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COCAINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Cocaine is an alkaloid derived from the shrub Erythroxylon coca, used for centuries by South American Indians as a stimulant (Gay et al, 1973; Gay et al, 1976).

Specific Substances

    1) Baseball (same as free-base)
    2) Crack, rock
    3) Free-base
    4) Speedball (cocaine and heroin)
    5) coke
    6) snow
    7) gold dust
    8) bernice
    9) lady
    10) nose-candy
    11) champagne
    12) Dama Blanca
    13) rich man's drug
    14) Benzoylmethylecgonine hydrochloride
    15) BATMAN (SLANG TERM FOR COCAINE)
    16) BIRDIE POWDER (SLANG TERM FOR COCAINE)
    17) BLAST (SLANG TERM FOR COCAINE)
    18) BLOW (SLANG TERM FOR COCAINE)
    19) BOY (SLANG TERM FOR COCAINE)
    20) BRICK (SLANG TERM FOR COCAINE)
    21) BUBBLE GUM (SLANG TERM FOR COCAINE)
    22) BUMP (SLANG TERM FOR COCAINE)
    23) BUSH (SLANG TERM FOR COCAINE)
    24) CADILLAC (SLANG TERM FOR COCAINE)
    25) CAINE (SLANG TERM FOR COCAINE)
    26) CALIFORNIA CORNFLAKES (SLANG TERM FOR COCAINE)
    27) COKE (SLANG TERM FOR COCAINE)
    28) CRACK (SLANG TERM FOR COCAINE)
    29) EVERCLEAR (SLANG TERM FOR COCAINE)
    30) FLORIDA SNOW (SLANG TERM FOR COCAINE)
    31) FOO FOO STUFF (SLANG TERM FOR COCAINE)
    32) FOOLISH POWDER (SLANG TERM FOR COCAINE)
    33) FREEZE (SLANG TERM FOR COCAINE)
    34) ICE (SLANG TERM FOR COCAINE)
    35) NUMBER 3 (SLANG TERM FOR COCAINE)
    36) PRESS (SLANG TERM FOR COCAINE)
    37) RACEHORSE CHARLIE (SLANG TERM FOR COCAINE)
    38) RANE (SLANG TERM FOR COCAINE)
    39) READY ROCK (SLANG TERM FOR COCAINE)
    40) ROXANNE (SLANG TERM FOR COCAINE)
    41) RUSH (SLANG TERM FOR COCAINE)
    42) TEETH (SLANG TERM FOR COCAINE)
    43) WINGS (SLANG TERM FOR COCAINE)
    44) WITCH (SLANG TERM FOR COCAINE)
    1.2.1) MOLECULAR FORMULA
    1) C17-H21-N-O4

Available Forms Sources

    A) FORMS
    1) Cocaine is available legally in this country as either the free-base which is soluble in organic solvents or as the hydrochloride salt which is water soluble. Both forms are white, crystalline powders. Cocaine is used clinically in 4% to 11.8% solutions for topical and nasopharyngeal anesthesia.
    2) HEALTH FOOD TEAS: Cocaine has been detected in "decocainized tea leaves" and in health food stores as "Health Inca Tea" or "Mate de Coca" (Siegel et al, 1986; Floren & Small, 1993).
    a) The concentration of cocaine is identical to that found in untreated cultivated coca leaves (0.13% to 0.68%, or about 4.8 to 5.7 mg per tea bag).
    b) Benzoylecgonine has been detected in the urine of persons drinking these teas. One patient drank an infusion of 80 tea bags and developed classic cocaine toxicity (Siegel et al, 1986).
    c) Jackson et al (1991) studied four males who ingested one cup each of Health Inca Tea. Each tea bag contained 4.8 mg of cocaine. Maximum urinary benzoylecgonine concentrations ranged from 1.4 to 2.8 mg/L, occurring from 4 to 11 hours postingestion (Jackson et al, 1991).
    3) FREE-BASING
    a) Free-base is prepared by treating cocaine hydrochloride with a basic solution (baking soda, sodium hydroxide or ammonia). The precipitated free alkaloid is filtered or dissolved in ether and then removed by drying. These procedures result in 37% to 96% recovery.
    1) Cocaine free-base is usually smoked in a water pipe. Heat from a lighter or matches is applied to volatilize the cocaine for inhalation. Usually only 1% to 5% of the original amount of cocaine remains intact in the smoke, although some street methods may produce more than 67%.
    2) When sprinkled onto tobacco or in marijuana cigarettes, the pyrolysis product contains about 6% cocaine. Free-basing is also known as base balling or smoking "base".
    3) NOTE: Smoking "base" may also refer to smoking of coca paste (pasta, bazooka, cocaine base, basuco), a crude extract of the coca leaf treated with sulfuric acid and then precipitated with sodium carbonate, which contains 40% to 85% cocaine sulfate (Siegel, 1984).
    b) Cocaine smoked in the United States is relatively pure compound of cocaine alkaloid, also known as free-base. Street "free-base" is not easily distinguished from cocaine base by the user who may buy either compound. Free-base kits are readily available to convert cocaine hydrochloride to cocaine alkaloid and to remove the compounds with which it is often adulterated.
    c) A form of pre-converted free-base cocaine, known as "crack" is widely available. Crack is prepared by mixing the hydrochloride salt with baking soda and water and heating to form a "rock", which is then smoked.
    d) In combination with heroin, it is known as a "speedball." More recently several cases have been reported where "Spinhalers(R)" have been used to aid in the nasal inhalation of cocaine.
    4) ADULTERANTS
    a) Street cocaine is often impure. The content of pure cocaine ranges from 10% to 50% (most commonly 15% to 20%). Some street samples were 40% to 60% pure (Gold & Verebey, 1984). In an 11-year survey (1973-1983) of anonymous samples submitted for analysis, 39% were cut with adulterants, and 24% were cut with diluents or sugars (commonly mannitol and inositol and less commonly lactose, glucose, or sucrose). TABLE 1 summarizes the types of adulterants found.
    TABLE 1 COMMON ADULTERANTS (Messinger, 1984)
    1973-1975:Lidocaine, procaine, tetracaine, benzocaine, caffeine, ephedrine
    1976:In addition to above: amphetamine, methamphetamine, benzoylecgonine (decomposition product) acetaminophen, phenacetin, salicylamide, heroin, opioids, quinine
    1977-1979:In addition to above: niacinamide, methaqualone
    1980:In addition to above: antipyrine
    1981:In addition to above: dibucaine, diethylpropion
    1982:In addition to above: ascorbic acid, theophylline
    1983:Most frequent adulterants: ephedrine, phenylpropanolamine, niacinamide, lidocaine, tetracaine, mannitol, inositol
    1984:Lidocaine, procaine, lactose, phencyclidine, diethylpropion, antipyrine, magnesium sulfate (Schnoll et al, 1984)

    1) Crack cocaine adulterated with phenytoin in order to lower cost or augment intoxication has resulted in phenytoin toxicity in 5 patients (Katz et al, 1992).
    b) An HPLC-DAD method was developed and successfully used to detect caffeine, lidocaine, phenacetin, benzocaine, and diltiazem as adulterants in cocaine samples seized in Brazil between 2007 and 2012. At least one of the adulterants was present in 45.2% of 115 samples (n=52), with caffeine being the most frequently detected adulterant (in 43 samples). Phenacetin was found in 5 samples and diltiazem was found in only one sample. The cocaine samples included cocaine paste, cocaine base, and cocaine hydrochloride, with cocaine contents ranging from undetectable to 97.2% (Floriani et al, 2014).
    c) LEVAMISOLE/CASE REPORTS
    1) Severe agranulocytosis (ANC 0 X10(9)/L) and fever have been reported in several patients with a history of cocaine use. Urine toxicology testing detected the presence of cocaine (or its metabolite) and levamisole. All patients recovered following G-CSF and antibiotic therapy. It is suspected that the cocaine used by these patients had been adulterated with levamisole (Zhu et al, 2009). Other effects that may occur as a result of using cocaine adulterated with levamisole include allergic reactions (difficulty breathing, swelling of lips, tongue, or face, and hives), confusion, loss of consciousness, extreme fatigue, memory loss, muscle weakness, paresthesias, seizures, and speech disturbances (Kinzie, 2009).
    2) Neutropenia and retiform purpura, characterized by purpuric macules, papules, and plaques on the pinna, earlobes, cheeks, trunk, and extremities, have been reported in two patients with histories of cocaine use. Urine toxicology screens of both patients confirmed the presence of cocaine. Although the presence of levamisole was unconfirmed, the authors speculate that levamisole contamination may be the causative agent (Waller et al, 2010).
    d) BRODIFACOUM: Severe coagulopathy was reported in a patient who smoked "crack" cocaine that was mixed with brodifacoum, a rodenticide. The patient, a 37-year-old man, presented to the emergency department with epistaxis of several hours in duration. Laboratory data revealed a prothrombin time of 65.8 sec (normal range 9.7 to 12.5), an international normalized ratio of 5.8, and an activated partial-thromboplastin time of 46.4 sec (normal range 21 to 30.6). Toxicologic analysis of a serum sample from the patient indicated a brodifacoum serum level of 680 ng/mL. With supportive therapy, the patient recovered (Waien et al, 2001).
    e) BENZOCAINE: A 34-year-old man, who ingested a packet of cocaine, developed seizures approximately 1 hour after presenting to the emergency department. The patient's skin was blue in color, arterial blood gas analysis revealed a PaO2 of 65.1 kPa and a true fraction of hemoglobin bound to oxygen of 82.5%, and the patient's blood was dark in color. Co-oximetry determined the methemoglobin concentration of 13.8%, indicating methemoglobinemia. Urine mass spectrometry confirmed the presence of cocaine, phenytoin, lidocaine, and benzocaine. It is suspected that the seizures and the methemoglobinemia were the result of ingesting benzocaine-adulterated cocaine (Chakladar et al, 2010).
    5) SUBSTITUTES: In an 11-year survey (1973-1983) of anonymous samples submitted for analysis, other substances were frequently substituted for cocaine. By 1983, only 61% of submitted samples actually contained cocaine. TABLE 2 summarizes the types of substitutes seen.
    TABLE 2 COMMON SUBSTITUTES (Messinger, 1984)
    1973-1975:Lidocaine, procaine, tetracaine, benzocaine, caffeine, ephedrine, amobarbital, PCP, heroin, other opioids, LSD
    1976:In addition to above: methapyrilene, acetaminophen, salicylamide, phenacetin, heroin, other opioids
    1977:In addition to above: ketamine, methaqualone
    1983:Most frequent substitutes: ephedrine, phenylpropanolamine, niacinamide, lidocaine, tetracaine, mannitol, inositol
    1984:Caffeine, ephedrine, lidocaine, procaine, phencyclidine, antipyrine, diphenhydramine, methamphetamine, phenacetin, aminopyrine, quinine, salicylate
     (Schnoll et al, 1984)

    6) COCAINE LOOK ALIKES: Many cocaine look-alikes are available on the market under various trade names including Cocoa Leaf, Coco Snow, Crystal Caine, Base-O-Caine, Florida Snow, Milky Trails, Pro Crystal, Pseudo Caine, Real Caine, Repro Crystals, Rock Crystal, Suma Caine, Synth Coke, Toot, Ultra Caine, and White Lady (Rehrig, 1982).
    a) Look-alikes generally contain sympathomimetics (phenylpropanolamine, ephedrine), caffeine, and a local anesthetic (eg, benzocaine, tetracaine, lidocaine) (Rehrig, 1982).
    B) USES
    1) BODY PACKING: It is the act of swallowing multiple packets containing an illegal drug in order to smuggle large amounts, usually across international borders. Fatal cocaine poisoning may occur with the rupture of a single package (Souka, 1999).
    2) COCAINE-FILLED CONDOMS: "Body packers" may ingest cocaine wrapped in condoms or other latex material. Each condom may contain 5 to 7 g of cocaine hydrochloride (85% to 99% pure) and may be adulterated with lidocaine 1% to 15% (McCarron & Wood, 1983).
    3) SMUGGLING: Cocaine may be found in food products imported from coca-producing countries. Smugglers may poison a whole or partial shipment of food, which may later enter distribution.
    a) STRUCTURE: Cocaine powder wrapped in cellophane and three or four layers of latex (condoms or toy balloons), tied with a non-absorbable ligature.
    4) BODY STUFFERS hastily ingest cocaine packets to evade law enforcement officials. Leaking from these poorly wrapped packets can produce mild to severe cocaine toxicity (June et al, 2000; Eng et al, 1999).
    5) PONY MALTA: A Colombian soft drink primarily sold in Hispanic neighborhoods in the USA has been used as a vehicle for cocaine smuggling. Bottles were found to contain an average of 30 g of cocaine each and deaths have been reported from consumption of this adulterated product (Martz et al, 1991).
    6) COCA PASTE: Is the most widely used form of cocaine in South America. It is smoked and behaves like free cocaine. It may contain greater than 5% manganese, other alkaloids, and gasoline residue components (ElSohly, 1991).
    7) LOCAL ANESTHESIA: Cocaine toxicity has been reported in children receiving topical adrenaline and cocaine for local anesthesia (Barnett, 1998). While this is most commonly reported when large doses are used on mucous membranes, it has also been reported after dermal application.

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Cocaine is used as a topical vasoconstrictor for otolaryngology procedures. The most common clinical scenario with cocaine involves abuse for its psychostimulant effects.
    B) ADULTERANTS: Caffeine, lidocaine, phenacetin, benzocaine, diltiazem, and levamisole have been detected as adulterants in cocaine.
    C) PHARMACOLOGY: The psychostimulant effects of cocaine are due to blockade of reuptake of monoamine (dopamine, norepinephrine, and serotonin) in CNS neurons. The net effect is CNS excitation and an increase in sympathetic nervous system activity. Decreased reuptake of norepinephrine may cause vasoconstriction. The direct cardiac effects of cocaine are due to antagonism of voltage-gated sodium channels in cardiomyocytes.
    D) TOXICOLOGY: Increased sympathetic activity may cause hallucinations, seizures, hypertension, and agitation. Vasospasm may cause cerebral or cardiac ischemia and may contribute to hypertension. These effects may occur with recreational doses of cocaine. Cardiac sodium channel antagonism only occurs with cocaine overdose and will delay intracardiac conduction, causing decreased myocardial function and triggering dysrhythmias. Absorption occurs after injection, ingestion, insufflation, or topical application.
    E) EPIDEMIOLOGY: Cocaine use is common. Cocaine intoxication is frequently associated with emergency department presentation for related complaints (chest pain) or indirectly related complaints (trauma). Severe toxicity is less common. Body stuffers (patients who rapidly ingest small to moderate amounts of cocaine in an attempt to avoid arrest) are common. Body packers (patients who ingest large quantities of cocaine in an attempt to smuggle the cocaine for later distribution) are occasionally seen in locations where international travel is common.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Patients may develop anxiety, hallucinations, chest pain, hypertension, palpitations, or agitation. In some cases, recreational doses of cocaine may cause cardiac or cerebral ischemia.
    2) SEVERE TOXICITY: Patients with severe toxicity may present with either seizures or severe agitation. If uncontrolled, this may progress to severe hyperthermia, rhabdomyolysis, acute renal failure, hepatic injury, coagulopathy, and decreased myocardial function. Severe intoxication may progress rapidly to dysrhythmias and cardiovascular collapse.
    3) ROUTES OF ADMINISTRATION (eg, intranasal, oral, rectal, IV, inhaled, or intravaginal) have been associated with clinical toxicity.
    a) Effects usually develop quickly (within a few minutes to an hour) and are of short duration, although delayed, prolonged effects have been reported after rupture of cocaine-filled condoms in the gastrointestinal tract.
    4) LEVAMISOLE ADULTERATION: A large percentage of cocaine bulk shipments entering the United States have been found to be adulterated with levamisole. Multiple cases of levamisole toxicity (eg, agranulocytosis, neutropenia, vasculitis, retiform purpura) have been reported in patients using cocaine adulterated with levamisole. Refer to the LEVAMISOLE management for further information.
    0.2.3) VITAL SIGNS
    A) WITH POISONING/EXPOSURE
    1) Hyperthermia is a common and potentially life-threatening event related to cocaine toxicity.
    0.2.20) REPRODUCTIVE
    A) Cocaine abuse during pregnancy is associated with various congenital anomalies as well as abruptio placentae, low birth weight, and behavioral abnormalities. Neonatal intoxication may also occur.
    B) Cocaine is in the FDA Pregnancy Category C for medicinal use and Category X for nonmedicinal use.
    1) Category C: Studies have shown that the drug exerts animal teratogenic or embryocidal effects, but there are no controlled studies in women, or no studies are available in either animals or women. Drugs should be given only if the potential benefit justifies the potential risk to the fetus.
    2) Category X: Studies in animals or humans have demonstrated fetal abnormalities or there is evidence of fetal risk based on human experience, or both, and the risk clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.
    0.2.21) CARCINOGENICITY
    A) Little is known about the risk of human cancer from cocaine.
    B) Smoking cocaine may entail some of the carcinogenic risks of cigarette smoking from pyrolysis products in the smoke. One case of Pott's puffy tumor has been reported in a patient who chronically abused cocaine; this type of tumor is thought to be secondary to chronic sinusitis from smoking cocaine.

Laboratory Monitoring

    A) Patients with minimal toxicity do not require laboratory studies.
    B) Patients with possible cardiac chest pain should be evaluated with serial troponin levels.
    C) Patients with severe toxicity should be monitored for acidosis, renal and hepatic failure, coagulopathy, and rhabdomyolysis.
    D) A head CT scan and lumbar puncture should be considered in patients with persistent abnormal mental status.
    E) Continuous cardiac monitoring and ECG should be performed in patients with chest pain or severe toxicity.
    F) Radiologic evaluation may be of value in evaluating body packers.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Patients with mild to moderate CNS excitation should be treated with benzodiazepines. Most patients will respond to low to moderate doses (lorazepam 1 to 4 mg, diazepam 5 to 20 mg). Patients with chest pain or cardiac ischemia should be treated with benzodiazepines, vasodilators (nitroglycerin), and aspirin. Beta-blockers should be AVOIDED in the setting of acute cocaine toxicity. Patients with ST-segment elevation suggesting acute myocardial infarction (MI) should undergo emergent cardiac catheterization. The use of thrombolytic medications for acute MI or stroke associated with cocaine use has not been studied.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Seizures are usually self-limited, but prolonged or repeated seizures should be treated with standard doses of benzodiazepines (lorazepam 1 to 4 mg, diazepam 5 to 20 mg). Sinus tachycardia does not require specific treatment. Beta-blockers should NOT be used in the setting of acute cocaine toxicity. Wide complex dysrhythmias are treated with hypertonic sodium bicarbonate boluses (1 to 2 mEq/kg every 5 minutes, endpoint is narrowing of QRS complex and arterial pH of 7.45 to 7.55). Hypotension is treated with fluid boluses. Refractory cases should be treated with a direct-acting vasopressor such as epinephrine (1 mcg/min starting dose) or norepinephrine (1 mcg/min starting dose). Consider intravenous lipid emulsion in patients with dysrhythmias, hypotension or severe CNS toxicity secondary to cocaine intoxication. Agitation is treated with benzodiazepines, given incrementally every 5 to 10 minutes and titrated to mild sedation (lorazepam 2 to 4 mg, diazepam 5 to 20 mg IV initially; large total doses may be needed). Patients who are not rapidly controlled should be paralyzed and intubated. All patients should have core temperatures measured, and patients with an elevated temperature (higher than 39 degrees C) require rapid, aggressive cooling. (Keep skin moist by spraying water or applying wet sheets, and accelerate evaporation with fans directed at the skin. In extreme cases partially submerge the patient in cold water.) Radiologic evaluation may be of value in body packers.
    C) DECONTAMINATION
    1) PREHOSPITAL: Activated charcoal is not recommended due to rapid absorption of cocaine and the risk of seizures.
    2) HOSPITAL: Decontamination is not useful for most exposures due to cocaine's rapid absorption. Activated charcoal decreases the absorption of oral cocaine and may be used for asymptomatic body stuffers or body packers. Body packers should also be treated with whole bowel irrigation.
    D) AIRWAY MANAGEMENT
    1) Most patients will not require airway management. Patients who have multiple seizures, severe agitation, or dysrhythmias should be intubated.
    E) ANTIDOTE
    1) There is no specific antidote.
    F) SEIZURES
    1) Administer IV benzodiazepines, add barbiturates or propofol if seizures recur or persist.
    G) DYSRHYTHMIAS
    1) Sinus tachycardia does not require specific treatment. Beta-blockers should NOT be used in the setting of acute cocaine toxicity. Wide complex dysrhythmias are treated with hypertonic sodium bicarbonate boluses; start with 1 to 2 mEq/kg and repeat as needed. Endpoints include resolution of dysrhythmia, narrowing of QRS complex, and arterial pH of 7.45 to 7.55. Use lidocaine if unresponsive to bicarbonate.
    H) FAT EMULSION
    1) Patients who develop significant cardiovascular toxicity may be treated with intravenous lipids. Administer 1.5 mL/kg of 20% lipid emulsion over 2 to 3 minutes as an IV bolus, followed by an infusion of 0.25 mL/kg/min. Evaluate the patient's response after 3 minutes at this infusion rate. The infusion rate may be decreased to 0.025 mL/kg/min (ie, 1/10 the initial rate) in patients with a significant response. This recommendation has been proposed because of possible adverse effects from very high cumulative rates of lipid infusion. Monitor blood pressure, heart rate, and other hemodynamic parameters every 15 minutes during the infusion. If there is an initial response to the bolus followed by the re-emergence of hemodynamic instability during the lowest-dose infusion, the infusion rate may be increased back to 0.25 mL/kg/min or, in severe cases, the bolus could be repeated. A maximum dose of 10 mL/kg has been recommended by some sources. Where possible, lipid resuscitation therapy should be terminated after 1 hour or less, if the patient's clinical status permits. In cases where the patient's stability is dependent on continued lipid infusion, longer treatment may be appropriate.
    I) HYPERTHERMIA
    1) Control agitation with benzodiazepines; sponge or spray skin with tepid water and direct fans at patients to enhance evaporative cooling. Use hypothermia blanket or ice water immersion if tepid water ineffective.
    J) HYPERTENSION
    1) Benzodiazepine sedation is adequate for most cases; if severe hypertension or end organ damage use nitroprusside 0.1 mcg/kg/min or phentolamine 5 mg IV, titrate to effect.
    K) HYPOTENSION
    1) IV 0.9% NaCl, if persistent use direct-acting vasopressor such as norepinephrine or epinephrine.
    L) CHEST PAIN
    1) Benzodiazepine sedation, nitroglycerin. Beta-blocking agents should be AVOIDED. Consider phentolamine in patients with persistent chest pain and suspected acute coronary syndrome. Percutaneous coronary intervention is preferred to thrombolysis in patients with cocaine-associated ST-elevation myocardial infarction.
    M) ENHANCED ELIMINATION
    1) Diuresis, hemodialysis, and urinary acidification are NOT effective in enhancing elimination of cocaine.
    N) PATIENT DISPOSITION
    1) OBSERVATION CRITERIA: Patients with cocaine-associated chest pain who meet low-risk criteria can be observed for 6 hours in the emergency department. Patients with a single seizure or mild agitation who rapidly recover and who have normal vital signs after a 6-hour observation period can be discharged.
    2) ADMISSION CRITERIA: Patients who have multiple seizures, dysrhythmias, or severe agitation or who require heavy sedation should be admitted to an intensive care setting; those who have chest pain who do not meet low-risk criteria should be admitted to a telemetry setting. Body packers and body stuffers should be admitted for observation and monitoring until ingested packets have passed through the gastrointestinal tract.
    O) PITFALLS
    1) Failure to aggressively treat hyperthermia and agitation. Failure to recognize the possibility of delayed toxicity in body packers and stuffers. Precaution should be taken in the presence of a mixed overdose of cocaine with an opioid; administration of naloxone may provoke serious sympathomimetic toxicity by removing the protective opioid-mediated CNS depressant effects.
    P) PHARMACOKINETICS
    1) Rapidly absorbed after ingestion, inhalation, or insufflation. Half-life in the range of 30 to 90 minutes depending on route of exposure. Rapid hydrolysis by serum cholinesterase; some hepatic metabolism, and 10% to 20% is excreted unchanged in urine. Metabolite benzoylecgonine generally detected in urine for 3 days after use.
    Q) TOXICOKINETICS
    1) In overdose, serum cocaine concentrations may exceed the binding capacity of plasma proteins, leading to a dramatic increase in free cocaine concentrations.
    R) DIFFERENTIAL DIAGNOSIS
    1) Other stimulant intoxication, tricyclic antidepressant toxicity, thyrotoxicosis, or psychosis.

Range Of Toxicity

    A) Toxicity may occur with recreational doses, but there are reports of patients surviving with markedly elevated serum cocaine concentrations. The lethal dose is not well established and is quite variable.

Clinical Effects

Summary Of Exposure

    A) USES: Cocaine is used as a topical vasoconstrictor for otolaryngology procedures. The most common clinical scenario with cocaine involves abuse for its psychostimulant effects.
    B) ADULTERANTS: Caffeine, lidocaine, phenacetin, benzocaine, diltiazem, and levamisole have been detected as adulterants in cocaine.
    C) PHARMACOLOGY: The psychostimulant effects of cocaine are due to blockade of reuptake of monoamine (dopamine, norepinephrine, and serotonin) in CNS neurons. The net effect is CNS excitation and an increase in sympathetic nervous system activity. Decreased reuptake of norepinephrine may cause vasoconstriction. The direct cardiac effects of cocaine are due to antagonism of voltage-gated sodium channels in cardiomyocytes.
    D) TOXICOLOGY: Increased sympathetic activity may cause hallucinations, seizures, hypertension, and agitation. Vasospasm may cause cerebral or cardiac ischemia and may contribute to hypertension. These effects may occur with recreational doses of cocaine. Cardiac sodium channel antagonism only occurs with cocaine overdose and will delay intracardiac conduction, causing decreased myocardial function and triggering dysrhythmias. Absorption occurs after injection, ingestion, insufflation, or topical application.
    E) EPIDEMIOLOGY: Cocaine use is common. Cocaine intoxication is frequently associated with emergency department presentation for related complaints (chest pain) or indirectly related complaints (trauma). Severe toxicity is less common. Body stuffers (patients who rapidly ingest small to moderate amounts of cocaine in an attempt to avoid arrest) are common. Body packers (patients who ingest large quantities of cocaine in an attempt to smuggle the cocaine for later distribution) are occasionally seen in locations where international travel is common.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Patients may develop anxiety, hallucinations, chest pain, hypertension, palpitations, or agitation. In some cases, recreational doses of cocaine may cause cardiac or cerebral ischemia.
    2) SEVERE TOXICITY: Patients with severe toxicity may present with either seizures or severe agitation. If uncontrolled, this may progress to severe hyperthermia, rhabdomyolysis, acute renal failure, hepatic injury, coagulopathy, and decreased myocardial function. Severe intoxication may progress rapidly to dysrhythmias and cardiovascular collapse.
    3) ROUTES OF ADMINISTRATION (eg, intranasal, oral, rectal, IV, inhaled, or intravaginal) have been associated with clinical toxicity.
    a) Effects usually develop quickly (within a few minutes to an hour) and are of short duration, although delayed, prolonged effects have been reported after rupture of cocaine-filled condoms in the gastrointestinal tract.
    4) LEVAMISOLE ADULTERATION: A large percentage of cocaine bulk shipments entering the United States have been found to be adulterated with levamisole. Multiple cases of levamisole toxicity (eg, agranulocytosis, neutropenia, vasculitis, retiform purpura) have been reported in patients using cocaine adulterated with levamisole. Refer to the LEVAMISOLE management for further information.

