PharmacoEconomics Open (2018) 2:141–151 https://doi.org/10.1007/s41669-017-0047-y ORIGINAL RESEARCH ARTICLE Economic Evaluation of Midazolam–Droperidol Combination, Versus Droperidol or Olanzapine for the Management of Acute Agitation in the Emergency Department: A Within-Trial Analysis 1 2 3 • • • Celene Y. L. Yap Ya-seng (Arthur) Hsueh Jonathan C. Knott 4 5 1,6 • • David McD Taylor Esther W. Chan David C. M. Kong Published online: 24 July 2017 The Author(s) 2017. This article is an open access publication Abstract patient) compared with the droperidol and olanzapine Background The combination of midazolam and droperi- groups (AU$92.18 and AU$110.45 per patient, respec- dol has proven superior to droperidol or olanzapine tively). The main cost driver for all groups was the cost of monotherapy in the management of acute agitation in the labour required during the initial adequate sedation. emergency departments (EDs). The combination afforded an additional 10–13 min of Objective This is the ﬁrst economic analysis to evaluate mean agitation-free time gained, which can be translated to the cost–beneﬁt and cost effectiveness of the midazolam– additional savings of AU$31.24–42.60 per patient com- droperidol combination compared with droperidol or pared with the droperidol and olanzapine groups. The olanzapine for the management of acute agitation in EDs. beneﬁt–cost ratio for the midazolam–droperidol combina- Methods This analysis used data derived from a ran- tion was 12.2:1.0, or AU$122,000 in total beneﬁt for every domised, controlled, double-blind clinical trial conducted AU$10,000 spent on management of acute agitation. Sen- in two metropolitan Australian EDs between October 2014 sitivity analyses over key variables indicated these results and August 2015. The economic evaluation was from the were robust. perspective of Australian public hospital EDs. The main Conclusions The midazolam–droperidol combination may outcomes included agitation management time and the be a cost-saving and dominant cost-effective regimen for agitation-free time gained. Sensitivity analyses were the treatment of acute agitation in EDs as it is more undertaken. effective and less costly than either droperidol or olanza- Results The midazolam–droperidol combination was the pine monotherapy. least costly regimen (Australian dollars [AU$]46.25 per Melbourne School of Population and Global Health, The & David C. M. Kong David.Kong@monash.edu University of Melbourne, 207 Bouverie Street, Carlton, VIC 3053, Australia Celene Y. L. Yap Celene.Yap@monash.edu Emergency Department, Royal Melbourne Hospital, Grattan Street, Parkville, VIC 3052, Australia Ya-seng (Arthur) Hsueh firstname.lastname@example.org Emergency Department, Austin Health, Studley Road, Heidelberg, VIC 3084, Australia Jonathan C. Knott Jonathan.Knott@mh.org.au Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing David McD Taylor Faculty of Medicine, The University of Hong Kong, 2/F David.Taylor@austin.org.au Laboratory Block, 21 Sassoon Road, Pokfulam, Hong Kong Esther W. Chan Pharmacy Department, Ballarat Health Services, 1 email@example.com Drummond St N, Ballarat, VIC 3350, Australia Centre for Medicine Use and Safety, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia 142 C. Y. L. Yap et al. safety proﬁles are comparable. However, whether this combination regimen is more cost saving is unknown. For Key Points For Decision Makers the purpose of this study, the primary analysis is a cost– beneﬁt analysis. The secondary analysis is a cost-effec- The combination of midazolam and droperidol is tiveness analysis that explores the effectiveness (i.e. agi- more effective and cost saving than droperidol or tation-free time gained) of the midazolam–droperidol olanzapine monotherapy in managing acute agitation combination versus droperidol or olanzapine monotherapy in the emergency department (ED). for the management of acute agitation in EDs. The rapid effect of the midazolam–droperidol combination could allow clinical and security staff to spend less time restraining agitated patients, leading 2 Methods to a reduced burden on personnel requirements in EDs. 2.1 Study Design, Setting and Population This economic evaluation was conducted from the Aus- tralian public hospital ED perspective. Clinical outcomes 1 Introduction and resource utilisation were obtained from an RCT  (Australian and New Zealand Clinical