Toxicology

Excited Delirium: Acute Management in the ED Setting

Excited delirium syndrome is a common yet poorly characterized ED presentation with a wide differential diagnosis. Patients are often identified initially by law enforcement, but attempts to control individuals experiencing ExDS via physical, chemical, or electrical restraints are associated with an exceedingly high rate of morbidity and mortality.

Case
A 25-year-old man presents to the ED brought in by EMS for altered mental status (AMS). Prior to arrival, paramedics provide a radio report stating that patient was found agitated, behaving aggressively, and then climbed on the hood of the ambulance. He was noted to be extremely strong and difficult to restrain. Paramedics administered 5 mg midazolam intramuscularly and were able to physically restrain him, but upon arrival he remains extremely agitated, yelling and slamming himself against the stretcher sidebars. He does not answer any questions and his speech is nonsensical. On exam, the patient is markedly tremulous, hot to touch, with myoclonic jerks and bruxism. Extensive superficial abrasions are noted about his abdomen, thorax, and extremities. He is too agitated to obtain initial vitals. What are your next steps?

Background
Excited delirium syndrome (ExDS) is a common yet poorly characterized ED presentation with a wide differential diagnosis. Described in the literature for more than 100 years,1 it is hypothesized to involve catecholaminergic excess involving endogenous stress‐related catecholamines, exogenous catecholaminergic drugs,2 and/or overstimulation of dopamine and NMDA glutamate receptors in the setting of psychiatric or organic medical illness. Causes can be grouped broadly into metabolic/endocrine, neurologic, infectious, toxicologic, and psychiatric etiologies (Table 1).

 

Most common among these is the concurrent presence of acute drug intoxication, particularly sympathomimetics, and history of mental illness with psychotic features. The incidence of ExDS varies widely, with rising incidence in the 1980s3 linked to increased use of cocaine,4 amphetamines, and phencyclidine. Recently, synthetic cathinones and cannabinoids have been implicated.5,6

Patients are often identified initially by law enforcement. Intervention by law enforcement to control individuals experiencing ExDS via physical, chemical, or electrical restraints are associated with an exceedingly high rate of morbidity and mortality; ExDS is implicated in more than 3% of police interventions involving use of force, is associated with more than 10% of deaths in police custody, and between 38%-86% of ExDS related mortality has occurred in police custody, particularly associated with police coercion methods and/or positional asphyxia.2

By itself, ExDS carries an extremely high mortality risk, with approximately 2/3 of ExDS patients dying in the prehospital setting7 in the absence of any major trauma, physical restraint, or police intervention. Mortality is most strongly associated with respiratory depression, severe hyperthermia, acidemia, or a combination thereof.8 Of these, profound hyperthermia has the strongest association with mortality:9 extreme core temperatures can alter blood–brain barrier permeability, contribute to protein malfunction or degradation, and potentiate glutamate induced neurotoxicity.10

Differential Diagnosis
To date, there is no universally recognized definition for ExDS. The initial description developed from post-mortem identification based on history and was an encompassing term used across many medical and legal settings. In a 2009 White Paper, the American College of Emergency Physicians described ExDS as a subset of AMS and recommended that despite the vagueness of the clinical entity, salient features of history should be combined with the differential diagnosis for common causes of AMS to describe the presentation. ExDS has been described as “a syndrome of uncertain etiology characterized by delirium, agitation, and hyperadrenergic autonomic dysfunction”, with “characteristic symptoms of bizarre and aggressive behavior, shouting, paranoia, panic, violence toward others, unexpected physical strength, and hyperthermia.”1 ExDS patients typically present with any combination of agitation, heightened pain tolerance, tachypnea, and diaphoresis; these patients have a propensity to develop severe acidemia with progression to sudden cardiac arrest.11 The common presenting features of the syndrome and the broad overlap with other conditions necessitates the investigation of other underlying etiologies, as noted in Table 1.

Management
Management is tailored to patient presentation and should be centered on 4 pillars of evidence-based care: control of agitation, correction of hyperthermia, avoidance of acidosis, and investigation into the underlying etiology (Table 1).

