Learning Objectives: After reading this article, the physician should be able to:
- Discuss the incidence and clinical features of the delirious and violently agitated cocaine intoxicated patient.
- Describe the pathophysiology in the delirious and violently agitated cocaine intoxicated patient.
- Summarize the ED diagnostic approach for a delirious and violently agitated cocaine intoxicated patient.
Release Date: October 2007
Uncontrolled agitation and delirium in an ED patient not only hampers the clinician's ability to begin proper diagnosis and treatment, it may rarely result in sudden unexpected cardiac arrest. I have highlighted in past columns the severe metabolic acidosis that can result from even a few minutes of struggling against restraints, and cardiac arrest in relatively healthy restrained patients has been documented to coincide with this derangement.
It takes only a few short minutes for the arterial pH to drop below 7 and for significant hyperthermia to ensue, especially in a severely agitated patient who is strapped down on a hot and humid day after a three-block chase. Patients most at risk are psychotic, drunk, or drugged. Prime candidates are brought to the hospital by police under the influence of cocaine, PCP, or amphetamines, but any individual who struggles violently while physically restrained is a potential candidate for sudden unexpected cardiac arrest. Particularly problematic is the common (now mostly erstwhile) procedure of hobbling or hogtying the violent individual, a setting in which the recently subdued are placed in a prone position with their hands and feet bound together behind the back. When testosterone-laden police pile on, potential medical problems escalate. This often induces even more violent struggling.
Demise in police custody, especially of a young and presumed healthy 20-year-old in the ED, usually makes the 6 o'clock news, and the police and the hospital are often on the center stage of criticism. The doctor should be squeaky clean on this one because emotions run high and litigation is sure to follow. The detrimental effect of the prone restraint position on respiration had been documented, but is likely overestimated and not lethal in itself. Likewise, the term “positional asphyxia” is greatly overused. Physical restraints, however, probably do little to control violently agitated patients who have an altered mental status, and such attempts often cause the encephalopathic individual to struggle even more. This can worsen the downward metabolic spiral.
When the patient is totally out of control, it's time to get the security guards and police out of the room and major sedatives into the patient's bloodstream. Only then can a proper medical evaluation and treatment be initiated. Only after this concept is understood can the clinician function in the patient's best interests. Although most delirious patients merely tax your patience and consume valuable clinical time, the prescient and sagacious clinician is always on the lookout for the rare individual who fits this scenario.
Even with the best of intentions, a common hurdle to overcome is the natural inclination of medical personnel and police to turn their otherwise sympathetic ears and hours of sensitivity training into hostility and violence against a heinous criminal, rapist, murderer, or simply obnoxious, threatening citizen. It takes a very cool head and more than a modicum of experience to resist this human urge and realize that it's time for decisive medical, not physical, intervention. The physician must gain control of the patient in an expeditious and medically reasonable way, usually recruiting some type of chemical restraint. These patients cannot be talked down or made to understand the importance of cooperating with treatment, and their condition represents as much of a medical emergency as does the patient who presents with crushing substernal chest pain.
Importantly, many chronic cocaine users have potentially life-threatening clandestine cardiac disease, even the young ones, that is brought to clinical light only when they are hauled into your ED. This month's column specifically focuses on the clinical approach to severe cocaine-induced delirium, but the principles apply to any violently agitated patient.
Fatal Excited Delirium Following Cocaine Use: Epidemiologic Findings Provide New Evidence from Mechanisms of Cocaine Toxicity
Ruttenber AJ, et al
J Forensic Sci
1997; 42(1):25
This must-read article emphasizes the concept that acute cocaine intoxication may precipitate agitation, delirium, aberrant thermal regulation, rhabdomyolysis, and sudden death. Although the syndrome has been previously described, it may not be apparent or intuitively obvious to many practicing clinicians. The authors report their data from a registry of cocaine-related deaths in Florida from 1969 to 1990. Victims of cocaine-induced delirium exhibit bizarre and violent behavior, characterized by aggression, combativeness, hyperactivity, paranoia, unbelievable strength, and total incoherent and undirected mental and physical aggression. This rather classic description usually precedes fatal cardiopulmonary arrest, and it is predictably accompanied by hyperthermia.
