Disclosure
Background: The ancient Incas of Peru believed cocaine to be a gift from the gods. However, it is a modern-day curse to the emergency physician (Gold, 1992). Aside from alcohol and tobacco, cocaine is the most common cause of drug-related ED visits in the United States, accounting for nearly twice the number of reports to the Drug Abuse Warning Network (DAWN) as does marijuana or hashish, the second leading cause. Patients who present to the ED with cocaine toxicity often have a combination of other drugs and cocaine in their system. The combined use of alcohol and cocaine is the most common reason for drug-related ED visits in the United States and may be the major cause of drug-related deaths. The ubiquity of the acute or chronic effects of cocaine may cause patients to voice complaints involving virtually every organ system. Trauma is often associated with cocaine use. Even the absence of cocaine may precipitate an ED visit because patients may seek care for problems resulting from cocaine withdrawal. History of use and abuse Use of cocaine spans thousands of years, with a duality of effects noted throughout its history. Knowledge of its mind-altering function dates to at least 2000 BC. For centuries, indigenous mineworkers in Andean countries have used cocaine derived from the chewing of coca leaves as an endurance-enhancement agent. Spanish physicians reported the first European use of coca for medicinal purposes in 1596. Cocaine was not isolated from coca leaves until 1859. Nevertheless, by 1863, a wine fortified with 6 mg of cocaine alkaloid extract per ounce was marketed in France. By 1880, the US pharmaceutical company Parke-Davis sold a fluid extract containing 0.5 mg/mL of a crude cocaine. In 1884, William Stewart Halsted performed the first nerve block using cocaine as the anesthetic. Halsted subsequently became the first cocaine-impaired physician on record. That same year, Sigmund Freud published the essay "Uber Coca," in which he advocated the use of cocaine in the treatment of asthma, wasting diseases, and syphilis. As with Halsted, Freud also became dependent on cocaine. In 1885, John Styth Pemberton registered French Wine Cola in the United States. The popular product, which contained 60 mg of cocaine per 8-oz serving, was later renamed Coca-Cola. By 1893, occasional reports of fatality were associated with cocaine use, and, in 1895, The Lancet reported a series of 6 deaths. By 1909, more than 10 tons of cocaine was being imported into the United States each year. Many over-the-counter medical products and elixirs had been created. One product for nasal application contained 420 mg of cocaine per ounce and was called Dr. Tucker's Asthma Specific. The Harrison Narcotics Act of 1914 banned nonprescription use of cocaine-containing products. The resulting reduction in the use of cocaine marked the end of the first American cocaine epidemic. In the 1950s, amphetamine gradually replaced cocaine as the most common stimulant of abuse. However, this trend was reversed in the 1970s, with crack ushering in second epidemic of US cocaine use in 1985. Crack, which is generally sold in the form of "rocks," may also be sold in large pieces called slabs. These are approximately the size and shape of a stick of chewing gum and are sometimes scored to form smaller pieces. Users of cocaine in its crack form tend to be young adults aged 18-30 years who live in the central city and who are from low socioeconomic backgrounds. In 1986, the National Office of Drug Control Policy reported that young inner-city drug users were beginning to disdain crack as a ghetto drug. In Miami, for example, crack use had become unfashionable, and individuals continuing to use it, particularly African Americans, were trying to hide it from their peers. Cocaine powder is currently marketed to adults from all ethnic backgrounds and socioeconomic groups, predominated by White men older than 30 years who live in the central city. In several locales, cocaine is mentioned as a club drug, but it is not as prominent as methamphetamine and some hallucinogens in the club environment. Cocaine transported into the United States originates from coca plants in South America, 75% of which are in Columbia. In 2002, the National Drug Threat Intelligence Center reported that 353 metric tons of export-quality cocaine was available for US markets, with 75% passing through the Mexican–Central American corridor, 27% passing through the Caribbean, and 1% coming directly from South America. According to the National Office of Drug Control Policy in 2001, "The wholesale price for powder cocaine ranged from $10,000 to $36,000 per kilogram, $400 to $1,800 per ounce, and $20 to $200 per gram. Prices for crack cocaine ranged from $3 to $50 per rock, with prices usually ranging from $10 to $20." The average nationwide purity of powder cocaine was 69% for kilogram quantities and 56% for gram quantities. As reflected in the Synonyms, Key Words, and Related Terms, cocaine, alone or in combination, is known by a number of street names. The White House Office of National Drug Control Policy periodically updates street terms in its Drugs and the Drug Trade, a reference that may prove helpful when a patient uses an unfamiliar drug-related term. However, the clinician should always keep in mind the drug patients believe they purchased may not be what they received and took.
