• 
• 

Three Part Question

In [patients presenting with excited delirium syndrome in the prehospital environment], is the use of [benzodiazepines, antipsychotics or ketamine] [superior in producing rapid and uncomplicated sedation]?

Clinical Scenario

A 30-year-old male presents to Emergency Medical Services with a Richmond Agitation-Sedation Scale of + 4 after reported use of intravenous amphetamines. A preliminary diagnosis of Excited Delirium Syndrome (ExDS) is made based on the history obtained and the decision is made to chemically sedate the patient. Whilst preparing for sedation, you wonder which pharmacological agent will produce the fastest and safest sedation in this patient population.

Search Strategy

United States of America National Library of Medicine (Thru May 2018)

((Excited Delirium[Title/Abstract] OR ExDS[Title/Abstract] OR Agitation[Title/Abstract] OR Acute Behavioural Disturbance[Title/Abstract])) AND (Prehospital[Title/Abstract] OR pre-hospital[Title/Abstract] OR paramedic[Title/Abstract] OR EMS[Title/Abstract] OR Emergency Medical Services[Title/Abstract])

Cumulative Index to Nursing and Allied Health Literature (Thru May 2018)

TX ( paramedic or ems or emergency medical service or prehospital or pre-hospital or ambulance or emergency medical technician or emt ) AND TX ( excited delirium syndrome OR ExDS OR agitation OR acute behavioural disturbance )

Literature was considered relevant if it described a piece of primary research in the prehospital setting, with a focus on the pharmacological management of ExDS. Literature was excluded if the research was undertaken in a hospital-based setting, or if it was non-interventional in nature.

Search Outcome

United States of America National Library of Medicine
75 results, of which eight were considered relevant.

Cumulative Index to Nursing and Allied Health Literature
107 results, of which seven were considered relevant. None in addition to those identified previously.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Rosen, C. Ratliff, A. Wolfe, R. Branney, S. Roe, E. & Pons, P. 1997 United States of America	Convenience sample of adult males transported to a single emergency department, described as 'combative' by paramedics.	Single-Blind, Randomised Controlled Trial comparing 5mg IV Droperidol vs Placebo.	Reduction in Agitation	71% reduction in agitation at 10 minutes (p<0.001) in intervention group	Convenience sample with overly broad exclusion criteria, particularly considering the small volume system. Unvalidated sedation scale used to assess level of agitation. Over half the patients within the placebo group never required sedation, bringing the internal validity of the research into question. Unclear whether outcome assessors were blind to allocation.
			Requirement for Further Sedation	45% of patients in placebo group required further sedation, compared with 13% in the Droperidol group (p=0.01)
			Adverse Reactions	One patient in Droperidol group developed akathisia.
Ho, J. Smith, S. Nystrom, P. Dawes, D. Orzco, B. Cole, J. & Heegaard, W. 2013	Two patients treated with Ketamine for Prehospital Agitation	Retrospective Case Series	Time-to-Sedation	Four minutes and Three minutes	No population for comparison Poorly described outcomes from the case series Unclear why Ketamine was chosen in these patients, compared with the standard therapies for this agency.
Scheppke, K. Braghiroli, J. Shalaby, M. & Chait, R. 2014	Patients treated according to EMS agencies Excited Delirium Protocol with Ketamine 4mg/kg	Retrospective Case Series	Time-to-Sedation	Mean 2 minutes (Range 1-5 minutes)	No comparator population. Significant amount of missing data from patient records, with total reliance on this incomplete data for reporting of adverse events. No indication of how patient records were screened for inclusion in the analysis. No objective measure of sedation reported. Some patients received follow-up intravenous midazolam, without significant subgroup analysis.
			Depth of Sedation	'Adequate' Sedation (Safe for Transport) achieved in 50 of 52 patients.
			Haemodynamic or Respiratory Events	3 cases of significant respiratory events noted, no haemodynamic events.
Isenberg, D. & Jacobs, D. 2015	Adult patients treated according to EMS agencies protocol for Behavioural Disturbances and Psychiatric Emergencies.	Open-label, randomised controlled trial of Midazolam 5mg I.M. versus Haloperidol 5mg I.M.	Time to RASS of + 1 or less	In Haloperidol group mean time to RASS of + 1 or less was 24.8 minutes (95% CI 8-49), against a mean time of 13.5 minutes (95% CI 8-19) in the Midazolam group	Sample size too small to make conclusions, with trial discontinued after 2 years (5 in each arm) Single-centre trial with small volume of patients (never likely to achieve required enrolments) Although patients assessed with RASS, they were enrolled based on protocol definitions Five additional patients excluded by the EMS Agency Medical Control without reason given.
			Requirement for Additional Sedation	Two patients in the Haloperidol group required additional sedation, against none of the patients receiving Midazolam
			Adverse Reactions	None in either group
Keseg, D. Cortez, E. Rund, D. & Caterino, J. 2015	All patients managed with Ketamine 4mg/kg by single EMS agency	Retrospective Case Series	Patients Recorded as 'Improved' on Patient Report Form	Improvement recorded in 91% of cases (95% CI 77-98%)	No comparator group. Small sample size (32 patients examined) Review of clinical outcomes not blinded to intervention Incomplete data present for a number of patients Subjective measure as primary outcome
			Requirement for Additional Sedation	40% of cases required additional sedation (95% CI 24-58%)
			Requirement for Endotracheal Intubation	23% of cases required intubation (95% CI 10-40%)
Cole, J. Moore, J. Nystrom, P. Orozco, B. Stellpflug, S. Kornas, R. Fryza, B. Steinberg, L. O’Bri 2016	Adult patients with an Altered Mental Status Scale (AMSS) of + 2 or + 3 transported to the study hospital, receiving either 10mg Haloperidol or 5mg/kg Ketamine.	Prospective Observational Study	Time to AMSS of less than + 1	Ketamine produced an AMSS or less than + 1 12 minutes faster than Haloperidol (P<0.0001, 95% CI 9-15 minutes)	Excluded patients with extreme agitation Unblinded, non-randomised study design. Patients were allocated treatment based on season. EMS agency serves multiple hospitals, with patients only enrolled if they were transported to one hospital. Unclear why this was the chosen study design.
			Depth of Sedation	95% of patients receiving Ketamine achieved an AMSS of less than +1, compared with only 65% in the Haloperidol group (P<0.0001)
			Adverse Reactions	49% of patients in the Ketamine group experienced an adverse event, when compared against 5% in the Haloperidol group (P<0.0001)
Cole, J. Klein, L. Nystrom, P. Moore, J. Driver, B. Fryza, B. Harrington, J. & Ho, J. 2018	Patients with active physical violence to themselves or others and an AMSS of +4, receiving Ketamine 5mg/kg	Retrospective Case Series	Time to AMSS of less than +1	Median time was 4.2 minutes (95% CI 2.5-5.9)	EMS agency serves multiple hospitals, meaning only 56 of 158 potentially eligible patients were analysed Rates of complications much higher than in other published literature, raising questions of external validity. No comparator group.
			Depth of Sedation	AMSS of less than +1 achieved in 90% of cases
			Adverse Events	Complications occurred in up to 57% of patients
Page, C. Parker, L. Rashford, S. Bosley, E. Isoardi, K. Williamson, F. & Isbister, G. 2018	Patients with an Acute Behavioural Disturbance as primary complaint and a Sedation Assessment Tool (SAT) of 2 or greater, receiving either Midazolam 5mg or Droperidol 10mg	Controlled Before-and-After Study	Time to reduction in SAT by 2 or more	Median time to sedation in Droperidol group was 22 minutes (IQR 16-35) compared with 30 minutes for Midazolam group (IQR 20-44)	Small enrolment bias (7% of cases missed on analysis) Higher proportion of SAT score of 3 in the Midazolam group, with possible confounding
			Requirement for Additional Sedation	Additional sedation required in 4% of patients receiving Droperidol (95% CI 1-9%) compared with 14% of patients receiving Midazolam (95% CI 8-24%) p=0.0001
			Adverse Reactions	16% higher rate of adverse events in the Midazolam group compared with the Droperidol group (p=0.0001)