The term used by the authors, fatal excited delirium, is very descriptive to define an unexpected death in patients experiencing severe cocaine toxicity. This type of death accounted for approximately 16 percent of all accidental cocaine toxicity deaths in this series, and it included patients who used cocaine by all common routes. The authors compared the sudden death in this group with a control group of patients who died while under the influence of cocaine but did not experience this specific antimortem scenario. The cocaine-related deaths occurred more frequently in young males, in the absence of seizures, and in the presence of hyperthermia. There were no other mitigating circumstances, such as alcohol intoxication, other drugs, myocardial infarction, CNS bleed, or trauma that could explain the deaths. Curiously, the blood levels of cocaine in the delirium deaths were not higher than other accidental cocaine-related deaths, suggesting that there was something inherent in the biochemical/physiologic make-up of the patient, in addition to cocaine intoxication, that contributed to the fatality.
Although a mechanism for the condition was not uncovered, the pattern of cocaine use in the fatal excited delirium cases suggested that repeated binges of cocaine, known to result in intrasynaptic dopamine alteration, may have contributed to the cardiac arrest. The extensive muscular activity of the agitated patients also was thought to contribute to the hyperthermia. From a pathophysiologic standpoint, the authors hypothesized that chronic cocaine use disrupts dopaminergic function and was the underlying pathophysiology of the agitation, delirium, hyperthermia, and sudden death coupled with recent cocaine use.
Comment: The authors were able to identify 58 patients with cocaine-induced delirium who suffered sudden unexpected cardiac arrest. This is a rather amazing observation because most clinicians have not encountered a single case. Patients were more likely to have died in police custody, to have been restrained, and to have developed hyperthermia (greater than 104°F) prior to their cardiac arrest. Many patients probably never had their temperature taken because of their combative state. The exact type of cardiac arrest was not mentioned, but previous reports have documented PEA/asystole rather than ventricular tachycardia or fibrillation. Deaths during hot and humid weather, in young male patients, and chronic cocaine use and binges were other important characteristics noted in this subset.
In the mid-1980s this exact syndrome was described by numerous other authors. (J Forensic Sci 1985;30:873; Am J Med Pathol 1986;7:246), and the bibliography notes many similar if not identical reports. Since then, greater appreciation of the concepts, coupled with a more educated and restrained police force (and perhaps increasing use of the taser) have likely decreased incidence. I personally have never encountered a death under these circumstances, although agitated delirium continues to be normal flora in most EDs. Although it has never been proven that physician intervention can alter the outcome, it is paramount to note that 51 of 58 patients had some medical treatment prior to their death. The type of intervention is unspecified. It may be wishful thinking, but assuming that this syndrome can be prevented if it is recognized and treated in an expeditious manner, the physician encounters appeared suboptimal. I would intuit that some minimally symptomatic patients (perhaps bodypackers/stuffers) were not taken seriously or were given the medical once-over and quickly handed back to police.
Police departments of various cities have come under significant criticisms for deaths that occurred in agitated and restrained individuals in their custody, but education has largely halted the use of chokeholds and hogtying so emergency physicians are now less likely to see patients brought to the hospital under these circumstances. Such deaths are often very high profile and peppered with police brutality and racial issues, so the clinician's errors or shortcomings do not need to be included in the press release. These days you can be assured that all involved in the death of a 20-year-old in police custody will be scrutinized for negligence. You don't want to be the doctor who just coded someone who has been the object of a violent encounter with police (now often caught on video and sure to appear on YouTube).
The exact etiology of delirium-related deaths is unknown, but it certainly must be related to the specific pathophysiology of cocaine use, both chronic and acute. It is now known that cocaine causes characteristic changes in heart conduction and function that predispose to sudden death. Premortem evidence of such cardiac pathology is rarely obvious. Cocaine somehow alters the normal physiologic milieu, rendering otherwise healthy individuals at risk for hyperthermia and cardiac arrest when stressed. Hyperthermia has been attributed to brainstem D-1 dopamine receptor downregulation secondary to cocaine use (increased intrasynaptic dopamine). (J Pharmacol Exp Ther 1994;271:1678.) Cocaine causes a neuroleptic malignant syndrome scenario. (Am J Emerg Med 1996;14:425.)