All of the cocaine injected IV is delivered to the circulatory system versus 20-30% of cocaine that is ingested or inhaled. With repeated use, tolerance develops because the acute effects of cocaine intoxication become less intense and the duration decreases. People who use cocaine long term may use as much as 10 g/d, with dosing as frequent as every 10 minutes and binges lasting as long as 7 days. Reverse tolerance, with onset of seizures and paranoid ideation at decreased doses, has been observed in animals and is thought to occur in humans as well. Approximately 80-90% of injected cocaine is rapidly metabolized. Decreased hepatic perfusion, secondary to conditions such as hypotension or low-output congestive heart failure (CHF), results in elevation of cocaine levels. A similar result may be observed in pregnant women, fetuses, infants, patients with liver disease, and elderly men because their plasma cholinesterase activity is decreased. In addition, some people have a genetic deficiency of plasma pseudocholinesterase or a nutritional predisposition to abnormally low pseudocholinesterase levels. Some have postulated that these patients may metabolize cocaine slowly and have increased sensitivity to small doses of cocaine, which places them at risk for increased toxicity and sudden death. Evidence supporting this postulate is scant. Approximately 30-50% of cocaine is metabolized by hepatic esterases and plasma pseudocholinesterase, resulting in the formation of ecgonine methyl ester. Spontaneous nonenzymatic hydrolysis of another 30-40% results in benzoylecgonine. Both products are water-soluble, metabolically active, and capable of increasing BP. Benzoylecgonine, which has a half-life of 7.5 hours, can induce seizures, perhaps even hours to days after the last use. Most of the remaining amount of cocaine is metabolized by hepatic N-demethylation into norcocaine, which is metabolically active. Pregnancy, during which circulating progesterone levels are high, and the exogenous administration of progesterone, increases the activity of hepatic N-demethylation, increasing the formation of norcocaine, which is more vasoconstrictive than is cocaine. Thus, as a result of hormonal potentiation, women may be more sensitive to the cardiotoxic effects of cocaine than men. Approximately 1-5% of cocaine is excreted, unaltered, through the kidneys within 6 hours of use. With the multiplicity of physiologic and pharmacologic modifiers cited above, the literature reflects tremendous variability in the reported lethal dose of cocaine in humans. The range is as little as 20 mg IV to a mean of 500 mg ingested orally to 1.4 g. Drug interactions and polypharmacy More than 38 pharmacologically active substances have reportedly been used with cocaine; alcohol and nicotine are the most common. Although alcohol and nicotine are individually well known for their potential sequelae, their use with cocaine may acutely increase morbidity and mortality risks. Between 30% and 60% of individuals who take cocaine combine it with alcohol. Clinical data indicate that the concurrent use of alcohol and cocaine is associated with increased mortality and morbidity from cardiovascular complications, hepatotoxicity, and behaviors leading to personal injury. In 74% of cocaine-related fatalities in the United States, another drug, usually ethanol, had been co-ingested. The addition of alcohol to cocaine increases the risk of sudden death 25-fold. The concomitant use of alcohol and cocaine results in the in vivo formation of a third active compound of toxicologic importance, namely, ethylbenzoylecgonine, commonly known as cocaethylene. Although its behavioral pharmacology and psychomotor stimulant effects are similar to those of cocaine, its toxicity is greater. The plasma half-life of cocaethylene is longer than that of cocaine, and inferential evidence suggests that the lethal dose to kill 50% of subjects (LD50) is lower. Almost most cocaine metabolism involves serum cholinesterase, some of the drug is metabolized in the liver by carboxylesterases. In the presence of alcohol, a nonspecific carboxylesterase catalyses ethyl transesterification of cocaine to cocaethylene; cocaine is the rate-limiting substrate in this reaction. Cocaethylene can be detected in urine and blood within 100 minutes after a person uses alcohol and intranasal cocaine. Whereas the half-life of cocaine is approximately 40 minutes, the half-life of cocaethylene is 2.5 hours, which may explain why cocaine-related symptoms can continue for some time after cocaine is last used. The human brain, heart, liver, and placenta bind cocaine and cocaethylene. As with cocaine, cocaethylene binds to dopamine and norepinephrine transporters and inhibits catecholamine reuptake (primarily norepinephrine) into synaptosomes. The increased "high" reported with concurrent use of alcohol and cocaine may be the result of the additive effect of cocaine and