Vital Signs

    3.3.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Hyperthermia is a common and potentially life-threatening event related to cocaine toxicity.
    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) HYPERTHERMIA is common and life-threatening and may be due to increased muscular activity, vasoconstriction, and perhaps a direct effect on the hypothalamus (Tanen et al, 2000; Wetli et al, 1996; Bauwens et al, 1989; Wetli & Fishbain, 1985). It is often associated with rhabdomyolysis, seizures, and renal failure (Saleem et al, 2001; Merigian et al, 1994; Hoffman et al, 1992; Bauwens et al, 1989; Lombard et al, 1988; Menashe & Gottlieb, 1988; Merigian & Roberts, 1987).
    a) CASE REPORT: Mild hyperthermia (38.8 degrees C) developed during general anesthesia for repair of a mandibular fracture in a patient with recent cocaine use and no other risk factors for hyperthermia (Ravi et al, 1993).
    b) A small randomized, double-blind study (n=7 healthy, cocaine-naive volunteers) found that low doses of cocaine (2 mg/kg intranasally) augmented the esophageal temperature and impaired vasodilation and sweating in response to heat stress, compared with lidocaine used as a control. Cocaine also attenuated the discomfort perceived by the subjects associated with heat stress. The mechanism is not fully understood, but it was speculated that cocaine-induced shifts in the threshold for cutaneous vasodilation and sweating are mediated centrally. In this study, cocaine appeared to impair the perception of heat stress, which may be evidence that cocaine acts centrally to alter thermoregulatory responses (Crandall et al, 2002).
    c) These findings were challenged based on the small experimental dose of cocaine used, which was not considered representative of the psychomotor agitation that is often seen in patients with cocaine toxicity (Schier et al, 2002).
    d) Cocaine potentiates dopaminergic neurotransmission in the basal ganglia, thus participating in the regulation of core body temperature leading to hyperthermia (Callaway & Clark, 1994).
    e) ANIMAL STUDIES: Experimental animal studies suggest that hyperthermia may be the most important factor contributing to death from cocaine poisoning (Catravas & Waters, 1981).
    f) CALCIUM CHANNEL BLOCKER pretreatment in humans diminished the effect of cocaine on skin temperature in one study. Further studies are necessary to determine the clinical usefulness of this observation (Rowbotham et al, 1987).