Trials Registry Aggression or acute agitation caused by alcohol or illicit identiﬁer: ACTRN12614000980639) undertaken in the ED drug intoxication with or without underlying mental illness of two metropolitan public hospitals in Melbourne, Aus- is a common occurrence in emergency departments (EDs) tralia, from October 2014 to August 2015. [1–3]. Patients presenting with acute agitation in the ED Patients were eligible for inclusion in the trial if they often require more intensive resources for their manage- were aged 18–65 years and required intravenous sedation ment than do general medical patients [4, 5]. for acute agitation. A total of 349 patients were randomised The recommended standard approach to managing acute to an intravenous bolus of midazolam 5 mg–droperidol agitation in EDs is early verbal de-escalation followed by 5 mg combination or droperidol 10 mg or olanzapine the use of sedative medications and mechanical restraint if 10 mg . Two additional doses were administered if verbal de-escalation fails [6–8]. Existing guidelines rec- required: midazolam 5 mg, droperidol 5 mg or olanzapine ommend at least ﬁve staff (e.g. two nurses, one doctor and 5 mg, respectively. If adequate sedation was not achieved two security staff) should be available during the process of 5 min after the two additional doses, additional open-label restraint and sedation to ensure the procedure can be per- sedative medication(s) could be administered at the doc- formed safely and effectively [1, 7–9]. Given the labour- tor’s discretion. intensive nature of the management, a prolonged period of This economic analysis was approved by the Melbourne agitation places substantial strain on the human resources Health Human Research Ethics Committees. Reporting of of EDs and is costly to the hospital. this analysis followed the Consolidated Health Economic Benzodiazepines (e.g. midazolam, diazepam) or Evaluation Reporting Standards (CHEERS) checklist . antipsychotics (e.g. droperidol, olanzapine) are commonly used for sedation in EDs to manage acute agitation 2.2 Outcome Measurement [10–13]. A recent systematic review concluded that a combination regimen (i.e. benzodiazepines and antipsy- The clinical outcome was adequate sedation, which was chotics in combination) is associated with more rapid deﬁned as a score \ 2 based on a 6-point, validated Acute sedation and fewer adverse events (AEs) than benzodi- Arousal Scale (5 = highly aroused, violent toward azepine monotherapy . While a number of trials have self, others, or property; 4 = highly aroused and possibly demonstrated that antipsychotics are at least as effective as distressed or fearful; 3 = moderately aroused, agitated, benzodiazepine monotherapy [11, 13], clinical data com- more vocal, unreasonable, or hostile; 2 = mildly aroused, paring the use of antipsychotics alone versus combination pacing, willing to talk reasonably; 1 = settled, minimal regimens are lacking. agitation; 0 = asleep). A multicentre randomised controlled trial (RCT) com- In the RCT, the time required to achieve the initial paring the efﬁcacy and safety of the midazolam–droperidol adequate sedation, the need for and frequency of re-seda- combination with that of droperidol or olanzapine tion within 60 min after achieving the initial adequate monotherapy was recently reported . The trial indicated sedation and sedation AEs were assessed . When a that the midazolam–droperidol combination is superior to patient required re-sedation within 60 min after achieving both droperidol and olanzapine monotherapy and that the initial adequate sedation, frequency of re-sedation, Economic Evaluation of Sedatives for Acute Agitation Management 143 mean duration of clinical and security staff attendance, 2.4 Measurement of Costs dose and medication used were recorded. Overall, 22 patients required re-sedation within 60 min after achieving The costs of management related to the use of the sedative the initial adequate sedation. The mean duration of clinical medication, consumables and personnel to manage the acute agitation and the airway; the savings resulted from and security staff attendance for one re-sedation episode was 27 min. A total of 14 patients experienced airway the decrease in human resource utilisation (i.e. agitation- free time gained). obstruction: seven with the midazolam–droperidol combi- nation, three with droperidol and four with olanzapine. 