cocaethylene. Yet another reason may be the relationship between these substances and serotonin. The binding of serotonin by cocaine may modulate the high and may be the cause of the dysphoric effects of cocaine. Cocaethylene, which is 40 times less potent than cocaine in binding to the serotonin receptor, does not share this negative property. In dog studies, cocaethylene was a more potent precipitant of convulsions and cause of lethality than cocaine. Cocaethylene blocks sodium channels more potently than cocaine. Although the toxic level of cocaethylene in humans is not known, the LD50 in mice was 93 mg/kg for cocaine versus 60 mg/kg for cocaethylene. The process of cocaethylene formation continues for several hours; this may explain why sudden deaths may occur 6-12 hours after cocaine ingestion. Cocaethylene, which is ultimately metabolized to benzoylecgonine, is not the only factor augmenting the effects of cocaine with ethanol (Rose, 1994). Consumption of ethanol before cocaine use also increases the bioavailability of cocaine. Signs et al present an exception to the weight of the literature in a study based on 57 ED patients who tested positive for both alcohol and cocaine. In these patients, systolic and diastolic BP, heart rate, and body temperature did not significantly differ between those testing positive for both alcohol and cocaine and drug-free control subjects. This may be because chronic cocaine users reportedly develop tolerance to the cardiovascular effects of the drug. Sign et al concluded that the incidence of serious cardiovascular complications resulting from simultaneous use of cocaine and ethanol does not appear to be significantly higher than that observed in patients using only cocaine, only ethanol, or no drug. Nicotine is the second drug most commonly combined with cocaine. Many of the physiologic effects of nicotine are identical to those of cocaine. Nicotine produces a hypertensive and tachycardic response that is mediated by stimulation of the sympathetic ganglia and the adrenergic medulla. This response is coupled with the discharge of catecholamines from sympathetic nerve endings. Cigarette smoking also causes arterial endothelial desquamation and ultrastructural changes, a reduction of endothelial-cell prostacyclin production, increased serum fibrinogen levels, activation of platelets with enhancement of adhesiveness and aggregability, diminished coronary flow reserve, and an alpha-adrenergically mediated increase in coronary artery tone in patients with coronary atherosclerosis. Most patients with cocaine-induced myocardial infarction (MI) also smoke cigarettes, a finding which suggests that simultaneous use of cocaine and tobacco may enhance coronary vasospasm. Of patients with cocaine-induced MI, 38% had normal coronary arteries; 77% of this group (average age, 32 y) had an anterior-wall MI. More than two thirds were moderate-to-heavy cigarette smokers (>1-2 packs daily). The average number of additional coronary risk factors, however, was less than 1. Combining cocaine and heroin into a speedball causes frequent complications, as evidenced by the high-profile cases of actors John Belushi, River Phoenix, and Chris Farley. Speedballing accounts for 12-15% of cocaine-related episodes in patients presenting to EDs in the United States. In speedballing, heroin is injected or snorted, followed immediately by the smoking of cocaine. Because cocaine is harder to purchase during the summer months than at other times, some heroin users speedball with crack in the summer. The effects of heroin last longer than do those of crack, and, it modulates symptoms secondary to withdrawal from crack. In both cases, the second drug is used to supplement, rather than substitute, the primary drug. Persons addicted to crack may also use heroin to dampen the agitation produced by extended crack use. Body packers, or smugglers who use their GI tract as a hiding place for large quantities of carefully wrapped packages of cocaine, often use a similar approach. They may take benzodiazepines to prevent becoming too high should a package rupture. Some premedicate themselves with a constipating agent, such as diphenoxylate with atropine to prevent themselves from having a bowel movement before they arrive at their destination. Dissolving and injecting crack is less expensive than purchasing enough cocaine powder to produce the same effect. Some users dissolve crack in lemon juice or vinegar before injecting it IV, a practice that reportedly produces a more intense rush than smoking the same amount of crack. If the vein is missed, the result is pain and potential abscess formation. Various agents can heighten the effects of cocaine and contribute to complications. Organophosphates may be taken to deplete pseudocholinesterase, prolonging the effects of cocaine. However, because it produces organophosphate toxicity, the risk of fatality is increased. Cholinesterase