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) SUMMARY: Mydriasis is common. Madarosis, retina granulomas, retinal occlusion, iritis, corneal epithelial lesions, infectious corneal ulcers, and orbital inflammation have been reported occasionally.
    2) MYDRIASIS: Mydriasis due to the sympathomimetic effect of cocaine is common (Hantson et al, 2011; Zeiter et al, 1990).
    3) CRACK EYE: Chemosis, hyperemia in association with corneal epithelial defects, lacrimation, pain, and photophobia have been reported. Microbial keratitis may complicate the syndrome of crack eye (Miller & Sherman, 2009; Strominger et al, 1990). Several explanations for this syndrome have been postulated, including a direct toxic effect of crack cocaine smoke on the corneal epithelium, which may be exacerbated by a decreased corneal blink reflex that is due to the anesthetic properties of cocaine. Other possible explanations include a decrease in the integrity of the corneal epithelium due to devitalization of the corneal nerves resulting in keratopathy; chronic chemical burns caused by repeated exposure to the cocaine smoke; or excessive eye rubbing due to the direct irritant effect of the smoke leading to infection (Miller & Sherman, 2009).
    4) CORNEAL ULCERS: Both fungal and bacterial corneal ulcers as well as sterile epithelial defects have been reported after crack cocaine abuse (Miller & Sherman, 2009; Sachs et al, 1993).
    5) SPLASH CONTACT: Ocular exposure can cause corneal epithelial sloughing and transient anisocoria (Bonadio & Wagner, 1990).
    6) RETINAL ARTERY THROMBOSIS: Visual loss secondary to central retinal artery occlusion and spasm have been reported with chronic IV cocaine abuse and following crack use (Libman et al, 1993; Hoffman & Reimer, 1993; Wallace et al, 1992; Zeiter et al, 1992; Devenyi et al, 1988).
    7) OPTIC NEURITIS: Orbital inflammation and optic nerve dysfunction have been reported secondary to chronic cocaine-induced sinusitis (Goldberg et al, 1989).
    8) CASE REPORT: ALOPECIA: Madarosis (loss of eyebrow and eyelash hair) has been described in 1 patient who smoked crack (Tames & Goldenring, 1986).
    9) RETINAL GRANULOMA: Possible foreign body granuloma of the retina associated with IV cocaine use has been described (Michelson et al, 1979).
    10) CASE REPORT: Iritis was associated with nasal use of cocaine in a 31-year-old man (Wang, 1991).
    11) CASE REPORT: BILATERAL AMBLYOPIA: One case of bilateral amblyopia following crack use has been reported, presumably secondary to cocaine-induced vasoconstriction (Hoffman & Reimer, 1993).
    12) CASE REPORT: PRESEPTAL CELLULITIS: A 40-year-old man with diabetes and a history of nasal cocaine abuse developed preseptal cellulitis; erosion of the nasal septum, medial wall of the left orbit, and maxillary bones; and partial erosion of the cribriform plate (Underdahl & Chiou, 1998).
    3.4.4) EARS
    A) WITH POISONING/EXPOSURE
    1) CASE REPORT: METALLIC SENSATION: Half a gram of crack cocaine lodged in the external auditory canal for 4 months caused a metallic sensation around the ear which resolved when the crack was removed. There was no evidence of injury to the ear canal (Kohrs, 1992).
    3.4.5) NOSE
    A) WITH POISONING/EXPOSURE
    1) EFFECTS ON NASAL MUCOSA: Used intranasally, cocaine may cause nasal congestion, hyperemia, irritation, mucosal thickening, ulceration, infection, granulomas, septal perforation, or aspiration of the detached nasal septum (Sevinsky et al, 1995; Libby et al, 1992; Chow et al, 1990; Daggett et al, 1990; Schwartz & Oderda, 1980; Becker & Hill, 1988; Schweitzer, 1986; Rappolt et al, 1976).
    2) Extensive bony destruction of the orbital walls with associated orbital cellulitis may occur in patients with a history of chronic intranasal cocaine abuse (Alexandrakis et al, 1999).
    3) ALLERGIC RHINITIS: Chronic use may produce or complicate symptoms of allergic rhinitis, asthma, or pollinosis (Snyder & Snyder, 1985).
    4) CASE REPORT: Botulism resulting from the elaboration of botulism toxin from a Clostridium botulinum sinusitis has been reported from intranasal cocaine use (Kudrow et al, 1988).
    5) CASE REPORT: Staph sepsis has been reported secondary to mucosal damage from chronic cocaine sniffing in a patient with staph colonization of the nasal passages (Silverman & Smith, 1985).
    6) CASE REPORT: A 45-year-old former cocaine addict presented with hypernasal speech and nasal regurgitation of liquids. Rhinoscopy showed a completely eroded nasal septum and erosion of the lateral nasal chamber walls up to the maxillary sinuses. Severe atrophic rhinitis was present, with the anterior wall of the sphenoid sinus being deficient (Braverman et al, 1999).
    7) PSEUDOVASCULITIS: Cocaine-induced pseudovasculitis was reported in a 27-year-old woman with progressive onset of pharyngitis, fatigue, and skin lesions on her face, legs, arms, and back. CT scan of the sinuses showed nasal septum destruction and mucosal thickening of the ethmoidal and maxillary sinuses. Nasal endoscopy showed almost total erosion of the nasal septum and nasopharynx with velopharyngeal insufficiency. Acute and chronic inflammation with fibrinopurulent exudate were observed in the soft palate biopsy specimens (Friedman & Wolfsthal, 2005).
    3.4.6) THROAT
    A) WITH POISONING/EXPOSURE
    1) SUMMARY: Dysphagia, oropharyngeal injury, dental erosions, and laryngeal burns have been seen in patients who smoke crack cocaine.
    2) OROPHARYNGEAL INJURY: Thermal injuries to the upper airway leading to epiglottitis, laryngeal injury, and mucosal necrosis have been reported after smoking crack or freebase cocaine (Bezmalinovic et al, 1988; Savitt & Colagiovanni, 1991; Savitt & Colagiovanni, 1991; Snyderman et al, 1991).
    3) DENTAL EROSIONS have been seen after chronic application of cocaine to the nasal or oral mucosa. Destruction of both enamel and dentin may be seen (Krutchkoff et al, 1990).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CARDIOVASCULAR FINDING
    1) WITH POISONING/EXPOSURE
    a) Severe cardiovascular effects including myocardial ischemia and infarction, arrhythmias, cardiomyopathy, aortic dissection, and endocarditis may develop with acute or chronic cocaine abuse. Sudden cardiac death has been reported (Havlik & Nolte, 2000; Rump et al, 1995; Willens et al, 1994; Om et al, 1993).
    b) Cocaine is a powerful sympathetic agonist. Vasoconstriction, hypertension, and tachycardia are common effects (Havlik & Nolte, 2000; Van der Woude, 2000; June et al, 2000; Chiu et al, 1986).
    c) In one study, 36% of patients presenting to the emergency department following cocaine use experienced palpitations, 61% had shortness of breath, and 39% were diaphoretic (Hollander et al, 1992).
    d) Cocaine-induced bradyarrhythmia has been reported (Castro & Nacht, 2000).
    e) QT VARIABILITY: A prospective study was conducted with 29 cocaine-experienced volunteers who received randomized IV infusions of placebo or cocaine (20 and 40 mg) in order to determine QT variability. The QT variability was expressed as the ratio of normalized QT variance to normalized heart rate variance. The QT variability significantly increased during the first 5 minutes of the cocaine infusions and peaked at 10 minutes at both the 20-mg and 40-mg dose levels (p less than 0.0001 compared with pre-infusion). The QT variability was significantly greater at the 40-mg dose level at 10 minutes as compared with the 20-mg dose level, indicating a dose-dependent effect. The effect disappeared by 45 minutes after the infusion. Seventeen volunteers were then rechallenged with the same infusions 1 week later. The mean QT variability was very similar, indicating that cocaine's effect on QT variability is reproducible. The increase in QT variability indicates a destabilizing effect on repolarization that may increase the risk for dysrhythmias and may partially account for the increased risk of sudden cardiac death associated with cocaine use (Haigney et al, 2006).
    B) MYOCARDIAL INFARCTION
    1) WITH POISONING/EXPOSURE
    a) Myocardial infarction (MI) may occur even in young patients without risk factors or preexisting cardiac pathology (Qureshi et al, 2001; Havlik & Nolte, 2000; Weber et al, 2000; Williams & Stewart, 1997; Lora-Tamayo et al, 1994; Hollander et al, 1992a; Kossowsky et al, 1989; Hadjimiltiades et al, 1988; Chiu et al, 1986; Isner et al, 1986; Cregler & Mark, 1985; Gould et al, 1985; Howard et al, 1985; Kossowsky & Lyon, 1984).
    1) MI is not uncommon and cannot be reliably predicted or excluded; therefore, all patients presenting with cocaine-related chest pain should be evaluated for possible MI (Feldman et al, 2000; Weber et al, 2000; Hollander et al, 1992).
    2) An MI may occur acutely up to 2 weeks after the last cocaine use (Levine & Nishikawa, 1991).
    3) TIMI RISK SCORE/OUTCOME PREDICTOR: TIMI risk scores have been used to predict cardiovascular outcomes (ie, acute myocardial infarction, revascularization, and death) within 30 days of emergency department (ED) presentation for chest pain. A prospective observational cohort study was conducted to determine the predictive value of using TIMI risk scores for cardiovascular outcomes in patients with cocaine-associated chest pain. The study included 261 patients, with a 30-day follow-up completed on 238 patients. Each patient received 1 point for each positive variable (age greater than 65 years, 2 or more coronary artery disease risk factors, known coronary artery stenosis, ST-segment deviation, aspirin use, 2 or more anginal events in 24 hours, and elevated cardiac biomarkers) that was then added to determine the total TIMI risk score. The primary composite outcome was all-cause mortality, acute MI, or revascularization within 30 days of ED presentation.
    a) The only variable to have a significant association with the composite outcome was the elevated cardiac biomarkers, with 42.6% of the patients experiencing one of the primary outcome events (relative risk, 8.8; 95% confidence interval, 4.51 to 17.21). There were 33 patients with composite outcome events, with the majority of outcomes occurring with low TIMI scores (3 or lower). TIMI risk scores cannot adequately predict cardiovascular outcomes within 30 days of ED presentation in patients with cocaine-associated chest pain (Chase et al, 2007).
    b) INCIDENCE: Not uncommon (about 65 reports in the literature) (Boniface & Feldman, 2000; Hoffman et al, 1992; Zimmerman, 1991; Amin et al, 1990; Isner & Chokshi, 1989; Coleman et al, 1982). MI may occur irrespective of route of administration and has occurred after therapeutic use (Ross & Bell, 1992; Chiu et al, 1986) , smoking (Haines & Sexter, 1987), IV use (Stenberg et al, 1989), and intranasal abuse (Wehbie et al, 1987). In one retrospective cohort study, the incidence of acute MI in patients with cocaine-associated chest pain was 6% (Weber et al, 2000).
    c) ONSET: MI may occur Immediately after IV use (Stenberg et al, 1989), It may be delayed as long as 15 hours (Ascher et al, 1988), but usually occurs within 90 minutes (Smith et al, 1987).
    d) PREDISPOSING FACTORS: Coronary artery disease, heavy smoking, and hypertension are predisposing factors (Smith et al, 1987). Age is not a factor; MI was reported in a 19-year-old man (Weiss, 1986).
    1) Certain criteria (age, number of cardiac risk factors, inferior infarction, bradydysrhythmias) may help to predict which cocaine MI patients have underlying coronary artery disease (Hollander et al, 1997; Hollander et al, 1997a; Hollander, 1996).
    e) DIAGNOSTICS: MI may occur without significant ECG changes (Gitter et al, 1991; Tokarski et al, 1990). Both Q-wave and T-wave infarctions are common (Kossowsky et al, 1989; Smith et al, 1987).
    1) Angiography may reveal normal coronary arteries (Minor et al, 1991; Kossowsky et al, 1989; Yen, 1989; Zimmerman, 1987; Zimmerman, 1987; Howard et al, 1985).
    2) A prospective study was conducted of 97 patients (19 with recent cocaine use) who had been admitted to the hospital to rule out MI. In patients without MI, cardiac troponin I and CK-MB were similar in both groups (cocaine exposed and unexposed), while myoglobin concentrations were higher in the cocaine-exposed group (179 vs 74 ng/mL) (Hollander et al, 1998).
    f) CREATININE KINASE ELEVATIONS: Acute MI with elevated CPK MB fraction has been reported in patients who complained of chest pain after cocaine use but with nondiagnostic ECG results (Tokarski et al, 1990). Creatine kinase (CK) levels tend to be elevated in cocaine users due to the release of the enzyme from skeletal muscle; therefore, an elevated CK level on admission for cocaine-associated chest pain may be misleading. CPK MB levels may also be elevated in cocaine users without evidence of infarction (Hollander, 1996).
    g) ETIOLOGIES: Thrombosis or stenosis may be present (Roh & Hamele-Bena, 1990; Stenberg et al, 1989; Hadjimiltiades et al, 1988), but vasospasm is an important factor (Oster et al, 1991; Lange et al, 1989; Ascher et al, 1988).
    h) WITHDRAWAL ISCHEMIA/INFARCTION: Silent ischemia has been observed upon cocaine withdrawal (Nademanee et al, 1989); infarction has also been reported (Del Aguila & Rosman, 1990).
    i) OTHER: Large IV doses may cause immediate death from cardiac failure due to direct myocardial toxicity.
    j) RIGHT VENTRICULAR INFARCTION: A 56-year-old man, with a history of hypertension, polysubstance abuse, and chronic pancreatitis secondary to alcohol consumption, presented as unresponsive and hypotensive with dilated pupils. An ECG revealed normal sinus rhythm with T wave inversion, and an echocardiogram demonstrated severe dilation of the right ventricle with a positive McConnell sign. Laboratory data indicated hyperkalemia (potassium 5.6 mmol/L), elevated BUN, serum creatinine, and hepatic enzymes, a troponin level of 3.8 ng/mL (peak of 16 ng/mL on hospital day 2), brain natriuretic peptide of 5677 pg/mL, and a D-dimer of 4.6 mg/L (upper limit 0.52). A urine toxicologic screen was positive for cocaine and marijuana. The patient admitted he had been snorting cocaine prior to presentation. With supportive care, the patient's condition improved with a repeat echocardiogram showing improvement in his right ventricular function and size. He was subsequently discharged with continued stability at his 3-month follow-up visit (Smer et al, 2015).
    C) VASOCONSTRICTION
    1) WITH POISONING/EXPOSURE
    a) SUMMARY: Cocaine induces vasoconstriction in both diseased and nondiseased coronary arteries (Brogan et al, 1992).
    b) Recurrent cocaine-induced coronary vasoconstriction is temporally related to peak blood concentrations of the major metabolites, benzoylecgonine and ethyl methyl ecgonine (Pitts et al, 1997; Brogan et al, 1992).
    c) Labetalol reduced mean arterial pressure but did not reverse cocaine-induced coronary artery constriction in human volunteers (Boehrer et al, 1993).
    d) Fatal aortic vasoconstriction occurred in a 32-year-old woman following a 5-day use of crack cocaine (Williams & Wasserberger, 2006).
    e) Cocaine-induced vasoconstriction appears to be due to alpha-adrenergic stimulation. Unopposed alpha-adrenergic stimulation, associated with beta-adrenergic blocking agents, may result in the potentiation of coronary vasoconstriction with concomitant administration of cocaine and a beta-blocker (Williams & Wasserberger, 2006; Williams et al, 1996; Lange et al, 1990).
    1) Other substances that may potentiate cocaine-induced coronary vasoconstriction when used concomitantly with cocaine include cigarette smoke and ethanol (Pitts et al, 1997).
    D) MYOCARDITIS
    1) WITH POISONING/EXPOSURE
    a) Cocaine-related myocarditis with lymphocytic or eosinophilic infiltrates has been reported (Virmani et al, 1988; Isner et al, 1986; Simpson & Edwards, 1986; Isner et al, 1985).
    b) CASE REPORT: A 34-year-old healthy woman presented to the emergency department with dyspnea and palpitations after having used cocaine for the first time. An ECG revealed sinus tachycardia, and laboratory studies showed serial troponins peaked at 1.2 ng/dL. An echocardiogram indicated anterior and septal hypokinesis with an ejection fraction of 40% along with a significant reduction in radial strain. A diagnosis of acute heart failure consistent with acute myocarditis was made and treatment included aspirin 100 mg once daily and carvedilol 6.25 mg twice daily for 1 week. The patient was then discharged to home after a repeat echocardiogram indicated normal systolic function and a normal strain pattern (Ocal et al, 2015).
    E) ENDOCARDITIS
    1) WITH POISONING/EXPOSURE
    a) IV cocaine abuse was associated with endocarditis more frequently than other IV drugs of abuse; most patients were concurrently using heroin (Chambers et al, 1987).
    F) CARDIOMYOPATHY
    1) WITH POISONING/EXPOSURE
    a) SUMMARY: Cardiomyopathy has been attributed to cocaine abuse (Chokshi et al, 1989; Karch & Billingham, 1988; Wiener et al, 1986).
    b) REVERSIBLE CARDIOMYOPATHY: Severe cocaine-induced biventricular congestive heart failure was completely reversed in a 32-year-old man after 7 months of abstinence and in another 38-year-old man after 9 months of abstinence (Om et al, 1992; Henzlova et al, 1991).
    c) CARDIOMEGALY: A study of 30 chronic cocaine abusers revealed increased left ventricular mass on echocardiogram as compared with controls (Brickner, 1991).
    d) CASE REPORT: Severe chronic dilated cardiomyopathy was reported in a patient who abused freebase cocaine (Willens et al, 1994).
    e) RIGHT VENTRICULAR HEART FAILURE: A 65-year-old heart transplant recipient died of acute right ventricular heart failure. The donor had a history of binge drinking and cocaine abuse. The donor's toxicology screen was positive for cocaine, and autopsy findings revealed cocaine cardiomyopathy (Houser et al, 2000).
    G) CONDUCTION DISORDER OF THE HEART
    1) WITH POISONING/EXPOSURE
    a) SUMMARY: Sinus tachycardia and transient hypertension are the most common findings. Premature ventricular contractions (PVCs), ventricular arrhythmias, and hypotension are seen with more severe overdoses. Cocaine-induced bradyarrhythmia has been reported.
    b) DYSRHYTHMIAS: Sinus tachycardia is the most common finding. Other cocaine-associated dysrhythmias include supraventricular tachycardia (Merigian et al, 1994), PVCs, bigeminy (Orr & Jones, 1968), accelerated ventricular rhythm (Benchimol et al, 1978), ventricular tachycardia (Merigian, 1993), bradycardia (Tanen et al, 2000; Havlik & Nolte, 2000), and ventricular fibrillation (Havlik & Nolte, 2000; Anon, 1979).
    1) Prolonged QRS and QT intervals of 136 msec and 522 msec, respectively, with right bundle branch-block and rightward axis deviation were reported in a man who ingested at least 2 g of crack cocaine (Goto & Delaney, 1999).
    2) The combination of cocaine and ethanol increased heart rate significantly more than did cocaine or ethanol alone in human volunteers (Higgins et al, 1993; McCance-Katz et al, 1993).
    c) BRADYCARDIA: If hypertension is significant, a reflex bradycardia may occur (Havlik & Nolte, 2000). Cocaine-induced syncope and bradyarrhythmia (46 beats/min) were reported in a 36-year-old woman after she used cocaine (Castro & Nacht, 2000).
    1) CASE REPORT: A 38-year-old man experienced prolonged toxicity that lasted over 16 hours from the time of ingestion of approximately 0.25 ounce of crack cocaine (28 rocks). He developed status epilepticus, wide and narrow complex bradydysrhythmias, ventricular dysrhythmias, and delayed hyperthermia; he eventually needed electrical pacing to control bradydysrhythmias (Tanen et al, 2000).
    d) NALOXONE INTERACTION: In a patient who used both IV cocaine and heroin, naloxone administration was followed by the onset of ventricular tachycardia, suggesting a possible drug interaction (Merigian, 1993).
    e) CASE REPORT: A 51-year-old woman experienced seizures with loss of consciousness and cardiac arrest approximately 4 hours after presenting to the emergency department following ingestion of packets, later determined to contain cocaine contaminated with tetramisole. Following successful resuscitation, an echocardiogram indicated bradycardia, right bundle branch block and terminal phase alterations. Over the next several days, the patient's clinical course was complicated by development of hypotension, worsening of renal, hepatic, and pancreatic function, with elevated hepatic transaminase, lipase, and serum creatinine concentrations, and rhabdomyolysis. With supportive therapy and removal of more than 100 packets, the patient gradually recovered and was discharged on hospital day 17 (Giuliani et al, 2012).
    f) CASE REPORT: A 26-year-old man presented to the emergency department (ED) comatose (Glasgow Coma Scale score of 5) with seizures after smoking a large quantity of crack cocaine throughout the night prior to presentation. At the ED, the patient developed status epilepticus, successfully controlled with a benzodiazepine infusion, tachycardia, and respiratory acidosis, and an initial ECG revealed wide-complex tachycardia (QRS interval 148 ms) with a prolonged QTc interval (595 ms). Despite supportive therapy, the patient's hemodynamic status continued to deteriorate with development of severe hypotension (85/60 mmHg). The patient was given 100 mL of 20% lipid emulsion intravenously and, within 10 minutes, there was narrowing of his wide-complex tachycardia and improvement in his blood pressure. A repeat ECG demonstrated normalization of his QRS and QTc intervals (82 ms and 412 ms, respectively) (Arora et al, 2013).
    H) BRUGADA SYNDROME
    1) WITH POISONING/EXPOSURE
    a) BRUGADA ECG PATTERN: An 18-year-old man with cocaine intoxication developed a Brugada ECG pattern initially interpreted as an acute ST-elevation myocardial infarction. His initial ECG revealed sinus tachycardia with downsloping ST elevation in leads V1 through V3. However, his cardiac enzymes were normal and he did not have chest pain or dyspnea. A repeat ECG, performed 9 hours postpresentation, showed resolution of the Brugada ECG pattern (Bebarta & Summers, 2007).
    b) An ECG of a 46-year-old man, whose blood and urine toxicology screen results were positive for cocaine metabolites, revealed sinus tachycardia with a right bundle-branch block pattern, a Brugada type I pattern (coved ST-segment elevation in leads V1 and V2, and T-wave inversion), and QTc interval prolongation (474 msec). Laboratory results revealed renal dysfunction (creatinine 2.3 mg/dL), severe hyperkalemia (7 mmol/L), and rhabdomyolysis (creatine kinase concentration of 3216 international units/L (normal 38 to 174); myoglobin concentration of 7712 ng/mL (normal 0 to 110)). With supportive care, the patient recovered with resolution of ECG abnormalities and improvement of his renal function (Irani et al, 2009).
    I) DISSECTION OF AORTA
    1) WITH POISONING/EXPOSURE
    a) AORTIC INJURY: Aortic dissection and rupture have been reported following cocaine use (Sherzoy et al, 1994; Cohle & Lie, 1992; Fisher & Holroyd, 1992; Hoffman et al, 1992; Gadaleta et al, 1989; Grannis et al, 1988; Edwards & Rubin, 1987; Barth et al, 1986).
    b) CASE SERIES: A retrospective chart review of patients hospitalized with aortic dissection between 1995 and 2001 was done to determine if the cardiac event was related to cocaine use. Of the 38 cases found, 14 cases (37%) were associated with self-reported cocaine use. Urine toxicology was positive for cocaine in 9 of the 14 cases. Although the results may not be applicable to other patient populations, common findings in this urban, inner-city setting were a history of untreated hypertension, black race, younger age (as compared with the controls; 41 years versus 59 years), cigarette smoking, a clinical finding of left ventricular hypertrophy, and an equal number of patients with types A and B dissection. The authors concluded that the pathophysiological mechanism associated with aortic dissection are likely multifactorial (Hsue et al, 2002).
    c) CASE REPORT: Recurrence of aortic dissection was associated with intermittent cocaine use in a patient who refused surgery (Chang & Rossi, 1995).
    d) CASE REPORT: A 61-year-old woman, with a past medical history of a chronic Stanford type B aortic dissection, developed a type A aortic dissection and pseudoaneurysm of the distal aortic arch following inhalational use of crack cocaine. The patient recovered uneventfully following surgical intervention (Feldhendler et al, 2007).
    e) CHRONIC USE: A 26-year-old man who consumed IV heroin and crack cocaine on a regular basis (confirmed by hair analysis) died of thoracic aorta dissection. Autopsy results showed detachment of the intima and media in the distal tract for a length of 4.3 cm, where the wall was made up of the adventitia only. Detachment affected the entire circumference of the aorta (Palmiere et al, 2004).
    f) RETROSPECTIVE ANALYSIS: According to analysis of patients enrolled in the International Registry of Acute Aortic Dissection (IRAD) from 1996 to 2012, 1.8% of patients (n=3584) with aortic dissections reportedly used cocaine. Of the cocaine users, type A aortic dissection, involving the ascending aorta, occurred in 52.4% of the patients, and type B aortic dissection, not involving the ascending aorta, occurred in 47.6% of the patients. In this study, the cocaine users with aortic dissection were significantly younger than the non-cocaine users. Tobacco use was also greater in the cocaine users than the non-cocaine users and the body mass index was significantly greater in the type B cohort of the cocaine users compared to the non-cocaine users. There were no significant differences among cohorts regarding hypertension and atherosclerosis, and there were no differences between cohorts regarding the type of management they received or the occurrence of in-hospital complications (ie, cerebrovascular accident, coma, or myocardial infarction); however, in-hospital mortality was significantly lower in the cocaine-users with type A aortic dissections compared to the non-cocaine users (6.1% vs 25.5%; p=012). This difference was believed to be related to the younger age of the cocaine-using patient at presentation (Dean et al, 2014).
    J) DISSECTING ANEURYSM OF CORONARY ARTERY
    1) WITH POISONING/EXPOSURE
    a) A case of fatal cocaine-associated spontaneous coronary artery dissection and a case of cocaine-associated left anterior descending artery dissection have been reported (Steinhauer & Caulfield, 2001).
    K) MEDIASTINAL EMPHYSEMA
    1) WITH POISONING/EXPOSURE
    a) INHALATIONAL EFFECTS: Pneumomediastinum and pneumopericardium may be seen after cocaine inhalation. The practice of inhaling drug crystals or vapors and then applying positive ventilatory pressure has been associated with clinical presentation of pneumopericardium (Adrouny & Magnusson, 1985).
    b) ORAL EFFECTS: Pneumopericardium has been reported following cocaine ingestion. A 20-year-old man developed diffuse left-sided and retrosternal chest pain after he was forced to swallow crystal rocks. The ECG revealed diffuse ST-segment elevations. It was suggested that crack cocaine with solid contaminants in the crystalline mass could have caused a microscopic esophageal tear that produced a leak of air into the pericardial sac (Albrecht et al, 2000).
    L) PERIPHERAL ISCHEMIA
    1) WITH POISONING/EXPOSURE
    a) SUMMARY: The effects of cocaine on peripheral vasculature may lead to thrombosis, embolization, ischemia, infarction, vasculitis, or hemorrhage.
    b) CEREBELLAR INFARCTION
    1) CENTRAL NERVOUS SYSTEM: Infarction of the spinal cord (De Giacomo et al, 1995; Daras et al, 1994a; Mody et al, 1988), brainstem (Daras et al, 1994a; Levine et al, 1990), cerebellum (DeVore & Tucker, 1988), cerebrum(Sloan et al, 1998; Daras et al, 1994a; Levine et al, 1990; Petty et al, 1990; Seaman, 1990; Jacobs et al, 1989; Meza et al, 1989; Levine et al, 1987; Golbe & Merkin, 1986; Schwartz & Cohen, 1984; Brust & Richter, 1977), and mesencephalon (Rowley et al, 1989) have been reported following cocaine abuse (Havlik & Nolte, 2000). However, one study was unable to demonstrate an association between crack use and stroke or cerebral infarction (Qureshi et al, 1997).
    2) Transient ischemic attacks have occurred after cocaine use (Jacobs et al, 1989; Mody et al, 1988).
    3) Former cocaine addicts may be at risk for delayed strokes (Deringer et al, 1990).
    M) ANGINA
    1) WITH POISONING/EXPOSURE
    a) Cocaine induces vasoconstriction in both diseased and nondiseased coronary arteries (Brogan et al, 1992; Brogan et al, 1991).
    b) Coronary artery vasospasm occurs with therapeutic doses of intranasal cocaine in smokers; this effect is more pronounced immediately after cigarette smoking (Moliterno et al, 1994).
    c) Femoral artery vasospasm following cocaine abuse has been reported (Myers et al, 1991).
    N) DEEP THROMBOPHLEBITIS
    1) WITH POISONING/EXPOSURE
    a) DEEP VENOUS THROMBOSIS: An increased incidence of upper extremity deep venous thrombosis has been noted in cocaine abusers (Lisse et al, 1989).
    O) DEAD - SUDDEN DEATH
    1) WITH POISONING/EXPOSURE
    a) Sudden death has been described in agitated cocaine-intoxicated patients who were struggling during attempts to restrain or arrest them (Mirchandani et al, 1994).
    b) Widespread contraction band necrosis of the myocardium has been found after cocaine-associated sudden death occurred (Karch et al, 1986; Karch & Billingham, 1988).
    P) TORSADES DE POINTES
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 34-year-old woman with a history of IV drug use and chronic alcoholism developed torsade de pointes after nasal insufflation of cocaine. The ECG revealed a sinus bradycardia, a U wave, and a prolongation of the QT interval. It is suggested that sympathomimetic effect as well as some toxic effect on the myocardium may have contributed to the appearance of torsade. This patient also had congenital prolonged QT syndrome and hypomagnesemia (Nogue et al, 2000).
    Q) SYNCOPE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Cocaine-induced syncope and bradyarrhythmia (46 beats/min) were reported in a 36-year-old woman after using cocaine (Castro & Nacht, 2000).
    R) HYPERTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Moderate doses result in a dose-related increase in heart rate and blood pressure (Havlik & Nolte, 2000; Resnick & Schwartz, 1977; Fennell et al, 1976). With larger doses hypotension may occur following the loss of sympathetic tone before the onset of a tachyarrhythmia.
    b) In one study, chronic cocaine use was associated with acute hypertension (not chronic) in middle-aged black men (Brecklin et al, 1998).
    S) ACUTE CORONARY SYNDROME
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 43-year-old man presented to the emergency department with left-sided chest pain that began 1 hour after insufflating cocaine, hypertension (160/92 mmHg), and tachycardia (130 beats/min). An ECG revealed sinus tachycardia, peaked T waves in the precordial leads, and ST-segment depression in leads V5 and V6. Despite administration of aspirin, nitroglycerin sublingual and IV , and diazepam IV, the patient's signs and symptoms persisted. The patient was then given 3 doses of phentolamine 1 mg IV, with each dose given at 5-minute intervals. Within 5 minutes after receiving the last phentolamine dose, the patient recovered with resolution of his symptoms and ECG abnormalities (Chan et al, 2006).
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEMORRHAGE
    a) WITH POISONING/EXPOSURE
    1) In a sheep model, chronic cocaine intoxication impaired the ability to maintain mean arterial blood pressure and cardiac output and caused a paradoxical bradycardia in response to graded hemorrhage in anesthetized sheep. In awake sheep chronic cocaine intoxication produced paradoxical bradycardia to graded hemorrhage, but no other hemodynamic effects were noted (Bernards et al, 1997).
    2) MYOCARDIAL DEPRESSION
    a) WITH POISONING/EXPOSURE
    1) In dogs, the concomitant administration of cocaine and ethanol produced additive myocardial depression (Wilson et al, 2001; Uszenski et al, 1992). In addition, the concomitant administration resulted in prolonged cardiac toxicity and was dysrhythmogenic (Wilson et al, 2001).
    3) CORONARY VASOCONSTRICTION
    a) WITH POISONING/EXPOSURE
    1) Administration of cocaine 2 mg/kg IV to dogs resulted in an increase in coronary vascular resistance and a reduction in the diameter of the left anterior descending coronary artery 2 minutes postadministration. Pretreatment with phentolamine, an alpha-adrenergic receptor antagonist, prevented the increase in coronary vascular resistance and reduction in the left anterior descending artery, indicating that the cocaine-associated coronary vasoconstrictive effects are mediated by alpha-adrenergic receptor stimulation (Kuhn et al, 1990).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) APNEA
    1) WITH POISONING/EXPOSURE
    a) Most effects arise from medullary stimulation or depression (Ritchie & Greene, 1980). The initial effect is an increase in rate and depth of respiration followed by rapid shallow breathing that may deteriorate to a Cheyne-Stokes pattern with larger doses (Chiu et al, 1986). Respiratory arrest may follow (Wetli et al, 1996; Schwartz & Oderda, 1980).
    b) Pulmonary infarction has been reported following crack use (Delaney & Hoffman, 1991).
    B) ACUTE LUNG INJURY
    1) WITH POISONING/EXPOSURE
    a) Pulmonary edema is a common finding at autopsy (Lora-Tamayo et al, 1994; Finkle & McCloskey, 1978) and has been reported clinically in association with crack cocaine smoking and IV cocaine use (Restrepo et al, 2007; Wilson & Hobbs, 1993; Kline & Hirasuna, 1990; Cucco et al, 1987; Allred & Ewer, 1981).
    b) CASE REPORT: Postoperative pulmonary edema occurred in a 33-year-old patient who had stopped using cocaine 2 weeks prior to surgery (Bloomfield, 1992).
    c) CASE REPORT: Pulmonary edema developed in a 3.5-week-old infant after presumed passive inhalation of crack cocaine (Batlle & Wilcox, 1993).
    C) BRONCHOSPASM
    1) WITH POISONING/EXPOSURE
    a) Dyspnea, pleuritic chest pain, bronchospasm, and wheezing have been associated with smoking freebase or snorting cocaine in patients with or without a history of asthma (Restrepo et al, 2007; Krantz et al, 1993; Rubin & Neugarten, 1990; Gordon, 1989; Rebhun, 1988).
    b) CASE REPORT: A 28-year-old man with asthma experienced fatal irreversible bronchospasm following crack smoking (Rao et al, 1990).
    D) PNEUMONIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: PULMONARY INFILTRATES: Transient pulmonary infiltrates, fever, and bronchospasm developed in a patient on 3 separate occasions after inhalation of cocaine. The pathogenic mechanism of "crack lung" (cocaine-induced lung disease) was believed to be immunologic as pruritus, eosinophilia, and elevated IgE levels occurred (Kissner et al, 1987).
    b) INTERSTITIAL PNEUMONITIS has been associated with crack cocaine smoking (O'Donnell et al, 1991).
    c) CASE REPORT: A 32-year-old man presented with bradycardia, hypotension, and respiratory distress approximately 8 hours after drinking and using cocaine. An arterial blood gas was drawn while the patient was on 100% O2, revealing a pH of 6.95, PaO2 of 40 mmHg, and a PaCO2 of 80 mmHg. Despite aggressive supportive measures, the patient continued to deteriorate, developing refractory ventricular fibrillation and worsening acidosis and hypoxemia (pH 6.84, PaO2 28 mmHg, PaCO2 87.5 mmHg). The patient subsequently progressed to asystole and was pronounced dead approximately 1 hour postpresentation. An autopsy revealed pulmonary vascular congestion and mixed alveolar inflammation, with eosinophils as the predominant inflammatory cells, indicating acute eosinophilic pneumonia (McCormick & Nelson, 2007).
    E) PNEUMOTHORAX
    1) WITH POISONING/EXPOSURE
    a) Pneumomediastinum and/or pneumothorax following crack smoking (Restrepo et al, 2007; Bernasko et al, 1997; Uva, 1997; Brody et al, 1988) and snorting or smoking of alkaloidal cocaine have been reported (Torre & Barberis, 1998; Christou et al, 1990; Lieberman et al, 1990; Seaman, 1990; Brody et al, 1988; Goldberg et al, 1987; Salzman et al, 1987; Wiener & Putman, 1987; Aroesty et al, 1986; Schweitzer, 1986; Shesser et al, 1981).
    1) Pneumomediastinum is thought to be secondary to performance of a valsalva maneuver during inhalation, rather than a direct toxic effect of cocaine. All cases reported have resolved uneventfully (Palat et al, 1988).
    2) BAROTRAUMA: Use of freebase cocaine has been associated with barotrauma from shearing forces on the alveolar structures. This allows free air to dissect to the mediastinum, pericardium, neck, and pleura (Albertson et al, 1995).
    b) SUBCUTANEOUS EMPHYSEMA has been associated with cocaine inhalation (Christou et al, 1990; Palat et al, 1988; Khouzam, 1987; Aroesty et al, 1986) and free-basing cocaine (Riccio & Abbott, 1990).
    F) HEMOPTYSIS
    1) WITH POISONING/EXPOSURE
    a) Hemoptysis, black sputum, pleuritic chest pain, impaired pulmonary diffusion capacity, and acute alveolar hemorrhage have been associated with smoking freebase cocaine (Restrepo et al, 2007; Tashkin et al, 1992; Murray et al, 1988; Rebhun, 1988; Tashkin et al, 1987).
    b) CASE REPORT: A 48-year-old woman, with a recurrent history of alveolar hemorrhage secondary to crack cocaine use, presented with progressive dyspnea on exertion. The patient was on long-term oxygen therapy, with the occurrence of exertional desaturation. A CT of the thorax revealed diffuse coarse reticular opacities with traction bronchiecstasis and minimal ground glass opacities, indicative of severe interstitial fibrosis. Given the patient's history, it is believed that the interstitial fibrosis was due to recurrent episodes of alveolar hemorrhage secondary to smoking crack cocaine. Despite administration of antibiotics and diuresis, the patient's oxygen demands continued to increase (ie, 5 L via nasal cannula). A contrast echocardiogram subsequently indicated severe pulmonary hypertension with a right-to-left shunt via a patent foramen ovale. The patient was then transferred to a facility for symptom management and end-of-life care (Vidyasankar et al, 2015).
    G) PULMONARY HYPERTENSION
    1) WITH POISONING/EXPOSURE
    a) Hypertrophy of the pulmonary vasculature was associated with cocaine-smoking deaths. Cocaine also has a direct effect on pulmonary vascular smooth muscle constriction (Albertson et al, 1995; Robertson et al, 1976).
    H) RESPIRATORY CONDITION DUE TO CHEMICAL FUMES AND/OR VAPORS
    1) WITH POISONING/EXPOSURE