Comment(s)

Despite the frequency with which patients suffering from ExDS will present to practitioners in the prehospital environment, literature examining the management of these patients is primarily founded in the setting of an emergency department with little consensus on the optimal sedative for use in this patient population. Although the prehospital and emergency department settings share a number of features, the prehospital environment is a profoundly resource-poor setting with unpredictable characteristics. This is of particular importance when considering not simply the efficacy, but the safety of pharmacological management of patients presenting with ExDS.

Clinical Bottom Line

There is insufficient evidence to recommend one pharmacological agent in the management of ExDS within the prehospital environment. Although Ketamine is associated with the most rapid onset of adequate sedation in patients with ExDS, it is also associated with the highest rate of adverse events and its use is frequently reported to result in the requirement for endotracheal intubation. Antipsychotic agents such as Haloperidol and Droperidol appear to have a superior safety profile when compared against Ketamine and Midazolam although they are associated with a protracted time to adequate sedation, which is of particular relevance in the setting of an ExDS patient. The choice of pharmacological agent for sedation of the patient with ExDS will depend on availability, clinician comfort and available resources to manage unexpected complications. Further high-quality controlled trials of benzodiazepines, antipsychotics and Ketamine are required before any recommendation for widespread use of any agent could be made.

References

1. Rosen, C. Ratliff, A. Wolfe, R. Branney, S. Roe, E. & Pons, P. The efficacy of intravenous Droperidol in the prehospital setting. Journal of Emergency Medicine 1997;15(1):13-17
2. Ho, J. Smith, S. Nystrom, P. Dawes, D. Orzco, B. Cole, J. & Heegaard, W. Successful Management of Excited Delirium Syndrome with Prehospital Ketamine: Two Case Examples Prehospital Emergency Care 2013;17(2):274-279
3. Scheppke, K. Braghiroli, J. Shalaby, M. & Chait, R. Prehospital Use of I.M. Ketamine for the Sedation of Violent and Agitated Patients Western Journal of Emergency Medicine 2014;15(7):736-741
4. Isenberg, D. & Jacobs, D. Prehospital Agitation and Sedation Trial (PhAST): A Randomised Controlled Trial Prehospital and Disaster Medicine 2015;30(5):491-495
5. Keseg, D. Cortez, E. Rund, D. & Caterino, J. The Use of Prehospital Ketamine for Control of Agitation in a Metropolitan Firefighter-Based EMS System Prehospital Emergency Care 2015;19(1):110-115
6. Cole, J. Moore, J. Nystrom, P. Orozco, B. Stellpflug, S. Kornas, R. Fryza, B. Steinberg, L. O’Brien-Lambert, A. Bache-Wiig, P. Engebretsen, K. & Ho, J. A prospective study of ketamine versus haloperidol for severe prehospital agitation. Clinical Toxicology 2016;54(7):556-562
7. Cole, J. Klein, L. Nystrom, P. Moore, J. Driver, B. Fryza, B. Harrington, J. & Ho, J. A prospective study of ketamine as primary therapy for prehospital profound agitation. American Journal of Emergency Medicine 2018;36(5):789-796
8. Page, C. Parker, L. Rashford, S. Bosley, E. Isoardi, K. Williamson, F. & Isbister, G. A Prospective Before and After Study of Droperidol for Prehospital Acute Behavioural Disturbance Prehospital Emergency Care 2018;20:1-9