2.4.1 Cost of Management Two primary outcome measurements were used in the current economic evaluation: agitation management time (i.e. time required to achieve initial adequate seda- A bottom-up approach was used to calculate the mean costs tion ? number of re-sedations 9 27 min) (Table 1) and by tracing the actual use of resources and medications for the agitation-free time gained. In the RCT, the maximum each patient recruited . Discounting was not applied time required to manage an episode of agitation was because of the short duration of the ED presentations. All 185 min (proximately[3 h); therefore, we assumed that all costs were expressed in Australian dollars (AU$) for the ﬁnancial year 2015–2016. episodes of agitation can be managed within 3.5 h (i.e. 210 min). For that reason, agitation-free time gained was We took a conservative approach by focusing on the cost of management incurred during the initial adequate calculated as 210 min minus the agitation management time for the patient. sedation, the re-sedation and the airway management. The direct medical costs of managing agitation do not include 2.3 Assumptions non-agitation management costs such as costs related to other underlying medical or psychiatric problems and costs The following assumptions were made when measuring the for the entire ED length of stay (LOS). Estimated unit costs cost of management: used are listed in Table 2. The costs per initial adequate sedation were categorised 1. The cost of consumables (e.g. intravenous line, tubing as labour costs or medication costs. Labour costs were and oxygen) were identical for all three regimens. calculated by multiplying the time required to achieve 2. All patients required the attendance of ﬁve staff (one initial adequate sedation by the sum of the average hourly ED doctor; two senior ED registered nurses [RNs]— wages of ﬁve hospital staff involved in the sedation process one grade 2 RN with at least 5 years of experience and (see Sect. 2.3). The mean hourly wages of ED doctors with one grade 3 RN, usually a ﬂoor coordinator; and two different years of experience (varying from year 1 to 6), security staff) to administer the sedative medication and the mean hourly wages for grade 2 RNs (year 5–10) from initial drug administration until adequate sedation were used. Hourly wages for security staff were obtained and during each re-sedation episode. from the hospital human resources department, hourly 3. If airway obstruction occurred, only one episode of wages for ED doctors were obtained from the Australian airway management was required throughout the Medical Association Victoria [19, 20] and hourly wages for sedation period for each patient. RNs were obtained from the Australian Nursing and 4. No additional pathology, imaging or monitoring tests Midwifery Federation . Medication costs were the were required as a consequence of sedation. mean costs of medications to achieve initial adequate Table 1 Mean agitation management time using midazolam–droperidol combination, droperidol or olanzapine monotherapy Outcomes Mean agitation management time (SD), min Midazolam–droperidol (n = 118) Droperidol (n = 111) Olanzapine (n = 120) Sedated with no re-sedation 9.6 (14.7) 20.2 (25.7) 22.2 (30.1) Sedated with one re-sedation 35 (7.0) 34 (0.7) 62 (24.8) Sedated with two re-sedation – 74 (16.5) 83 (36.7) a a Sedated with three re-sedation 92 –88 Overall 11.7 (17.3) 22.1 (27.1) 25.6 (33.0) SD standard deviation Only one case with three re-sedation events within 60 min after initial sedation; actual time was reported and no SD could be calculated 144 C. Y. L. Yap et al. sedation, which included both study medications and other the sum of the labour cost and the cost of consumables [i.e. open-label sedative medications. Medication acquisition oropharyngeal airway (OPA) or nasopharyngeal airway costs were obtained from the Australian Health Purchasing (NPA)]. The labour cost was calculated by multiplying the Victoria Catalogue 2012-058 . The doses administered estimated time for one airway management (i.e. 30 min) by were rounded up and costed to the nearest vial size to the sum of the average hourly rate of one ED doctor and account for wastage. one grade 3 RN. The time per airway management was The costs of sedation with re-sedation were calculated estimated based on the experiential knowledge of the ED by adding the cost of initial adequate