    a) PASSIVE COCAINE INHALATION: Urine levels of cocaine and its metabolite benzoylecgonine have been detected in a drug-free individual up to 24 hours following passive exposure to freebase cocaine (Baselt et al, 1991).
    b) CASE SERIES/PEDIATRIC: The deaths of 16 infants have been associated with passive exposure to freebase (crack) cocaine smoke (Mirchandani et al, 1991).
    c) CASE REPORT/PEDIATRIC: Pulmonary edema developed in a 3.5-week-old infant after presumed passive inhalation of crack cocaine (Batlle & Wilcox, 1993).
    d) CASE REPORT: Upper airway burns have been reported from inadvertent inhalation of a wire mesh screen used when smoking crack cocaine (Ludwig & Hoffner, 1999).
    e) Abnormalities in pulmonary gas exchange may persist after cessation of cocaine use (Weiss et al, 1987; Itokenen et al, 1984).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) Seizures may be seen following abuse of cocaine by snorting, smoking, or the IV, oral, or rectal routes.
    b) Generalized tonic-clonic, partial motor, and partial complex seizure have all been reported (Arora et al, 2013; Giuliani et al, 2012; Havlik & Nolte, 2000; Lora-Tamayo et al, 1994; Mott et al, 1994; Hoffman et al, 1992; Kramer et al, 1990; Pascual-Leone et al, 1990; Choy-Kwong & Lipton, 1989a; Mody et al, 1988; Myers & Earnest, 1984; Schwartz & Oderda, 1980; Pearman, 1979; Finkle & McCloskey, 1978).
    1) Seizures may be recurrent, and status epilepticus has been reported, particularly in children (Tanen et al, 2000; Winbery et al, 1998; Merigian et al, 1994; Conway et al, 1990; Garland et al, 1989; Rivkin & Gilmore, 1989; Daya et al, 1988; Merriam et al, 1988).
    c) Children may develop seizures following passive inhalation of smoke containing cocaine (Bateman & Heagarty, 1989).
    d) As compared to seizures associated with tricyclic antidepressants, antidysrhythmics, theophylline, or isoniazid, cocaine-induced seizures are generally brief and self-limited. They generally do not require treatment (Olson et al, 1994).
    e) CASE REPORT: A 36-year-old man presented with generalized tonic-clonic seizures progressing to status epilepticus, delirium, and extreme agitation. A urine toxicology screen was positive for cocaine, and a CT scan of the patient's abdomen indicated several intra-colonic foreign bodies. Subsequent chemical analysis confirmed the presence of cocaine. With supportive care and removal of the packets via colonoscopy, the patient recovered and was discharged 8 days later (Ni Chroinin & Gaine, 2012).
    B) CHOREOATHETOSIS
    1) WITH POISONING/EXPOSURE
    a) Choreiform movements involving the head, trunk, and upper and lower extremities have been described in several patients following the use of cocaine (Daras et al, 1994a).
    b) In a study of cocaine-dependent subjects, choreoathetoid movements as assessed by the nonfacial abnormal involuntary movement scale (AIMS) were significantly increased in younger cocaine users compared with matched nonusers. Older cocaine users were similar to matched nonusers on the AIMS evaluation (Bartzokis et al, 1999).
    C) CEREBELLAR INFARCTION
    1) WITH POISONING/EXPOSURE
    a) Infarction of the spinal cord (De Giacomo et al, 1995; Daras et al, 1994a; Mody et al, 1988) , brainstem (Daras et al, 1994a; Levine et al, 1990), cerebellum (DeVore & Tucker, 1988), cerebrum(Sloan et al, 1998; Daras et al, 1994a; Levine et al, 1990; Petty et al, 1990; Seaman, 1990; Jacobs et al, 1989; Meza et al, 1989; Levine et al, 1987; Golbe & Merkin, 1986; Schwartz & Cohen, 1984; Brust & Richter, 1977), and mesencephalon (Rowley et al, 1989) have been reported following cocaine abuse (Havlik & Nolte, 2000). However, one study was unable to demonstrate an association between crack use and stroke or cerebral infarction (Qureshi et al, 1997).
    1) Transient ischemic attacks have occurred after cocaine use (Jacobs et al, 1989; Mody et al, 1988).
    2) Former cocaine addicts may be at risk for delayed strokes (Deringer et al, 1990).
    b) In a double-blind, placebo-controlled study, IV cocaine (0.2 or 0.4 mg/kg) induced cerebral vasoconstriction (5 of 8 subjects receiving 0.4 mg/kg, 3 of 9 subjects receiving 0.2 mg/kg, and 1 of 7 subjects receiving placebo). Subjects with a greater lifetime exposure to cocaine were more likely to develop vasoconstriction (Kaufman et al, 1998).
    D) INTRACRANIAL HEMORRHAGE
    1) WITH POISONING/EXPOSURE
    a) Intracranial hemorrhage (intracerebral or subarachnoid) has been described secondary to cocaine abuse (McEvoy et al, 2000; Daras et al, 1994; Ramadan et al, 1991; Levine et al, 1990; Henderson & Torbey, 1988; Mangiardi et al, 1988; Altes-Capella et al, 1987; Cregler & Mark, 1987; Tuchman et al, 1987; Cregler & Mark, 1986; Lichtenfeld et al, 1984; Schwartz & Cohen, 1984). Underlying abnormalities such as berry aneurysms are often present (Oyesiku et al, 1993; Levine et al, 1990; Jacobs et al, 1989). It has been suggested that intracranial hemorrhages occurred in the absence of readily detectable vascular abnormalities (Aggarwal et al, 1996).
    b) In a retrospective chart review, 151 patient records were examined to analyze the relationship between cocaine use and outcomes of aneurysmal subarachnoid hemorrhage (SAH). The analyses included a modification of the Hunt and Hess grade for classification (determination of surgical risk as it relates to repair of an intracranial aneurysm) of SAH, the occurrence of vasospasm as evaluated by angiography, and overall outcome as measured by Glasgow Outcome Scale. In this study, cocaine users presented with a higher mean arterial blood pressure (mean 132 mmHg as compared with 121 mmHg in nonusers), had a higher Hunt and Hess grade (55.6% grade IV or V as compared with 11% in nonusers), and a 2.8-fold greater risk of development of vasospasm (95% confidence interval, 1.86 to 4.22). Of those patients that presented with SAH and had used cocaine within the past 24 hours, there was an increased risk for both a higher degree of hemorrhage and vasospasm. Only 3 patients out of 36 in the cocaine user group had a good outcome (Glasgow Outcome Scale 4 or 5). The authors concluded that cocaine use significantly affects patient presentation and outcome in the management of SAH (Howington et al, 2003).
    E) DYSTONIA
    1) WITH POISONING/EXPOSURE
    a) DYSTONIA has been related to cocaine withdrawal. In addition, a high incidence of neuroleptic-induced dystonias have been reported in cocaine users. Chronic brain dopamine depletion is postulated as an etiologic factor.(Hegarty et al, 1991; Choy-Kwong & Lipton, 1989).
    b) Acute dystonic reactions have followed cocaine use without concomitant neuroleptic use (Catalano et al, 1997; Fines et al, 1997; Schubert & Wason, 1992; Farrell & Diehl, 1991).
    F) HEADACHE
    1) WITH POISONING/EXPOSURE
    a) Headache may occur after cocaine use. Severe headache may be seen with occlusive or hemorrhagic stroke (Levine et al, 1990).
    b) Migraine-like headaches may be related to cocaine-induced increases in serotonin (Satel & Gawin, 1989) and may be more common in patients with a history of previous migraines (Lipton et al, 1989; Mossman & Goadsby, 1992).
    c) Researchers have identified 3 patterns of cocaine-induced headaches with migrainous features (Dhuna et al, 1991):
    1) PATTERN 1: Develops immediately (within minutes) and lasts 2 to 48 hours. Headaches are occipital or bilateral with associated throbbing, photophobia, nausea, and vomiting.
    2) PATTERN 2: Occurs during a cocaine binge (4 to 14 days of continuous use, 1 to 3 g/day), with onset after a few days and increasing severity over the period of the binge. Headaches are frontal with associated throbbing and nausea, with 1 report of diplopia and dizziness.
    3) PATTERN 3: Occurs 1 to 4 days after the last dose of cocaine and worsens over 6 days with continued abstinence. Headaches are frontal with associated throbbing, nausea, vomiting, and photophobia, with 1 report of neck stiffness.
    G) DISTURBANCE IN THINKING
    1) WITH POISONING/EXPOSURE
    a) SUMMARY: Cortical areas are affected first, with effects progressing caudally. Mental status changes range from euphoria, excitement, restlessness, and anxiety to delirium and acute paranoid psychosis (Mott et al, 1994; Post, 1975).
    b) A "washed-out" syndrome, characterized by decreased level of consciousness and profound lethargy, has been described after binging (Sporer & Lesser, 1992). CNS depression may also develop after acute exposure, particularly in children (Mott et al, 1994; Edell, 1993).
    c) Dose-related associations between neurobehavioral performance and cocaine dose and alcohol dose have been reported. Concurrent use of cocaine and ethanol may produce additive effects on the brain as compared with the use of only 1 of these substances (Bolla et al, 2000).
    H) HYPERREFLEXIA
    1) WITH POISONING/EXPOSURE
    a) Motor activity is increased and is at first well coordinated (Pearman, 1979), but as lower motor centers are affected, tremulousness, hyperreflexia, and fasciculations are evident (Ritchie & Greene, 1980; Schwartz & Oderda, 1980; Pearman, 1979; Caldwell & Sever, 1974).
    I) MUSCLE WEAKNESS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Cocaine was associated with unmasking and exacerbating myasthenia gravis in a 24-year-old woman with an 8-year history of regular cocaine use (1 to 3 times daily) (Berciano et al, 1991).
    J) SPASMODIC MOVEMENT
    1) WITH POISONING/EXPOSURE
    a) TOURETTE SYNDROME: Cocaine has been reported to exaggerate Tourette syndrome (Mesulam, 1986).
    K) CEREBROVASCULAR DISEASE
    1) WITH POISONING/EXPOSURE
    a) CEREBRAL ATROPHY: Cocaine abuse may be associated with cerebral atrophy (Pascual-Leone et al, 1991).
    b) CASE REPORT: A 29-year-old man developed headache and a pupillary-sparing oculomotor nerve paresis (ptosis; diplopia; limitation of superior, inferior, and medial right eye movements) after smoking cocaine. Cerebral arteriogram and MRI results were normal, and the patient gradually improved. The mechanism was postulated to be ischemia of the third cranial nerve secondary to cocaine-induced vasoconstriction (Migita et al, 1997).
    L) AMNESIA
    1) WITH POISONING/EXPOSURE
    a) One study found that abstinent subjects with a history of crack abuse had short-term memory disturbances (Manschreck et al, 1990).
    M) VASCULITIS
    1) WITH POISONING/EXPOSURE
    a) Biopsy-confirmed cerebral vasculitis has been associated with cocaine abuse (Morrow & McQuillen, 1993; Fredericks et al, 1991; Krendel et al, 1990; Kaye & Fainstat, 1987).
    b) CASE REPORT: Widespread focal, predominantly lymphocytic vasculitis of the small vessels of the brain that was associated with acute infarct in the brainstem but not in the cortex was found at autopsy in a 25-year-old woman. The patient had a long history of cocaine (intranasal only) and ethanol abuse and died of hypoxic encephalopathy after cardiac arrest following cocaine use (Morrow & McQuillen, 1993).
    N) PARKINSONISM
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 35-year-old man with a 15-year history of cocaine abuse (and a history of amphetamine and cannabis abuse from ages 15 to 20) developed resting tremor and loss of mobility and facial expression that improved with levodopa and carbidopa administration. CT and MRI revealed global cerebral atrophy.(Domingo & Martinez, 1997).
    O) DELIRIUM
    1) WITH POISONING/EXPOSURE
    a) The cocaine-associated agitated delirium syndrome is composed of 4 components that appear in sequence: hyperthermia, delirium with agitation, respiratory arrest, and death. These patients usually have low to moderate cocaine blood levels (Wetli et al, 1996).
    b) CASE REPORT: A 36-year-old man presented with generalized tonic-clonic seizures progressing to status epilepticus, delirium, and extreme agitation. The patient's seizures resolved with intravenous anticonvulsive therapy; however, his delirium and agitation persisted despite administration of IV benzodiazepines. A urine toxicology screen was positive for cocaine, and a CT scan of the patient's abdomen indicated several intra-colonic foreign bodies. Subsequent chemical analysis confirmed the presence of cocaine. With supportive care and removal of the packets via colonoscopy, the patient recovered and was discharged 8 days later (Ni Chroinin & Gaine, 2012).
    P) TOXIC ENCEPHALOPATHY
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 21-year-old man was unresponsive with bilateral hyperreflexia following IV administration of cocaine in a suicide attempt. The patient had no history of previous cocaine use. Following hospital admission, his initial EEG was normal; however, 3 and 12 days postadmission, his EEG periodically showed long episodes (2 to 30 seconds) of EEG flattening with no response to visual or tactile stimulation. On day 21, his MRI of the brain revealed diffuse symmetrical white matter changes with hyperintense signal on the T2-weighted images. On day 24, the patient died of pneumonia without regaining consciousness. An autopsy revealed severe leukoencephalopathy with demyelination and liquefying of the central cerebral white matter (Kondziella et al, 2007).
    b) CASE REPORT: A 46-year-old man became comatose (Glasgow Coma Scale of 3) with hypotension (80/60 mmHg), a respiratory rate of 12 breaths/min, and a heart rate of 124 beats/min following a cocaine overdose. With supportive care, his GCS score improved to 7. On hospital day 7, a brain MRI and fluid-attenuated inversion recovery (FLAIR) images showed hypersignal intensity within both pallidi and also within the splenium of the corpus callosum. Elevated glutamine/glutamate levels were noted on magnetic resonance spectroscopy. A repeat MRI 3 weeks later showed liquefaction necrosis of both pallidi along with extensive white matter changes within both cerebral hemispheres. A 2-month follow-up with the patient revealed that he was experiencing akinetic mutism and mixed extrapyramidal and pyramidal spasticity (De Roock et al, 2007).
    Q) AMYOTROPHIC LATERAL SCLEROSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT/CHRONIC USE: A 31-year-old man, who was a regular cocaine user (every other day for 3 years), first experienced weakness of the muscles of his right thumb approximately 2 days after insufflating 3.5 g of cocaine. Over the next 18 months, the patient continued to experience progressive muscular weakness and atrophy of his right forearm and hand muscles and of his right lower extremities. Muscle fasciculations were also present in the distal and proximal muscles of the upper extremities and the right lower extremity. The Amyotrophic Lateral Sclerosis (ALS) Functional Rating Scale score had decreased from 33 to 24, indicating that the patient had developed sporadic early-onset ALS, which the authors believed might be secondary to the patient's acute abuse and chronic use of cocaine (Argyriou et al, 2011).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) WITH POISONING/EXPOSURE
    a) Nausea and vomiting may ensue secondary to stimulation of the CNS medullary centers (Pearman, 1979).
    B) VASCULAR INSUFFICIENCY OF INTESTINE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Ischemia of the bowel was associated with inhalation of crack cocaine in a previously healthy 26-year-old woman (Yang et al, 1991).
    b) CASE REPORT: Splenic infarction was associated with IV cocaine, pentazocine, and methylphenidate use in a woman with sickle cell trait (Novielli & Chambers, 1991).
    c) CASE SERIES: After smoking crack, 3 patients developed intestinal perforations requiring surgical correction. It was suggested that cocaine blocks the reuptake of norepinephrine, leading to mesenteric vasoconstriction and focal tissue ischemia and perforation (Muniz & Evans, 2001).
    d) Intestinal ischemia following cocaine ingestion, injection, or crack use has been described (Sudhakar et al, 1997; Jawahar et al, 1997).
    1) Mechanical bowel obstruction caused by impacted or ruptured cocaine packets may predispose to bowel infarction (Mustard et al, 1992; Freudenberger et al, 1990; Cregler & Mark, 1986; Nalbandian et al, 1985).
    2) CASE REPORT: Diffuse intestinal ischemia that resulted in necrosis of the distal ileum and the entire colon and rectum and that required resection was reported in a 49-year-old woman following the use of crack cocaine (Wang et al, 1992).
    3) CASE REPORT: Ischemic colitis with perforation developed in a 47-year-old man following IV cocaine use (Brown et al, 1994).
    C) TRAUMATIC AND/OR NON-TRAUMATIC INJURY
    1) WITH POISONING/EXPOSURE
    a) THERMAL BURN
    1) CASE REPORT: A 55-year-old man experienced reversible thermal injury to the esophagus secondary to smoking freebase cocaine after unintentionally swallowing some of the boiling liquid during inhalation. Two days later the patient experienced continuous pain in the left shoulder and arm along with diaphoresis while lifting boxes. The patient was admitted to the hospital with transient cardiac ischemia; a cardiac catheterization revealed patent coronary arteries. An esophagogastroduodenoscopy revealed a candy-cane (alternating pink and white bands) appearance to the distal 10 cm of the esophagus, along with chronic gastritis and bacteria consistent with H pylori. In the literature, this type of injury has been associated with chest pain, dysphagia, odynophagia, and abdominal pain. The patient was successfully treated with a proton pump inhibitor and antibiotics (Cohen & Kegel, 2002).
    D) GASTRIC ULCER
    1) WITH POISONING/EXPOSURE
    a) Perforated gastric ulcers related to crack use have been reported in young men (Abramson et al, 1989; Abramson et al, 1991).
    b) CASE REPORT: A 39-year-old man who was body packing latex-wrapped cocaine packets developed a giant prepyloric gastric ulcer. Fifteen packets had become impacted in the gastric antrum in the area overlying the ulcer.(Miller et al, 1998).
    E) HEMORRHAGIC DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Hemorrhagic diarrhea was noted in a previously healthy 4-year-old girl acutely exposed to crack cocaine (Riggs & Weibley, 1991).
    F) PNEUMOPERITONEUM
    1) WITH POISONING/EXPOSURE
    a) Pneumoperitoneum has been reported after smoking crack cocaine (Uva, 1997).
    G) INFLAMMATORY DISEASE OF MUCOUS MEMBRANE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 25-year-old man presented to the emergency department (ED) with complaints of mouth numbness that lasted for approximately an hour after intentionally chewing and swallowing approximately 3 g of crack cocaine. The patient also developed difficulty swallowing following ingestion of the cocaine. Other than a pulse of 140 beats/minute, all other vital signs were normal and an ECG was unremarkable. After administration of lorazepam for agitation and polyethylene glycol solution to enhance elimination, the patient was discharged to home following release from police custody. Approximately 12 hours later, the patient returned to the ED, complaining of mouth pain, lip swelling and a burning sensation of his oral cavity. Examination revealed diffuse sloughing of the oral mucosa with a whitish discoloration, and bright red underneath the mucosa. The patient was given morphine for pain relief. Abdominal and chest X-rays were normal; however, the patient left against medical advice and there was no follow-up regarding his subsequent medical condition (O'Connor et al, 2015).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) TOXIC HEPATITIS
    1) WITH POISONING/EXPOSURE
    a) IV cocaine use is associated with hepatitis B infection (Estroff et al, 1986).
    b) Fatal hepatitis B infection has been reported in crack abusers whose sexual partners included IV drug abusers (Estroff et al, 1986).
    c) CASE SERIES: Acute hepatitis induced by intranasal cocaine was reported in 3 HIV-infected patients with viral hepatitis. Aminotransferase levels increased to very high values (approximately 10,000 international units/L) in all 3 patients (Peyriere et al, 2000).
    d) CASE REPORT: A 22-year-old woman with a history of chronic hepatitis C virus developed acute hepatitis and thrombotic microangiopathy (thrombocytopenia and hemolytic anemia) after using ethanol (80 g/day) and IV cocaine (1 to 2 g/week) for 3 years. She admitted using more cocaine (more than 2 g/day) in the previous week. Two days later, she developed rapidly progressive respiratory and renal failure, hypotension, and tonic-clonic seizures, requiring tracheal intubation. Laboratory test revealed the following levels: creatinine, 5.4 mg/dL; aspartate aminotransferase, 860 units/L; alanine aminotransferase, 950 units/L; total bilirubin, 71.4 mg/dL; and troponin I, 28.6 ng/mL. Multifocal hepatic necrosis and microvesicular steatosis were observed in transjugular liver biopsy, suggesting toxic hepatitis. Following plasma exchange using 5% albumin and supportive therapy, she recovered (Balaguer et al, 2005).
    B) LIVER DAMAGE
    1) WITH POISONING/EXPOSURE
    a) SUMMARY: Hepatic injury with elevations of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase is common (Giuliani et al, 2012; Kothur et al, 1991; Silva et al, 1991; Gubbins et al, 1990; Marks & Chapple, 1967).
    b) Hepatic necrosis (centrilobular, midzonal, and panlobar) has been reported in severe overdose (Radin, 1993; Silva et al, 1991; Perino et al, 1987).
    1) The presence of disseminated intravascular coagulation, hypotension, hyperpyrexia, acute renal failure, and early liver dysfunction (less than 48 hours) indicates severe, life-threatening cocaine intoxication (Silva et al, 1991).
    c) IN VIVO STUDIES: Ethanol potentiates cocaine toxicity in cultured human hepatocytes (Jover et al, 1991).
    C) LIVER ENZYMES ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) ALT/PROGNOSTIC INDICATOR: A retrospective cross-sectional study evaluated patient records from the Center for Toxicological Information of Santa Catarina from 2003 through 2010, identifying 93 patients admitted for cocaine intoxication. The mean ALT level was 86.25 +/-191.05 International Units/L. ALT levels were categorized into tertiles according to gender. The upper tertile was defined as 48 International Units/L or greater in men and 36 International Units/L or greater in women. Compared to patients with ALT levels less than the upper tertile, patients with ALT levels above the upper tertile demonstrated significant increases in AST levels (85.5 vs 24.0 International Units/L; p<0.001), creatine phosphokinase (CPK) levels (1441 vs 256 International Units/L; p<0.01), CPK-MB levels (29 vs 8 International Units/L; p<0.03), creatinine levels (1.04 vs 0.9 mg/dL; p<0.017), and INR (1.18 vs 1.09; p<0.031). In addition, the incidence of acute renal failure and death during hospitalization was significantly greater in the patients with ALT levels above the upper tertile (34.4% and 15.6%, respectively, n=32) compared to the patients with ALT levels less than the upper tertile (9.8% and 3.3%, respectively, n=61) (p=0.004 and 0.045, respectively) (Guollo et al, 2015).
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) MICE: Cocaine is hepatotoxic in mice. Glutathione depletion or treatment with cytochrome P450 inducers enhances toxicity while pretreatment with cysteine or cytochrome P450 inhibitors is protective (Powell et al, 1994; Peterson et al, 1983; Stewart et al, 1979; Thompson et al, 1979). A reactive metabolite of norcocaine oxidation has been implicated as the hepatotoxin (Ndikum-Moffor et al, 1998; Kloss et al, 1984).
    a) Chronic ethanol consumption increases hepatotoxicity in mice injected daily with cocaine (Odeleye et al, 1993).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) RENAL FAILURE SYNDROME
    1) WITH POISONING/EXPOSURE
    a) Renal failure is presumably secondary to myoglobinuria and rhabdomyolysis and is common in severe overdoses (Van der Woude, 2000; Lucatello et al, 1992; Enriquez et al, 1991; Ahijado et al, 1990; Gubbins et al, 1990; Singhal et al, 1990; Parks et al, 1989; Singhal et al, 1989; Herzlich et al, 1988; Lombard et al, 1988; Menashe & Gottlieb, 1988a; Merigian & Roberts, 1987).
    b) CASE REPORT: Reversible scleroderma renal crisis was reported in a 33-year-old woman after intranasal cocaine use (Lam & Ballou, 1992).
    c) Scleroderma renal crisis, characterized by accelerated hypertension, rapidly progressive renal failure, and hyperreninemia may occur with heavy cocaine abuse. In addition, severe renal arteriosclerosis without hypertension may occur with cocaine use (Van der Woude, 2000).
    d) CASE REPORT: Acute renal failure and rhabdomyolysis were reported in a 46-year-old man whose blood and urine toxicology screen tested positive for cocaine metabolites. Laboratory results revealed hyperkalemia (potassium 7 mmol/L) and a serum creatinine concentration of 2.3 mg/dL (normal 0.6 to 1.4 mg/dL). With supportive care, the patient recovered (Irani et al, 2009).
    e) Acute renal failure (serum creatinine peak approximately 600 mcmol/L) associated with rhabdomyolysis was reported in a 51-year-old woman who ingested more than 100 packets, subsequently determined to contain cocaine contaminated with tetramisole. The patient recovered with supportive care and removal of the packets (Giuliani et al, 2012).
    B) ABNORMAL RENAL FUNCTION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 25-year-old African American man developed renal infarction after nasal insufflations of cocaine. Laboratory examination revealed leukocytosis, hematuria, and elevated levels of lactate dehydrogenase (Saleem et al, 2001).
    b) CASE REPORT: RENAL INFARCTION was seen in a 32-year-old man approximately 30 seconds following IV cocaine use. Presumably this was due to adrenergic stimulation combined with an existing arterial thrombus (Sharff, 1984).
    c) CASE REPORT: A 48-year-old woman presented with renal insufficiency due to cocaine-induced renal arterio-arteriosclerosis. Her serum creatinine was 4.17 mg% and the blood urea nitrogen was 196 mg%. On a daily basis, she smoked 40 cigarettes and used cocaine. A kidney biopsy showed 2 out of 5 glomeruli that were very sclerotic. Other glomeruli had increased mesangial matrix with a slight distension of the urinary space. The subcapsular region showed scarring with interstitial fibrosis, atrophic tubuli, and resorptive mononuclear infiltrates. Subendothelial hyaline depositions were found in the arterioles and there was a very marked arterio-arteriosclerosis (van der Woude & Waldherr, 1999).
    C) GLOMERULONEPHRITIS
    1) WITH POISONING/EXPOSURE
    a) Antiglomerular basement membrane antibody-mediated glomerulonephritis has been reported (Van der Woude, 2000a).
    D) INTERSTITIAL NEPHRITIS
    1) WITH POISONING/EXPOSURE
    a) Acute interstitial nephritis has been reported (Wojciechowski et al, 2008; Van der Woude, 2000a; Alvarez et al, 1999).
    E) ABNORMAL SEXUAL FUNCTION
    1) WITH POISONING/EXPOSURE
    a) Decreased libido, impotence, unexplained breast development, galactorrhea, amenorrhea, and sexual dysfunction have been reported in chronic cocaine abusers (Cocores et al, 1986).
    F) PRIAPISM
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Priapism with subsequent disseminated intravascular coagulation, necrosis, gangrene, and auto-amputation of the penis was reported after intraurethral cocaine administration (Mahler et al, 1988).
    b) Priapism has been observed after topical application of cocaine to the glans penis (Rodriguez-Blasquez et al, 1990).
    G) SEMEN EXAM: ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) In vitro cocaine has been shown to bind well to human spermatozoa without interfering with sperm motility (Yazigi et al, 1991).
    H) RENAL INFARCTION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 40-year-old man developed renal artery dissection and thrombosis leading to renal infarction several hours after using cocaine. Ultrasound showed variable attenuation in the right lower pole of the kidney. An abdominal CT scan showed a segmental perfusion defect in the lower pole of the right kidney in the distribution of the posterior segment of the renal artery. Several months later, he experienced similar symptoms on 2 different occasions. An abdominal CT scan showed multiple infarctions in the right kidney, visible clot in the aorta and right renal artery. Hypercoagulable workup showed a double heterozygous methyltetrahydrofolate reductase A1298C/C677T thermolabile polymorphism with an elevated serum homocysteine (18 mcmol/L [range 5 to 14 mcmol/L]). He was prescribed folic acid 1 mg daily orally and warfarin. Following supportive therapy, he was discharged without further sequelae (Edmondson et al, 2004).
    I) GANGRENOUS DISORDER
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Fournier's gangrene of the penis was reported in a 47-year-old man following multiple subcutaneous injections of a cocaine solution (cocaine mixed with 5 mL of tap water) into his penis. The patient had presented with a 6-day history of penile swelling and fever. Initial vital signs indicated tachycardia, fever, and hypotension. Discharging pus of the penile shaft skin and laboratory data revealing leukocytosis and an elevated C-reactive protein level indicated the presence of sepsis. Following surgical debridement and antibiotic therapy, the patient gradually recovered with partial restoration of erectile function (Khan et al, 2013).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) Severe metabolic acidosis has been reported along with seizures, agitation, and hypotension (Stevens et al, 1994; Jonsson et al, 1983).
    b) Acidemia has been reported to contribute to conduction delays, dysrhythmias, and depressed myocardial contractility in patients with cocaine toxicity. Correction of acidemia through supportive care measures such as hyperventilation, sedation, active cooling, and sodium bicarbonate may improve outcome cardiac conduction disorders (Wang, 1999).
    B) LACTIC ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) Lactic acidosis has been reported with physical exertion following cocaine use (Bethke et al, 1990; Bozzuto, 1988), including lactic acidosis with seizures (Giammarco, 1987).
    b) CASE REPORT: A 24-year-old man presented to the emergency department with agitation, delirium, and hypertension after using cocaine. Despite being restrained with handcuffs for his own protection, the patient continued to exhibit combativeness requiring sedation, muscular paralysis, and mechanical ventilation. Laboratory analysis revealed a plasma lactate level of 20 mg/dL, and arterial blood gases showed a pH of 7.10, pCO2 44 mmHg, and a PaO2 of 327 mmHg, indicating lactic acidosis. With supportive care and continued sedation and mechanical ventilation, the patient recovered with complete resolution of his lactic acidosis. The patient was extubated without complications (Alshayeb et al, 2010).
    C) RESPIRATORY ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) Respiratory acidosis may occur in patients with significant CNS depression or seizures, but it is less common than metabolic acidosis (Arora et al, 2013; De Roock et al, 2007; Stevens et al, 1994).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) DISSEMINATED INTRAVASCULAR COAGULATION
    1) WITH POISONING/EXPOSURE
    a) Disseminated intravascular coagulation may be seen in severe poisoning cases, often associated with hyperthermia, rhabdomyolysis, renal failure, and hepatic dysfunction (Silva et al, 1991; Bauwens et al, 1989; Campbell, 1988).
    B) THROMBOCYTOPENIC DISORDER
    1) WITH POISONING/EXPOSURE
    a) Thrombocytopenia has been reported following cocaine abuse and may be an autoimmune phenomenon (Burday & Martin, 1991; Orser, 1991; Leissinger, 1990). Corticosteroids, gamma globulin, and splenectomy have been used as therapy (Burday & Martin, 1991; Leissinger, 1990).
    b) The acute transient thrombocytopenia associated with cocaine abuse can closely mimic signs of severe preeclampsia in pregnant women (Abramowicz et al, 1991).
    C) THROMBOTIC MICROANGIOPATHY
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 22-year-old woman with a history of chronic hepatitis C virus developed acute hepatitis and thrombotic microangiopathy after using ethanol (80 g/day) and IV cocaine (1 to 2 g/week) for 3 years. She admitted using more cocaine (more than 2 g/day) in the previous week. She developed severe thrombocytopenia (platelets 21,000/mcL) and hemolytic anemia (hematocrit, 23%; lactate dehydrogenase, 5060 units/L; indirect bilirubin, 49 mg/dL; haptoglobin, 50 mg/dL; reticulocyte count, 3.9%; and direct and indirect Coombs tests, negative). Following plasma exchange using 5% albumin and supportive therapy, she recovered. The proposed mechanisms of thrombotic microangiopathy include an immune reaction and direct damage of vascular endothelium such as occurs in malignant hypertension, preeclampsia, and burns (Balaguer et al, 2005).
    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) PLATELET ADHESIVENESS INCREASED
    a) WITH POISONING/EXPOSURE
    1) Cocaine injection induces platelet aggregation in dogs (Kugelmass et al, 1995).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) DISORDER OF SKIN
    1) WITH POISONING/EXPOSURE
    a) Skin infarction thrombi have been noted following IV and freebase cocaine use (Zamora-Quezada et al, 1988; Heng & Haberfeld, 1987).
    B) SYSTEMIC SCLEROSIS
    1) WITH POISONING/EXPOSURE
    a) Scleroderma may be associated with the use of cocaine (Kilaru et al, 1991; Kerr, 1989).
    C) SKIN FINDING
    1) WITH POISONING/EXPOSURE
    a) CRACK HANDS: A syndrome of multiple linear or circular, blackened, hyperkeratotic lesions of the fingers and palms has been described in crack cocaine smokers. The lesions are caused by the heat of the glass cocaine pipe (Feeney & Briggs, 1992).
    D) STEVENS-JOHNSON SYNDROME
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 26-year-old man developed Stevens-Johnson syndrome 3 days after cocaine snorting. There were multiple erosions up to 2 cm on his cheeks, tongue, lips, penile glans, and inner aspect of the foreskin. He also exhibited ocular signs, including conjunctival vasculitis as seen in erythema exudativum multiforme (Hofbauer et al, 2000).
    E) VASCULITIS
    1) WITH POISONING/EXPOSURE
    a) PSEUDOVASCULITIS: Cocaine-induced pseudovasculitis has been reported in a 27-year-old woman with progressive onset of pharyngitis, fatigue, and skin lesions on her face, legs, arms, and back. Her skin had multiple diffusely spread erythematous pustular and ulcerating lesions with purulent exudates. Skin biopsy specimens showed extensive and destructive neutrophilic infiltrates throughout all levels of the dermis with only a few small blood vessels, surrounded by acute inflammatory infiltrates and edema, displaying fibrinoid necrosis (Friedman & Wolfsthal, 2005).
    F) GANGRENOUS DISORDER
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 43-year-old woman who had no history of vascular disease developed gangrene of both hands and legs that necessitated digital and above-knee amputations, following repeated use of crack cocaine. Histopathologic examination revealed smooth muscle hyperplasia in small vessels and intimal hyperplasia of intermediate-sized vessels, believed to be due to multiple previous crack cocaine-related vasospastic episodes. There was no evidence of thrombus formation (Dhawan & Wang, 2007).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) RHABDOMYOLYSIS
    1) WITH POISONING/EXPOSURE
    a) Rhabdomyolysis is commonly described in cocaine poisoning. Muscle symptoms do not predict increases in CPK levels (Havlik & Nolte, 2000; Van der Woude, 2000; Hoffman et al, 1992; Horst et al, 1991; Silva et al, 1991; Welch et al, 1991; Ahijado et al, 1990; Singhal et al, 1990; Parks et al, 1989; Roth, 1989; Steingrub et al, 1989; Herzlich et al, 1988; Krohn et al, 1988; Lombard et al, 1988; Menashe & Gottlieb, 1988a; Merigian & Roberts, 1987).
    b) Although the mechanism of cocaine-associated rhabdomyolysis is unclear, it may include ischemia due to vasoconstriction, direct toxicity, hyperpyrexia, and increased muscle activity from agitation or seizure activity (Van der Woude, 2000a).
    c) CASE REPORT: Elevated creatine kinase and myoglobin concentrations (3216 international units/L (normal 38 to 174) and 7712 nanograms/mL (normal 0 to 110), respectively) were reported in a 46-year-old man whose blood and urine toxicology screen results were positive for cocaine metabolites. The patient also developed acute renal failure, severe hyperkalemia, and ECG abnormalities that included sinus tachycardia with a right bundle-branch block pattern, a Brugada type I pattern (coved ST-segment elevation in leads V1 and V2, T-wave inversion), and QTc interval prolongation (474 msec). With supportive care, the patient recovered (Irani et al, 2009).
    d) Acute renal failure associated with rhabdomyolysis (creatine kinase peak of 42,087 units/L) was reported in a 51-year-old woman who ingested more than 100 packets, subsequently determined to contain cocaine contaminated with tetramisole. The patient recovered with supportive care and removal of the packets (Giuliani et al, 2012).
    B) MUSCLE WEAKNESS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Cocaine abuse was associated with severe weakness requiring prolonged mechanical ventilation in a 26-year-old woman with a glycogen storage disease, who had previously been asymptomatic (Wilson & Hobbs, 1993).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERPROLACTINEMIA
    1) WITH POISONING/EXPOSURE
    a) Withdrawal from cocaine may result in hyperprolactinemia. Bromocriptine 0.625 mg orally twice daily may be of value for treating hyperprolactinemia related to cocaine withdrawal (Cocores et al, 1986).
    B) HYPERTHYROIDISM
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: One case of hyperthyroidism possibly related to cocaine abuse has been reported (Burton et al, 1989).
    b) One study found no differences in thyroid function tests between chronic heavy cocaine users and controls (Dhopesh et al, 1991).
    C) DIABETIC KETOACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) In a retrospective case-control study of hospital admissions for diabetic ketoacidosis (DKA), 27 cocaine users accounted for 102 of 720 admissions (14%) (Warner et al, 1998).
    1) Cocaine abusers were less likely to have an intercurrent illness as an identified precipitant for DKA, were more likely to have missed 1 or more doses of insulin, and had slightly higher serum glucose levels (593 mg/dL vs 531 mg/dL) than did nonusers. There were no differences in severity of illness or outcome.
    3.16.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) GLUCOCORTICOIDS INCREASED
    a) WITH POISONING/EXPOSURE
    1) SHEEP: In pregnant sheep cocaine induces an increase in maternal and fetal cortisol levels 15 minutes after administration (Owiny et al, 1991).

