Fatal Excited Delirium Following Cocaine Use: Epidemiologic Findings Provide New Evidence for Mechanisms of Cocaine Toxicity

Ruttenber, A. James; Lawler-Heavner, Janet; Yin, Ming; Wetli, Charles V.; Hearn, William Lee; Mash, Deborah C.

doi:10.1520/jfs14064j

Cited by 155 publications

(80 citation statements)

References 42 publications

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“…Patients admitted to emergency departments for bath salts overdose, who have toxicological verification of MDPV consumption, display symptoms, including agitation, psychosis, violent behavior, hyperthermia, and tachycardia (Borek and Holstege, 2012;Kyle et al, 2011;Murray et al, 2012;Spiller et al, 2011). The constellation of adverse effects produced by high-dose MDPV resembles the life-threatening excited delirium syndrome associated with acute cocaine toxicity (Mash et al, 2009;Ruttenber et al, 1997). Accordingly, the preclinical findings in the present study, demonstrating powerful cocaine-like actions of MDPV, suggest that efforts to remediate symptoms of bath salts overdose should aim to manage excessive dopaminergic and noradrenergic stimulation.…”

Section: Discussionmentioning

confidence: 99%

Powerful Cocaine-Like Actions of 3,4-Methylenedioxypyrovalerone (MDPV), a Principal Constituent of Psychoactive ‘Bath Salts’ Products

Baumann

Partilla

Lehner

et al. 2012

Neuropsychopharmacol

374

453

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The abuse of psychoactive 'bath salts' containing cathinones such as 3,4-methylenedioxypyrovalerone (MDPV) is a growing public health concern, yet little is known about their pharmacology. Here, we evaluated the effects of MDPV and related drugs using molecular, cellular, and whole-animal methods. In vitro transporter assays were performed in rat brain synaptosomes and in cells expressing human transporters, while clearance of endogenous dopamine was measured by fast-scan cyclic voltammetry in mouse striatal slices. Assessments of in vivo neurochemistry, locomotor activity, and cardiovascular parameters were carried out in rats. We found that MDPV blocks uptake of [ 3 H]dopamine (IC 50 ¼ 4.1 nM) and [ 3 H]norepinephrine (IC 50 ¼ 26 nM) with high potency but has weak effects on uptake of [ 3 H]serotonin (IC 50 ¼ 3349 nM). In contrast to other psychoactive cathinones (eg, mephedrone), MDPV is not a transporter substrate. The clearance of endogenous dopamine is inhibited by MDPV and cocaine in a similar manner, but MDPV displays greater potency and efficacy. Consistent with in vitro findings, MDPV (0.1-0.3 mg/kg, intravenous) increases extracellular concentrations of dopamine in the nucleus accumbens. Additionally, MDPV (0.1-3.0 mg/kg, subcutaneous) is at least 10 times more potent than cocaine at producing locomotor activation, tachycardia, and hypertension in rats. Our data show that MDPV is a monoamine transporter blocker with increased potency and selectivity for catecholamines when compared with cocaine. The robust stimulation of dopamine transmission by MDPV predicts serious potential for abuse and may provide a mechanism to explain the adverse effects observed in humans taking high doses of 'bath salts' preparations.

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Section: Discussionmentioning

confidence: 99%

Powerful Cocaine-Like Actions of 3,4-Methylenedioxypyrovalerone (MDPV), a Principal Constituent of Psychoactive ‘Bath Salts’ Products

Baumann

Partilla

Lehner

et al. 2012

Neuropsychopharmacol

374

453

View full text Add to dashboard Cite

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“…13 Chronic cocaine use may further predispose individuals to develop fatal excited delirium, though the mechanism remains to be elucidated. 14 Continued combativeness despite restraints, especially in the setting of sympathomimetic agents such as cocaine, seems to be a marker for a patient at high risk for death, regardless of pathophysiology. Physical restraint techniques may provoke further struggle, with possible development of overwhelming acidosis.…”