Importantly, long-term elevations in adrenaline and noradrenalin result in cardiac myocyte calcium overload and cell destruction, producing characteristic contraction bands and microfocal myocardial fibrosis, similar to the well known adverse cardiac effects of pheochromocytoma. (J Royal Soc Med 1999;92:110; Hum Pathol 1986;17:9.) Such observations make an alteration in dopaminergic transmission and a damaged heart the likely synergistic culprits. The perfect storm of cocaine-mediated aberrant thermoregulation, dopamine dysfunction, structural and functional underlying cardiac damage, and extreme physical exertion are the current explanations for delirium-related deaths.
Importantly, these are not usually massive acute cocaine overdoses based on simple analysis of blood concentrations. Cocaine is rapidly metabolized, levels are drawn postmortem, and there is post-mortem drug redistribution, making the machine-read cocaine levels difficult to interpret at best. Because blood levels at autopsy do not correlate well with toxicity, it may be difficult to convince detractors and litigators that cocaine was not the fatal culprit, preferring to blame the police or the doctor. Many unsophisticated autopsy reports will not conclude that cocaine was the cause of death unless blood levels are sky high. Many coroners are not cognizant of this major analytical error.
The bottom line for emergency physicians is this: Severely agitated and violent patients cannot be ignored, disregarded, nor physically restrained until “they decide to cooperate.” These patients are totally out of control and unable to participate in their care. They cannot be convinced that they may die as a direct result of their hyperagitated and hyperthermic state and underlying cardiomyopathy. The EP must treat such patients as true medical emergencies and resist the common temptation to respond to the patient's violence with their own natural inclination to teach them manners. I can assure you that the tied-down patient never remembers being a complete jerk the next day. Obviously the most reasonable way to approach this problem is to use potent parenteral sedatives liberally in doses high enough and frequently enough to get the job done.
Acute Rhabdomyolysis Associated with Cocaine Intoxication
Roth D, et al
N Engl J Med
1988;319:673
This classic article should be read by all. It was one of the first reports to appear in the mainstream medical literature that highlighted the now well known metabolic derangements secondary to acute cocaine toxicity in severe agitation and hyperthermia. The authors identified 39 patients seen over eight years who manifested acute rhabdomyolysis after cocaine use. Most were severely combative or agitated on arrival. All had a significantly elevated CPK levels, and 13 (33%) of the 39 patients developed acute renal failure. There were six fatalities (15%) secondary to multisystem failure. The mean CPK of those with renal failure was 28,000 u/L (range 8000-85,000 u/L). Eight required hemodialysis.
Cocaine was the only drug found to explain the pathology. Profound hypotension, hyperpyrexia, and markedly elevated CPK levels were markers and predictors of those who were destined to develop renal failure. Severe derangement to the coagulation profile, specifically DIC, developed in seven patients with renal failure. Coagulopathy was a harbinger of death, and all patients who died had preterminal DIC. Severe liver failure was found in 11 patients, also directly attributed to cocaine. The authors conclude that the mortality rate is high among patients with multisystem failure secondary to acute cocaine toxicity, particularly those with rhabdomyolysis, coagulopathy, and associated renal failure.
Comment: A mortality rate of 15 percent from any toxic agent is certainly quite impressive. If you have not seen this syndrome, either you are not paying attention or you don't treat enough patients with acute cocaine toxicity. It is not rare, and in my experience it is one of those ED diseases that EPs must immediately recognize and treat aggressively. EPs should be the hospital's experts in this syndrome, but you may not be the lifesaver. Once the syndrome has fully developed, no intervention may alter the outcome. I intuit that it often has a predetermined outcome, and the course has been set prior to medical intervention.
;)
Figure: Unexpected Cocaine-Related Deaths* The Consequence of Delirium, Physical Restraint, Hyperthermia, and Acidosis
Most metabolic derangements that occur secondary to acute cocaine-induced delirium will be suggested in the initial ED evaluation. If one hopes to halt or limit the ultimate process, aggressive intervention must be started in the ED. You can't wait for the intensivist or admitting house staff to intervene. The first challenge, therefore, is to realize that an acutely agitated cocaine-using patient is not just an annoyance on a busy Saturday night, but an individual who is truly at high risk for developing specific medical problems, including rhabdomyolysis, renal failure, and multisystem derangement.