sedation and the cost consultants and senior ED nurses, who have extensive of re-sedation according to the number of re-sedations experience in managing airway compromise requiring air- required. The cost per re-sedation was calculated by adding way adjuncts. the labour costs and the medication costs associated with one re-sedation. The labour cost was calculated by multi- 2.5 Cost–Beneﬁt Analysis plying the mean time required to re-sedate the patient (i.e. 27 min) by the sum of the average hourly wages of ﬁve As cost–beneﬁt analyses express both inputs and conse- hospital staff. Adjusted medication costs were based on the quences of different regimens in monetary units , probabilities of each medication used for re-sedation within agitation-free time gained was multiplied with total cost of 60 min after achieving initial adequate sedation. the response team per minute (i.e. AU$2.84/min) to mea- For patients requiring airway management, additional sure the economic beneﬁts gained. Beneﬁt–cost ratios for costs were added to the total cost of managing the acute all three sedation regimens were calculated by dividing the agitation. The added cost of one airway management was economic beneﬁts by the management costs. Table 2 Estimated unit costs Items Description Unit costs (AU$) Labour costs ED doctor (per minute) 0.84 ED RN grade 2 (per minute) 0.52 ED RN grade 3 (per minute) 0.59 Security staff (per minute) 0.44 Total cost of response team (per minute) 2.84 Medication costs Midazolam 5 mg/5 ml 0.23 Droperidol 2.5 mg/ml 4.54 Olanzapine 10 mg 20.22 Water for injection 10 ml 0.12 Cost of re-sedation within 60 min after achieving ED doctor time (27 min ) 22.97 initial adequate sedation Two security staff time (27 min ) 23.76 One grade 2 RN (27 min ) 14.24 One grade 3 RN (27 min ) 15.98 Adjusted medication costs 6.46 Total cost of one re-sedation 83.41 Cost of airway management ED doctor time (30 min) 25.32 Grade 3 RN time (30 min) 17.62 Consumable costs (NPA, OPA) 4.63 Total cost of one airway management 47.56 Costs are presented in Australian dollars, year 2015–2016 values ED emergency department, NPA nasopharyngeal airways, OPA oropharyngeal airways, RN registered nurse Response team consists of one ED doctor, one ED RN grade 2, one RN grade 3 (ﬂoor coordinator) and two security staff Average time for one security alert for a re-sedation episode Adjusted medication costs are calculated based on the probabilities of each medication (midazolam, droperidol, olanzapine, ketamine) being used for re-sedation within 60 min The mean cost of the unit price for NPA and OPA Economic Evaluation of Sedatives for Acute Agitation Management 145 2.6 Cost-Effectiveness Analysis 3 Results In this study, the cost-effectiveness analysis compared dif- 3.1 Base-Case Analysis ferent sedation regimens in terms of cost per minute of agi- tation-free time gained. The incremental cost-effectiveness The midazolam–droperidol combination was found to be ratio (ICER) is the difference in the cost of management more cost saving than droperidol or olanzapine between the comparators (e.g. midazolam–droperidol and monotherapy; it is also a dominant regimen, i.e. it was droperidol) divided by the difference in their effectiveness cheaper and more effective. The overall mean cost of (i.e. agitation-free time gained). A positive ICER implies the management with the midazolam–droperidol combination sedation regimen increased agitation-free time gained at a was AU$46.25 (95% CI 36.77–55.74) per patient compared certain cost; the ICER will be important for policy makers to with AU$92.18 (95% CI 76.66–107.70) per patient with make decisions based on the willingness-to-pay value . droperidol and AU$110.45 (95% CI 91.51–129.39) per Whilst a negative numerator (cheaper cost) and a positive patient with olanzapine (Table 4). Despite the higher costs denominator (e.g. more agitation-free time gained) imply the of re-sedation and airway management with the midazo- intervention is more effective at a lower cost (i.e. a dominant lam–droperidol combination, the overall mean cost of this strategy), the ICER will not be calculated [24, 25]. combination regimen was 50 and 58% lower than that of droperidol or olanzapine monotherapy, respectively 2.7 Sensitivity Analyses (Table 4). The main cost driver for all groups was the labour costs required during the initial adequate sedation The robustness of the