Section: Discussionmentioning

confidence: 99%

Metabolic Acidosis in Restraint‐associated Cardiac ArrestA Case Series

Hick

Smith

Lynch

1999

Academic Emergency Medicine

156

130

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Abstract. The mechanism of death in patients struggling against restraints remains a topic of debate. This article presents a series of five patients with restraint-associated cardiac arrest and profound metabolic acidosis. The lowest recorded pH was 6.25; this patient and three others died despite aggressive resuscitation. The survivor's pH was 6.46; this patient subsequently made a good recovery. Struggling against restraints may produce a lactic acidosis. Stimulant drugs such as cocaine may promote further metabolic acidosis and impair normal behavioral regulatory responses. Restrictive positioning of combative patients may impede appropriate respiratory compensation for this acidemia. Public safety personnel and emergency providers must be aware of the life threat to combative patients and be careful with restraint techniques. Further investigation of sedative agents and buffering therapy for this select patient group is suggested. Key words: metabolic acidosis; restraint -physical; heart arrest; cardiac arrest. AC-ADEMIC EMERGENCY MEDICINE 1999; 6:239 -243 M ANAGEMENT of violent and agitated patients is a significant problem for public safety and emergency medical agencies, and death occasionally occurs during restraint of these patients. The cause of death in these circumstances has not been elucidated. Speculation has focused on autonomic reflexes, restraint stress, 1 agitated delirium from stimulant drugs, 1 and positional asphyxia due to use of the hobble (or ''hog-tie'') position as potential contributing factors.2 -4 Acidosis has not been cited as a contributing factor in restraint-associated death. Severe metabolic acidosis has, however, been noted with stimulant drug use (notably cocaine), 5 and when exertion and stimulant drug use are combined.6 -8 Profound metabolic acidosis can have significant negative cardiovascular effects, including promotion of dysrhythmias and autonomic instability, which may contribute to cardiovascular collapse.We present five cases of cardiovascular collapse occurring in ED patients who were struggling despite maximal restraint techniques. They were all profoundly acidotic. Our experience with these cases led to institution of an aggressive proactive CASE 1A 36-year-old man was acting extremely agitated and belligerent on a downtown sidewalk. When approached, he attacked a police officer and ran. He was subsequently subdued by several officers. He was transported to the ED, where he continued to fight vigorously while lying prone with his hands cuffed behind him. Breath analysis was negative for ethanol. Shortly thereafter, the patient had a witnessed respiratory arrest. He was intubated within 4 minutes of his apnea. Shortly after intubation, a 15-second episode of asystole was noted; he recovered a sinus rhythm at a rate of 140 beats/ min after epinephrine, atropine, and hyperventilation. His initial arterial blood gas (ABG) obtained 5 minutes after intubation was pH 6.46, pCO 2 49 mm Hg, pO 2 523 mm Hg, and a bicarbonate (HCO 3 ) of 4 mEq/L. Aggressive fluid resus...

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“…Fatal ED victims exhibited an acute onset of bizarre and violent behavior, which was characterized by one or more of the following: aggression, combativeness, hyperactivity, extreme paranoia, demonstration of unexpected strength, or incoherent shouting (Wetli and Fishbain, 1985;Wetli et al, 1996). The syndrome of fatal ED is defined as accidental cocaine toxicity in subjects who exhibited bizarre and violent behavior (as described above) followed by sudden death (Ruttenber et al, 1997). C ases were assigned to the ED subgroup if at least two of the behavioral signs and hyperthermia were present before death.…”

Section: Materials Ioxy 2-(mentioning

confidence: 99%

κ₂Opioid Receptors in Limbic Areas of the Human Brain Are Upregulated by Cocaine in Fatal Overdose Victims

et al. 1997

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Cocaine is thought to be addictive because chronic use leads to molecular adaptations within the mesolimbic dopamine (DA) circuitry that affect motivated behavior and emotion. Although the reinforcing effects of cocaine are mediated primarily by blocking DA reuptake into the presynaptic nerve terminal, reciprocal signaling between DA and endogenous opioids has important implications for cocaine dependence. The present study used the opioid antagonist 6to examine the effect of cocaine exposure on the distribution and density of 2 receptors in autopsy studies of human cocaine fatalities. The selective labeling of the 2 receptor subtype was demonstrated by competition binding studies, which gave a pharmacological signature (IOXY Ն (ϩ)-bremazocine Ͼ Ͼ U50,488 Ն U69,593) distinct from either the 1 or 3 receptor subtypes. Visualization of [ 125 I]IOXY labeling revealed that 2 receptors localize to mesocortical and subcortical limbic areas, including the cingulate, entorhinal, insular, and orbitofrontal cortices and the nucleus accumbens and amygdala. The number of 2 receptors in the nucleus accumbens and other limbic brain regions from cocaine fatalities was increased twofold as compared with age-matched and drugfree control subjects. Cocaine overdose victims, who experienced paranoia and marked agitation before death, also had elevated densities of 2 receptors in the amygdala. These findings demonstrate for the first time that 2 receptor numbers are upregulated by cocaine exposure. The molecular adaptation of 2 receptor numbers may play a role in the motivational incentive associated with episodes of binge cocaine use and in the dysphoria that follows abrupt cocaine withdrawal.

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Fatal Excited Delirium Following Cocaine Use: Epidemiologic Findings Provide New Evidence for Mechanisms of Cocaine Toxicity

Cited by 155 publications

References 42 publications

Powerful Cocaine-Like Actions of 3,4-Methylenedioxypyrovalerone (MDPV), a Principal Constituent of Psychoactive ‘Bath Salts’ Products

Powerful Cocaine-Like Actions of 3,4-Methylenedioxypyrovalerone (MDPV), a Principal Constituent of Psychoactive ‘Bath Salts’ Products

Metabolic Acidosis in Restraint‐associated Cardiac ArrestA Case Series

κ₂Opioid Receptors in Limbic Areas of the Human Brain Are Upregulated by Cocaine in Fatal Overdose Victims

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Fatal Excited Delirium Following Cocaine Use: Epidemiologic Findings Provide New Evidence for Mechanisms of Cocaine Toxicity

Cited by 155 publications

References 42 publications

Powerful Cocaine-Like Actions of 3,4-Methylenedioxypyrovalerone (MDPV), a Principal Constituent of Psychoactive ‘Bath Salts’ Products

Powerful Cocaine-Like Actions of 3,4-Methylenedioxypyrovalerone (MDPV), a Principal Constituent of Psychoactive ‘Bath Salts’ Products

Metabolic Acidosis in Restraint‐associated Cardiac ArrestA Case Series

κ2Opioid Receptors in Limbic Areas of the Human Brain Are Upregulated by Cocaine in Fatal Overdose Victims

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κ₂Opioid Receptors in Limbic Areas of the Human Brain Are Upregulated by Cocaine in Fatal Overdose Victims