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Three Part Question

In [adult patients] presenting to the Emergency Department with suspected [excited delirium syndrome], what are the [clinical features associated with significant morbidity and mortality]?

Clinical Scenario

You are working a shift in an Emergency Department (ED), and you receive a call from prehospital providers requesting advice in management of a violent and incoherent patient with strength far in excess of expected for his size. This seems consistent with reports you have read of Excited Delirium Syndrome (EXDS). You recall reports of sudden death in these patients and wonder if you can prevent this.

Search Strategy

Medline 1946 - 05/2013 using OVID interface, Cochrane Library (2013), PubMed clinical queries
[(excited delirium.mp) OR (exp overdose AND exp delirium)]. Limit to English language, humans.

Search Outcome

73 papers were identified, 11 studies were relevant to the clinical question.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Wetli and Fisbain 1985 USA	7 cocaine users with EXDS and sudden death.	Systematic retrospective case review of cases with sudden unexplained death and cocaine intoxication.	Drug(s)	Cocaine	Retrospective case series. No standardized data colletion/reporting.
			EXDS perimortem findings	Hyperthermia, metabolic acidosidois pulmonary congestion and edema, cerebral edema, mild non-lethal injuries common. Myofibrillar degeneration in 1 of 7. No seizures.
			Mechanism of death	Death attributed to cardiac dysrhythmia, autonomic dysregulation, or restraint stress.
Mash et al. 2009 USA	90 sudden deaths associated with EXDS	Retrospective analysis, neurochemical analysis	Drug(s)	Cocaine and/or amphetamine (94%); Also ethanol, methamphetamine, MDMA, ephedrine, pseudoephedrine, risperidone and citalopram, or none (N=4)	Retrospective. Only includes cases submitted by law enforcement for further review so may be subject to selection bias.
			EXDS perimortem findings	Hyperthermia, elevated heat shock protein and transcript in brains of EXDS patients. Lower amounts of dopamine transporter in brains of patients with EXD.
			Mechanism of death	Death attributed to hyperdopaminergic state, neurocardiac dysregulation, and individual phenotype.
Ruttenber et al. 1999 USA	58 cases fatal EXDS, 150 cases of cocaine-associated rhabdomyolysis, 125 cases fatal cocaine toxicity.	Case series and literature review (Includes data derived from prior reports).	Drug(s)	Cocaine	Literature review limited to cocaine-associated rhabdomyolysis. Postmortem temperature not recorded routinely unless elevated, possibly producing confirmation bias if not suspected. Proposes EXDS closely linked to rhabdomyolysis but does not report percentage EXDS with rhabdomylysis.
			EXDS perimortem findings	Hyperthermia present in 97% of cases of fatal EXDS. Rhabdomyolysis, seizure (27.5%), ethanol, and other drug use more commonly reported in fatal EXDS.
			Mechanism of death	Rhabdomyolysis,possibly related to hypothalamic dopaminergic temperature dysregulation.
O\'Halloran and Lewman 1993 USA	11 cases with EXDS and sudden death.	Retrospective case analyses	Drug(s)	Cocaine, methamphetamine, LSD, amantadine, valproate, multiple, or none (3)	Case series without description of how cases collected. Perimortem and autopsy findings inconsistently reported. Inconsistency regarding illicit or therapeutic drugs or mental conditions. Only consistent factor is restraint.
			EXDS perimortem findings	Axillary hyperthermia reported in one case All cases involved restraint. 2 cases with CEW. One with myocardial contraction bands.
			Mechanism of death	One patient with no drugs had history neuroleptic malignant syndrome. Cardiac dysrhythmia or respiratory arrest secondary to increased oxygen demand and decreased delivery.
Pollanen et al. Jun 1998 Canada	All cases unexpected death with EXDS in Ontario, 1988 - 1995, N=25.	Retrospective case analyses	Drug(s)	Cocaine (38%) or multiple (5%); psychiatric disorder (57%).	Retrospective. Minimal perimortem analysis. No quantification of purported mechanism of death, e.g. respiratory acidosis. Does not discuss nonlethal cases of EXDS or whether purported mechanism of death increases mortality likelihood.
			EXDS perimortem findings	Restraint in all cases. No life-threatening injuries noted on autopsy. Conjunctival petechiae after neck compression (N=2), subpleural and epicardial petechiae (N=3). Serum cocaine levels similar to recreational users. Heart disease in 19%. Pepper spray exposure in 19%.
			Mechanism of death	Positional asphyxia
Stratton et al. May 1995 USA	2 cases of unexpected death and EXDS	Retrospective case analyses	Drug(s)	Amphetamine, cocaine, ethanol	Retrospective, small number of cases. Positional asphyxia as cause of death determined by coroner based only on patient position, respiratory arrest, and lack of other apparent cause of death. Minimal physiologic data to support conclusion.
			EXDS perimortem findings	Nonlethal blood methamphetmaine, cocaine, and ethanol level. Pulmonary edema and congestion noted in one case.
			Mechanism of death	Positional asphyxia from hogtie position.
Ross Nov 1998 USA	61 cases of sudden death-associated EXDS, restrained while in police custody (1988-1997)	Retrospective case analyses	Drug(s)	Cocaine, ethanol, methamphetamine, amphetamine, methylphenidate, LSD, THC, lithium, valproate, haloperidol. Schizophrenia and bipolar disorder in some cases.	Case collection methodology not well explained. Minimal supporting evidence (e.g. perimortem findings) for purported mechanism of death. Police custody and restraint was part of selection criteria so causality from position cannot be inferred.
			EXDS perimortem findings	Hypertermia (mean 104F), mechanical restraints (100%).
			Mechanism of death	Acute drug toxicity, positional asphyxia, cardiorespiratory arrest, exhaustive mania.
Murray et al. Mar 2012 USA	1 case of EXDS and sudden death	Case Report	Drug(s)	Methylenedioxypyrovalerone (MDPV; bath-salts)	Case report. Clinical and toxicologic analyses well reported but minimal postmortem data. History of bipolar disorder which has also been associated with EXDS.
			EXDS perimortem findings	Widened QRS with peaked T waves. Initially normothermic but hyperthermic at time of cardiovascular collapse; subsequent rhabdomyolysis, DIC, metabolic acidosis, anoxic brain injury.
			Mechanism of death	Autonomic dysfunction including hyperthermia secondary to hypothalamic dopaminergic dysregulation.
Stratton et al. May 2001 USA	18 cases of sudden death in restrained patients with EXDS withnessed by EMS providers.	Retrospective case analyses	Drug(s)	Cocaine and/or amphetamine (14/18); THC (1/18), none (3/18).	Hobble restraint was standard procedure for all EXDS patients (including 196 nonfatal EXDS during study period), so causation of sudden death by hobble restraint cannot be determined. Temperature not included in data collection. Various initial arrhythmia and asystole recorded, but progression from initial arrhythmia not reported.
			EXDS perimortem findings	Wrists and ankles bound behind back (18/18). Chronic disease including cardiac disease, obesity. Initial EKG in 13 of 18 cases, ventricular tachycardia in one case; asystole, sinius tachycardia, bradycardia, junctional and agonal rhythym in remainder.
			Mechanism of death	Interaction of obesity, chronic disease, stimulant use, restraint asphyxia.