result was assessed using both one- (Fig. 1). way and two-way sensitivity analyses to examine the In terms of improved effectiveness, the mean agitation- uncertainty surrounding key variables. These analyses free time gained with the midazolam–droperidol combi- included changes in the drug-acquisition costs, mean initial nation was 199 (95% CI 196–202) min compared with 188 adequate sedation medication and labour costs, mean (95% CI 183–193) min with droperidol and 184 (95% CI duration of staff attendance during re-sedation, probabili- 179–190) min with olanzapine (Table 6). This additional ties of the need for re-sedation, costs of consumables, and agitation-free time gained resulted in additional economic duration of airway management. The variables and ranges beneﬁts of AU$31.24 and AU$42.60 per patient (Table 5), of variation are shown in Table 3. All analyses were per- respectively. formed using TreeAge Pro 2015, R1.0. (TreeAge Software, Overall, the total economic beneﬁts of the midazolam– Williamstown, MA, USA). droperidol combination compared with droperidol and Two-way sensitivity analysis was performed to examine olanzapine was AU$77.17 and AU$106.80 per patient, the worst- and the best-case scenarios based on the varia- respectively. The net beneﬁt–cost ratio for the midazolam– tion of the mean agitation-free time gained and the mean droperidol combination was 12.2:1.0 (Table 5), equivalent total management costs. An alternative scenario, with the to AU$122,000 cost savings for every AU$10,000 spent on ideal number of staff members (i.e. seven staff) involved in the management of acute agitation with this combination. both initial sedation and re-sedation was also evaluated. 3.2 Sensitivity Analyses 2.8 Statistical Analysis One-way sensitivity analyses indicated that the conclusion The sample size was calculated based on the primary end- of this evaluation was not sensitive to the variation of all points of the RCT rather than the economic evaluation . In the parameters at the range shown in Table 3. For two-way the RCT, of the 361 patients enrolled, only a small number sensitivity and alternative scenario analysis (Table 7), the (12; 3% of the total) were excluded for either missing the midazolam–droperidol combination remained the most primary endpoint or for repeated enrolment. Hence, only cases cost-saving (Table 5) and the dominant regimen (Table 6). with complete data were included in the analysis, which should have little impact on the accuracy of the results. As cost data distribution are positively skewed [23, 26], some studies 4 Discussion reported median and interquartile range values [27, 28]. However, the provision of information about mean costs is This is the ﬁrst analysis to evaluate the cost–beneﬁt and cost effectiveness of managing acute agitation in EDs with more helpful to policy makers, who require information on the total cost of implementing a strategy by multiplying the mean a midazolam–droperidol combination compared with either droperidol or olanzapine monotherapy. Importantly, costs by the total number of patients . Therefore, mean costs and 95% conﬁdence intervals (CIs) are reported. because much less time is required to manage one acute 146 C. Y. L. Yap et al. Table 3 Variation range for variables investigated in one-way sensitivity analyses Variables Base case Variation range Source of range Low High Cost of midazolam 5 mg 0.23 0.02 0.44 Base case value ±90% Cost of droperidol 2.5 mg 4.54 0.45 8.60 Base case value ±90% Cost of olanzapine 10 mg 20.22 2.02 38.40 Base case value ±90% Mean initial adequate sedation medication cost Midazolam–droperidol 9.74 9.24 10.24 95% CI of the mean value Droperidol 27.47 25.66 29.27 95% CI of the mean value Olanzapine 35.30 32.84 37.75 95% CI of the mean value Mean initial adequate sedation labour cost Midazolam–droperidol 27.35 19.82 34.87 95% CI of the mean value Droperidol 57.43 43.83 71.02 95% CI of the mean value Olanzapine 63.17 47.88 78.45 95% CI of the mean value Mean duration of clinical staff attendance during re-sedation (min) 27 11.6 42.4 ±SD (15.4 min) Probabilities of sedated with no re-sedation (%) Midazolam–droperidol 94.1 89.8 98.3 95% CI of the base case Droperidol 95.5 91.6 99.3 95% CI of the base case Olanzapine 91.7 86.7 96.6 95% CI of the base case Probabilities of sedated with one re-sedation (%) Midazolam–droperidol 5.1 1.1 9.0 95% CI of the base case