Because positional asphyxia, respiratory depression, severe hyperthermia, acidosis, and/or catecholamine-induced fatal arrhythmias12 may precipitate cardiovascular collapse, these should be prevented and managed aggressively. These pillars hold true in the prehospital setting as well as in the ED, as quick recognition, and deliberate, appropriate treatment by prehospital providers can lessen harm and prevent poor outcomes. Many EMS agencies have specific protocols to address ExDS, often emphasizing the primacy of safe positioning and prompt sedation with benzodiazepines and/or ketamine. Where not explicitly defined in protocol, prehospital providers should prioritize these approaches in practice, recognizing that ExDS patients are, or have the potential to become critically ill very quickly. Early identification by EMS personnel can allay risk for sudden death, alert receiving ED staff, and assist medical examiners in better understanding the presentation and identify the probability that the patient was experiencing ExDS.13

Control of Agitation
Consensus recommendations for the pharmacological management of AMS is to treat underlying etiology first and then address behavioral symptoms. However, ExDS is typified by a dangerously agitated state that nearly universally requires sedation.2 Severe agitation may preclude IV access or labs early in the patient encounter. As such, initial goals in the undifferentiated ExDS patient should be to quickly and effectively provide sedation while restraining the patient in a safe position. Following many in-hospital deaths of patients placed in restraints, the Joint Commission and many hospital policies elaborate specific requirements for safe physical restraints. These include frequent face-to-face provider reassessment of restraint necessity to minimize mechanical restraint time. Important principles when restraining a patient include avoidance of pressure on the face, neck, and chest, which would lead to asphyxiation, respiratory or metabolic acidosis, and death. Likewise, ExDS may be secondary to hypoxia, and placing a non-rebreather with 100% oxygen is preferable, as it doubles as a spit-mask. Additionally, it is often necessary to use 4- or 5-point restraints, placing the patient in the supine position with the head of the bed elevated to 30° while restraining one of the patient’s arms above the head and the other below the waist.

While the traditional mainstays for pharmacologic management of agitation includes benzodiazepines (particularly lorazepam and midazolam), antihistamines such as diphenhydramine, and antipsychotics, there are many drawbacks to these drugs in the ExDS patient (Table 2). As progression to cardiovascular collapse is most highly associated with hyperthermia, respiratory depression and acidemia, pharmacologic choices in sedation of patients with ExDS should complement efforts to counteract these alterations in physiology, not worsen them. In recent years, national shortages of IV diazepam and lorazepam,15 alongside a preponderance of evidence and provider preference has encouraged the use of ketamine for sedation management of ExDS, with typical dosing ranges provided in Table 2. Relative latitude in both calculation and route of dosing, rapid onset of action, and ease of progression from sedation to delayed or rapid sequence induction and intubation make ketamine a good primary choice in ExDS patients with or without IV access.16 Another benefit of ketamine is the fact that it preserves the patient’s airway reflexes, allowing them to continue spontaneous breathing. While most ketamine sedated patients do not necessitate aggressive airway management, attention to the patient’s airway, as well as monitoring for procedural sedation, should be utilized in all ExDS patients treated with ketamine. 

Correction of Hyperthermia
Management of hyperthermia is an important tenet of ExDS management, and should be initiated immediately after control of agitation. Temperature management in ExDS is similar to that in the setting of environmental hyperthermia, and may include removal of clothing, passive external cooling, forced air cooling blanket systems, and cold IV fluids.

Avoidance of Acidosis
Avoidance of any acidosis is important, and may be secondary to a variety of etiologies, including hypoperfusion, rhabdomyolysis, and respiratory depression. As part of initial workup, venous or arterial blood gases should be obtained to assess underlying acid/base derangements. Management should be targeted to the underlying pathology and may include intravenous fluid resuscitation or respiratory support. In the case of an ExDS patient managed with sedation, including ketamine, end-tidal CO2 (etCO2) monitoring is required for monitoring the rate, depth, and adequacy of respiration. 