Immunologic

    3.19.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) IMMUNE SYSTEM DISORDER
    a) ANIMAL STUDIES: Animal and in vitro studies have suggested cocaine-induced immunosuppression.
    1) Cocaine inhibited human mononuclear cell proliferation in vitro in a dose-dependent fashion (Delafuente & DeVane, 1991; Delafuente et al, 1989).
    2) In mice, cocaine and cocaethylene administration reduced spleen weight, number of splenocytes, and mitogen-stimulated production of gamma interferon, tumor necrosis factor, and interleukin-2 by splenocytes. Effects were more severe in cocaethylene-treated mice than in cocaine-treated mice (Pirozhkov et al, 1992).

Reproductive

    3.20.1) SUMMARY
    A) Cocaine abuse during pregnancy is associated with various congenital anomalies as well as abruptio placentae, low birth weight, and behavioral abnormalities. Neonatal intoxication may also occur.
    B) Cocaine is in the FDA Pregnancy Category C for medicinal use and Category X for nonmedicinal use.
    1) Category C: Studies have shown that the drug exerts animal teratogenic or embryocidal effects, but there are no controlled studies in women, or no studies are available in either animals or women. Drugs should be given only if the potential benefit justifies the potential risk to the fetus.
    2) Category X: Studies in animals or humans have demonstrated fetal abnormalities or there is evidence of fetal risk based on human experience, or both, and the risk clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.
    3.20.2) TERATOGENICITY
    A) CONGENITAL ANOMALY
    1) INCIDENCE: Among the offspring of 114 women with positive urine cocaine screen test results during pregnancy, 14% had 3 or more minor congenital abnormalities or 1 or more major abnormalities (Zuckerman et al, 1989).
    2) Significantly higher rates of birth defects were found in children born to women who used cocaine alone, compared with those who did not use drugs (Bingol et al, 1987). Although the risk of malformations cannot be accurately obtained, there are indications it may be as high as 15% to 20% (Schardein, 1993).
    B) EYE ABNORMALITY
    1) Neonates exposed to cocaine in utero were found to consistently have dilation and tortuosity of the iris vasculature. Neonates with this finding should have a urine assay for cocaine (Isenberg et al, 1987).
    a) This may be the result of the pharmacologic vasoconstricting action of cocaine on the vascular system at various times during development (Schardein, 1993).
    2) Children who were exposed to cocaine in utero exhibited structural eye abnormalities (43%) (Tsay et al, 1996). Prenatal exposure to crack cocaine was associated with poorer visual motor performance in a group of eighteen 4- to 6-year-old children (Bender et al, 1995).
    C) UROGENITAL MALFORMATION
    1) Cocaine use has been associated with genitourinary tract malformations including hydronephrosis, hypospadias, and genital and cloacal abnormalities (Greenfield et al, 1991; Chasnoff et al, 1988).
    2) In an in utero evaluation that used Doppler studies of the bladder and renal artery, cocaine-exposed fetuses had increased renal arterial resistance and decreased urine output compared with controls (Mitra et al, 1994).
    3) Increases in genitourinary tract malformations (a decrease in the hourly urine output, an increased incidence of hypospadia, horseshoe kidney, unilateral abnormal small kidney, duplex kidney, and renal tract dilatation) have been seen (Van der Woude, 2000).
    4) Prune belly syndrome has been described in infants exposed to cocaine in utero (Greenfield et al, 1991; Bingol et al, 1986; Chasnoff et al, 1985).
    5) In a group of 136 neonates with prenatal cocaine exposure, 11 patients (14%) had renal abnormalities upon ultrasound examination. Renal abnormalities have not previously been reported in cocaine-exposed newborns. They occurred independently from hypospadias, which was also increased in this group (Battin et al, 1995).
    D) GI MALFORMATION
    1) MULTIPLE INTESTINAL ATRESIAS involving the large and small bowel, areas of submucosal fibrosis, stenosis of the bowel lumen, calcification of the bowel wall, and dilated loops of bowel have been reported, demonstrating ischemic injury to the fetus as a result of maternal cocaine abuse (Spinazzola et al, 1992).
    2) NECROTIZING ENTEROCOLITIS: Infants born to mothers who were cocaine abusers demonstrated a 2.5-fold increased risk of developing necrotizing enterocolitis when compared with a group not exposed to cocaine (Czyrko et al, 1991).
    a) Bowel ischemia related to cocaine exposure has been suggested as the mechanism of action (Downing et al, 1991; Telsey et al, 1988).
    E) CNS CONGENITAL ANOMALY
    1) CRANIOFACIAL ANOMALIES: Major craniofacial and CNS anomalies were described in infants of 11 women who used cocaine during pregnancy; 5 were poly-drug abusers. Abnormalities included hydroencephaly, porencephaly, hypoplastic corpus callosum, intraparenchymal hemorrhage, encephalomalacia, arthrogryposis, facial diplegia, and cleft lip and palate. Four of the 11 infants died, and the remainder had serious developmental disabilities (Kobori et al, 1989).
    a) An infant born to a mother who abused cocaine and alcohol throughout pregnancy had multiple craniofacial abnormalities including a low nasal bridge, periorbital edema, prominent glabellar region, short nose, bitemporal narrowing, low-set crumpled ears, and profound developmental delay (Robin & Zackai, 1994).
    b) There have also been many reports of CNS infarctions or malformations, both in full-term and premature infants of cocaine-addicted mothers (Dogra et al, 1994; Singer et al, 1994; Heier et al, 1991; Dixon & Bejar, 1989).
    2) BEHAVIOR: Infants exposed to cocaine in utero have increased tremulousness, impaired orientation, increased startle responses, irritability, muscular rigidity, arousal deficits, impaired motor ability, and lower scores on the Brazelton Neonatal Behavioral Assessment Scale (measuring interactive behavior and response to environmental stimuli) and the Bayley Total Behavior Scale (Morrow et al, 2001; Chiriboga et al, 2007; Chiriboga et al, 1993; Mayes et al, 1993; Eisen et al, 1991; Chasnoff et al, 1989; Gingras et al, 1989; Cherukuri et al, 1988; Chasnoff et al, 1987; Chasnoff et al, 1985).
    a) Behavioral abnormalities including increased number of startles, intermittent inactivity, and increased general activity suggesting a direct effect on fetal CNS were noted following in utero exposure in one case report. These behaviors were noted for 8 weeks following initial fetal exposure (Hepper, 1995).
    b) Crack babies had worse outcomes for neurologic signs (and low birth weight) than did babies of mothers who abused other forms of cocaine (Kaye et al, 1989).
    3) MENTAL DEVELOPMENT: Cocaine/poly-drug exposed infants had significantly lower mental development scores than controls at 6 months of age. Differences resolved by 12 months of age (Chasnoff et al, 1992).
    a) In a prospective, longitudinal study of inner city children of low socioeconomic status, children exposed to cocaine in utero did not score differently than unexposed children at 4 years of age. Both groups performed poorly (Hurt et al, 1997).
    b) A group of first grade teachers who were blinded to the cocaine exposure status of the children in their classes rated the cocaine-exposed group as demonstrating more problem behaviors than unexposed children. This study did not control for confounders that may have affected the children's behavior (Delaney-Black et al, 1998).
    c) LONG-TERM FOLLOW-UP: In a study of cocaine-exposed children 3 to 6 years old, the effects of cocaine on a child's temperament and the capacity to have a satisfying interpersonal relationship were examined. Through examination of simulated situational interactions with others (including mothers of the children) and measures of EEG activity, children's temperaments in various settings were measured (Jones et al, 2004).
    1) The children prenatally exposed to cocaine showed less empathic behavior, more maternal-perceived behavior problems, and an inability to complete mildly frustrating tasks. The cocaine-exposed children had greater relative right frontal EEG asymmetry and greater overall EEG activation, which may indicate that they respond more negatively, and may have higher intensity responses even during nonstressful events
    4) LANGUAGE DEVELOPMENT: In a prospective study of full-term infants, the effects of prenatal cocaine exposure on the longitudinal (at 3, 5, and 7 years) development of language were examined. Longitudinal latent growth curve analyses were used to evaluate 2 components of language performance, a more stable aptitude and a time-varying developmental trajectory, across the designated time periods. Greater severity of prenatal cocaine exposure was associated with greater deficits within the more stable aptitude of language performance. No relationship was found between severity of prenatal exposure, and the time-varying trajectory of language development. Overall, the effects were found to be subtle between the exposed and nonexposed groups of children; further study was suggested (Bandstra et al, 2004).
    5) MOTOR DEVELOPMENT: Infants exposed to cocaine/poly-drugs had increased extensor tone, delayed integration of primitive reflexes, increased tremulousness, and poorer quality of movement than nonexposed infants at 4 months of age (Schneider & Chasnoff, 1992).
    6) EEGs: Abnormal EEG results were found in 17 of 38 cocaine-exposed neonates during the first week of life. CNS irritability was present in 34 infants. By 3 to 12 months of age, 16 of 17 of the EEG tests had normalized, with the outcome pending for the remaining infant (Doberczak et al, 1988).
    7) PARENCHYMAL CHANGES: Intrauterine cocaine exposure has been linked to the development of intracranial hemorrhage, cerebral infarction, ventricular enlargement, and cystic lesions suggestive of prior hemorrhagic or ischemic effects (Heier et al, 1991; Dixon & Bejar, 1989; Spires et al, 1989).
    a) Cerebral infarction was reported in a neonate following maternal intranasal cocaine use 72 hours prior to delivery (Chasnoff et al, 1986).
    b) Intracranial hemorrhage in utero was reported in a term infant born to a cocaine-abusing mother (Spires et al, 1989). Seizures have also been reported (Dusick et al, 1993).
    1) Brain hemorrhage is very common among cocaine babies, but one study found this to be just as frequent in very low-birth-weight babies who were negative for cocaine (Dusick et al, 1993).
    8) BRAIN STEM: One study found that cocaine-exposed infants have longer brainstem transmission time than controls for the first several months of life. This effect disappeared by the first year of life (Salamy et al, 1990).
    9) CATECHOLAMINES: A significant negative correlation was found between norepinephrine concentration and the orientation behavioral score at 24 and 48 hours of age in cocaine-exposed newborns. It was postulated that norepinephrine is increased in exposed newborns and may play a role in neurobehavioral abnormalities (Mirochnick et al, 1997).
    a) In one prospective study infants exposed to cocaine in utero had increased plasma concentrations of norepinephrine (923 picograms/mL) compared with unexposed newborns (667 picograms/mL). Samples were obtained 24 to 72 hours after birth.
    10) Smaller head circumference, greater incidence of periventricular-intraventricular hemorrhage, inferior Brazelton cluster scores, greater depression, less alertness, increased agitated behavior, and higher levels of urinary norepinephrine, dopamine, and cortisol, as well as lower plasma insulin levels, were seen in cocaine-exposed newborns (Scafidi et al, 1996).
    a) In a study of 251 infants, no differences in neurobehavioral performance were seen at 2 days of age, but by 3 weeks a dose-related effect was seen for poorer state regulation and greater excitability (Tronick et al, 1996).
    b) A cohort study of 21 children was conducted, involving 11 children exposed to cocaine prenatally (CE) and 10 non-cocaine exposed (NCE) children. All of the children were followed from birth and underwent brain MRI's at the age of 8 to 10 years. A subset of the 21 children (6 CE and 4 NCE) underwent brain imaging at 13 to 15 years of age as well. Using a pediatric atlas for automated subcortical segmentations, the volumes of the cerebral cortex, thalamus, and the putamen were significantly lower in the CE group compared to the NCE group at 8 to 10 years of age. Comparing the brain volumes of the CE patients scanned at ages 8 to 10 years with those scanned at 13 to 15 years, there did not appear to be any significant changes in the cortical, thalamic, or putaminal volumes in the 13 to 15 years of age adolescent cohort; however, there were significant changes in volume in the cerebral white matter (0.6 to 0.122; p=0.02), the hippocampus (0.36 to 0.18; p=0.02), and the amygdala (0.56 to 0.004; p=0.02). At birth, head circumference appeared to be smaller in the CE children compared to the NCE children. Head circumferences were also measured at 1 month, 9 years, and at 14 years of age in both groups. The head circumferences tended to be smaller at 1 month and at 9 years in the CE group compared to the NCE group. In the NCE group, the head circumferences at age 9 correlated well with the cortical volumes at ages 8 to 10. However, in the CE group, the head circumferences measured at 1 month and at age 9 correlated well with the cortical volumes at ages 8 to 10. The head circumference measurement at 1 month of age also appeared to correlate well with the cortical volumes in the adolescent group (ages 13 to 15). These smaller head circumferences at 1 month suggest that cocaine exposure prenatally may compromise fetal brain growth which may continue to be evident at ages 8 to 10 years (Akyuz et al, 2014).
    11) ANIMAL STUDIES: Offspring of female rats given 10 mg/kg/day of cocaine subcutaneously from day 4 through 18 of gestation showed behavioral effects (Smith et al, 1989). Prenatal exposure to a high dose of cocaine (20 mg/kg, in the form of the hydrochloride, on days 8 to 21 of gestation) produced behavioral alterations in rats (Sobrian et al, 1995).
    F) HEART MALFORMATION
    1) Neonates with drug test results positive for cocaine metabolites had a significantly higher rate of cardiac anomalies (9.4) than controls (Lipshultz et al, 1991).
    2) Epidemiologic data suggest a positive association between cocaine use during pregnancy and congenital cardiac anomalies (Shaw et al, 1991).
    3) Congenital heart defects were found in a group of infants born to 53 cocaine abusers (Little et al, 1989). Seven percent of infants born to cocaine-abusing women had patent ductus arteriosus requiring surgery, compared with 1% in nonabusers (Dusick et al, 1993).
    4) VENTRICULAR TACHYCARDIA: A neonate born to a woman who abused cocaine for 5 months during pregnancy and who used 1.5 g in the 24 to 48 hours prior to delivery developed sinus tachycardia, multiple premature ventricular contractions with couplets, and ventricular tachycardia. Repeat monitoring showed a progressive decrease in arrhythmias, with a normal rhythm at 19 weeks (Geggel et al, 1989).
    5) In an in vitro fetal myocardial model, the combination of ethanol (200 mg/L) and cocaine (200 mcg/L) depressed action potential amplitude and contractility to a greater extent than did cocaine alone (Richards, 1997).
    G) SKELETAL MALFORMATION
    1) Teratogenesis of the limbs has been reported in fetuses chronically exposed to cocaine. All of these cases were complicated by multiple drug use during pregnancy. (Hannig & Phillips, 1991; Van Den Anker et al, 1991; Hoyme et al, 1990).
    2) Limb-body wall complex, a complicated fetal malformation characterized by body wall disruption and limb anomalies, was reported in the fetuses of 2 women who smoked large amounts of cocaine during the first trimester of pregnancy (Viscarello et al, 1992).
    H) BIRTH WEIGHT SUBNORMAL
    1) SUMMARY: Cocaine abuse during pregnancy is associated with decreased fetal weight, length, and head circumference, lower gestational age at delivery, reduced size for gestational age, and lower Apgar scores (Gouin et al, 2011; Morrow et al, 2001; Sprauve et al, 1997; Bateman et al, 1993; Chasnoff et al, 1992; Dombrowski et al, 1991; Chasnoff et al, 1989; Neerhof et al, 1989; Zuckerman et al, 1989; Cherukuri et al, 1988; Bingol et al, 1987; Isenberg et al, 1987; LeBlanc et al, 1987; MacGregor et al, 1987; Ryan et al, 1987).
    a) In some studies, head size and weight remained significantly less through 24 to 30 months of age in children exposed to cocaine in utero (Hurt et al, 1995; Chasnoff et al, 1992; Chasnoff et al, 1989).
    2) A systematic meta-analysis of 31 controlled, retrospective, and prospective cohort studies conducted between 1983 and 2000 found that cocaine exposure during pregnancy significantly increased the risk of low birth weight, preterm, and small for gestational age births, with delivery and birth weights a mean of 1.47 weeks earlier (13 studies; n=1584; 95% confidence interval (CI), -1.97 weeks to -0.98 weeks; p less than 0.00001) and 491.52 g lighter (18 studies; n=4945; 95% CI, -562.18 g to -420.85 g; p less than 0.00001), respectively, than controls without cocaine exposure (n=2688 and 1910 , respectively). Risk of low birth weight was significantly higher among cocaine-exposed women (19 studies; n=3389; unadjusted pooled odds ratio (OR) 3.66 (95% confidence interval (CI), 2.9 to 4.63; p less than 0.00001) compared with controls (n=35,407), as was the risk with cocaine exposure of small for gestational age birth (14 studies; n=2475; unadjusted pooled OR 3.23 (95% CI, 2.43 to 4.3); p less than 0.00001) compared with controls (n=25,623). Preterm births (before 37 weeks) were also significantly associated with cocaine exposure during pregnancy (24 studies; n=3675; unadjusted pooled OR 3.38 (95% CI, 2.72 to 4.21); p less than 0.0001) compared with controls (n=36,185) (Gouin et al, 2011).
    3) Effects on birth weight and growth retardation may be related to the duration of cocaine use during pregnancy. Perinatal outcomes of these parameters were not significantly different in women who used cocaine during the first trimester and a drug-free group. Those who used cocaine throughout pregnancy did have a greater risk of these effects. Both cocaine groups demonstrated adverse neonatal behavioral effects (Chasnoff et al, 1989).
    4) Cocaine has been reported to have other physical effects on the unborn that would not be considered structural malformations. These include microcephaly, intrauterine growth retardation, low birth weight, and shorter length (Chasnoff, 1989; Fulroth et al, 1989; Kaye et al, 1989; Little et al, 1989). Infants of crack cocaine users fared more poorly for low birth weight than those of mothers using other forms of cocaine (Kaye et al, 1989).
    I) RESPIRATORY TRACT MALFORMATION
    1) Otherwise healthy infants who had been prenatally exposed to cocaine had a higher frequency of respiratory pauses and a significant reduction in minute ventilation in response to facial airstream stimulation than infants in a control group (Chen et al, 1991).
    2) Another study found that term babies exposed to cocaine had a higher rate of periodic breathing compared with controls, while premature cocaine-exposed infants had more obstructive apnea than nonexposed premature controls (Toubas et al, 1994).
    J) SUDDEN INFANT DEATH SYNDROME
    1) SUMMARY: Maternal chronic cocaine use during pregnancy has been suggested as a possible factor in sudden infant death syndrome (Bauchner & Zuckerman, 1990; Gingras et al, 1990; Chasnoff et al, 1987).
    2) In a prospective study of 61 cocaine-exposed infants, prolonged apnea was documented in the results of 12 of 59 pneumocardiograms. However, these results did not correlate with later development of SIDS (Riley et al, 1988).
    K) DRUG INTERACTION
    1) COCAINE/INDOMETHACIN: One case report described the development of fetal anuria, anasarca, and gastrointestinal hemorrhage after the mother was treated with indomethacin (400 mg over 2 days) for preterm labor (Carlan et al, 1991).
    a) Maternal urine screen was positive for cocaine and cannabinoids. The authors speculate that the rapid onset of severe fetal side effects may have been precipitated by some interaction between cocaine and indomethacin, although there is no direct evidence.
    L) NEONATAL DISORDER
    1) Besides birth defects and other physical effects, prenatal cocaine exposure has also been linked with increased neonatal morbidity and longer hospital stays (Neerhof et al, 1989).
    M) ANIMAL STUDIES
    1) In animal studies, intraperitoneal injection of cocaine in mice resulted in dilated or cystic ureters, hydronephrosis, grossly distended bladders, cryptorchidism, renal artery ablation, limb reduction abnormalities, gastrointestinal atresia, and cardiac abnormalities (Van der Woude, 2000).
    2) Cocaine, cocaethylene, norcocaine, ecgonine, benzoylecgonine, and ecgonine methylester each caused a dose-dependent decrease in pial arteriolar diameter when suffused over the brain surface in newborn piglets. Cerebral vasoconstriction induced by topically applied norepinephrine was enhanced by cocaine, norcocaine, and cocaethylene (Kurth et al, 1993).
    a) Phentolamine did not block vasoconstriction induced by cocaine or its metabolites, suggesting that this vasoconstriction is mediated by a nonsympathomimetic mechanism.
    3) In a sheep model, cocaine was infused into the amniotic fluid with subsequent determination of the concentrations of cocaine and cocaine metabolites in amniotic fluid, fetal and maternal serum, and meconium. Cocaine was metabolized in amniotic fluid primarily to ecgonine methyl ester (Mahone et al, 1994).
    a) Concentrations of cocaine and metabolites in serum and meconium were similar in fetal lambs that had undergone esophageal ligation and controls, suggesting that cocaine and metabolites enter fetal circulation by absorption through the umbilical cord or placental surface vessels rather than from swallowing amniotic fluid.
    4) Cocaine has been teratogenic in laboratory animals. It was teratogenic in mice when given as the hydrochloride at nontoxic doses during days 7 to 12 of gestation, and it produced eye and skeletal defects (Mahalik et al, 1980).
    a) Enlarged renal pelvis was seen in fetal rats exposed to high doses of cocaine on day 8, 9, or 10 of gestation (Hunter et al, 1995). Another study reported cocaine to be fetotoxic, but not teratogenic, in mice and rats when administered as the hydrochloride by IP injection on days 7 through 16 of gestation (Fantel & MacPhail, 1982).
    b) Limb reduction and CNS defects similar to those reported in humans have been seen in rats (Webster et al, 1991; Webster & Brown-Woodman, 1990).
    3.20.3) EFFECTS IN PREGNANCY
    A) SUMMARY
    1) INCIDENCE: Up to 17% of pregnant women reported using cocaine at least once during gestation (Frank et al, 1988).
    2) Cocaine abuse during pregnancy is associated with various congenital anomalies as well as low birth weight and behavioral abnormalities (Kain et al, 1992). Neonatal intoxication may also occur. Neonatal deaths have been reported in association with maternal cocaine use (Sturner et al, 1991; Meeker & Reynolds, 1990; Morild & Stajic, 1990).
    3) In an in vitro model, cocaine increased the spontaneous contractility of human myometrium and the maximal response to oxytocin (Hurd et al, 1998).
    4) Cocaine is reported to be biotransformed by the human placenta, perhaps providing some protection to the fetus. Cholinesterase probably transforms cocaine; individuals with low placental cholinesterase activity may have fetuses more at risk for severe cocaine toxicity (Roe et al, 1990).
    a) In an in vitro study of human placentas, a high-affinity, low-capacity binder and a low-affinity, high-capacity binder were found for cocaine and cocaethylene. The authors suggested that human placenta may serve as a reservoir for cocaine and cocaethylene (Bailey, 1997).
    b) In a study of placentas from cocaine abusers (n=29) compared with drug-free controls (n=15), moderate to severe villus edema was seen in 17% of cocaine users compared with none in the control group. Chorionic villus hemorrhage was observed in 17% of users and 20% of controls, and chorioamnionitis was seen in 58% of users and 66% of controls. Within the cocaine group, duration of cocaine use or trimester of cocaine use did not affect frequency of pathologic observations (Mooney et al, 1998).
    5) MILD TO MODERATE EXPOSURE: Among 34 women who used cocaine during pregnancy and 600 women who did not, there were no differences between the groups in infant growth, morphology, and behavior, or in obstetrical complications, suggesting that "moderate" use of cocaine during pregnancy does not affect these parameters (Richardson & Day, 1991).
    a) Brief exposure to cocaine in early pregnancy does not appear to affect the outcome or the infant's physical and cognitive development. In a report of 30 women who used cocaine socially, were not chemically dependent, and who stopped using cocaine soon after the discovery of pregnancy, there were not any adverse obstetric or neonatal effects (Graham et al, 1992).
    b) After adjustment for lifestyle and other factors in one study, cocaine use during pregnancy accounted for an average of 0.74-week shorter gestation, 154-g reduction in birth weight, 1.02-cm reduction in length, and 0.69-cm reduction in head circumference (Bateman et al, 1993).
    B) PLACENTAL DISORDERS
    1) ABRUPTIO PLACENTAE: Cocaine use in pregnancy is associated with an increased incidence of abruptio placentae, often accompanied by shock and premature labor with rapid delivery (Burkett et al, 1994; Dusick et al, 1993; Copur et al, 1991; Flowers et al, 1991; Collins et al, 1989; Neerhof et al, 1989; Chasnoff & MacGregor, 1988; Townsend et al, 1988; Bingol et al, 1987; Chasnoff et al, 1985; Acker et al, 1983).
    a) DOPPLER UMBILICAL VELOCIMETRY may be useful for detecting decreased umbilical blood flow and the possibility of placental abruptio. The mean umbilical systolic/diastolic ratios in cocaine users are usually normal, while abnormal ratios have been in found in cocaine abusers with abruptio placentae (Cohen et al, 1991; Hoskins et al, 1991).
    1) CASE REPORT: Maternal cocaine intoxication was noted in one patient to decrease uterine artery velocimetry which was associated with a positive nonreactive contraction stress test. As the effects of cocaine wore off, the contraction stress test became normal (reactive) and the uterine artery velocimetry returned to normal (George et al, 1995).
    a) No physiologic response was observed in the umbilical artery, which may be related to the cocaine-induced decrease in uterine blood flow, resulting in the delivery of less cocaine to the placenta and fetus.
    b) PLACENTAL CHANGES: A lower total number of beta-adrenergic placental binding sites were found in cocaine users compared with normal controls (p less than 0.01) (Wang & Schnoll, 1987).
    c) POLYHYDRAMNIOS: The effects of maternal substance use on amniotic fluid index (AFI), a biophysical profile marker, were examined. Despite no significant difference in AFI values, patients who admitted to substance abuse were found to have an increased incidence of polyhydramnios. Of the drugs examined (eg, cocaine, opiates, marijuana), cocaine was most frequently associated with polyhydramnios. The authors postulated that the vasoconstrictive effects of cocaine could result in fetal hypoxia, which suppresses fetal swallowing and causes an increase in polyhydramnios. Further study is suggested to evaluate the clinical significance of these findings (Panting-Kemp et al, 2002).
    C) LABOR ABNORMAL
    1) PRETERM LABOR: Cocaine use is associated with preterm labor (Burkett et al, 1994). A systematic meta-analysis of 31 controlled, retrospective, and prospective cohort studies conducted between 1983 and 2000 found that cocaine exposure during pregnancy significantly increased the risk of low birth weight, preterm, and small for gestational age births, with delivery and birth weights a mean of 1.47 weeks earlier (13 studies; n=1584; 95% confidence interval (CI), -1.97 weeks to -0.98 weeks; p less than 0.00001) and 491.52 g lighter (18 studies; n=4945; 95% CI, -562.18 g to -420.85 g; p less than 0.00001), respectively, than controls without cocaine exposure (n=2688 and 1910 , respectively). Risk of low birth weight was significantly higher among cocaine-exposed women (19 studies; n=3389; unadjusted pooled odds ratio (OR) 3.66 (95% confidence interval (CI), 2.9 to 4.63; p less than 0.00001) compared with controls (n=35,407), as was the risk with cocaine exposure of small for gestational age birth (14 studies; n=2475; unadjusted pooled OR 3.23 (95% CI, 2.43 to 4.3); p less than 0.00001) compared with controls (n=25,623). Preterm births (before 37 weeks) were also significantly associated with cocaine exposure during pregnancy (24 studies; n=3675; unadjusted pooled OR 3.38 (95% CI, 2.72 to 4.21); p less than 0.0001) compared with controls (n=36,185) (Gouin et al, 2011). Women with recent use are more likely to present with advanced cervical dilatation and to deliver rapidly than women with premature rupture of the membranes not associated with recent cocaine use (Dinsmoor et al, 1994).
    D) STILLBIRTH
    1) Cocaine use is associated with an increased incidence of spontaneous abortion and stillbirth, often related to abruptio placentae (Burkett et al, 1994; Bingol et al, 1987; Chasnoff et al, 1985).
    2) Significantly higher rates of intrauterine fetal death were seen in women with a history of recent cocaine use, confirmed by urinary analysis (Martinez et al, 1996).
    E) PREGNANCY DISORDER
    1) PATTERNS OF COCAINE USE: The associations between patterns of crack use and pregnancy complications were studied in 905 women. Women who binged erratically were most likely to develop vaginal bleeding, abruptio placentae, and stillbirths while chronic problems (small for gestational age infants, infections, anemia, low maternal weight) were more likely to develop in women who binged daily or in cycles. Prematurity, abruptio placentae, and vaginal bleeding were more likely to occur in women with recent cocaine use (positive drug screen) (Burkett et al, 1994).
    2) MATERNAL COMPLICATIONS: Pregnant women may experience any of the complications of cocaine abuse.
    a) Ruptured intracranial aneurysm and intracerebral hemorrhage in the peripartum period have been reported in association with cocaine abuse (Mercado et al, 1989; Henderson & Torbey, 1988).
    b) Two cases of ruptured ectopic pregnancy with onset of abdominal pain occurring almost immediately after cocaine use have been reported (Thatcher et al, 1989).
    c) Women abusing cocaine during the third trimester of pregnancy may present with signs and symptoms of eclampsia (hypertension, headache, blurred vision, abdominal pain, seizures) that are not accompanied by the usual laboratory changes (thrombocytopenia, increased AST, ALT, creatinine, or uric acid) and resolve spontaneously several hours after drug use (Towers et al, 1993).
    d) CASE REPORT: A 31-year-old woman and her fetus died from massive air embolization after her partner blew cocaine smoke into her vagina (Collins et al, 1994).
    F) PREGNANCY CATEGORY
    1) Cocaine is classified as US Food and Drug Administration Pregnancy Category C for medical use (Prod Info cocaine hcl topical solution, 2006).
    G) ANIMAL STUDIES
    1) Pregnant ewes given 0.5 to 2 mg/kg IV boluses of cocaine had a dose-dependent increase in maternal blood pressure and decrease in uterine blood flow. Uterine vascular resistance increased by 52% to 168% and was accompanied by marked fetal hypoxemia, hypertension, and tachycardia (Woods et al, 1987).
    2) In rats, cocaine lethality increased during late gestation. Maternal mortality after subcutaneous injection of cocaine 30, 40, and 50 mg/kg was 0%, 40%, and 72%, respectively, during late gestation. These doses were not associated with maternal mortality during mid gestation. The late gestation group also had higher benzoylecgonine levels than the mid gestation group (Church & Subramanian, 1997).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) SUMMARY: Cocaine toxicity has been reported in breastfed infants of cocaine-abusing mothers (AAP, 1994).
    a) CASE REPORT: A 2-week-old infant who was exclusively breastfed developed signs of cocaine toxicity (irritability, vomiting, mydriasis, diarrhea, tremors, high-pitched cry) after maternal use of intranasal cocaine during breastfeeding.
    1) High levels of benzoylecgonine were found in the infant's urine. Symptoms abated gradually over 48 hours after the last feeding (Chasnoff et al, 1987a).
    b) CASE REPORT: An 11-day-old infant developed cocaine toxicity (seizures, cyanosis, tachycardia) after breastfeeding following maternal application of cocaine powder to the nipples without rinsing (Chaney et al, 1988).
    3.20.5) FERTILITY
    A) FERTILITY DECREASED FEMALE
    1) The risk of women being infertile due to tubal complications was elevated 11-fold in cocaine users (Mueller et al, 1990).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS50-36-2 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.2) SUMMARY/HUMAN
    A) Little is known about the risk of human cancer from cocaine.
    B) Smoking cocaine may entail some of the carcinogenic risks of cigarette smoking from pyrolysis products in the smoke. One case of Pott's puffy tumor has been reported in a patient who chronically abused cocaine; this type of tumor is thought to be secondary to chronic sinusitis from smoking cocaine.
    3.21.3) HUMAN STUDIES
    A) CARCINOMA
    1) Little is known about the risk of human cancer from cocaine.
    2) Smoking cocaine may entail some of the carcinogenic risks of cigarette smoking from pyrolysis products in the smoke. One case of Pott puffy tumor has been reported in a patient who chronically abused cocaine; this type of tumor is thought to be secondary to chronic sinusitis from smoking cocaine (Noskin & Kalish, 1991).
    3) In one study, the odds ratio of children contracting rhabdomyosarcoma was elevated 4.5-fold and 2.1-fold if the mothers or fathers, respectively, had used cocaine within a year of the child's birth (Grufferman et al, 1991).
    3.21.4) ANIMAL STUDIES
    A) CARCINOMA
    1) Cocaine can be rapidly metabolized to formaldehyde in the rat nasal mucosa (Dahl & Hadley, 1983). Formaldehyde is an animal carcinogen and suspect human carcinogen. Structure-activity analysis has predicted that cocaine would be an animal carcinogen (Rosenkranz & Klopman, 1990).

Genotoxicity

    A) Cocaine inhibited DNA synthesis in young rat brains, but only if the animals were less than 15 days old. The hydrochloride form was reported to induce chromosome aberrations in Chinese hamster cells in vitro.
    B) Increased frequencies of chromosome aberrations and sister chromatid exchanges have been seen in lymphocytes of cocaine base users in Peru. They were also seen in placental cells from pregnant cocaine users.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Patients with minimal toxicity do not require laboratory studies.
    B) Patients with possible cardiac chest pain should be evaluated with serial troponin levels.
    C) Patients with severe toxicity should be monitored for acidosis, renal and hepatic failure, coagulopathy, and rhabdomyolysis.
    D) A head CT scan and lumbar puncture should be considered in patients with persistent abnormal mental status.
    E) Continuous cardiac monitoring and ECG should be performed in patients with chest pain or severe toxicity.
    F) Radiologic evaluation may be of value in evaluating body packers.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Blood or plasma cocaine levels are not clinically useful for guiding emergent therapy.
    2) CPK: Monitor serum creatine kinase (CK) for evidence of rhabdomyolysis; monitor renal function and urine output in patients with elevated CPK levels.
    3) Patients without underlying cardiac disease may have increased CK-MM only during episodes of myocardial necrosis and ischemia, making the distinction between rhabdomyolysis and myocardial ischemia more difficult (Knowlton, 1989; Rubin & Neugarten, 1989).
    4) Management of patients with chest pain after cocaine use requires evaluation of serial ECG results and troponin or CK isoenzyme levels. Enzymatic evidence of myocardial ischemia or infarction may be found in patients with unremarkable ECG results (Tokarski et al, 1990).
    5) Troponin levels may be more useful than CK in evaluating potential myocardial injury (Weber et al, 2003).
    6) PSEUDOCHOLINESTERASE: Lower plasma cholinesterase levels have been found in patients with more severe cocaine toxicity as compared with those with less serious toxicity (Hoffman et al, 1992; Devenyi, 1989). In one study, both cocaine-abusing groups had lower pseudocholinesterase levels than non-using controls (Hoffman et al, 1992).
    7) HOMOCYSTEINE: Plasma homocysteine, a potential risk factor for atherosclerosis and cardiovascular disease, was elevated in cocaine abusers compared with nonusers (Williams et al, 1999).
    B) OTHER
    1) TAC
    a) TAC: Topical application of TAC (tetracaine, epinephrine, and cocaine) solution resulted in plasma benzoylecgonine levels ranging from 40 to over 600 ng/mL and plasma ecgonine methylester levels of 59 to 985 ng/mL when measured 20 to 40 minutes after skin application (Fitzmaurice et al, 1990).
    b) CHILDREN: When measured 15 to 60 minutes after application of 3 mL of standard TAC solution to wounds, cocaine, but not tetracaine, was measurable in the serum of 75% of children at median levels of 1 to 2 ng/mL. Two children had cocaine levels greater than 100 ng/mL (Terndrup et al, 1992).
    c) In a study of 25 children presenting to the emergency department with lacerations requiring suturing, local anesthesia with a viscous topical TAC solution (cocaine concentration 5.9%) did not result in clinically important absorption of cocaine. Plasma cocaine and benzoylecgonine levels were measured by HPLC (Vinci et al, 1999).
    2) ANIMAL DATA
    a) POSTMORTEM: In experimental animals, the postmortem blood concentration of cocaine and its metabolites tends to vary over time with no consistent pattern (McKinney et al, 1992).
    4.1.3) URINE
    A) URINARY LEVELS
    1) Monitor urine for the presence of myoglobin.
    2) Cocaine metabolites can be identified in the urine and provide a method for qualitatively identifying suspected cocaine poisoning or abuse. Benzoylecgonine, the major metabolite of cocaine, can usually be detected in urine for 48 to 72 hours after cocaine use (Preston et al, 1997).
    3) There are a variety of tests that can detect cocaine or its major metabolite (benzoylecgonine {BE}) in the urine which differ in sensitivity. Common tests include chromatography, radioimmunoassay, enzyme immunoassay, fluorescence polarization immunoassay, and enzyme-multiplied immunoassay technique (EMIT) (Wilkins, 1997; Li et al, 1997; Korte et al, 1997).
    4) A standard cutoff point that has been used for determination of positive or negative qualitative cocaine urine screens is 300 ng/mL of the cocaine metabolite benzoylecgonine. This number is used in many clinical trials to assess cocaine use, and is also the same requirement used by the Mandatory Guidelines for Federal Workplace Drug Testing Programs (Preston et al, 1997).
    5) A ratio of benzoylecgonine:cocaine in urine of greater than 100 is suggestive of exposure more than 10 hours previously (Ambre, 1985).
    6) The concurrent use of ethanol and cocaine may result in the finding of cocaethylene (ethyl ester of benzoylecgonine) or its metabolites in the urine. This metabolite probably arises from transesterification of cocaine or ethylation of benzoylecgonine (Raffa & Epstein, 1979).
    7) EMIT(R) METHOD: Currently, urine screening procedures utilizing chromatographic techniques can detect unchanged drug for up to 4 to 6 hours; EMIT(R) can detect the metabolites for up to 2 to 4 days following administration (Personal Communication, 1985; Chang, 1987).
    a) Benzoylecgonine was detected in the urine for 10 to 22 days after cessation of cocaine use in 3 hospitalized patients with a history of chronic high-dose cocaine abuse. An EMIT procedure was used.
    b) In one study, benzoylecgonine was detectable in the urine (concentration = 300 ng/mL or greater) for up to 198 hours (8 days) using EMIT (Burke et al, 1990).
    c) TAC: Use of 2 to 3 mL of topical TAC solution for laceration repair resulted in positive urine screens for cocaine using EMIT for an average of 36 hours post-exposure (Altieri et al, 1990).
    8) PASSIVE INHALATION: Benzoylecgonine was detected in the urine of four formula-fed infants aged 6 weeks to 14 months who were exposed to cocaine by passive inhalation of vapors generated by adult caretakers smoking crack cocaine (Heidemann & Goetting, 1990).
    a) Urine levels of cocaine and its metabolite benzoylecgonine have been detected in a drug-free individual by radioimmunoassay and gas chromatography-mass spectrometry up to 24 hours following passive exposure to 200 mg of free-base cocaine vapors for 30 minutes in an unventilated closed room (144 cubic feet) (Baselt et al, 1991).
    9) RADIOIMMUNOASSAY METHOD: Radioimmunoassay can identify benzoylecgonine in urine for 90 to 144 hours (Hamilton et al, 1977).
    10) TDX METHOD: In another study of chronic cocaine users with a history of using 1 to 12 grams/week for 1 to 10 years, benzoylecgonine levels above the assay sensitivity (30 ng/mL) for the TDX method were found for 7 to 19 days after cessation of use. Unchanged cocaine was detected by GC/MS for 4 to 5 days (Cone & Weddington, 1989).
    11) COCA TEA CONSUMPTION: Consumption of coca tea by 5 healthy volunteers resulted in a positive urine cocaine assay from each of the 5 volunteers approximately 2 hours post-ingestion. The total amount of coca tea consumed by each volunteer ranged from 8 to 40 ounces. The urine samples of 3 of the 5 volunteers remained positive 36 hours post-ingestion. The mean urine benzoylecgonine concentrations in all 5 samples was 1777 ng/mL (Mazor et al, 2006).
    12) AMOXICILLIN INTERFERENCE: A cohort study was conducted, involving 33 patients who received at least 5 doses of amoxicillin (750 to 1000 mg/day in divided doses). Urine specimens of all 33 patients were then collected and underwent analysis via 4 different screening methods for the presence of benzoylecgonine (BE), a metabolite of cocaine. Thirty-one of the 33 specimens were negative for BE with all 4 screening methods. Two of the 33 specimens were positive for BE with all 4 screening methods. The presence of BE (greater than 150 ng/mL) was then confirmed via gas chromatography-mass spectrometry (GC-MS), and cocaine was detected in both positive specimens via GC-MS. The results of this analysis showed that, despite numerous anecdotal claims of amoxicillin producing false-positive urine drug screens for cocaine metabolites, there were no instances of false-positive results with the 33 subjects of this study (Reisfield et al, 2008).
    B) OTHER
    1) AEME: The pharmacology and role of urinary excretion of anhydroecgonine methyl ester (AEME) as a marker for cocaine smoking has yet to be studied (Jacob et al, 1990).
    2) POSTMORTEM: In experimental animals, postmortem urine concentrations of cocaine and its metabolites tend to vary over time with no consistent pattern (McKinney et al, 1992).
    3) CASUAL HANDLING: Single passive exposure to cocaine by means of aerosol or dermal application is unlikely to produce a positive urine screening test (Kavanagh et al, 1992; ElSohly, 1991).
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) No specific laboratory evaluation is needed unless otherwise indicated by the clinical status. CPK with enzyme fractionation or troponin levels may be useful in severe cocaine poisoning cases or when the patient complains of chest pain. Severely poisoned patients (seizures, hyperthermia, persistent mental status changes, hypotension, ventricular dysrhythmias) should have monitoring of electrolytes, BUN, creatinine, liver function tests, INR or PT, PTT, and CBC.
    b) Monitor core body temperature and vital signs.
    c) Pulmonary function tests are indicated in patients with acute respiratory signs or symptoms.
    d) Patients with persistent alterations of mental status should be evaluated for central nervous system hemorrhage, infarction, and/or infection (CT scan and lumbar puncture).
    e) INFANTS: Although prior authors have recommended routine urinalysis and ECG in all cocaine-exposed infants (CEIs), Beltran et al (1994) indicated that urinalysis, ECG, and CT scan in the asymptomatic CEIs yield little additional information impacting on medical management (Beltran et al, 1994).
    2) ECG
    a) Obtain an ECG. If myocardial infarction is suspected, serial ECG's are indicated.
    3) ECHOCARDIOGRAPHY
    a) Two-dimensional echocardiography may be useful in detecting the presence of new regional wall-motion abnormalities in patients experiencing cocaine-induced chest pain (Kloner & Rezkalla, 2003).