Droperidol 1.8 0 4.2 95% CI of the base case Olanzapine 5.0 1.1 8.9 95% CI of the base case Probabilities of sedated with two re-sedation (%) Midazolam–droperidol 0 0 30 Base-case value ?30% Droperidol 2.7 0 5.7 95% CI of the base case Olanzapine 2.5 0 5.3 95% CI of the base case Duration of airway management (min) 30 15 45 Base-case value ±50% Cost of consumables for airway management 4.63 2.32 9.26 Base-case value ±50% Costs are presented in Australian dollars, year 2015–2016 values CI conﬁdence interval, RCT randomised controlled trial, SD standard deviation Given the negative values for the lower bound of the 95% CI, zero was used to enable modelling No case was observed in the RCT and 30% was used to enable modelling agitation presentation, the midazolam–droperidol combi- droperidol combination increased the agitation-free time nation was more effective and cost saving than droperidol gained by approximately 50%, this will result in further and olanzapine monotherapies. This provides pivotal cost savings of AU$14,058 and AU$19,170, respectively. information to guide the use of these regimens in the ED Thus, the midazolam–droperidol combination could gen- setting for the management of acute agitation. Sensitivity erate a total annual cost savings of nearly AU$35,000 and analyses conﬁrmed the robustness of the results across a AU$48,000, respectively. broad range of variations. In addition to the beneﬁt of cost savings, using the In a tertiary-care ED with approximately 450 episodes midazolam–droperidol combination was also associated of sedation for acute agitation (security database, unpub- with additional agitation-free time gained. The published lished data, based on the experience of the Royal Mel- literature on agitation in the ED reports that these episodes bourne Hospital in 2014), the total annual mean cost to are more likely to occur in the evening or overnight, which manage these patients would be approximately AU$21,000 coincides with periods of minimal or reduced stafﬁng with the midazolam–droperidol combination compared [1, 29]. Liberating a team of healthcare staff for that with nearly AU$42,000 with droperidol and AU$50,000 amount of time would have the potential to enhance ED with olanzapine. Furthermore, as the midazolam– patient ﬂow. In a busy overnight shift, where it is possible Economic Evaluation of Sedatives for Acute Agitation Management 147 Table 4 Mean costs of management using midazolam–droperidol combination, droperidol or olanzapine monotherapy Outcomes at time Midazolam–droperidol Droperidol Olanzapine points Proportion Cost/pt Proportional Proportion Cost/pt Proportional Proportion Cost/pt Proportional a a a (%) cost (%) cost (%) cost Sedated with no re-sedation No airway 89.0 37.08 33.00 92.8 84.90 78.78 90.0 98.47 88.62 obstruction Airway 5.1 84.64 4.30 2.7 132.46 3.58 1.7 146.03 2.43 obstruction Sedated with one re-sedation No airway 4.3 120.31 5.10 1.8 168.13 3.03 4.2 181.70 7.57 obstruction Airway 0.8 167.87 1.42 0 215.69 0 0.8 229.26 1.91 obstruction Sedated with two re-sedation No airway 0 203.53 0 2.7 251.35 6.79 2.5 264.92 6.62 obstruction Airway 0 251.09 0 0 298.91 0 0 312.48 0 obstruction Sedated with three re-sedation No airway 0.8 286.76 2.43 0 334.58 0 0 348.15 0 obstruction Airway 0 334.32 0 0 382.14 0 0.8 395.71 3.30 obstruction Mean (95% CI) 46.25 92.18 110.45 costs of (36.77–55.74) (76.66–107.70) (91.51–129.39) management per pt Costs are presented in Australian dollars, year 2015–2016 values CI conﬁdence interval, pt patient The cost per patient was determined within each outcome, then multiplied by the proportion of patients, for the eight possible outcomes to get the proportional cost The proportional costs for each outcome were summed to give the mean cost per patient for each regimen to have up to eight episodes of acute agitation (Royal droperidol and the midazolam regimens. Consequently, Melbourne Hospital security database, unpublished data, direct comparison is not possible. based on the experience of the Royal Melbourne Hospital Our estimates of labour costs were built on the in 2014), using the midazolam–droperidol combination to assumption that three ED clinicians and two security staff manage these patients will amount to a substantial decrease would attend a security alert during both an initial and a re- in staff workload. sedation episode. Ideally, seven staff should be available The