inhibitors, such as carbamates, have a similar effect. Another practice involves coabusing crack cocaine and phenytoin to enhance the intoxication. In this practice, unbound phenytoin causes persons with hypoalbuminemia to become symptomatic at lowered drug levels; if death occurs, it usually is the result of respiratory and subsequent circulatory collapse. The risk of severe effects is increased when cocaine is combined with drugs such as monoamine oxidase inhibitors, tricyclic antidepressants (TCAs), alpha-methyldopa, and reserpine. These drugs alter the metabolism of epinephrine and norepinephrine, potentiating their effects and, in the presence of cocaine, inducing an adrenergic crisis. Serotonin syndrome may result when serotonin selective reuptake inhibitors (SSRIs), such as fluoxetine (Prozac), are taken concurrently with sympathomimetics. Illicit drugs are frequently admixed with additional chemicals, either to increase the apparent quantity of the street drug or to enhance its effect. For example, 8-20% of stimulants available on the street contain cocaine and methamphetamine hydrochloride. Adulterants are added to cocaine intentionally or left from the manufacturing process. Substitutes are compounds that have pharmacologic properties similar to those of cocaine and that are used in its place. The potential for adverse effects is considerably compounded by the presence of adulterants and substitutes. Among the substances used to cut cocaine are local anesthetics (eg, procaine, lidocaine, tetracaine), other stimulants (eg, amphetamine, caffeine, methylphenidate, strychnine), lysergic acid diethylamide (LSD), phencyclidine (PCP), heroin, marijuana and hashish, and phenytoin. Other products are quinine, talc (ie, magnesium silicate), ascorbic acid, boric acid, plaster of Paris, cornstarch, and lactose. Many of these substances cause pulmonary and systemic reactions when taken IV, by insufflation, or by smoking; therefore, they may substantially contribute to the toxicity of cocaine.
Pathophysiology: Most acute cocaine-related nontraumatic deaths are the result of tachydysrhythmias. Other causes of sudden death associated with cocaine use include stroke, subarachnoid hemorrhage, hyperthermia, and the consequences of agitated delirium. MI can result from acute vasospasm, dysrhythmias, or chronic accelerated atherogenic disease. Dysrhythmias The cardiovascular effects of cocaine result primarily from direct actions on the heart and secondarily from effects on the CNS. Cocaine causes central and peripheral adrenergic stimulation by inhibiting the reuptake of norepinephrine and dopamine at preganglionic sympathetic nerve endings. By preventing catecholamine reuptake at presynaptic terminals, cocaine causes a catecholamine to accumulate at the postsynaptic membranes. The action of the neurotransmitter on receptors, which catecholamine reuptake usually terminates, becomes sustained. The effects of endogenous catecholamines are thereby potentiated, resulting in tachycardia, hypertension, vasoconstriction, and increased myocardial oxygen consumption. Although cocaine-related tachydysrhythmias result primarily from the increases in catecholamine levels, the local anesthetic properties of cocaine can impair impulse conduction in the ventricle, providing a substrate for reentrant ventricular dysrhythmias. People who abuse cocaine may be exposed to toxic levels of circulating catecholamines. In 1 study, 48 mg of cocaine more than doubled circulating levels of norepinephrine (420 pg/mL increased to 900 pg/mL). However, most cocaine-related dysrhythmic fatalities occur in patients with low or modest levels of cocaine use. This finding suggests that the mechanism of death may be different in long-term cocaine users, in whom sudden death is most likely the consequence of adrenergic effects and long-term catecholamine toxicity, and in those who only occasionally use cocaine. In rat studies, long-term use of cocaine markedly increased norepinephrine content of the left ventricle, raising the possibility that long-term cocaine users, should they also accumulate excess norepinephrine, may be at risk for a malignant arrhythmia. Of note, coincident with the increase in ventricular catecholamine concentration, the rate of catecholamine synthesis was reduced, reflecting physiologic attempts to decrease sympathetic tone secondary to chronic cocaine stimulation. Alterations in cardiac histology may produce an arrhythmogenic anatomic substrate. Independent of coronary artery disease or clinically documented MI, cocaine use may induce scattered foci of myocarditis, microfocal fibrosis, and contraction band necrosis, the severity of which is correlated with serum and urine concentrations of cocaine. Although common in the hearts of cocaine and other stimulant abusers, such findings are found in only a minority of hearts examined. Other conditions providing such an anatomic substrate