Cocaine-Associated Agitated Delirium and the Neuroleptic Malignant Syndrome

CHARLES V. WETLI, MD, *DEBORAH MASH, PHD, 1 STEVEN B. KARCH, MD:I:

The incidence of this previously rare disorder, cocaine-associated agi- asphyxia related to hogtying, or other police procedures tated delirium, appears to have increased drastically within the last 18 such as restraining neck hold, pepper sprays, or electrical months. The underlying neurochemical abnormalities have recently been stun devices. 4,5 However, it is important to note that many characterized, but most clinicians have had little experience with manage- victims of this disorder die suddenly and without the ment of agitated delirium. The basic clinical and pathological features of application of any law enforcement restraining techniques. this disorder are reviewed, and common pitfalls in diagnosis and management that frequently lead to needless but very expensive litiga- In their original report, Wetli and Fishbain ~ described the tion are discussed. (Am J Emerg Med 1996;14:425-428. Copyright © 1996 syndrome in seven cases. All had fairly stereotypical histo- by W.B. Saunders Company) ries. Typical was the case of a 33-year-old man who started pounding on the door of a house he had moved out of some time previously. He was shouting that he wanted to see his The first modern mention of cocaine-associated agitated wife and daughter. The occupants informed him that nobody delirium was in 1985.1 Reports of patients with similar by that name resided there, yet he pursued his actions. Four symptoms had appeared in the early 1900s, 2 but because bystanders finally restrained him and assisted police units these reports were deeply interwoven with elements of racist upon their arrival. The subject was handcuffed and put into a hysteria they were never taken seriously. The syndrome is police car, whereupon he began to kick out the windows of comprised of four components which appear in sequence: the vehicle. The police subsequently restrained his ankles hyperthermia, delirium with agitation, respiratory arrest, and and attached the ankle restraints and handcuffs together. He death. Individuals succumbing to this disorder uniformly was than transported to a local hospital. While en route, the have low to modest cocaine blood levels and do not behave police officers noted that he became tranquil (about 45 like patients with massive overdose (continuous seizures, minutes after the onset of the disturbance). On arrival at the respiratory depression, and death). Recent data also show hospital a few minutes later, the subject was discovered to be that these victims have high blood levels of benzoylecgo- in a respiratory arrest. Resuscitative attempts were futile. A nine, the principal cocaine metabolite. 3 The incidence of this postmortem examination was performed 1 hour and 45 disorder is not known with any certainty. There is, however, minutes later (about 3 hours after the onset of the distur- little doubt that the number of cases has increased markedly bance), and a rectal temperature of 41°C (106°F) was since the late 1980s, and it seems likely that the increase is recorded. He had needle marks typical of intravenous drug related to the widespread popularity of crack cocaine. abuse, as well as pulmonary and cerebral edema. Abrasions In the early stages of the disorder, victims are hyperther- and contusions of the ankles and wrist were also evident mic and grossly psychotic, with marked physical agitation. from his struggling against the restraints. Toxicologic analy- They often perform amazing feats of strength, particularly sis of postmortem blood disclosed 52.3 mg/L of lidocaine after citizens or police attempt to restrain them. Shortly after and 0.8 mg/L of cocaine. No lidocalne was administered to being restrained, agitation ceases and the victim is fre- the victim during resuscitative attempts. quently found dead, or near death, just moments later. Not The clinical presentation of agitated psychotic cocaine uncommonly, victims have been "hogtied"; their wrists and abusers is quite different from that of nonpsychotic cocaine ankles are bound together behind their back while they lie abusers with sudden death or massive drug overdose. The prone. 4 Victims who do not come to police attention are psychotic cocaine users are almost always men, they are often found dead in their bathrooms. Because of their more likely to die in custody, and they are more likely to live hyperthermia they will often be found surrounded by wet for 1 hour after onset of symptoms. In Miami, men with towels and clothing, sometimes even with empty ice trays agitated delirium account for 10% of cocaine deaths. scattered about. Since the victims frequently die in police Approximately 39% of the victims of excited delirium custody, there are often allegations that death resulted from deaths in Miami occurred in police custody (Mash, Rutten- ber, et al, personal communication, August 1995). Their From the *Suffolk County Medical Examiner, Suffolk County, NY; deaths tend to occur in summer, especially when the weather the ]-Department of Neurology, University of Miami School of Medi- is warm and humid. Two thirds of the victims die on the cine, Miami, FL; and the :l:Assistant Medical Examiner, City and County of San Francisco, CA. scene or while being transported by paramedics to the Manuscript received September 6, 1995, accepted October 28, hospital. The few who live long enough to be hospitalized 1995. succumb to disseminated intravascular coagulation, rhabdo- Reprints are not available. myolyis, and renal failure. In the Miami patients, the average Key Words:Agitated delirium, cocaine, dopamine receptors, "hog- temperature at the time of first medical encounter was nearly tied," positional asphyxia. Copyright © 1996 by W.B. Saunders Company 105°F. 3 The demographics appear to be similar in other 0735-6757/96/1404-002355.00/0 locals. 6 425 426 AMERICAN JOURNAL OF EMERGENCY MEDICINE • Volume 14, Number 4 • July 1996