cost-effectiveness analysis also revealed that the during the process of restraint and sedation: one security midazolam–droperidol combination is the dominant regi- staff member for each limb and one senior ED nurse for the men, being less costly and more effective than the other head (to prevent the patient from biting and to ensure the two monotherapy regimens. Decision making should be patient’s airway is not compromised), and another ED straightforward. Hence, the ICER is of little value in this nurse to prepare medication for the ED doctor to administer situation because the additional gain is not obtained with . In situations involving seven staff, this would further additional costs. add to the economic advantage of using the midazolam– Despite the resource implications, only one published droperidol combination. cost-minimisation analysis has evaluated the costs of The current evaluation suggests that airway obstruction managing acute agitation in the ED . However, that had limited impact on resource utilisation because of the study did not consider the differences in frequency of re- overall low rate of occurrence. Midazolam is associated sedation within 60 min and AE rates between the with an increased risk of respiratory complications that 148 C. Y. L. Yap et al. Fig. 1 Composition of different 120 mean cost components in overall management of acute agitation in emergency departments. Costs are presented in Australian dollars, year 2015–2016 values Initial sedation labour cost Initial sedation medication cost Re-sedation cost Airway management cost midazolam-droperidol droperidol olanzapine Table 5 Results of two-way analyses (base-, worst- and best-case scenario) for cost–beneﬁt analysis Scenario Mean costs of Economic beneﬁts Incremental economic Beneﬁt–cost management beneﬁts ratio per patient Base case Midazolam–droperidol 46.25 (36.77–55.74) 565.16 (556.64–573.68) – 12.2:1.0 Droperidol 92.18 (76.66–107.70) 533.92 (519.72–548.12) –31.24 5.8:1.0 Olanzapine 110.45 (91.51–129.39) 522.56 (508.36–539.60) –42.60 4.7:1.0 Worst case Midazolam–droperidol 55.74 556.64 – 10.0:1.0 Droperidol 76.66 548.12 –8.52 7.2:1.0 Olanzapine 91.51 539.60 –17.04 5.9:1.0 Best case Midazolam–droperidol 36.77 573.68 – 15.6:1.0 Droperidol 107.70 519.72 –53.96 4.8:1.0 Olanzapine 129.39 508.36 –65.32 3.9:1.0 Costs are presented in Australian dollars, year 2015–2016 values Economic beneﬁts = mean agitation-free time gained (min) 9 total cost of response team (AU$2.84) per minute; negative sign indicates that the midazolam–droperidol combination generated greater economic beneﬁts Mean (95% conﬁdence interval) may lead to intubation [10, 13], whereas droperidol raises subsequently reduced the risk of these severe AEs, the rare concerns of QT prolongation and Torsades de Pointes incidence of these AEs and the associated costs were (TdP) . It was not possible to estimate the impact of unlikely to change the conclusions of this study. Similarly, intubation and TdP in the current within-trial analysis as no other minor AEs such as hypotension and oxygen desatu- patient experienced these AEs in the RCT . As the ration were not considered in this evaluation because those midazolam–droperidol combination reduced the need for AEs were assumed to be self-limiting and would not have a high-dose midazolam or droperidol monotherapy, and signiﬁcant impact on resource utilisation. mean total cost (AU$) Economic Evaluation of Sedatives for Acute Agitation Management 149 Table 6 Results of two-way analyses (base-, worst- and best-case scenario) for cost-effectiveness analysis Scenario Mean costs of management Incremental Effectiveness (mean agitation-free Incremental ICER per patient cost time gained, min) effectiveness (min) Base case Midazolam– 46.25 (36.77–55.74) – 199 (196–202) – Dominant droperidol Droperidol 92.18 (76.66–107.70) 45.93 188 (183–193) –11 Dominated Olanzapine 110.45 (91.51–129.39) 64.20 184 (179–190) –15 Dominated Worst case Midazolam– 55.74 – 196 – Dominant droperidol Droperidol 76.66 20.92 193 –3 Dominated Olanzapine 91.51 35.77 190 –6 Dominated Best case Midazolam– 36.77 – 202 – Dominant droperidol Droperidol 107.70 70.93 183 –19 Dominated Olanzapine 129.39 92.62 179 –23 Dominated Costs are presented in Australian dollars, year 2015–2016 values ICER incremental cost-effectiveness ratio Mean (95% conﬁdence interval) Table 7 Results of alternative scenario