include Wolff-Parkinson-White (WPW) syndrome and left ventricular enlargement. Even low levels of cocaine can cause tachydysrhythmias. In a study of 19 people who had survived cocaine-related cardiac arrest, 8 had asystolic arrest (5 because of massive overdose) and the remaining 11 had arrest during ventricular fibrillation (VF). Of the latter group, all had an anatomic substrate for the dysrhythmia: 2 patients had an MI, 3 had WPW, and 6 had left ventricular hypertrophy or cardiomyopathy. On subsequent electrophysiologic testing, several patients had dysrhythmias, which were induced only after they had been given cocaine. Electrical conduction becomes disorganized in enlarged hearts, a finding that assumes added significance because cardiac enlargement is observed with chronic cocaine use. Rat studies have demonstrated that cocaine causes genetic changes in cardiac myocytes. Hemodynamic overload results in the production of high levels of atrial natriuretic factor (ANF). Increased levels of mRNA coding for ANF are measurable within 4 hours after rats were injected with 40 mg/kg of cocaine. When that same dose was administered to rats over 28 days, levels of mRNA coding for collagen and heavy-chain myosin increased, and left ventricular mass increased by 20%. Increased collagen production and increased left ventricular mass are independent risk factors for sudden death. Similar findings also are observed in humans. The hearts of cocaine users are 10% heavier than those of nonusers. In a study of 200 asymptomatic patients in a rehabilitation program who had used cocaine long term, one third had increased QRS voltage, which was electrocardiographically diagnostic of left ventricular enlargement. Another study of asymptomatic patients in rehabilitation revealed that more than 40% had an echocardiographically demonstrable increased in left ventricular mass. In such patients, after the necessary anatomic substrate has been established because of long-term exposure to high levels of cocaine, even low cocaine levels can be lethal. Cocaine also has quinidine-like direct cardiotoxic effects, causing intraventricular conduction delays, as reflected in widening of the QRS and prolongation of the QT segment. In large doses, blockade of the fast sodium channels prolongs the slope of phase 0 of the cardiac action potential, which may result in a negative inotropic response, bradycardia, and, often as a precursor to death, hypotension from decreased contractility and dysrhythmias. With high blood levels of cocaine, such as those observed in a body packer or stuffer when a cocaine packet ruptures or in a binge user with unlimited cocaine supply, the membrane-stabilizing effects of cocaine may cause cardiac arrest from asystole. In such cases, blood levels may exceed 50,000 ng/mL. Cardiac arrest is even likely if the patient also has been consuming alcohol, with resultant production of cocaethylene. Tolerance rapidly develops to the euphoriant effects of cocaine but not to its local anesthetic effects of membrane stabilization. MI and acute coronary syndromes Patients with cocaine-related MI often have fixed atherosclerotic lesions. Although these lesions may themselves be of clinical significance, cocaine-induced elevations in pulse and BP increase myocardial work. The additional metabolic requirements that result may convert an asymptomatic obstruction into one of clinical significance. Substantial evidence indicates that cocaine use causes accelerates coronary atherosclerosis. According to a 1995 study of trauma fatalities among men with a mean age of 34 years and an incidental finding of cocaine metabolites, 25% had lesions in 2 or more vessels, and 19% had disease in 3-4 vessels. Of the control subjects, only 6% had 2-vessel disease, and none had 3- or 4-vessel disease. In another study of 22 long-term cocaine users with a mean age of 32 years, all of whom died suddenly with detectable serum cocaine levels, severe narrowing of more than 75% cross-sectional area was found in 1 or more coronary arteries in 36% of patients. Hollander and Hoffman reviewed and analyzed the literature of 91 patients with cocaine-induced MI. Cardiac catheterization in 54 patients demonstrated that 31% had significant coronary atherosclerosis. Autopsy studies of patients with cocaine-related MI revealed atherosclerotic lesions in more than one half of patients. In another review of medical examiners' records, 495 deceased patients had positive toxicologic findings of cocaine; 6 of them, whose mean age was 29 years, had MI with total thrombotic occlusion primarily involving the left anterior descending coronary artery. All of the patients had significant coronary atherosclerosis, with 83% having lesions that caused luminal stenosis of more than 75% cross-sectional area in 1 or more vessels. Of the patients who Hollander and Hoffman reviewed, 24% had a thrombotic occlusion in the absence of clinically