Radiographic Studies

    A) RADIOGRAPHIC-OTHER
    1) Abdominal x-rays may be of value in locating cocaine packets in cocaine smuggler body packers (Souka, 1999; Beerman et al, 1986). However, in one study, it was not of value for stuffers ingesting cellophane-wrapped packets (June et al, 2000).
    2) Abdominal flat plate x-ray should be performed to establish diagnosis and location. Not all package types can be visualized on x-ray (McCarron & Wood, 1983) or may disappear from view following treatment with activated charcoal (Harchelroad, 1992).
    a) Upper abdominal CT scan and abdominal x-ray with Gastrografin(R) have been reported to result in better visualization (June et al, 2000; Diamant-Berger et al, 1988; Marc et al, 1990; Hartoko et al, 1988). A case of a false-negative abdominal CT scan without contrast in a cocaine body stuffer has been reported (Eng et al, 1999).
    3) Magnetic resonance does not visualize packets because of the lack of protons (Kersschot et al, 1985).
    4) X-rays must be repeated after each procedure until all packages have been removed.
    5) Plain radiography may be inadequate to detect the presence of crack vials in the GI tract (Hoffman et al, 1990).
    6) Transesophageal echocardiography may be useful in evaluating suspected aortic dissection (Sherzoy et al, 1994).
    7) The Kidney Ureter Bladder Radiograph (KUB) is usually positive in body packers; however, KUB is often negative in body stuffers (Eng et al, 1999).

Methods

    A) MULTIPLE ANALYTICAL METHODS
    1) BLOOD/SERUM: Due to the usual acute nature of a cocaine overdose and the short half-life of the drug in the body, laboratory determinations of blood or serum levels have little value in assessing the clinical state of the patient. In one study, no statistical correlation was observed between cocaine or any metabolite concentration and the severity of clinical symptoms, disposition, need for treatment or outcome (Blaho et al, 2000).
    a) Cocaine itself is unstable in blood, especially when stored at room temperature. The degradation products, benzoylecgonine and ecgonine methyl ester, remained fully detectable at concentrations as low as 50 ng/mL in blood stored at room temperature or under refrigeration for up to 30 days (McCurdy et al, 1989).
    b) Blood specimens should be stored in fluoride-containing tubes in order to inactivate cholinesterase which degrades cocaine.
    c) GC/MS: The detection limit of cocaine in serum is 10 ng/mL. The detection limit of benzoylecgonine in urine is 0.3 mg/L (Shannon et al, 1989). In one case report, gas chromatography/mass spectrometry revealed high concentrations of cocaine in the blood and tissue (Havlik & Nolte, 2000).
    d) COCAETHYLENE: A metabolite found in the blood of patients who use both cocaine and ethanol, may be measured using a quantitative procedure by GC-NPD with confirmation by ion trap mass spectrometry (Hime et al, 1991).
    e) GC/FID AND HPLC/UV DETECTOR: These two chromatographic methods were used to detect cocaine and its metabolites in human blood and urine. The recoveries ranged from 66% to 83% and 61% to 95% for GC and HPLC, respectively. The detection limit for all the analytes was below 76 ng/mL (Bujan et al, 2001).
    2) URINE: Semiquantitative and qualitative EMIT(R) homogeneous enzyme immunoassays are available for benzoylecgonine.
    a) GC/FID AND HPLC/UV DETECTOR: These two chromatographic methods were used to detect cocaine and its metabolites in human blood and urine (Bujan et al, 2001).
    b) The detection limit of the semiquantitative assay is 1.6 mcg/mL; the detection limit of the qualitative assay is 0.75 mcg/mL.
    1) In CDC proficiency testing, this method correlated very well with GC and was more reliable than TLC.
    c) URINE TDX: The assay sensitivity for benzoylecgonine was reported to be 30 ng/mL (Cone & Weddington, 1989).
    d) ECGONINE METHYLESTER: A major metabolite of cocaine, has been measured using a gas chromatograph with a nitrogen-selective detector (Vasiliades, 1991; Ramcharitar et al, 1995).
    e) RAPID LATEX-PARTICLE AGGLUTINATION-INHIBITION: This test has been described as "quick and easy" and for use in the field. Its sensitivity is 95% to 96%; specificity 94% to 100%; it can detect cocaine metabolites only at levels of 300 ng/mL or more (Birnbach et al, 1997; Welch et al, 1993; Schwartz et al, 1990).
    f) ENZYME IMMUNOASSAY: The EZ-SCREEN(R) test for cocaine and marijuana metabolites is a qualitative test with a sensitivity of 95%, specificity of 89%, and efficiency of 87% for samples containing 300 ng/mL or more of cocaine metabolites. Two false negatives and 5 false positives were recorded of 38 samples tested (Schwartz et al, 1990a).
    g) COMPARISON: The Abuscreen(R) and TDx(R) tests were compared with GC/MS analysis by Baugh et al (1991). The correlation coefficients were 0.467 for the Abuscreen(R) and 0.766 for the TDx(R) tests.
    h) DIAPERS: Disposable diaper batting does not change cocaine or benzoylecgonine levels in urine (Dempsey et al, 1994).
    i) LEVAMISOLE DETECTION: Levamisole has been frequently reported as an adulterant in cocaine. Liquid chromatography-tandem mass spectrometry (LC-MS-MS) was developed to detect levamisole exposure in the urine of cocaine users. Of 949 urine drug screens ordered through a clinical laboratory during 2009, a cocaine immunoassay determined that 191 urine drug screens were positive for cocaine (20%), confirmed by LC-MS-MS. Of the 191 cocaine-positive urine drug screens, levamisole was detected in 169 of the samples (88%). The levamisole concentrations within these samples ranged from 5 to 32,720 ng/mL The limit of detection, using this chromatographic method, was 0.5 ng/mL (Lynch et al, 2011).
    3) SALIVA: Cocaine concentrations in the saliva of 2 male human subjects was found to correlate with plasma concentrations following intravenous cocaine doses of 15, 20, and 40 mg (Thompson et al, 1987).
    4) HAIR: Cocaine and metabolites can be detected in human hair in appreciable quantities. Hair testing may be preferred to urine testing for information on long term drug use (Selavka & Rieders, 1995; DuPont & Baumgartner, 1995; Kintz & Mangin, 1995; Sachs, 1995). In the presence of a negative urine test, the cocaine hair test appears to be highly sensitive and specific in identifying past cocaine use (Ursitti et al, 2001).
    a) False positives may occur due to environmental contamination (Cone et al, 1991).
    b) In infants, hair analysis may be more accurate than maternal history or urine immunoassay in detecting in utero exposure (Callahan et al, 1992; Koren, 1995). The neonatal hair test for cocaine is a powerful tool to diagnose intrauterine exposure to cocaine (Koren et al, 1998).
    c) Studies suggest that subjects with environmental cocaine exposure only will have detectable levels of cocaine and benzoylecgonine in unwashed hair samples that disappear after washing with ethanol. In cocaine users cocaine and benzoylecgonine levels in hair change little after ethanol washing (Koren et al, 1992). The type of hair (thickness, color, dyeing) influences the ease with which contamination from external sources can be removed (Blank & Kidwell, 1995).
    d) Segmental hair analysis may provide information on the history of drug abuse in an individual (Jurado et al, 1995) Strsno-Rossi et al, 1995).
    e) In one study, segmental analysis for cocaine and metabolites by HPLC in hair of suspected drug overdose cases proved to be an important tool to distinguish deadly chronic abuse from single acute drug overdosage (Clauwaert et al, 2000).
    5) MECONIUM: Screening meconium specimens by fluorescence polarization immunoassay followed by gas chromatography/mass spectrometry of positive samples appears to provide a more sensitive measure of fetal exposure to maternal cocaine use than do blood or urine specimens (Ostrea et al, 1992; Lewis et al, 1992; Callahan et al, 1992).
    a) Cocaethylene, norcocaine, and methahydroxy-benzoylecgonine can also be detected in meconium using HPLC or gas chromatography/mass spectroscopy (Lewis et al, 1993; Brown et al, 1994; Lewis et al, 1994).
    6) POSTMORTEM: Specimens obtained postmortem should be preserved with sodium fluoride, refrigerated, and analyzed quickly. Tissue specimens should be frozen.
    a) NASAL SWABS: Cocaine may be recovered postmortem on nasal swabs taken up to several days after death (Karch, 1991).
    b) DEGREE OF DECOMPOSITION: Cocaine has been detected in relatively small amounts of desiccated tissue on skeletal remains. The method used was GC-MS in combination with solid-phase extraction methods for decreasing background interference (Manhoff et al, 1991).
    c) Experimental animal studies suggest that there is wide interindividual variability in both the direction and magnitude of postmortem changes in the concentration of cocaine and metabolites (McKinney et al, 1995).
    d) VITREOUS HUMOR: In animals, the postmortem vitreous humor concentration of cocaine and its metabolites consistently increased over time, but did not equal blood concentration by 8 hours (McKinney et al, 1992).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who have multiple seizures, dysrhythmias, or severe agitation or who require heavy sedation should be admitted to an intensive care setting; those who have chest pain and who do not meet low-risk criteria should be admitted to a telemetry setting.
    B) Body packers and body stuffers should be admitted for observation and monitoring until ingested packets have passed through the gastrointestinal tract.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with cocaine-associated chest pain who meet low-risk criteria can be observed for 6 hours in the emergency department. Patients with a single seizure or mild agitation who rapidly recover and have normal vital signs after a 6-hour observation period can be discharged.
    B) Body packers may be discharged when all packets have been passed. This process may take several days and may require repeated barium-enhanced abdominal radiographs or CT scans to document evacuation of all packets (Hoffman et al, 1990).
    C) In a prospective cohort study, 302 patients with cocaine-associated chest pain (by report or urine drug screen) were admitted to an observation unit and treated with aspirin (93% of patients), nitrates (90% of patients), and benzodiazepines (30% of patients). The duration of chest pain was less than 6 hours in 59% (n=171 of 290 patients) of patients; 41% (n=118) had no pain in less than 3 hours, and 16% (n=45) had no pain after 1 hour (Weber et al, 2003).
    1) None of the patients required fibrinolytic agents and only 4 patients received a beta antagonist. Congestive heart failure or dysrhythmias were not reported. After 9 hours of observation, a cardiology consult was obtained, with 158 of the 302 patients undergoing stress testing before discharge. Only 4 patients tested positive and underwent cardiac catheterization. Thirty-day survival was obtained in 300 patients with no deaths related to cardiovascular events; 4 patients who continued cocaine use after discharge did develop nonfatal myocardial infarctions.
    2) The authors concluded that patients with cocaine-associated chest pain can be safely evaluated, treated, and discharged to home after a 9- to 12-hour observation period. However, patients with recurrent symptoms, ECG or laboratory evidence of myocardial ischemia, or dysrhythmias require further evaluation and treatment.

