What is the pathophysiology of delirium in cocaine toxicity?

Updated: Dec 31, 2020
  • Author: Lynn Barkley Burnett, MD, EdD, JD; Chief Editor: Sage W Wiener, MD  more...
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Patients presenting with agitated delirium, also known as excited delirium, are at high risk for sudden death, with a fatality rate of approximately 10%. [16] Agitated delirium is a common presentation in patients dying from cocaine toxicity. Of cocaine-associated deaths investigated by the Medical Examiner's Department of Metropolitan Dade County, Florida, between 1979 and 1990, excited delirium was the terminal event in approximately 1 of every 6 fatalities. Patients with excited delirium had an immediate onset of bizarre and violent behavior, which included aggression, combativeness, hyperactivity, hyperthermia, extreme paranoia, unexpected strength, and/or incoherent shouting. All of these were followed by cardiorespiratory arrest. [15]

Although heart weight, ventricular hypertrophy, and past MI are not risk factors, repeated binges of cocaine use are associated with fatal excited delirium, with a kindling effect proposed as a mechanism. [17] The frequency of use that increases risk has, however, not been determined.

Individuals with excited delirium may be more sensitive to the life-threatening effects of catecholamine surges than other cocaine users. Excited delirium appears to be generated by increased intrasynaptic dopamine concentrations resulting from a defect in the regulation of the dopamine transporter. Cocaine recognition sites on the striatal dopamine transporter are increased in users without excited delirium compared with drug-free controls. Persons dying from excited delirium have no such increase; therefore, they may have problems in clearing dopamine from the synapses, a condition that can easily result in agitation and delirium.

Hyperthermia, which may also be caused by downregulation of dopamine receptors, increases the incidence of fatal excited delirium. Death from excited delirium is more common in the summer months than at other times (55% vs 33% for other accidental cocaine toxicity deaths); therefore, high ambient temperature and humidity may play roles in the development of hyperthermia. An independent risk factor for fatal excited delirium is a body mass index (weight in kilograms/height in square meters) in the upper 3 quartiles, with the risk appearing to increase after a threshold is exceeded rather than in a dose-response fashion.

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