significant coronary disease. Cocaine's effect of increasing levels of plasma plasminogen activator enhances clot formation. In addition, cocaine activates platelets both directly and indirectly by means of an alpha-adrenergic mediated increase in platelet aggregation. Cocaine increases the production of the potent vasoconstrictor endothelin, and simultaneously decreases the production of nitrous oxide, a powerful vasodilator. As a result of alpha-adrenergic stimulation, cocaine may exert a direct vasoconstrictive effect by increasing the influx of calcium across endothelial cell membranes. These factors may produce coronary artery spasm. Although this may occur even in patients who do not have significant coronary artery disease, spasm is most pronounced in portions of the coronary artery that are already narrowed, a phenomenon that is particularly prominent in cocaine users. Therefore, in patients who do have high-grade obstruction, including patients whose stenoses were previously asymptomatic, coronary artery spasm of even modest degree can have devastating consequence. In healthy coronary arteries, endothelial cells release endothelium-derived relaxing factor (EDRF) and prostacyclin, which synergistically interact to relax vascular smooth muscle and to inhibit platelet adhesion and aggregation. Mild atherosclerosis and hypercholesterolemia impair endothelium-mediated vasodilation in coronary arteries, and evidence from animal studies suggests that endothelial dysfunction predisposes a person to vasoconstriction and arterial spasm. Hypersensitivity to the vasoconstrictor effects of catecholamines has also been demonstrated in humans with endothelial dysfunction. Therefore, individuals with mild coronary disease who use cocaine may be predisposed to occlusive vascular spasm at the site of early atherosclerotic lesions. The combination of intimal hyperplasia, accelerated atherosclerosis, and endothelial dysfunction create a prothrombotic milieu. Cocaine also potentiates platelet thromboxane production and decreases protein C and antithrombin III production, as well as the production and release of prostacyclin. Aggregating platelets are an important source of serotonin. In patients with dysfunctional endothelium, serotonin causes intense vasoconstriction because of its unopposed effects on vascular smooth muscle. Chronic use of cocaine appears to deplete stores of dopamine in peripheral nerve terminals. In patients undergoing cocaine withdrawal, more than one third have frequent episodes of ST-segment elevation (similar to variant angina), as documented on Holter monitoring. Inhibition of dopamine-mediated coronary vasodilatation secondary to dopamine depletion has been advanced as the hypothetical cause. Patients with cocaine-related ischemic chest pain, even those who have had MIs, tend to do well after they stop using cocaine. The effects of cocaine on the heart also include myocarditis and dilated cardiomyopathy. Myocarditis may be 5 times more common in people who use cocaine than in control subjects. It may be the result of microvascular injury, and it is a common autopsy finding in patients dying from cocaine toxicity. The mechanisms producing these effects are unknown, but hypotheses include a direct effect on lymphocyte activity, cytotoxicity of myocardial cells secondary to an increase in the activity of natural killer cells, hypersensitivity reactions (suggested by the eosinophilic infiltrate), and induction of focal myocarditis from catecholamine administration. Cocaine causes a direct negative inotropic effect on cardiac muscle, resulting in transient toxic cardiomyopathy. In 1 small series, 8 of 10 subjects who used cocaine long term had chest pain and no MI but left ventricular ejection fractions less than 50%. In 1 case report, Jouriles describes a 35-year-old woman who developed hypotension, seizures, and hypoxemia after smoking crack cocaine; she had an ejection fraction of 10%, as observed on echocardiography. Neurologic effects Cocaine acts as a CNS stimulant by inhibiting presynaptic reuptake of norepinephrine, dopamine, and serotonin. It also causes release of epinephrine by the adrenal glands. The intensity and duration of the stimulant effects of cocaine are mediated by the rate at which blood levels of cocaine rise (a function of the route of administration, see Table 1) and the peak of blood levels. Cocaine-induced seizure is a severe manifestation of toxicity. Cocaine may cause generalized tonic and clonic convulsions, as well as focal seizures. Intense stimulation of sigma and muscarinic receptors by cocaine, and increased synaptic concentration of serotonin have been proposed as causal. Cocaine lowers the threshold for seizures and may produce a kindling effect on neurons that promotes convulsions. The frequency of seizures is as low as 1% to as high as 29%, perhaps a reflection of an increase in cocaine use from one time period to