The mean cocaine concentration in 45 cases seen by the cally high dopamine levels may occur after a "binge" and Dade County Medical Examiner was 1.32 mg/L (range .05 that, in turn, may lead to psychosis. to 11.8 rag/L, n = 34), while the benzoylecgonine level was Psychotic and nonpsychotic cocaine users can also be 3.78 mg/L (range .08 to 14.75 rag/L, n = 38). In these same distinguished by the number of dopamine binding sites. In patients, the mean brain cocaine concentration was 1.90 most people, chronic cocaine abuse leads to striking de- mg/kg (range .05 to 4 mg/kg, n = 10), while the mean creases in the density of the D 1 receptor subtype throughout benzoylecgonine concentration was 2.69 mg/kg (range .85 the striatal reward centers, probably as a result of receptor to 3.5 mg/kg, n = 6). 3 A consistent finding at autopsy was down-regulation. The fact that cocaine users quickly be- cardiomegaly. The median heart weight in 44 men was over come tolerant to the drug's euphoriant effects is probably 420 grams. explained by the change in the number of dopamine receptor The cellular and neurochemical changes associated with sites. Striatal D2 receptors in nonpsychotic cocaine abusers this disorder are starting to become clearer. Using ligand are unchanged. However, in the psychotic subgroup, marked binding and autoradiographic methods, researchers have reductions in the number of D2 receptors were found within identified three different neurochemical abnormalities in the temperature regulatory centers of the hypothalamus. Since brains of cocaine abusers dying of agitated delirium. 7-9 One these receptors are known to decrease core body tempera- factor that is clearly implicated in the effects of cocaine is ture, decreased numbers of D2 receptors may explain the the neurotransmitter dopamine. Some of the abnormalities in occurrence of malignant hyperthermia in the psychotic the dopamine system involve alterations in certain types of patients. With fewer D2 receptors available, Dl-mediated dopamine receptors and in the cocaine's ability to block the temperature increases would be unopposed. reuptake pump or "transporter" by which dopamine is Agitated delirium can be the result of other medical recycled back to the nerve terminal. The net effect is that disorders, not just cocaine toxicity. In fact, the syndrome is cocaine prevents dopamine from being taken back up by the said to have first been described in the 1800s, years before sending neuron, promoting its actions on dopamine recep- cocaine was isolated from the coca leaf, According to tors. Cocaine users often go on binges, consuming a large Wendkos, 1~ Bell first described patients with agitated delirium in 1849. Episodes occurring in patients with non-drug- amount of the drug over a few days. The neurochemical related psychosis were further characterized by Shulack in changes over the "binge" and crash periods involve adap- 1938.H Recently it has been suggested that this constellation tive alterations of the dopamine receptors on receiving cells. of symptoms is actually a variant of neuroleptic malignant Dopamine receptors were initially classified into two syndrome. 6,12,13 Neuroleptic malignant syndrome (NMS) is a main groups. With advances in molecular biology, these two highly lethal disorder seen in patients taking dopamine main subtypes are now known to be comprised of five antagonists and in individuals who have been withdrawn different receptors, but they are still considered as two from dopaminergic agents such as bromocriptine and levodo- receptor families: the "D l-like receptors" (dopamine recep- pa. ~4,15 NMS is usually associated with muscle rigidity, tors D1 and D5), and the "D2-1ike receptors" (dopamine although variants of the syndrome without rigidity are also receptors D2, D3, and D4). ~° recognized. 13 The situation is somewhat confusing and difficult to Alterations in the number of dopamine receptors and understand, largely because of the nomenclature used to cocaine recognition sites on the dopamine transporter may describe dopamine receptors. Most antipsychotic drugs not be the sole explanation for the death of these individuals. block the D2 receptors with affinities that correlate with their There is mounting evidence that the stress of restraint makes clinical potency. The atypical antipsychotic clozapine has fatal outcomes more likely. Rats injected daily with moder- been shown to prefer the putative D4 receptor subtype. D 1 ate doses of cocaine (30 mg/kg) and then restrained are three and D2 receptors interact with each other and enhance each times more likely to die from seizures than rats injected with other's actions within the neuron, possibly by causing the same amount of drug and allowed free access to their subunits of G proteins to alter the cascade of second cages. ~6 Since so many of the agitated delirium patients die messenger signaling. In schizophrenia, D2 and D3 receptor while restrained, it has been suggested that the mechanism density is elevated by 10%, while the D4 receptors are of death may involve a surge of catecholamines released by elevated even more. It has been suggested that cocaine the stress response, superimposed on a myocardium already "craving" may result in part because of alterations in D3 sensitized by cocaine, a7 This notion is further supported by receptor signaling within limbic sectors of the striatum the observation of myocardial enlargement, presumably (Staley, Mash, et al, unpublished observations). catecholamine related, in most victims.18 The occurrence of agitated delirium probably has some- Autopsy findings are generally minimal and nonspecific, thing to do with the fact that both D 1 and D2 receptors and and associated injuries are generally minor. However, be- dopamine transporters are altered by chronic cocaine use. ~° cause blood concentrations of cocaine tend to be fairly low, In comparison with drug-free controls, the brains of nonpsy- and because there is confusion about the interpretation of chotic cocaine abusers contain an elevated number of cocaine blood levels anyway, it is often tempting to attribute cocaine recognition sites on the striatal dopamine trans- the cause of death to one of the minor injuries, such as minor porter. 7 No such increase is seen in the agitated delirium head injury. 17 Needless litigation is often the result. When victims. 9 The fact that the psychotic cocaine users fail to cocaine users with agitated delirium die, cocaine should be demonstrate this compensatory increase means that they considered the cause of death, unless there is clear physical cannot clear excess dopamine from their synapses. Pathologi- evidence that death is due to some mechanism other than WETLI ET AL [] COCAINE-ASSOCIATED AGITATED DELIRIUM 427