Investigation into Underlying Etiology
After patient has been stabilized and sedated, workup should be guided by the physical exam and history. Complete physical exam is critical- patients with ExDS may have significant underlying injuries, and efforts to restrain can exacerbate any pre-existing trauma. Initial investigations should include blood glucose, CBC, BMP, and toxicologic screens for any co-ingestants. Consider CPK if suspicious for rhabdomyolysis, blood cultures and/or LP if concern for sepsis and/or septic meningitis. Imaging may be pursued to investigate any potential underlying trauma.

Case Conclusion
Following transfer to ED stretcher, patient was placed in 4-point soft restraints with a nonrebreather and 100% oxygen with assistance from hospital security; 5 mg/kg ketamine IM was administered, with significant reduction in agitation. The patient was placed on etCO2 and brought to the resuscitation bay for close monitoring. He was found to be tachycardic with a pulse of 150, hypertensive at 150/94, hyperthermic at 39.6° C. End-tidal showed 38mmHg CO2 and 20 respirations/minute. Labs revealed no abnormalities. Cold packs were placed to axilla and groin, and 2 L of cooled lactated ringers was administered IV with improvement in temperature. 

Based on the physical exam and history, concern was for excited delirium secondary to an unknown sympathomimetic agent with hallucinogenic qualities, and the patient was admitted to ICU stepdown with supportive care. 

The patient’s agitated delirium resolved on hospital day 2, and he was transferred to inpatient psychiatry for continued observation. He was discharged on day 4 with referral to psychiatric services and support for drug use.


References
1. Mash D. Excited Delirium and Sudden Death: A Syndromal Disorder at the Extreme End of the Neuropsychiatric Continuum. Front Physiol. 2016;7:435.
2. Gonin P, Beysard N, Yersin B, Carron PN. Excited delirium: a systematic review. Acad Emerg Med. 2018;25(5):552-565.
3. Vilke GM, DeBard ML, Chan TC, et al. Excited Delirium Syndrome (ExDS): defining based on a review of the literature. J Emerg Med. 2012;43(5):897-905.
4. Wetli CV, Fishbain DA. Cocaine-induced psychosis and sudden death in recreational cocaine users. J Forensic Sci. 1985;30(3):873-880.
5. Atis SE, Yilmaz G, Bozan O, Cekmen B. A Terrifying Drug Threats the Streets: Flakka - A Case Report. J Mol Imag Dynamic. 2018;8(1):142.
6. Prosser JM, Nelson LS. The toxicology of bath salts: a review of synthetic cathinones. J Med Toxicol. 2012;8(1):33-42.
7. Gottlieb M, Long B, Koyfman A. Approach to the Agitated Emergency Department Patient. J Emerg Med. 2018;54(4):447-457.
8. Otahbachi M, Cevik C, Bagdure S, Nugent K. Excited delirium, restraints, and unexpected death: a review of pathogenesis. Am J Forensic Med Pathol. 2010;31(2):107-112.
9. Mash DC. Excited Delirium and Sudden Death: A Syndromal Disorder at the Extreme End of the Neuropsychiatric Continuum. Front Physiol. 2016;7:435.
10. Plush T, Shakespeare W, Jacobs D, Ladi L, Sethi S, Gasperino J. Cocaine-induced agitated delirium: a case report and review. J Intensive Care Med. 2015;30(1):49-57.
11. DeBard ML, Adler J, Bozeman W, Chan T, et al: ACEP Excited Delirium Task Force. White Paper Report on Excited Delirium Syndrome. 2009.
12. Death S. BET 1: Excited delirium syndrome and sudden death. Emerg Med J. 2013;30(11):958-960.
13. Vilke GM, Bozeman WP, Dawes DM, Demers G, Wilson MP. Excited delirium syndrome (ExDS): Treatment options and considerations. J Forensic Leg Med. 2012;19(3):117-121.
14. City of New Orleans. Region One Protocol Effort. State of Louisiana. 2013.
15. Tassey T. Out of Ativan?! The Drug Shortage Crisis in the U.S. EM Resident. 2016;43(1):28-29.
16. Mankowitz SL, Regenberg P, Kaldan J, Cole JB. Ketamine for Rapid Sedation of Agitated Patients in the Prehospital and Emergency Department Settings: A Systematic Review and Proportional Meta-Analysis. J Emerg Med. 2018;55(5):670-681.

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