another or the concurrent use of other drugs. Of 474 patients with medical complications of cocaine abuse, 8% experienced first-time seizures and, of these, 85% had seizures during administration of the drug. Cocaine-associated seizures may occur in naive and long-term users and are mostly single tonic-clonic, resolving without intervention. However, status epilepticus may occur. The first stage of status epilepticus is manifested by generalized tonic-clonic seizures associated with hypertension, hyperpyrexia, and diaphoresis. After approximately 30 minutes, the second stage may occur, in which cerebral autoregulation fails, cerebral blood flow diminishes, and systemic hypotension occurs. During this phase, the only clinical manifestations may be minor twitching, though cerebral electrical seizure activity continues. Drugs that increase intrasynaptic dopamine change the density and sensitivity of dopamine receptors, with different effects on different receptor subtypes in different areas of the brain (Ruttenber et al, 1997). Excited delirium, cocaine-associated rhabdomyolysis (CAR), and neuroleptic malignant syndrome (NMS) share many common features that can be explained by aberrant dopaminergic function. Long-term cocaine use decreases the density of dopamine-1 (D1) receptors throughout the striatal reward centers, but it does not affect the number of dopamine-2 (D2) receptors. Antagonism of nigrostriatal dopamine function may cause extrapyramidal motor dysfunction, including dystonic reactions, bradykinesia, akinesia, akathisia, pseudoparkinsonism, and catalepsy. Neuroleptic agents are the principal medications that cause dystonic reactions by means of their blockade of dopamine receptors in the nigrostriatal pathways. Cocaine may increase the risk of neuroleptic-induced dystonias, a problem compounded by the street marketing of substances such as haloperidol sold as cocaine. Over time, the continued use of cocaine may result in a net depletion of dopamine. Therefore, cocaine may be an independent cause of dystonic reactions. Two biochemical events, dopamine receptor blockade by neuroleptics and dopamine depletion by cocaine, result in the same effect, namely, the absence of physiologic dopamine in the nigrostriatal area of the brain. These events may represent the pathophysiologic basis for cocaine-associated dystonias. Intrauterine exposure to cocaine has been suggested as a cause of dystonia in infants. Agitated (excited) delirium Agitated delirium, also known as excited delirium, is a common presentation in patients dying from cocaine toxicity. Of cocaine-associated deaths that the Medical Examiner's Department of Metropolitan Dade County, Florida, investigated 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. Although heart weight, ventricular hypertrophy, and past MI are not risk factors, repeated binges of cocaine use are associated with fatal excited delirium. However, the frequency of use that increases risk has 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 cocaine 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 also may 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. Restraints have been implicated as an exacerbating factor, particularly when the patient is prone. Sudden death occurring during prone restraint of a person in excited delirium appears to be induced by a combination of at least 3 factors that increase oxygen demand and decrease oxygen delivery:
Hyperthermia Temperature dysregulation is also a problem, as demonstrated by Calloway and Clark, who reported that patients presented with rectal temperatures as high as 45.6°C. Hyperthermia is a marker for severe toxicity, and it is associated with a number of complications, including renal failure, disseminated intravascular coagulation, acidosis, hepatic injury, and rhabdomyolysis. Because dopamine plays a role in the regulation of core body temperature, increased dopaminergic neurotransmission may contribute to psychostimulant-induced hyperthermia in people, including those with excited delirium. D2 receptors are involved with processes that decrease core temperature. The number of D2 receptors in the temperature regulatory centers of the hypothalamus is substantially reduced in persons with excited delirium. These decreases in D2 receptors lead to unopposed increases in temperature mediated through D1 receptors, which are not affected in individuals who die from excited delirium. Ruttenber et al hypothesize that hyperthermia may result from extensive muscular activity in the setting of warm ambient temperature and, perhaps, humidity in combination with aberrant thermoregulation in the hypothalamus and mesolimbic system. Antagonism of central and peripheral catecholamine receptors may be required to protect against psychostimulant-induced hyperthermia because peripherally released catecholamines may directly stimulate muscle or other thermogenic tissue. Cocaine-induced seizures