse event during the ED visit. Fifth, one possible factor to consider for the QTc variation in our population is the relation between QTc prolongation and electrolyte abnormalities. Our study population includes a portion of patients who had nausea and vomiting, and therefore changes in serum potassium are possible, affecting QTc intervals prior to the administration of droperidol [43]. Lastly, the incidence of non-serious adverse events may be overestimated. Because of unblinding, prospective data collec- tion, and the Hawthorne effect [44], patients may have overreported their symptoms after the administration of droperidol. Also, because there was no control group in this study, it is not possible to claim that droperidol was independently responsible for the QTc prolongation or the non-serious adverse events.

Table 4

Mean differences between the QTc interval (ms) before (baseline) and after the start of droperidol at different time marks.

	Bolus				Infusion
	N	Mean (SD)	Mean difference (95% CI) p value?		N	Mean (SD)	Mean difference (95% CI) p value?
10 min
Before	40	447.3 (26.7)	+10.5 ms		25	447.6 (22.5)	+3.0 ms
10 min	40	457.8 (27.5)	(+5.2 to +15.9)		25	450.6 (24.4)	(-4.5 to +10.6)
			p = 0.003				p = 0.4155
20 min
Before	34	449.1 (28.0)	+4 ms		23	447.4 (21.2)	+3.9 ms
20 min	34	453.1 (25.6)	(-2.2 to +10.2)		23	451.3 (20.5)	(-3.9 to +11.7)
			p = 0.1969				p = 0.3083
30 min
Before	35	446.3 (28.0)	+8.0 ms		20	447.1 (22.9)	+10.3 ms
30 min	35	454.2 (29.9)	(+1.8 to +14.1)		20	457.3 (29.0)	(+2.8 to +17.7)
			p = 0.0128				p = 0.0094
40 min
Before	- - -			22		449.0 (22.8)	+4.8 ms
40 min	- -			22		453.8 (20.8)	(-3.9 to +13.4)
							p = 0.2629
46 min
Before	- - -			22		449.0 (22.8)	+5.1 ms
46 min	- -			22		454.1 (23.9)	(-3.2 to 13.3)
							p = 0.2172

* P values were obtained through paired t-test with alpha set at 0.05.

1. Conclusion

The QTc intervals slightly increased 10 to 30 min after droperidol ad- ministration, but these prolongations were brief, mostly below 500 msec and did not lead to arrhythmias. These data suggest that low-dose droperidol (<= 2.5 mg) is safe from the cardiac perspective for the use in non-agitated ED patients, and that the yield of continuous car- diac monitoring in this patient population is probably low.

Financial support

This work was supported in part by grant R25 HL092621-13 from the National Institutes of Health (Luis Hernandez-Rodriguez), and CTSA Grant Number UL1 TR000135 from the National Center for Ad- vancing Translational Sciences (NCATS), a component of the National Institutes of Health (Daniel Cabrera). Its contents are solely the respon- sibility of the authors and do not necessarily represent the official view of NIH.

Presentations

Preliminary analysis of this work was presented in an internal con- ference at the Mayo Clinic.

Author contributions

FB, DC, and LOJS conceived and designed the study. LHR, DV, and AEG conducted the acquisition of the data. LOJS analyzed the data. LHR, FB, DC, and LOJS interpreted the data. LHR and LOJS drafted the manuscript and all authors contributed substantially to its revision with critical revision of the manuscript for important intellectual con- tent.

Conflicts of interest

The authors disclosed no conflicts of interest related to this work.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi. org/10.1016/j.ajem.2021.12.039.

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