analysis Alternative Mean cost of Incremental Effectiveness Incremental Economic Economic Beneﬁt- ICER scenario management per patient cost effectiveness beneﬁts beneﬁts cost (min) difference ratio Midazolam– 56.63 (44.47–68.80) – 199 (196–202) – 742.27 – 13.1:1 Dominant droperidol Droperidol 111.87 (91.89–131.85) 55.24 188 (183–193) –11 701.24 –41.03 6.3:1 Dominated Olanzapine 133.21 (109.05–157.37) 76.58 184 (179–190) –15 686.32 –55.95 5.2:1 Dominated Costs are presented in Australian dollars, year 2015–2016 values; ﬁgures in parentheses are 95% conﬁdence intervals Economic beneﬁts = mean agitation-free time gained (min) 9 total cost of response team (AU$3.73) per minute; negative sign denotes the midazolam–droperidol combination generated greater economic beneﬁts ICER incremental cost-effectiveness ratio, RN registered nurse Seven staff case scenario (one doctor, one grade 3 RN, one grade 2 RN, and four security staff). Total cost of the response team: AU$3.73/min Mean agitation-free time gained, min We acknowledge several limitations in this study. First, , we found that the ED LOS was not sensitive to the the results of this study can only be interpreted in the choice of sedation regimen. Patient disposition can be context of acutely agitated patients in the ED setting, and inﬂuenced by other non-sedation-related factors, including the results cannot be generalised to psychiatric inpatients. underlying medical comorbidities, availability of inpatient Furthermore, estimates of the mean costs of management beds, time of the day, etc. . Therefore, the exclusion of were based on data from only one RCT, and more eco- hospitalisation costs for the entire ED LOS would afford a nomic evaluations on the cost–beneﬁt and cost effective- more accurate measure of the efﬁciency of the different ness of other sedative regimens for the management of sedation regimens in managing the acute agitation. acute agitation in EDs are warranted. Finally, the re-sedation rate after 60 min was not To understand the immediate impact of the combination included in this analysis because the need for further regimen, our evaluation was conﬁned to the initial ade- sedation after 60 min is subject to a patient’s risk of violent quate sedation stage. Thus, hospitalisation costs for the behaviour after the initial adequate sedation. Prolonged entire ED LOS were not considered. However, in the RCT sedation is not the goal of acute agitation management. 150 C. Y. L. Yap et al. Open Access This article is distributed under the terms of the However, taking such costs into account would likely have Creative Commons Attribution-NonCommercial 4.0 International no important inﬂuence on the cost savings of the midazo- License (http://creativecommons.org/licenses/by-nc/4.0/), which per- lam–droperidol combination because the cost of re-seda- mits any noncommercial use, distribution, and reproduction in any tion was not the main cost driver. medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 5 Conclusions References The midazolam–droperidol combination may be more effective and less costly than both droperidol and olanza- 1. Downes MA, Healy P, Page CB, Bryant JL, Isbister GK. Struc- pine monotherapy. This study provides support, from an tured team approach to the agitated patient in the emergency department. 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The outcome of a rapid training program on nurses’ attitudes regarding the prevention of aggression in emergency Author contributions All authors conceived and designed the study. departments: a multi-site evaluation. Int J Nurs Stud. CY managed collation of the data and entry into the study database. 2013;50(11):1434–45. CY and AH undertook the data analysis. All authors contributed to 7. Psychotropic Expert Group. Therapeutic guidelines: psy- interpretation of the results, drafting and revision of the manuscript. chotropic. Version 7. Melbourne: Therapeutic Guidelines Lim- All authors take responsibility for the paper as a whole. ited; 2013. 8. Richmond JS, Berlin JS, Fishkind AB, Holloman GH, Zeller SL, Compliance with Ethical Standards Wilson MP, et al. Verbal de-escalation of the agitated patient: consensus statement of the American Association for Emergency This study is part of the randomised controlled trial  (Australian Psychiatry Project BETA De-escalation Workgroup. 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