In my experience, even minimal agitation and possibly even recreational cocaine use will produce an elevated CPK and early myoglobinuria. This may be due to severe muscular exertion, but it's also probably secondary to the intense vasoconstriction and muscle ischemia from cocaine. Most clinicians are concerned about myocardial infarction when they see an elevated CPK in the presence of cocaine delirium. Acute MI is relatively uncommon, however, even in the severely agitated patient. Rhabdomyolysis is so common in cocaine toxicity that it is virtually a marker for this drug. Certainly patients intoxicated with PCP or amphetamines can manifest similar metabolic derangements, but cocaine should be the prime suspect.
Previously, heroin or amphetamine overdose were the leading causes of drug-induced acute rhabdomyolysis. Patients with status epilepticus also were at high risk. The high incidence of renal failure in this series should be emphasized. Importantly, acute renal failure was a predictor of ultimate death, probably because metabolic derangements severe enough to produce this syndrome will affect other organ systems. The more severe the degree of rhabdomyolysis, the more likely there is a chance for renal failure. Although hypotension and decreased renal blood flow may be cofactors, this is most likely myoglobinuria-induced renal failure. Rhabdomyolysis from any cause can precipitate intravascular coagulation by the release of thromboplastin and other activators of the coagulation cascade, so renal failure should be considered a marker for possible coagulopathy. The hepatic damage noted in these patients also has been confirmed in subsequent reports. The cause of the liver failure is not known with certainty, but it may be related to hypotension or cocaine-induced vascular constriction.
The mean CPK elevation in these patients was only 12,187 u/L (range 1756-85,000 u/L), but rhabdomyolysis did not occur if the CPK was less than 8000 u/L. The mean level for those with renal failure was 28,000 u/L. In my experience, rhabdomyolysis producing peak CPK elevations of up to 5000 u/L are generally clinically inconsequential eventually, but I have seen initially benign CPK levels rise to well more than 100,000 u/L. Importantly, the first CPK level may only be the tip of the iceberg, and the ultimate zenith is impossible to predict. It may take 24 hours for CPK levels to peak. One approach is to obtain two levels over four to six hours to see if levels are rising, but it's logistically difficult to rule out patients at risk for subsequent renal failure in the ED time frame. Whether intervention will alter the outcome is unknown, but standard treatment for myoglobinuria includes saline diuresis, perhaps urinary alkalinization, and occasionally mannitol.
The EP can make the diagnosis of myoglobinuria at the bedside. One merely needs to dip the urine with a standard dipstick and document the presence of 4+ blood in the presence of clear urine. The dipstick reacts with myoglobin as it does with hemoglobin. This finding is enough to prompt intravenous fluids (at least 3–4 ml/kg/hr as a starting point) and plan on admission. Finally, don't expect the patient to tell you that his muscles hurt and don't expect to see swollen or bruised extremities. Cocaine-induced rhabdomyolysis is generally asymptomatic, or at least does not produce enough symptoms in the cocaine intoxicated individual to use pain or swelling as criteria for investigation. Sicker patients are more likely to develop rhabdomyolysis, but seizures, hyperthermia, hypotension, or prolonged violent agitation are not absolute prerequisites.
Characteristics of Excited Delirium Death in Cocaine Abusers
- ▪ Accounts for 15 to 20 percent of cocaine-related deaths.
- ▪ Young men usually affected.
- ▪ More likely to occur in hot humid weather.
- ▪ Tends to occur in chronic/binge users.
- ▪ Not associated with trauma, prior known heart disease, or prolonged seizure activity.
- ▪ Secondary to all routes of administration.
- ▪ Not necessarily related to a massive cocaine overdose or high blood concentrations.
- ▪ Hyperthermia is commonly seen (greater than 104∞F), probably due to aberrant thermoregulation in hypothalamus.
- ▪ Individuals exhibit severe agitation, delirium, hypermetabolic state, excessive muscular activity.
- ▪ Delirium occurs prior to physical restraints, but restraints may aggravate condition.
- ▪ Patients may appear deceptively quiet just prior to sudden unexpected death.
- ▪ Etiology may be related to alteration in dopamine receptors, leading to increased intrasynaptic neurotransmitters.
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