Bound (fmoUmg) >25 20-25 15-20 10-15 5-10 <5

FIGURE l. In vitro autoradiograpllic maps of [3H]WIN 35,428 labeling of the dopamine transporter in coronal sections of the human brain from a representative (A) age-matched and drug free subject, (B) a cocaine overdose victim, and (C) a cocaine-related agitated delirium victim. The brain maps illustrate the adaptive increase in dopamine transporter density over the striatum in the cocaine overdose victims and the lack of any apparent elevation in the victim presenting with agitated delirium. Since the dopamine transporter regulates the synaptic concentration of neurotransmitter, the lack of compensatory upregulation may result in a dopamine overflow following a cocaine "binge." Elevated synaptic dopamine with repeated exposures may kindle the emergence of agitated delirium syndrome. Gray scale codes are presented at the right and are matched for the range of density values across the groups (black = high densities; gray = intermediate; light gray to white = low to background densities). Abbreviations: Cd, candate; NA, nucleus accumbens, Pt, putamen. cocaine toxicity, such as positional or mechanical asphyxia. capable of such measurements and should be contacted It is well to remember that in most cases of agitated delirium immediately for instructions (1-800-UM-BRA1N). death occurs without significant police restraint, and frivo- lous speculation about the cause or mechanisms of death will only invited needless litigation. REFERENCES Emergency physicians rendering care to victims of this 1. Wetli C, Fishbain D: Cocaine-induced psychosis and sudden disorder are also at risk for needless litigation. However, death in recreational cocaine users. J Forensic Sci 1985;30:873-880 some of the risks can be minimized. Allegations that 2. Williams E: Negro cocaine "fiends" are a new southern men- positional asphyxia occurred in transit are difficult to prove ace. New York 1914:1 when the victim is monitored and observed during transport. 3. Wetli C, Raval M: Update on agitated delirium. Presented at the Emergency medical services (EMS) boards need to establish American Academy of Forensic Science Annual Meeting, Seattle, protocols for the field management of such patients, not only WA, February 15, 1995 4. O'Halloran R, Lewman L: Restraint asphyxiation in excited to improve chances for patient survival but also to limit delirium. Am J Forensic Med Patho11993;14:289-295 paramedic and physician liability. It is also worthwhile 5. Luke J, Reay D: The perils of investigating and certifying death remembering that the diagnosis of agitated delirium can be in police custody. Am J Forensic Med Patho11992;13:98-100 made by postmortem measurement of dopamine synaptic 6. Daras M, Kukkoluras L, Tuebman A, Koppel B: Rhabdomyolysis markers in the striatum and hypothalamus. The pattern in and hyperthermia after cocaine abuse: A variant of neuroleptic agitated delirium is very different from that in cases of malignant syndrome. Acta Neurol Scand 1995;92:161 -165 7. Staley J, Basile M, Wetli C, et al: Differential regulation of the simple cocaine overdose (Figure I) and is totally different dopamine transporter in cocaine overdose deaths. In Harris LS: NIDA from the pattern that would be anticipated with mechanical Research Monograph 141. Baltimore, MD, 1994, pp 32-38 or positional asphyxia. Of course, it is possible for someone 8. Staley J, Hearn L, Ruttenber A, et al: High affinity cocaine with agitated delirium to be strangled, but establishing that recognition sites on the dopamine transporter are elevated in fatal the deceased suffered from a highly fatal disease may cocaine overdose victims. J Pharm Exp Ther 1994;271:1678-1685 9. Staley J, Wetli C, Ruttenber A, et al: Altered dopaminergic dampen some litigants' enthusiasm. If postmortem neuro- synaptic markers in cocaine psychosis and sudden death. In Harris chemical measurements are to be made, the brain must be LS: NIDA Research Monograph 153, 1995; 153:491-504 removed and processed within 12 to 18 hours. Neurochemis- 10. Seeman P, Van Tol H: Dopamine receptor pharmacology. try laboratories located at several referral hospitals are Trends Pharmacol Sci 1994; 15:264-270 428 AMERICAN JOURNAL OF EMERGENCY MEDICINE • Volume 14, Number 4 • July 1996

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