can also contribute to hyperthermia, though cocaine can induce hyperthermia in the absence of seizures. In animal studies, hyperthermia was the most significant parameter in the lethality of continuous cocaine infusion. Agitation secondary to intoxication or withdrawal increases motor activity, which increases heat production. The patient's volume needs are thereby increased, and, when not met, they lead to decreased renal perfusion. Heat production also may contribute to increased muscle breakdown, resulting in myoglobinuria. Myoglobinuria, in conjunction with decreased renal perfusion, causes acute tubular necrosis. Cocaine-associated rhabdomyolysis Excitement, delirium, and hyperthermia frequently precede the onset of CAR. If excited delirium and CAR have a similar cause, the spectrum of severity ranges from rhabdomyolysis with no excited delirium or hyperthermia to various combinations of these 3 conditions. Long-term, rather than short-term, cocaine use is responsible for persistent changes in dopaminergic function that place users at risk for excited delirium and CAR. Elevations in muscle-enzyme levels are observed in asymptomatic people who use cocaine long term and in untreated persons with schizophrenia. This evidence lends support to the hypothesis that chronic alterations in dopaminergic function can affect the physiology of skeletal muscle. Acidemia Acidemia is clinically significant toxicity and may play an important role in cocaine-related death. In experimental studies, calcium delivery to myofilaments is decreased and contractile proteins become less responsive in the presence of lowered intracellular pH, resulting in depression of myocardial contractility. Acidosis also potentiates dysrhythmias by repolarization and depolarization abnormalities that lead to reexcitation states. As pH decreases, calcium is spontaneously released from the sarcoplasmic reticulum, resulting in a transient depolarizing current that can precipitate dysrhythmias during diastole. In addition, acidosis decreases conductance between the gap junctions of cardiac cells, which slows propagation of the action potential. In the presence of cocaine, which diminishes sodium conductance, a severe reduction in conduction velocity may occur, increasing likelihood of dysrhythmia production by means of reentry excitation. Frequency:
Mortality/Morbidity:
Race: White patients accounted for 50% of all mentions of cocaine in the 2003 DAWN data of ED visits, whereas African Americans accounted for 32% and Hispanic individuals accounted for 9%. Sex:
Age: Table 2. Data from the 2002 National Survey on Drug Use and Health
Table 3. Mentions of Cocaine in 2003 DAWN Reports of ED Visits
History: The factors addressed below focus on drug use. They supplement the questions and elements of the standard medical-history interview. A drug history is indicated in all patients and should be particularly complete in those presenting with drug reactions, acute anxiety, or other psychological problems, as well as in those with acute cardiovascular, pulmonary, or neurologic symptoms. If the patient is confused or unresponsive, query relatives, friends, or witnesses about antecedent activities and seizures or syncope. This is crucial, especially if patients are carrying cocaine in their body because they often have no stigmata of drug abuse.
Physical: Multisystemic effects of cocaine Cocaine has multisystemic effects, and virtually every organ system may be a site of action. Suspect cocaine association in patients, especially young patients, with altered mental status, new-onset seizures, hypertension, chest pain, myocardial ischemia or infarction, shortness of breath, intracranial hemorrhage, epistaxis, or psychiatric illness. Pay particular attention to the assessment of vital signs and to a detailed examination of the cardiac, pulmonary, and neurologic systems, as listed below. Association with trauma Trauma is becoming increasingly associated with use of cocaine. Cocaine can cause agitation, paranoia, distractibility, distorted perception, and depression. All of these may increase the likelihood of violence, suicide, or accidental injury. When cocaine is combined with alcohol, the frequency of ED presentations is substantially greater than when cocaine is used alone. Differential diagnosis Cocaine overdose is difficult to differentiate from serotonin syndrome, lithium toxicity, toxicity due to TCAs, thyroid storm, and NMS. Consider the diagnosis of phenytoin toxicity in cocaine users who present with lethargy or cerebellar findings. Signs of phenytoin toxicity are correlated with serum levels and include nystagmus, ataxia, dysarthria, lethargy, hypotension, and coma.
Causes:
Heat Exhaustion and Heatstroke
CNS structural considerations (eg, hematoma, tumor, emboli, abscess, contusion) |
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Lab Studies:
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