Comment(s)

EXDS is a clinical presentation of bizarre behaviour, violence and agitation, typically in patients taking illicit stimulant drugs. Patients are often described as having strength in excess of what would be expected, and often require forcible restraint by multiple law enforcement or medical personnel. This syndrome is infrequent but is associated with significant morbidity and mortality, producing challenges to prehospital and emergency medicine providers. Most notably, some patients have sudden cardiovascular collapse. No convincing data exist regarding mechanism of death, and various authors ascribe mortality to complications of dopaminergic overdrive, autonomic dysregulation, hyperthermia, rhabdomyolysis, cardiac arrhythmia, or impaired respiratory mechanics. Given the lack of consensus about the pathological mechanism, treatment for these patients is challenging.

Editor Comment

CEW, conducted electrical weapon (taser); DIC, disseminated intravascular coagulation; EMS, emergency medical services; EXDS, excited delirium syndrome; MDMA, 3,4-methylenedioxy-N-methylamphetamine; THC, tetrahydrocannabinol.

Clinical Bottom Line

Early recognition of EXDS remains paramount as patients may have sudden cardiovascular collapse with little warning. Several authors do describe laboured respiratory efforts before death, so prompt airway and haemodynamic control may be necessary. Patients may benefit from chemical rather than physical restraint. Acidosis and hyperthermia should also be aggressively managed. Law enforcement and prehospital personnel should also be educated regarding the potential complications of EXDS.

References

1. Wetli CV, Fisbain DA. Cocaine-induced psychosis and sudden death in recreational cocaine users. Journal of Forensic Sciences 1985;30:873–80.
2. Mash DC, Duque L, Pablo J et al. Brain biomarkers for identifying excited delirium as a cause of sudden death. Forensic Science International 2009;190:e13–19.
3. Ruttenber AJ, McAnally HB, Wetli CV. Cocaine-associated rhabdomyoysis and excited delirium: different stages of the same syndrome. The American Journal of Forensic Medicine and Pathology. 1999;20:120–7.
4. O\'Halloran RL, Lewman LV. Restraint asphyxiation and excited delirium. American Journal of Forensic Medicine and Pathology 1993;14:289–95.
5. Pollanen MS, Chiasson DA, Cairns JT et al. Unexpected death related to restraint for excited delirium: a retrospective study of deaths in police custody and in the community. Canadian Medical Association Journal 1998;158:1603–7.
6. Stratton SJ, Rogers C, Green K. Sudden death in individuals in hobble restraints during paramedic transport. Annals of Emergency Medicine 1995;25:710–12.
7. Ross DL. Factors associated with excited delirium deaths in police custody. Modern pathology 1998;11:1127–37.
8. Murray BL, Murphy CM, Beuhler MC. Death following recreational use of designer drug. Journal of Medical Toxicology 2012;8:69–75.
9. Stratton SJ, Rogers C, Brickett K et al. Factors associated with sudden death of individuals requiring restraint for excited delirium. American Journal of Emergency Medicine 2001;19:187–91.