Monitoring

    A) Patients with minimal toxicity do not require laboratory studies.
    B) Patients with possible cardiac chest pain should be evaluated with serial troponin levels.
    C) Patients with severe toxicity should be monitored for acidosis, renal and hepatic failure, coagulopathy, and rhabdomyolysis.
    D) A head CT scan and lumbar puncture should be considered in patients with persistent abnormal mental status.
    E) Continuous cardiac monitoring and ECG should be performed in patients with chest pain or severe toxicity.
    F) Radiologic evaluation may be of value in evaluating body packers.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Activated charcoal is not recommended due to rapid absorption of cocaine and the risk of seizures.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) As most cocaine exposures are through the intranasal, IV, or intrapulmonary (smoking) routes, attempts at preventing absorption are not generally useful (Schwartz & Oderda, 1980).
    a) In cases in which a recent large oral ingestion of cocaine powder is suspected, attempts to empty the stomach are warranted.
    b) If the patient is comatose, seizing, or without a gag reflex, the patient's airway should be protected with a cuffed endotracheal tube and gastric lavage done, followed by instillation of activated charcoal 60 to 100 g.
    c) IN VITRO ADSORPTION: Activated charcoal adsorbs cocaine in vitro under both acidic and alkaline conditions (Tomaszewski et al, 1992).
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) For most mild intoxications involving sinus tachycardia and mildly elevated blood pressure, supportive care is the treatment of choice (Orr & Jones, 1968).
    B) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    7) RECURRING SEIZURES
    a) If seizures are not controlled by the above measures, patients will require endotracheal intubation, mechanical ventilation, continuous EEG monitoring, a continuous infusion of an anticonvulsant, and may require neuromuscular paralysis and vasopressor support. Consider continuous infusions of the following agents:
    1) MIDAZOLAM: ADULT DOSE: An initial dose of 0.2 mg/kg slow bolus, at an infusion rate of 2 mg/minute; maintenance doses of 0.05 to 2 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: 0.1 to 0.3 mg/kg followed by a continuous infusion starting at 1 mcg/kg/minute, titrated upwards every 5 minutes as needed (Loddenkemper & Goodkin, 2011).
    2) PROPOFOL: ADULT DOSE: Start at 20 mcg/kg/min with 1 to 2 mg/kg loading dose; maintenance doses of 30 to 200 mcg/kg/minute continuous infusion dosing, titrated to EEG; caution with high doses greater than 80 mcg/kg/minute in adults for extended periods of time (ie, longer than 48 hours) (Brophy et al, 2012); PEDIATRIC DOSE: IV loading dose of up to 2 mg/kg; maintenance doses of 2 to 5 mg/kg/hour may be used in older adolescents; avoid doses of 5 mg/kg/hour over prolonged periods because of propofol infusion syndrome (Loddenkemper & Goodkin, 2011); caution with high doses greater than 65 mcg/kg/min in children for extended periods of time; contraindicated in small children (Brophy et al, 2012).
    3) PENTOBARBITAL: ADULT DOSE: A loading dose of 5 to 15 mg/kg at an infusion rate of 50 mg/minute or lower; may administer additional 5 to 10 mg/kg. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: A loading dose of 3 to 15 mg/kg followed by a maintenance dose of 1 to 5 mg/kg/hour (Loddenkemper & Goodkin, 2011).
    4) THIOPENTAL: ADULT DOSE: 2 to 7 mg/kg, at an infusion rate of 50 mg/minute or lower. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusing dosing, titrated to EEG (Brophy et al, 2012)
    b) Endotracheal intubation, mechanical ventilation, and vasopressors will be required (Brophy et al, 2012) and consultation with a neurologist is strongly advised.
    c) Neuromuscular paralysis (eg, rocuronium bromide, a short-acting nondepolarizing agent) may be required to avoid hyperthermia, severe acidosis, and rhabdomyolysis. If rhabdomyolysis is possible, avoid succinylcholine chloride, because of the risk of hyperkalemic-induced cardiac dysrhythmias. Continuous EEG monitoring is mandatory if neuromuscular paralysis is used (Manno, 2003).
    8) ANIMAL STUDY: In a rat model, pretreatment with diazepam did not prevent cocaine-induced death from etiologies other than seizures. The incidence of death was reduced if prazosin was used with diazepam prior to cocaine intoxication (Tseng et al, 1993).
    9) ANIMAL STUDY: In a study of newly approved antiepileptic drugs in a murine model, treatment with agents that enhance GABA-mediated neuronal inhibition, especially gabapentin, offered better protection against cocaine-induced seizures than agents with sodium and calcium channel blockade as a primary mechanism of action (Gasior et al, 1999).
    C) HYPOTENSIVE EPISODE
    1) Because chronic cocaine abuse results in depletion of norepinephrine, an indirect vasopressor, such as dopamine, would be theoretically less effective than a direct agonist, such as norepinephrine.
    2) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    3) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    D) HYPERTENSIVE EPISODE
    1) Little morbidity or mortality has been attributable to cocaine-induced hypertension. Hypertension is usually short-lived and often followed by significant hypotension. Mild hypertension generally responds to sedation with benzodiazepines (Goldfrank et al, 1981; Bettinger, 1980; Gilman et al, 1980; Schwartz & Oderda, 1980).
    2) Monitor vital signs regularly. For mild/moderate hypertension without evidence of end organ damage, pharmacologic intervention is generally not necessary. Sedative agents such as benzodiazepines may be helpful in treating hypertension and tachycardia in agitated patients, especially if a sympathomimetic agent is involved in the poisoning.
    3) For hypertensive emergencies (severe hypertension with evidence of end organ injury (CNS, cardiac, renal), or emergent need to lower mean arterial pressure 20% to 25% within one hour), sodium nitroprusside is preferred. Nitroglycerin and phentolamine are possible alternatives.
    4) HYPERTENSIVE EMERGENCY
    a) CASE REPORT: Acute hypertension was associated with aortic dissection in one case (Grannis et al, 1988a).
    b) SODIUM NITROPRUSSIDE/INDICATIONS
    1) Useful for emergent treatment of severe hypertension secondary to poisonings. Sodium nitroprusside has a rapid onset of action, a short duration of action and a half-life of about 2 minutes (Prod Info NITROPRESS(R) injection for IV infusion, 2007) that can allow accurate titration of blood pressure, as the hypertensive effects of drug overdoses are often short lived.
    c) SODIUM NITROPRUSSIDE/DOSE
    1) ADULT: Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required (American Heart Association, 2005). Frequent hemodynamic monitoring and administration by an infusion pump that ensures a precise flow rate is mandatory (Prod Info NITROPRESS(R) injection for IV infusion, 2007). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 micrograms/kilogram/minute (Kleinman et al, 2010).
    d) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION
    1) The reconstituted 50 mg solution must be further diluted in 250 to 1000 mL D5W to desired concentration (recommended 50 to 200 mcg/mL) (Prod Info NITROPRESS(R) injection, 2004). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    e) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS
    1) Severe hypotension; headaches, nausea, vomiting, abdominal cramps; thiocyanate or cyanide toxicity (generally from prolonged, high dose infusion); methemoglobinemia; lactic acidosis; chest pain or dysrhythmias (high doses) (Prod Info NITROPRESS(R) injection for IV infusion, 2007). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    f) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS
    1) Monitor blood pressure every 30 to 60 seconds at onset of infusion; once stabilized, monitor every 5 minutes. Continuous blood pressure monitoring with an intra-arterial catheter is advised (Prod Info NITROPRESS(R) injection for IV infusion, 2007).
    g) NITROGLYCERIN/INDICATIONS
    1) May be used to control hypertension, and is particularly useful in patients with acute coronary syndromes or acute pulmonary edema (Rhoney & Peacock, 2009).
    h) NITROGLYCERIN/ADULT DOSE
    1) Begin infusion at 10 to 20 mcg/min and increase by 5 or 10 mcg/min every 5 to 10 minutes until the desired hemodynamic response is achieved (American Heart Association, 2005). Maximum rate 200 mcg/min (Rhoney & Peacock, 2009).
    i) NITROGLYCERIN/PEDIATRIC DOSE
    1) Usual Dose: 29 days or Older: 1 to 5 mcg/kg/min continuous IV infusion. Maximum 60 mcg/kg/min (Laitinen et al, 1997; Nam et al, 1989; Rasch & Lancaster, 1987; Ilbawi et al, 1985; Friedman & George, 1985).
    j) PHENTOLAMINE/INDICATIONS
    1) Useful for severe hypertension, particularly if caused by agents with alpha adrenergic agonist effects usually induced by catecholamine excess (Rhoney & Peacock, 2009).
    k) PHENTOLAMINE/ADULT DOSE
    1) BOLUS DOSE: 5 to 15 mg IV bolus repeated as needed (U.S. Departement of Health and Human Services, National Institutes of Health, and National Heart, Lung, and Blood Institute, 2004). Onset of action is 1 to 2 minutes with a duration of 10 to 30 minutes (Rhoney & Peacock, 2009).
    2) CONTINUOUS INFUSION: 1 mg/hr, adjusted hourly to stabilize blood pressure. Prepared by adding 60 mg of phentolamine mesylate to 100 mL of 0.9% sodium chloride injection; continuous infusion ranging from 12 to 52 mg/hr over 4 days has been used in case reports (McMillian et al, 2011).
    l) PHENTOLAMINE/PEDIATRIC DOSE
    1) 0.05 to 0.1 mg/kg/dose (maximum of 5 mg per dose) intravenously every 5 minutes until hypertension is controlled, then every 2 to 4 hours as needed (Singh et al, 2012; Koch-Weser, 1974).
    m) PHENTOLAMINE/ADVERSE EFFECTS
    1) Adverse events can include orthostatic or prolonged hypotension, tachycardia, dysrhythmias, angina, flushing, headache, nasal congestion, nausea, vomiting, abdominal pain and diarrhea (Rhoney & Peacock, 2009; Prod Info Phentolamine Mesylate IM, IV injection Sandoz Standard, 2005).
    n) CAUTION
    1) Phentolamine should be used with caution in patients with coronary artery disease because it may induce angina or myocardial infarction (Rhoney & Peacock, 2009).
    E) VENTRICULAR ARRHYTHMIA
    1) VENTRICULAR DYSRHYTHMIAS SUMMARY
    a) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.
    2) SODIUM BICARBONATE
    a) Sodium bicarbonate may be useful in the treatment of QRS widening and ventricular dysrhythmias associated with acute cocaine use. A reasonable starting dose is 1 to 2 mEq/kg repeated as needed. Monitor arterial blood gases, target pH 7.45 to 7.55.
    b) In one animal study, it was shown that sodium bicarbonate reverses the dose-dependent slowing of cardiac conduction produced by cocaine. The lack of efficacy of sodium chloride suggests that this reversal is mediated by alkalosis rather than by an increase in extracellular sodium concentration (Parker et al, 1999).
    c) EXPERIMENTAL ANIMALS: Sodium bicarbonate decreased cocaine-induced QRS prolongation to nearly baseline in anesthetized dogs (Beckman et al, 1991).
    1) In another study, cocaine-induced conduction abnormalities and resultant hemodynamic compromise were observed in 15 anesthetized mongrel dogs given 3 successive doses of cocaine (7 mg/kg). The doses given were an attempt to be similar to a recreational dose that might be used in an individual. After sodium bicarbonate was administered to the treatment group (n=5; two dogs died of dysrhythmias prior to treatment), the QRS duration immediately decreased by 30% and returned to baseline more quickly than in the placebo group. Cardiac output (measured 3 minutes after administration) improved by 78% and remained significantly increased throughout the observation period. The authors concluded that sodium bicarbonate improved ECG changes secondary to cocaine toxicity and improved myocardial function (Wilson & Shelat, 2003).
    3) LIDOCAINE
    a) LIDOCAINE/INDICATIONS
    1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).
    b) LIDOCAINE/DOSE
    1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.
    a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).
    2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).
    c) LIDOCAINE/MAJOR ADVERSE REACTIONS
    1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).
    d) LIDOCAINE/MONITORING PARAMETERS
    1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    e) CAUTIONS: Because lidocaine is a local anesthetic agent as is cocaine, it may theoretically not be the antiarrhythmic of choice for cocaine-induced ventricular arrhythmias.
    f) In a retrospective study of 155 patients with cocaine-associated myocardial infarction, medical records were available for 26 of 29 patients who received lidocaine. One patient developed confusion which may have been related to the lidocaine; no other adverse effects were recorded.(Shih et al, 1994).
    g) ANIMAL DATA
    1) In one rat study, lidocaine potentiated cocaine-induced seizures and death (Derlet et al, 1991).
    2) Lidocaine, used either as a pretreatment or therapy, did not increase the duration of seizures in cocaine-intoxicated swine (McKinney et al, 1993; McKinney et al, 1992).
    4) AMIODARONE
    a) AMIODARONE/INDICATIONS
    1) Effective for the control of hemodynamically stable monomorphic ventricular tachycardia. Also recommended for pulseless ventricular tachycardia or ventricular fibrillation in cardiac arrest unresponsive to CPR, defibrillation and vasopressor therapy (Link et al, 2015; Neumar et al, 2010). It should be used with caution when the ingestion involves agents known to cause QTc prolongation, such as fluoroquinolones, macrolide antibiotics or azoles, and when ECG reveals QT prolongation suspected to be secondary to overdose (Prod Info Cordarone(R) oral tablets, 2015).
    b) AMIODARONE/ADULT DOSE
    1) For ventricular fibrillation or pulseless VT unresponsive to CPR, defibrillation, and a vasopressor therapy give an initial dose of 300 mg IV followed by 1 dose of 150 mg IV. For stable ventricular tachycardias: Infuse 150 milligrams over 10 minutes, and repeat if necessary. Follow by a 1 milligram/minute infusion for 6 hours, then a 0.5 milligram/minute. Maximum total dose over 24 hours is 2.2 grams (Neumar et al, 2010).
    c) AMIODARONE/PEDIATRIC DOSE
    1) Infuse 5 milligrams/kilogram as a bolus for pulseless ventricular tachycardia or ventricular fibrillation; may repeat twice up to 15 mg/kg. Infuse 5 milligrams/kilogram over 20 to 60 minutes for perfusing tachycardias. Maximum single dose is 300 mg. Routine use with other drugs that prolong the QT interval is NOT recommended (Kleinman et al, 2010).
    d) ADVERSE EFFECTS
    1) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010).
    5) CALCIUM CHANNEL BLOCKERS
    a) In a human study of isradipine treatment on the effects of cocaine use, isradipine did not attenuate cocaine-induced increase in blood pressure in 6 otherwise healthy subjects (Johnson et al, 1999).
    1) Experimental animal studies of calcium channel blockers in cocaine toxicity have had mixed results. Calcium channel blockers suppressed cocaine-induced arrhythmias, vasoconstriction, and myocardial depression but may increase the incidence of seizures. Influence on survival has been variable.
    2) Diltiazem, flunarizine, nifedipine, and verapamil completely suppressed cocaine-induced ventricular fibrillation in cocaine-intoxicated dogs (Billman, 1993).
    3) Nitrendipine protected against cocaine toxicity (increased survival time and lethal dose) in 2 experimental animal studies (Nahas et al, 1985; Trouve et al, 1985).
    4) Nitrendipine offered slight protection from the functional depressant effects of higher concentrations of cocaine on rat myocardial cell cultures, but it did not prevent cocaine-induced membrane damage or morphological alterations (Melchert et al, 1991).
    5) In rats, nitrendipine pretreatment inhibited arteriolar vasoconstriction induced by cocaine (Vicaut et al, 1991).
    6) In rats, pretreatment with diltiazem, nifedipine, and verapamil potentiated cocaine-induced seizures and lethality (Derlet & Albertson, 1989).
    6) ALPHA-ADRENERGIC BLOCKERS
    a) ANIMAL STUDY: In a dog model, pretreatment with alpha blockers prevented the development of ventricular fibrillation (VF) in animals exposed to the combination of cocaine and ischemia, independent of heart rate. Cocaine was administered to exercising dogs, who were then subjected to 2 minutes of coronary occlusion. VF developed in 34 of 41 animals that received no pretreatment. In animals pretreated with prazosin, 3 of 15 developed VF, while 2 of 14 animals pretreated with propranolol developed VF. However, when the study was repeated in the propranolol group (n=4) and in the prazosin group (n=5), but the heart rate was matched to the highest heart rate noted in the control cocaine exercise test and held constant with cardiac pacing, propranolol did not prevent VF in any animal in the propranolol group, whereas prazosin did prevent VF in all 5 animals in the prazosin group. The results of this study suggest that alpha-adrenergic antagonists may be beneficial in preventing cocaine-induced malignant dysrhythmias independent of heart rate (Billman, 1994).
    F) FAT EMULSION
    1) Intravenous lipid emulsion (ILE) has been effective in reversing severe cardiovascular toxicity from local anesthetic overdose in animal studies and human case reports. Several animal studies and human case reports have also evaluated the use of ILE for patients following exposure to other drugs. Although the results of these studies are mixed, there is increasing evidence that it can rapidly reverse cardiovascular toxicity and improve mental function for a wide variety of lipid soluble drugs. It may be reasonable to consider ILE in patients with severe symptoms who are failing standard resuscitative measures (Lavonas et al, 2015).
    2) The American College of Medical Toxicology has issued the following guidelines for lipid resuscitation therapy (LRT) in the management of overdose in cases involving a highly lipid soluble xenobiotic where the patient is hemodynamically unstable, unresponsive to standard resuscitation measures (ie, fluid replacement, inotropes and pressors). The decision to use LRT is based on the judgement of the treating physician. When possible, it is recommended these therapies be administered with the consultation of a medical toxicologist (American College of Medical Toxicology, 2016; American College of Medical Toxicology, 2011):
    a) Initial intravenous bolus of 1.5 mL/kg 20% lipid emulsion (eg, Intralipid) over 2 to 3 minutes. Asystolic patients or patients with pulseless electrical activity may have a repeat dose, if there is no response to the initial bolus.
    b) Follow with an intravenous infusion of 0.25 mL/kg/min of 20% lipid emulsion (eg, Intralipid). Evaluate the patient's response after 3 minutes at this infusion rate. The infusion rate may be decreased to 0.025 mL/kg/min (ie, 1/10 the initial rate) in patients with a significant response. This recommendation has been proposed because of possible adverse effects from very high cumulative rates of lipid infusion. Monitor blood pressure, heart rate, and other hemodynamic parameters every 15 minutes during the infusion.
    c) If there is an initial response to the bolus followed by the re-emergence of hemodynamic instability during the lowest-dose infusion, the infusion rate may be increased back to 0.25 mL/kg/min or, in severe cases, the bolus could be repeated. A maximum dose of 10 mL/kg has been recommended by some sources.
    d) Where possible, LRT should be terminated after 1 hour or less, if the patient's clinical status permits. In cases where the patient's stability is dependent on continued lipid infusion, longer treatment may be appropriate.
    3) CASE REPORT: A 28-year-old man presented to the emergency department, following a suspected cocaine overdose, comatose (Glasgow Coma Scale (GCS) score of 3) with intermittent seizures. An arterial blood gas analysis revealed severe metabolic and respiratory acidosis, and an ECG demonstrated supraventricular and ventricular tachydysrhythmias, with hypotension concomitantly. Although his acidosis improved following tracheal intubation, he continued to exhibit cardiovascular instability despite treatment with sodium bicarbonate and vasopressors. Because of cocaine's lipophilicity, 20% lipid emulsion was administered intravenously, as an initial bolus dose of 1.5 mL/kg (120 mL), followed by an infusion of 15 mL/kg/hour (380 mL) over a 20-minute period. The patient's cardiovascular status immediately improved, with a restoration of sinus rhythm within 15 minutes of giving the bolus dose. The patient's neurologic status also improved (GCS of 15) with no evidence of seizure activity, and he was subsequently discharged to home 2 days later (Jakkala-Saibaba et al, 2011).
    4) CASE REPORT: A 26-year-old man presented to the emergency department (ED) comatose (Glasgow Coma Scale score of 5) with seizures after smoking a large quantity of crack cocaine throughout the night prior to presentation. At the ED, the patient developed status epilepticus, successfully controlled with a benzodiazepine infusion, tachycardia, and respiratory acidosis, and an initial ECG revealed wide-complex tachycardia (QRS interval 148 ms) with a prolonged QTc interval (595 ms). Despite supportive therapy, the patient's hemodynamic status continued to deteriorate with development of severe hypotension (85/60 mmHg). The patient was given 100 mL of 20% lipid emulsion intravenously and, within 10 minutes, there was narrowing of his wide-complex tachycardia and improvement in his blood pressure. A repeat ECG demonstrated normalization of his QRS and QTc intervals (82 ms and 412 ms, respectively) (Arora et al, 2013).
    G) ACIDOSIS
    1) Correction of acidemia through supportive care measures such as hyperventilation, sedation, active cooling, and sodium bicarbonate infusion resulted in improvement of conduction defects in a case series of 4 patients (Wang, 1999).
    H) BODY TEMPERATURE ABOVE REFERENCE RANGE
    1) Hyperthermia is frequently associated with a fatal outcome (Catravas & Waters, 1981) and should be treated aggressively if severe.
    a) Place patient in a cool room.
    b) Minimize physical activity and sedate with benzodiazepines (large doses may be necessary). Sponge or spray patient with tepid to cool water, and use fans to maximize evaporative heat loss.
    c) Place patient on a hypothermia blanket.
    d) Use ice water immersion if the above are not rapidly effective. Goal is to decrease core temperature to below 38.3 degrees C within 45 minutes to 1 hour.
    2) Refractory cases may require sedation and neuromuscular paralysis.
    I) DELIRIUM
    1) Agitated patients are best treated in a calm, reassuring manner. Place patient in a dark, quiet area if possible.
    2) Hypoglycemia may cause agitation and mimic acute cocaine intoxication. Consider as a differential diagnosis in patients presenting with mental status changes; obtain blood glucose level and administer dextrose solution IV if necessary (Brady & Duncan, 1999).
    3) Intravenous diazepam (Adults: 5 to 10 mg every 5 to 10 minutes as needed; Child: 0.1 to 0.2 mg/kg every 5 to 10 minutes as needed) may be helpful (Anon, 1984). Large doses may be necessary in severe cases. Monitor for respiratory depression and need for endotracheal intubation.
    J) CHEST PAIN
    1) Benzodiazepine sedation and nitroglycerin resolve most cases of chest pain. Alpha-blocking agents such as phentolamine should be considered in patients with persistent chest pain in whom acute coronary syndrome is suspected. Beta-blockers should be AVOIDED in the setting of acute cocaine use as they may increase vasoconstriction.
    2) BENZODIAZEPINES
    a) Administer IV benzodiazepines as early management in order to achieve light sedation and reverse tachycardia (McCord et al, 2008).
    3) NITROGLYCERIN
    a) Nitroglycerin appears to be safe and may be effective in treating cocaine-associated chest pain (McCord et al, 2008; Hollander et al, 1994). In a study of cocaine-related chest pain, 37 of 83 patients receiving nitroglycerin had relief of pain, 2 had resolution of ischemic changes on ECG, 2 had control of hypertension, and 1 had improvement of congestive heart failure (Hollander et al, 1994).
    b) One patient who sustained an inferior myocardial infarction with right ventricular involvement developed transient hypotension after nitroglycerin administration.
    c) Sublingual nitroglycerin, in a dose sufficient to reduce mean systemic arterial pressure by 10% to 15%, alleviates cocaine-induced vasoconstriction in diseased and nondiseased coronary arteries (Brogan et al, 1991).
    d) In one study, the concurrent use of diazepam and nitroglycerin for treatment of patients with potential cocaine-associated acute coronary syndrome did not offer any additional benefit over either agent alone (Baumann et al, 2000a).
    e) In a prospective, randomized trial of benzodiazepines and nitroglycerin (NTG) use as compared to nitroglycerin alone for the treatment of cocaine-induced acute coronary syndrome, nitroglycerin with lorazepam was more efficacious in relieving chest pain than nitroglycerin alone. The study consisted of 36 patients with an average age of 34.1 years, and 67% were men. Exclusion criteria included age greater than 45 years, documented coronary artery disease, pretreatment with nitroglycerin, or chest pain duration of more than 72 hours (Honderick et al, 2003).
    1) Group 1 consisted of 15 patients who received NTG 0.4 mg sublingually initially, followed by another dose as needed in 5 minutes if chest pain persisted. Group 2 had 12 patients who received NTG 0.4 mg sublingually and a lorazepam 1 mg IV bolus initially, followed by repeat doses of both medications 5 minutes later if chest pain persisted. All patients received oxygen and aspirin 325 mg. Pain measurement was scored with a self-reported numeric pain scale of 0 to 10. Baseline pain scores were 6.87 for group 1 and 6.54 for group 2; five minutes after initial treatment the mean scores were 5.2 and 3.96, respectively, with a difference of 1.24 (95% confidence interval (CI), -0.080 to 3.29). After an additional 5 minutes, the scores were 4.6 for group 1 and 1.5 for group 2, with a difference in means of 3.1 (95% CI, 1.22 to 4.98). No patient in either group met the criteria for an acute myocardial infarction or had cardiac complications. Limitations included self-reported cocaine use with limited or no laboratory confirmation. Further study is recommended.
    4) MONITORING OF PATIENT
    a) CARDIAC BIOMARKERS: Cardiac troponin levels are sensitive and specific biomarkers for the diagnosis of cocaine-associated myocardial infarction (MI). The measurement of cardiac troponin levels is preferred over the measurement of myoglobin and creatine kinase levels, which can be elevated in the setting of cocaine-associated rhabdomyolysis and may confound the diagnosis of cocaine-associated MI (McCord et al, 2008).
    b) DOBUTAMINE STRESS TESTING: In a pilot study to evaluate the safety of dobutamine stress echocardiography (DSE) in emergency department patients with cocaine-associated chest pain, none of the patients experienced exaggerated adrenergic response (Dribben et al, 2001).
    1) In a case series (n=6) of cocaine-associated chest pain patients, false-positive stress tests within 2 weeks after the last reported cocaine use led to unnecessary, costly, and potentially harmful invasive interventions. The stress imaging studies of each case revealed multi-vessel distribution of ischemia or a large area of myocardium at risk. However, in 5 cases, coronary angiograms were normal. Two-vessel coronary artery bypass grafting was performed in 1 patient for an apparent 70% stenosis of the left main coronary artery. Cardiac catheterization 2 days later for recurrent angina showed a patent left main but diffuse vasospasm in the distal left anterior descending and circumflex coronary arteries. The authors suggested that patients may have false-positive stress tests for at least 12 days after their last cocaine use. It is recommended that coronary evaluation be postponed until after 2 to 3 weeks of abstinence in clinically stable patients with cocaine-associated chest pain who have risk factors for ischemic heart disease (Littmann et al, 2004).
    5) THROMBOLYTICS
    a) In a retrospective study of 155 patients with cocaine-associated myocardial infarction (MI), 23 patients received thrombolytics. No major complications or deaths occurred, 1 patient developed a febrile reaction to streptokinase, and 1 developed vaginal bleeding not requiring transfusion (Hollander et al, 1994).
    b) In several studies, cautions about the use of thrombolytics in cocaine-associated acute MI have been made. These studies have suggested that because acute MI mortality may be low in young patients with cocaine use, the risks outweigh the benefits of thrombolytic therapy. Other studies reported that these cautions would require unnecessary toxicology screening before treatment of patients with acute MI who deny cocaine use, and unnecessarily delay treatment of patients with acute MI who admit to cocaine use (Boniface & Feldman, 2000).
    c) Percutaneous coronary intervention (PCI) is preferred over thrombolytic therapy in patients with cocaine-induced ST-segment elevation myocardial infarction (STEMI). Thrombolytic therapy should be reserved only for those patients with STEMI in whom PCI is not possible (McCord et al, 2008).
    d) Thrombolytics should be avoided in patients with cocaine-induced MI and uncontrolled hypertension, because of the increased risk of intracranial hemorrhage.
    6) PHENTOLAMINE
    a) Cocaine-induced coronary vasoconstriction and myocardial ischemia may be reversed by the intracoronary administration of phentolamine (Lange et al, 1989).
    b) CASE REPORT: Intravenous phentolamine (1 mg) relieved cocaine-induced chest pain in one case report (Hollander et al, 1992).
    c) CASE REPORT: A 43-year-old man developed cocaine-associated acute coronary syndrome (chest pain, hypertension, ECG with peaked T waves anteriorly and ST depression laterally) that was unresponsive to therapy with aspirin, sublingual and IV nitroglycerin, and IV diazepam and morphine. He recovered (resolution of chest pain, hypertension, and ECG changes) following 3 doses of phentolamine 1 mg IV, with each dose given at 5-minute intervals (Chan et al, 2006).
    d) In a canine model, cocaine-induced coronary vasoconstriction was prevented by pretreatment with phentolamine (Kuhn et al, 1990).
    7) TIROFIBAN
    a) In one case report, tirofiban, an antiplatelet agent that binds to the platelet receptor glycoprotein IIb/IIIa and inhibits platelet aggregation, was successfully used to treat cocaine-induced coronary artery thrombosis (Frangogiannis et al, 1999).
    8) AVOID BETA BLOCKERS
    a) Beta-adrenergic blocking agents should be avoided in patients with cocaine-associated myocardial ischemia or infarction. Cocaine-induced vasoconstriction appears to be due to alpha-adrenergic stimulation. Unopposed alpha-adrenergic stimulation, associated with beta-adrenergic blocking agents, may result in the potentiation of coronary vasoconstriction with concomitant administration of cocaine and a beta-blocker (McCord et al, 2008; Sen et al, 2006; Williams et al, 1996). (Lange et al, 1990).
    b) Propranolol has been associated with increased blood pressure in the setting of cocaine overdose, presumably due to unopposed alpha-adrenergic stimulation (Ramoska & Sacchetti, 1985). Beta-blockers have demonstrated poor clinical efficacy in several studies (Trouve et al, 1985).
    c) STUDY: In a study of 30 patients undergoing coronary angiography, the 15 patients who received intranasal cocaine had increased myocardial oxygen demand, deceased coronary sinus blood flow, and increased coronary vascular resistance compared with the patients who received intranasal saline. Five of the patients treated with intranasal cocaine then received intracoronary saline and had no alterations in hemodynamic or arteriographic response. Ten of the cocaine-treated patients subsequently received intracoronary propranolol. There was no change in myocardial oxygen demand, but coronary sinus blood flow decreased an additional 15%, and coronary vascular resistance increased an additional 19%. In 5 of the cocaine/propranolol subjects, 1 or more epicardial segments constricted more than 10%, and in one patient complete coronary artery occlusion occurred with associated ST-segment elevation and symptoms of myocardial ischemia which resolved with sublingual nitroglycerin (Lange et al, 1990).
    K) RHABDOMYOLYSIS
    1) SUMMARY: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be added if necessary to maintain urine output but only after volume status has been restored as hypovolemia will increase renal tubular damage. Urinary alkalinization is NOT routinely recommended.
    2) Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia. Control seizures, agitation, and muscle contractions (Erdman & Dart, 2004).
    3) FLUID REPLACEMENT: Early and aggressive fluid replacement is the mainstay of therapy to prevent renal failure. Vigorous fluid replacement with 0.9% saline (10 to 15 mL/kg/hour) is necessary even if there is no evidence of dehydration. Several liters of fluid may be needed within the first 24 hours (Walter & Catenacci, 2008; Camp, 2009; Huerta-Alardin et al, 2005; Criddle, 2003; Polderman, 2004). Hypovolemia, increased insensible losses, and third spacing of fluid commonly increase fluid requirements. Strive to maintain a urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hour) (Walter & Catenacci, 2008; Camp, 2009; Erdman & Dart, 2004; Criddle, 2003). To maintain a urine output this high, 500 to 1000 mL of fluid per hour may be required (Criddle, 2003). Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
    4) DIURETICS: Diuretics (eg, mannitol or furosemide) may be needed to ensure adequate urine output and to prevent acute renal failure when used in combination with aggressive fluid therapy. Loop diuretics increase tubular flow and decrease deposition of myoglobin. These agents should be used only after volume status has been restored, as hypovolemia will increase renal tubular damage. If the patient is maintaining adequate urine output, loop diuretics are not necessary (Vanholder et al, 2000).
    5) URINARY ALKALINIZATION: Alkalinization of the urine is not routinely recommended, as it has never been documented to reduce nephrotoxicity, and may cause complications such as hypocalcemia and hypokalemia (Walter & Catenacci, 2008; Huerta-Alardin et al, 2005; Brown et al, 2004; Polderman, 2004). Retrospective studies have failed to demonstrate any clinical benefit from the use of urinary alkalinization (Brown et al, 2004; Polderman, 2004; Homsi et al, 1997).
    L) DRUG WITHDRAWAL
    1) SUMMARY: A cocaine withdrawal syndrome including depression, irritability, sleep disturbances, gastrointestinal symptoms, and headache has been described (Schnoll et al, 1984), with onset 24 to 48 hours after drug use is discontinued and lasting 7 to 10 days. Cocaine dependency and withdrawal is a complex medical and psychosocial problem with no known effective treatment (Kleber & Gawin, 1984).
    M) EXPERIMENTAL THERAPY
    1) EXPERIMENTAL ANIMAL STUDIES: Magnesium pretreatment reduced cocaine lethality in rats (Mouton et al, 1992).
    2) ANIMAL STUDIES: In mice, N-methyl-D-aspartate (NMDA) antagonists reduced cocaine-induced seizures in a dose-dependent fashion. The NMDA antagonists were also more efficacious than traditional anticonvulsant agents, such as diazepam and phenobarbital, in the mouse model (Witkin et al, 1999).
    3) CARVEDILOL/CASE REPORT: A 34-year-old healthy woman presented to the emergency department with dyspnea and palpitations after having used cocaine for the first time. An ECG revealed sinus tachycardia, and laboratory studies showed serial troponins peaked at 1.2 ng/dL. An echocardiogram indicated anterior and septal hypokinesis with an ejection fraction of 40% along with a significant reduction in radial strain. A diagnosis of acute heart failure was made consistent with acute myocarditis and treatment included aspirin 100 mg once daily and carvedilol 6.25 mg twice daily for 1 week. The patient was then discharged to home after a repeat echocardiogram indicated normal systolic function and a normal strain pattern (Ocal et al, 2015).
    a) Unlike other beta-blocking agents, carvedilol has both beta-blocking and alpha-blocking capabilities, with minimal inverse agonist activity, resulting in a reduced negative chronotropic and inotropic effect thereby decreasing its risk of worsening symptoms of heart failure (Ocal et al, 2015; Prod Info COREG(R) oral tablets, 2015).
    N) SEROTONIN SYNDROME
    1) SUMMARY
    a) Benzodiazepines are the mainstay of therapy. Cyproheptadine, a 5-HT antagonist, is also commonly used. Severe cases have been managed with benzodiazepine sedation and neuromuscular paralysis with non-depolarizing agents(Claassen & Gelissen, 2005).
    2) HYPERTHERMIA
    a) Control agitation and muscle activity. Undress patient and enhance evaporative heat loss by keeping skin damp and using cooling fans.
    b) MUSCLE ACTIVITY: Benzodiazepines are the drug of choice to control agitation and muscle activity. DIAZEPAM: ADULT: 5 to 10 mg IV every 5 to 10 minutes as needed, monitor for respiratory depression and need for intubation. CHILD: 0.25 mg/kg IV every 5 to 10 minutes; monitor for respiratory depression and need for intubation.
    c) Non-depolarizing paralytics may be used in severe cases.
    3) CYPROHEPTADINE
    a) Cyproheptadine is a non-specific 5-HT antagonist that has been shown to block development of serotonin syndrome in animals (Sternbach, 1991). Cyproheptadine has been used in the treatment of serotonin syndrome (Mills, 1997; Goldberg & Huk, 1992). There are no controlled human trials substantiating its efficacy.
    b) ADULT: 12 mg initially followed by 2 mg every 2 hours if symptoms persist, up to a maximum of 32 mg in 24 hours. Maintenance dose 8 mg orally repeated every 6 hours (Boyer & Shannon, 2005).
    c) CHILD: 0.25 mg/kg/day divided every 6 hours, maximum dose 12 mg/day (Mills, 1997).
    4) HYPERTENSION
    a) Monitor vital signs regularly. For mild/moderate asymptomatic hypertension, pharmacologic intervention is usually not necessary.
    5) HYPOTENSION
    a) Administer 10 to 20 mL/kg 0.9% saline bolus and place patient supine. Further fluid therapy should be guided by central venous pressure or right heart catheterization to avoid volume overload.
    b) Pressor agents with dopaminergic effects may theoretically worsen serotonin syndrome and should be used with caution. Direct acting agents (norepinephrine, epinephrine, phentolamine) are theoretically preferred.
    c) NOREPINEPHRINE
    1) PREPARATION: Add 4 mL of 0.1% solution to 1000 mL of dextrose 5% in water to produce 4 mcg/mL.
    2) INITIAL DOSE
    a) ADULT: 2 to 3 mL (8 to 12 mcg)/minute.
    b) ADULT or CHILD: 0.1 to 0.2 mcg/kg/min. Titrate to maintain adequate blood pressure.
    3) MAINTENANCE DOSE
    a) 0.5 to 1 mL (2 to 4 mcg)/minute.
    6) SEIZURES
    a) DIAZEPAM
    1) MAXIMUM RATE: Administer diazepam IV over 2 to 3 minutes (maximum rate: 5 mg/min).
    2) ADULT DIAZEPAM DOSE: 5 to 10 mg initially, repeat every 5 to 10 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 30 milligrams.
    3) PEDIATRIC DIAZEPAM DOSE: 0.2 to 0.5 mg/kg, repeat every 5 minutes as needed. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after diazepam 10 milligrams in children over 5 years or 5 milligrams in children under 5 years of age.
    4) RECTAL USE: If an intravenous line cannot be established, diazepam may be given per rectum (not FDA approved), or lorazepam may be given intramuscularly.
    b) LORAZEPAM
    1) MAXIMUM RATE: The rate of IV administration of lorazepam should not exceed 2 mg/min (Prod Info Ativan(R), 1991).
    2) ADULT LORAZEPAM DOSE: 2 to 4 mg IV. Initial doses may be repeated in 10 to 15 minutes, if seizures persist (Prod Info ATIVAN(R) injection, 2003).
    3) PEDIATRIC LORAZEPAM DOSE: 0.1 mg/kg IV push (range: 0.05 to 0.1 mg/kg; maximum dose 4 mg); may repeat dose in 5 to 10 minutes if seizures continue. It has also been given rectally at the same dose in children with no IV access (Sreenath et al, 2010; Chin et al, 2008; Wheless, 2004; Qureshi et al, 2002; De Negri & Baglietto, 2001; Mitchell, 1996; Appleton, 1995; Giang & McBride, 1988).
    c) RECURRING SEIZURES
    1) If seizures cannot be controlled with diazepam or recur, give phenobarbital or propofol.
    d) PHENOBARBITAL
    1) SERUM LEVEL MONITORING: Monitor serum levels over next 12 to 24 hours for maintenance of therapeutic levels (15 to 25 mcg/mL).
    2) ADULT PHENOBARBITAL LOADING DOSE: 600 to 1200 mg of phenobarbital IV initially (10 to 20 mg/kg) diluted in 60 mL of 0.9% saline given at 25 to 50 mg/minute.
    3) ADULT PHENOBARBITAL MAINTENANCE DOSE: Additional doses of 120 to 240 mg may be given every 20 minutes.
    4) MAXIMUM SAFE ADULT PHENOBARBITAL DOSE: No maximum safe dose has been established. Patients in status epilepticus have received as much as 100 mg/min until seizure control was achieved or a total dose of 10 mg/kg.
    5) PEDIATRIC PHENOBARBITAL LOADING DOSE: 15 to 20 mg/kg of phenobarbital intravenously at a rate of 25 to 50 mg/min.
    6) PEDIATRIC PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 5 to 10 mg/kg may be given every 20 minutes.
    7) MAXIMUM SAFE PEDIATRIC PHENOBARBITAL DOSE: No maximum safe dose has been established. Children in status epilepticus have received doses of 30 to 120 mg/kg within 24 hours. Vasopressors and mechanical ventilation were needed in some patients receiving these doses.
    8) NEONATAL PHENOBARBITAL LOADING DOSE: 20 to 30 mg/kg IV at a rate of no more than 1 mg/kg/min in patients with no preexisting phenobarbital serum levels.
    9) NEONATAL PHENOBARBITAL MAINTENANCE DOSE: Repeat doses of 2.5 mg/kg every 12 hours may be given; adjust dosage to maintain serum levels of 20 to 40 mcg/mL.
    10) MAXIMUM SAFE NEONATAL PHENOBARBITAL DOSE: Doses of up to 20 mg/kg/min up to a total of 30 mg/kg have been tolerated in neonates.
    11) CAUTION: Adequacy of ventilation must be continuously monitored in children and adults. Intubation may be necessary with increased doses.
    7) CHLORPROMAZINE
    a) Chlorpromazine is a 5-HT2 receptor antagonist that has been used to treat cases of serotonin syndrome (Graham, 1997; Gillman, 1996). Controlled human trial documenting its efficacy are lacking.
    b) ADULT: 25 to 100 mg intramuscularly repeated in 1 hour if necessary.
    c) CHILD: 0.5 to 1 mg/kg repeated as needed every 6 to 12 hours not to exceed 2 mg/kg/day.
    8) NOT RECOMMENDED
    a) BROMOCRIPTINE: It has been used in the treatment of neuroleptic malignant syndrome but is NOT RECOMMENDED in the treatment of serotonin syndrome as it has serotonergic effects (Gillman, 1997). In one case the use of bromocriptine was associated with a fatal outcome (Kline et al, 1989).
    O) FLUMAZENIL
    1) Flumazenil is NOT recommended because of the risk of seizures.
    2) An experimental animal model found an increased risk of death from unmasked seizures when rats received flumazenil following intoxication with cocaine and diazepam (Derlet & Albertson, 1994).

Eye Exposure

    6.8.1) DECONTAMINATION
    A) If evidence of ocular exposure exists, such as anisocoria, the affected eye should be irrigated and examined for corneal abrasion (Bonadio & Wagner, 1990).

Enhanced Elimination

    A) SUMMARY
    1) Cocaine is rapidly metabolized. FORCED DIURESIS, DIALYSIS, and HEMOPERFUSION are ineffective in significantly altering elimination. URINE ACIDIFICATION is ineffective (Van Dyke et al, 1978; Fish & Wilson, 1969).
    B) PLASMA EXCHANGE
    1) CASE REPORT: Plasma exchange with fresh frozen plasma was initiated on day 1 in a 51-year-old woman who presented to the emergency department following ingestion of packets, later determined to contain cocaine contaminated with tetramisole, and subsequently developed seizures, coma, cardiac arrest, hypotension refractory to fluids and managed with vasopressors, and rhabdomyolysis. A total of 4 cycles of plasma exchange were completed, with each cycle undergoing approximately 3000 mL substitution. Following the first cycle, the patient's hemodynamic status improved and vasopressor therapy was discontinued (Giuliani et al, 2012).

Abstracts

Case Reports

    A) ADULT
    1) ADVERSE EFFECTS
    a) MYOCARDIAL INFARCTION: Numerous cases of myocardial infarction following cocaine abuse in patients with and without underlying coronary artery disease have been reported (Stenberg et al, 1989; Rod & Zucker, 1987; Wehbie et al, 1987; Howard et al, 1985).
    1) An acute myocardial infarction was reported in a 28-year-old woman without a previous history of cardiovascular disease or hypertension following topical cocaine anesthesia for closed reduction of a nasal fracture (Chiu et al, 1986).
    b) MESENTERIC ISCHEMIA: A 38-year-old man presented with acute mesenteric ischemia, intraperitoneal fecal contamination, and severe metabolic acidosis (pH 6.84; total bicarbonate 7 mmol/L) after IV self-administration of 4 g of cocaine 24 hours earlier (Freudenberger et al, 1990).
    1) Exploratory laparotomy revealed no anatomic lesions except for gangrenous bowel extending from midjejunum to distal ileum. Microscopic studies revealed acute ischemic necrosis of the bowel wall with no mesenteric vessel thrombosis, embolism, or atherosclerosis.
    c) PULMONARY: A 33-year-old woman developed acute bilateral pulmonary infiltrates following 18 hours of intense crack cocaine smoking. Pulmonary function progressively deteriorated to the point of being ventilator dependent. Treatment with prednisone (1 mg/kg/day for 8 weeks) was inefficacious and the patient subsequently died of respiratory failure (O'Donnell et al, 1991).
    1) Open lung biopsy revealed chronic interstitial pneumonitis with accumulation of silica within histiocytes associated with mild pulmonary fibrosis. The author warns that some cocaine may be contaminated with crystalline silica, which can lead to silicosis and the development of respiratory failure.
    d) CONGESTIVE HEART FAILURE: A 34-year-old previously healthy man with a history of smoking cigarettes for many years, snorting cocaine occasionally, and smoking marijuana presented with acute respiratory distress associated with congestive heart failure. Idiopathic hemochromatosis may have played a synergistic role with cocaine in depressing myocardial function (Goldenberg & Zeldis, 1987).
    e) MULTIORGAN SYSTEM FAILURE: Rupture of cocaine packets in the gastrointestinal tract has resulted in multiorgan system failure (Haznas et al, 1993).
    B) PEDIATRIC
    1) SEIZURES: Two cases of prolonged tonic-clonic seizures were reported in 9-month-old infants after they ingested cocaine left over from parties held in the homes (Garland et al, 1989; Rivkin & Gilmore, 1989).
    a) In both cases, seizures commenced shortly after ingestion and were difficult to control, requiring high doses of multiple anticonvulsants.

Range Of Toxicity

Summary

    A) Toxicity may occur with recreational doses, but there are reports of patients surviving with markedly elevated serum cocaine concentrations. The lethal dose is not well established and is quite variable.

Therapeutic Dose

    7.2.1) ADULT
    A) ROUTE OF ADMINISTRATION
    1) NASAL ANESTHESIA
    a) Dosage varies; use lowest dosage that would provide effective anesthesia (Prod Info C-Topical(TM) topical solution, 2012)
    b) The most commonly recommended adult dose is 3 mg/kg to a maximum of 200 mg (Lee & Atkinson, 1973; Hopkins, 1970; Verlander & Johns, 1981). Several authors have questioned this dose and recommended 1 mg/kg and 100 mg as the maximum amount (Pryor & Bush, 1973; AMA Council on Drugs, 1980).
    c) In one clinical trial, a total dose per nostril of 0.5 mL for 10% cocaine (seven puffs each nostril) nasal inhalation from a manual atomizer was effective in relieving discomfort following nasoendoscopy (Kasemsuwan & Griffiths, 1996).
    d) It was found that 47% of practicing otolaryngologists routinely used more than 200 mg of cocaine for nasal surgery, without significant adverse effects (Henderson & Johns, 1977).
    7.2.2) PEDIATRIC
    A) ROUTE OF ADMINISTRATION
    1) TOPICAL
    a) Dosage varies; use lowest dosage that would provide effective anesthesia (reduce dosage than that used in adults) (Prod Info C-Topical(TM) topical solution, 2012)
    b) Neither the minimum dose of TAC (tetracaine 0.5%, epinephrine 1:2000, and cocaine 11.8%) necessary for effective anesthesia nor the maximum dose that may be safely applied to dermal lacerations in children has been delineated. Less than 3 mL is sufficient to anesthetize most lacerations in children (Bonadio, 1989).
    1) Half-strength TAC (tetracaine 0.25%, epinephrine 1:4000, and cocaine 5.9%) is as efficacious as the full-strength preparation in providing anesthesia for 95% of wounds on the face, lip, or scalp (Bonadio, 1989).
    2) TAC solution is contraindicated for use on mucosal surfaces or burned or abraded areas because of the augmented systemic absorption. TAC should not be applied to tissues with an end-arteriolar blood supply (eg, ear lobes, penis, digits) since the vasoconstrictive properties of cocaine and epinephrine may induce ischemia and tissue necrosis (Bonadio, 1989).

Minimum Lethal Exposure

    A) ROUTE OF EXPOSURE
    1) TOPICAL
    a) Fatalities have been reported after application of 25 mg of cocaine to the mucous membranes (Gay, 1982), nasal applications of 400 mg (pp 8-14), and topical tracheobronchial application with 200 mg or less in 6 cases (pp 8-14).
    b) Death was reported in a 7.5-month-old girl who received 10 mL of TAC solution (cocaine 1180 mg, tetracaine 50 mg, and epinephrine 5 mg) for wound anesthesia of an upper lip laceration. Contact with nasal mucosa may have increased absorption (blood concentration, 11.9 mg/L) (Dailey, 1988).
    2) BODY PACKERS
    a) Death was reported in 5 cases in which a single plastic bag or balloon filled with cocaine was ingested. The amount was unspecified in 4 cases, and estimated to be 1 ounce in 1 case (Introna & Smialek, 1989).
    B) CASE REPORTS
    1) PEDIATRIC
    a) Fatality in 16 infants (aged 2 weeks to 10 months) has been associated with passive exposure to freebase (crack) cocaine smoke (Mirchandani et al, 1991).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) Addicts have been reported to use up to 10 g a day without experiencing serious acute toxicity.
    B) CASE REPORTS
    1) Topical tracheal application of 30 mg to a 14-month-old child resulted in mydriasis, hyperactivity, hyperventilation, and tachycardia (Schou et al, 1987).
    2) Serious toxicity and seizures developed in a 6-month-old child after application of 2 mL of TAC solution (cocaine 236 mg) to the hard palate. The infant made a complete recovery (Tipton et al, 1989).
    3) A 6.2-kg infant developed opisthotonus and dystonic movements, tachycardia, and tachypnea after receiving 2 drops of a 4% cocaine solution in the nares (at least 4 mg cocaine) (Schubert & Wason, 1992).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CONCENTRATION LEVEL
    a) TOXIC BLOOD LEVELS
    1) INJECTION: Blood concentrations in 18 fatal overdoses ranged from 0.9 to 21 mg/L (mean 5.2 mg/L) (Havlik & Nolte, 2000; Baselt, 1982). In a series of 53 fatalities, cocaine blood levels were 0 to 26 mg/L (Finkle & McCloskey, 1978).
    2) BENZOYLECGONINE/COCAINE: In 33 fatalities due to cocaine use the range of serum cocaine levels was 0 to 26.1 mg/dL and serum benzoylecgonine levels were 0 to 30.7 mg/dL (McKelway et al, 1990).
    3) PACKET RUPTURE: Blood concentrations in fatalities from cocaine packet rupture have ranged from 0.21 to 9.6 mg/L (Wetli & Mittleman, 1981).
    a) In a 31-year-old bodypacker, deep coma and severe neurological sequelae resulted when cocaine leaked from an ingested latex condom filled with 4 g of cocaine. Cocaine metabolite levels were higher than 100 mcg/mL (Wauters et al, 1992).
    b) Death occurred in a 49-year-old patient following rupture of a packet containing 6.5 to 11.5 g of cocaine (70%). The patient had a blood cocaine level of 1.9 mcg/mL, a vitreous humor level of 3.4 mcg/mL, and a benzoylecgonine level of 25 mcg/mL (Rouse & Fysh, 1992).
    c) Death occurred in a teenage drug courier who swallowed several cocaine packets that ruptured. Postmortem serum cocaine concentration was 104 mg/L (Patel, 1996).
    d) A 35-year-old bodypacker developed extreme agitation, severe hypertension, and tachycardia due to suspected leakage of cocaine packets. Initial laboratory data, obtained approximately 1 hour after symptom onset, revealed plasma cocaine, benzoylecgonine (BZE), and ecgonine methyl ester (EME) concentrations of 594 ng/mL, 9423 ng/mL, and 3261 ng/mL, respectively. Approximately 10 hours after surgical intervention and anal dilatation that removed 107 cocaine packets, repeat laboratory data revealed a significant decline in the plasma concentrations of cocaine, BZE, and EME (46 ng/mL, 4710 ng/mL, and 567 ng/mL, respectively)(Hantson et al, 2011).
    4) INTRANASAL: Blood concentrations after intranasal application of 2 mg/kg of 10% cocaine peaked at 0.061 to 0.408 mg/L (Van Dyke et al, 1978).
    5) An extremely high blood cocaine level of 330 mg/dL was found postmortem in an acute fatality of a chronic cocaine user. Urine cocaine level was 215 mg/L (Peretti et al, 1990).
    6) SOLUTION: A 32-year-old woman had a postmortem cocaine blood level of 51.7 mg/L following ingestion of a cocaine wrapper dissolved in water (Winek et al, 1987).

Workplace Standards

    A) ACGIH TLV Values for CAS50-36-2 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS50-36-2 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS50-36-2 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS50-36-2 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) Reference: RTECS, 1999
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 59 mg/kg
    2) LD50- (ORAL)MOUSE:
    a) 99 mg/kg
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) 81 mg/kg
    4) LD50- (INTRAPERITONEAL)RAT:
    a) 70 mg/kg
    5) LD50- (SUBCUTANEOUS)RAT:
    a) 250 mg/kg
    6) TCLo- (INHALATION)HUMAN:
    a) 3571 mcg/kg
    b) Male, 7143 mcg/kg
    c) Female, 10 mg/kg

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Cocaine is a naturally occurring alkaloid that is the ester of benzoic acid and an amino acid base. The drug is obtained from coca leaves (Erythroxylon coca) and was the first local anesthetic to be used clinically. The drug is both a local anesthetic and a powerful CNS stimulant.
    B) Other pharmacological effects include vasoconstriction, pyrogenicity, and mydriasis. Cocaine has powerful reinforcing effects in the CNS, such that experimental animals will self-administer the drug, favoring it to food or sex.
    C) Cocaethylene (metabolite formed when cocaine and ethanol are used concurrently) has cocaine-like pharmacologic activity. Cocaethylene appears to have an equipotent affinity for the dopamine transporter on dopaminergic presynaptic nerve terminals in the brain as cocaine (Landry, 1992; Randall, 1992; Hearn et al, 1991a).
    1) As both agents increase dopamine synaptic content, the net result is a greater buildup of dopamine than that induced by cocaine alone, provoking enhanced postsynaptic receptor stimulation. However, cocaethylene is about 40 times less potent than cocaine at binding the serotonin transporter, which inhibits dopaminergic activity and impedes dopamine-related euphoria.
    2) It appears that cocaethylene is more euphorigenic and reinforcing than cocaine and that cocaethylene's effects are additive or synergistic to those of cocaine.

Toxicologic Mechanism

    A) Cocaine prevents the reuptake of endogenous catecholamines, particularly dopamine and norepinephrine, which causes an initial sympathetic discharge but catechol depletion after chronic abuse (Staley et al, 1994).
    1) Forensic studies of chronic cocaine users found changes in the dopamine transporter molecule which increased the efficiency of dopamine uptake, presumably as an adaptive response.
    B) In large doses, cocaine has direct cardiotoxicity. Most deaths from overdoses result from depression of vital medullary centers, resulting in respiratory failure. Seizures and hyperthermia may also contribute.
    1) An animal study suggests that cocaine-induced cardiotoxicity is likely due to peripheral effects of cocaine on the cardiovascular system rather than centrally mediated increased sympathetic outflow (Dickerson et al, 1999).
    2) Local anesthetic effects of cocaine involve blocking sodium channels in cell membranes, producing a negative inotropic effect and reduction of conduction velocity in the myocardium (Rump et al, 1995).
    C) Incidence of adverse effects increases with increasing dose (Smith & Wesson, 1978). Acute tolerance to cardiovascular and subjective effects cocaine may develop, leading to an inadvertent toxic dose (Fischman et al, 1985).
    D) SUDDEN DEATH: Sudden death in cocaine users has been associated with contraction band necrosis in the myocardium (Karch & Billingham, 1988).
    1) Proposed mechanisms for sudden death include reentrant dysrhythmias due to patchy myocardial fibrosis and contraction band necrosis and focal ischemia due to small vessel contraction.
    E) MYOCARDIAL INFARCTION: Myocardial infarction has been described in patients with and without documented coronary artery thrombosis or atheromas. Obstruction due to intimal hyperplasia without collagen or elastin deposition has been described and may be a result of chronic immunologic abnormality (Simpson & Edwards, 1986).
    1) The sympathomimetic effects of cocaine increase myocardial oxygen demand, and the alpha-adrenergic mediated coronary vasoconstriction limits coronary artery blood flow. Cocaine inhibits endogenous fibrinolysis, increases thrombogenicity, and enhances platelet aggregation (Baumann et al, 2000; Pitts et al, 1997). Coronary artery spasm has been suggested but rarely documented angiographically (Ascher et al, 1988).
    2) ANIMAL STUDY: Administration of cocaine 2 mg/kg IV to dogs resulted in an increase in coronary vascular resistance and a reduction in the diameter of the left anterior descending coronary artery 2 minutes postadministration. Pretreatment with phentolamine, an alpha-adrenergic receptor antagonist, prevented the increase in coronary vascular resistance and reduction in the left anterior descending artery, indicating that the cocaine-associated coronary vasoconstrictive effects are mediated by alpha-adrenergic receptor stimulation (Kuhn et al, 1990).
    3) ANIMAL STUDY: In a rat model, intraperitoneal and IV cocaine administration resulted in increased levels of cardiac biochemical stress markers and reduced antioxidant capacity, indicating impairment of antioxidant defense mechanisms (Devi & Chan, 1999). Either positive or negative effects on cardiac performance were noted with cocaine administration. With moderate doses, the sympathomimetic effects of cocaine predominate, leading to an increase in blood pressure and heart rate. With higher doses of cocaine or more rapid infusion rates, blood pressure and cardiac output are negatively influenced. With larger amounts of cocaine, the peripheral sympathomimetic effects may be limited by either the direct negative inotropic effects of cocaine or by myocardial ischemia (Baumann et al, 2000).
    a) With low doses, sympathomimetic effects of cocaine predominate but tolerance develops. With higher doses, local anesthetic properties of cocaine predominate and become more pronounced with repeated administration; this may have implications for cocaine-related dysrhythmias, cardiovascular collapse, and sudden death (Wilson et al, 2000).
    4) IN VITRO STUDY: Cocaine enhances the magnitude of spontaneous tone in cattle coronary arteries. This appears to occur by increasing calcium influx via calcium L channels and is inhibited by nifedipine (Kalsner, 1993).
    5) MAST CELLS: Among 12 cocaine-related fatalities, there was an association between the number of mast cells and cross-sectional luminal narrowing in subjects with cocaine-associated thrombosis. Mast cell levels could not be correlated with sudden death due to thrombosis (Kolodgie et al, 1991).
    F) MESENTERIC ISCHEMIA: Acute ischemic bowel necrosis has been described in the absence of myocardial injury and thromboembolic or arteriosclerotic vessel disease. This has been attributed to the potent vasoconstrictive effect of cocaine on the mesenteric vasculature (Freudenberger et al, 1990).
    1) It has been suggested that cocaine blocks the reuptake of norepinephrine, leading to mesenteric vasoconstriction and focal tissue ischemia and perforation (Muniz & Evans, 2001a).
    G) CEREBROVASCULAR COMPLICATIONS: A direct causal relation cannot be established between cocaine and cerebrovascular complications despite surveys that imply an increased association between the two (Levine et al, 1990).
    1) Cocaine-induced cerebrovascular complications could be due to the cardiovascular effects of cocaine or to enhanced platelet-response to arachidonic acid (Levine et al, 1990; Togna et al, 1985).
    H) HEPATOTOXICITY: The exact mechanism for cocaine-induced hepatotoxicity has yet to be established.
    1) Depletion of intracellular NADPH and subsequent lipid peroxidation of cell membranes and cell walls with the production of norcocaine nitroxide have been proposed as a mechanism (Kloss et al, 1984).
    2) Glutathione depletion with nitrosonium ion production is another proposed mechanism (Gubbins et al, 1990).
    3) The increased catecholamines may be directly hepatotoxic and may serve as cofactors for the oxidation of norcocaine nitroxide to nitrosonium ion (Shuster et al, 1988).
    4) It has been suggested that the terminal oxidative metabolites of cocaine are responsible for its hepatotoxic effects. In mice, it was shown that hepatotoxicity of norcocaine nitroxide (a metabolite of cocaine through cytochrome P450-mediated oxidation) was dose-related and significant injury was detectable at doses of 20 to 30 mg/kg IP; severe hepatocellular necrosis was seen at doses of 40 and 50 mg/kg (Ndikum-Moffor et al, 1998).
    I) NEPHROTOXICITY: Both the vasoconstrictive effect of cocaine on renal vasculature and rhabdomyolysis have been proposed as mechanisms for nonoliguric acute tubular necrosis reported with cocaine abuse (Gubbins et al, 1990).
    J) BRONCHOSPASM: Central respiratory depression with bronchospasm can be fatal in asthmatics. Possible mechanisms include bronchial hyperreactivity, induction of IgE formation or direct release of bronchoconstrictors, and drug interactions between cocaine metabolites and asthma medications (Rao et al, 1990).
    K) METABOLITES: Cocaethylene is more lethal than cocaine in mice and rats. In humans, the combination of cocaine and ethanol appears to exert more cardiovascular toxicity than either drug alone. In addition, ethanol appears to potentiate cocaine hepatotoxicity (Katz et al, 1992; Landry, 1992; de la Torre et al, 1991; Jover et al, 1991; Hearn et al, 1991b; Higgins et al, 1990; Foltin & Fischman, 1988).
    1) The major metabolites of cocaine (benzoylecgonine and ethyl methyl ecgonine) have been associated with recurrent coronary vasoconstriction (Brogan et al, 1992).
    L) TERATOGENICITY: Ischemia/reperfusion and the production of superoxide radicals are proposed mechanisms for the teratogenic effects of cocaine in experimental animals and perhaps in humans (Fantel et al, 1992a; Fantel et al, 1992b).
    M) USE PATTERNS AND OVERDOSE LINKS: Purity, duration of drug effect, social learning (eg, snorting, crack pipe construction), expense, and efficiency of drug delivery to brain/heart/blood are factors which impact cocaine use patterns and overdose. Fewer overdoses have been reported in crack users as compared with patients who snort or inject cocaine (Pottieger AE, Tressel PA, Inciardi JA, Rosales TA, 1992).
    N) Tachyphylaxis occurs when cocaine effects rapidly decline despite its continued presence in plasma. Usually the user recalls that their first drug use was the most satisfactory (Lobl & Carbone, 1992).

Physicochemical

Physical Characteristics

    A) Bitter taste; produces a numbing sensation of the tongue and lips

Molecular Weight

    A) Cocaine hydrochloride: 339.81
    B) Alkaloidal cocaine: 303.35

Animal Toxicology

Clinical Effects

    11.1.3) CANINE/DOG
    A) ACUTE: Dogs will present initially with CNS excitement, hyperactivity, erratic behavior, and possibly seizures. They may be vomiting and salivating, and may be hyperthermic. Tachycardia and acidosis may develop. Later, dogs may become depressed and comatose.
    1) Death may be due to hyperthermia, cardiac arrest, or respiratory arrest.
    B) If they survive the acute signs, dogs may later develop pulmonary edema or pneumonia.

Treatment

    11.2.1) SUMMARY
    A) GENERAL TREATMENT
    1) Begin treatment immediately.
    2) Keep animal warm and do not handle unnecessarily.
    3) Sample vomitus, blood, urine, and feces for analysis.
    4) Remove the patient and other animals from the source of contamination.
    5) Treatment should always be done on the advice and with the consultation of a veterinarian. Additional information regarding treatment of poisoned animals may be obtained from a Board Certified (ABVT) Veterinary Toxicologist (check with nearest veterinary school or veterinary diagnostic laboratory) or the National Animal Poison Control Center.
    6) ANIMAL POISON CONTROL CENTERS
    a) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
    b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
    c) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.
    7) Due to lack of reports of large animal intoxication with this substance, the following sections address small animals (dogs and cats) only. In the case of a poisoning involving large animals, consult a veterinary poison control center.
    11.2.2) LIFE SUPPORT
    A) GENERAL
    1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.
    11.2.4) DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) GENERAL TREATMENT
    a) DECONTAMINATION
    1) DECONTAMINATE AS QUICKLY AS POSSIBLE, before clinical signs appear. Emesis may be indicated; however, sedation followed by enterogastric lavage may be the safer route of gastric decontamination (Dumonceaux & Beasley, 1990).
    b) EMESIS AND LAVAGE
    1) If within 2 hours of exposure, induce emesis with 1 to 2 mL/kg syrup of ipecac by mouth. Dogs may vomit more readily with 1 tablet (6 mg) apomorphine diluted in 3 to 5 mL water and instilled into the conjunctival sac or by mouth.
    a) Dogs may also be given apomorphine IV at 40 mcg/kg, although this route may not be as effective. Do not use an emetic if the animal is hypoxic.
    b) In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage. Pass large bore stomach tube and instill 5 to 10 mL/kg water or lavage solution, then aspirate. Repeat 10 times (Kirk, 1986).
    c) EMESIS AT HOME
    1) Advise owner to induce emesis at home using 5 mL hydrogen peroxide orally; dose can be repeated every 10 minutes for 3 doses. Alternatively, owner can try 1 to 2 mL/kg syrup of ipecac by mouth.
    a) CAUTION: Carefully examine patients with chemical exposure before inducing emesis. If signs of oral, pharyngeal, or esophageal irritation, a depressed gag reflex, or central nervous system excitation or depression are present, EMESIS SHOULD NOT BE INDUCED.
    d) WHOLE BOWEL IRRIGATION
    1) Whole bowel irrigation or full enterogastric lavage may help pass packets of cocaine or whole crack rocks. This will not be effective for chewed rocks or open bags.
    e) ACTIVATED CHARCOAL
    1) Administer activated charcoal. Dose: 2 g/kg orally or via stomach tube. Avoid aspiration by proper restraint, careful technique, and if necessary, tracheal intubation.
    f) CATHARTIC
    1) Administer a dose of a saline cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 g/kg). If access to these agents is limited, give 5 to 15 mL magnesium oxide (Milk of Magnesia) orally for dilution.
    g) OCULAR
    1) Rinse eyes with copious amounts of tepid water for 15 minutes. See veterinarian as soon as possible.
    h) INHALATION
    1) Move patient to fresh air. Monitor patient for respiratory distress. Emergency airway support and supplemental oxygen with assisted ventilation may be needed. If a cough or difficulty in breathing develops, evaluate for respiratory tract irritation or bronchitis.
    i) DERMAL
    1) In case of dermatologic exposure, bathe in mild detergent (animal shampoo or Ivory liquid). Wear gloves to avoid human exposure. Clip hair as necessary to facilitate removal.
    11.2.5) TREATMENT
    A) SEIZURES
    1) DIAZEPAM
    a) Dose of diazepam for dogs and cats: 0.5 to 1 mg/kg IV bolus; may repeat dose every 10 minutes for 4 total doses. Give slowly over 1 to 2 minutes.
    2) PHENOBARBITAL
    a) May be used as adjunct treatment at 5 to 30 mg/kg IV over 5 to 10 minutes.
    3) REFRACTORY SEIZURES
    a) Consider anaesthesia or heavy sedation. Administer pentobarbital to dogs and cats at a dose of 3 to 15 mg/kg IV slowly to effect. May need to be repeated in 4 to 8 hours. Be sure to protect the airway.
    B) HYPERTHERMIA
    1) Monitor body temperature and correct for abnormalities. Use a constant rectal probe if possible. If hyperthermic, pack in ice or use cooling baths or fans to reduce body temperature. Hyperthermia was the factor most closely associated with death in one toxicity study (Catravas & Waters, 1981).
    C) ECG
    1) The ECG results must be monitored; tachyarrhythmias may be seen. With general improvement of condition (reducing hyperthermia and CNS excitement), arrhythmias may be self-correcting.
    a) PROPRANOLOL: Its use is controversial. In one study, use of propranolol was associated with a higher death rate than no treatment at all in cocaine-intoxicated dogs (Catravas & Waters, 1991). Propranolol may be best used in life-threatening tachyarrhythmias. If used, monitor ECG results and overall status carefully.
    1) DOSE: DOGS: Administer propranolol 0.5 to 1 mg/kg IV or IM as needed to control arrhythmias. CATS: 0.25 mg diluted in 1 mL saline and give 0.2 mL boluses IV to effect.
    D) CNS SEDATION
    1) Chlorpromazine use is controversial. Pretreatment in dogs given cocaine showed a beneficial effect; however, when chlorpromazine is given to symptomatic dogs, it may lower the seizure threshold.
    2) Chlorpromazine may be best used immediately after exposure, before the dog is symptomatic. It also may be useful in reversing life-threatening hyperthermia (Beasley et al, 1990). DOSE in DOGS: 12 mg/kg IV to effect. Monitor carefully and be prepared to treat seizure activity.
    3) A pure dopamine 1 receptor blocker may be the most efficacious in reducing CNS signs. Currently, this is not available.
    E) ARTERIOSPASM
    1) Nitroglycerin may be used to treat systemic arteriospasm.
    F) BODY PACKING/CRACK ROCKS
    1) Abdominal radiographs and/or barium swallow may identify packets of cocaine or crack rocks in the gastrointestinal tract.
    2) SURGICAL REMOVAL is indicated if packets are visible on radiographs and the animal is symptomatic or if, in the course of whole bowel irrigation, the animal becomes symptomatic or the intestine becomes obstructed.
    3) Surgery is not very effective for open packages or chewed rocks; however, if the animal is repeatedly seizing, consider surgical removal.
    G) ASYMPTOMATIC EXPOSURES
    1) If the animal may have chewed on or swallowed a bag but is asymptomatic, use this protocol: Admit animal and monitor for at least 24 hours. Plain abdominal radiographs/barium swallow may allow visualization of crack rocks or cocaine packets. Administer multiple-dose charcoal. Be prepared to treat as acute exposure (as above).

Range Of Toxicity

    11.3.2) MINIMAL TOXIC DOSE
    A) DOG
    1) LD100 INTRAVENOUS: 39.5 mg/kg
    B) HUMAN
    1) 20 mg has been lethal.

Continuing Care

    11.4.1) SUMMARY
    11.4.1.2) DECONTAMINATION/TREATMENT
    A) GENERAL TREATMENT
    1) Begin treatment immediately.
    2) Keep animal warm and do not handle unnecessarily.
    3) Sample vomitus, blood, urine, and feces for analysis.
    4) Remove the patient and other animals from the source of contamination.
    5) Treatment should always be done on the advice and with the consultation of a veterinarian. Additional information regarding treatment of poisoned animals may be obtained from a Board Certified (ABVT) Veterinary Toxicologist (check with nearest veterinary school or veterinary diagnostic laboratory) or the National Animal Poison Control Center.
    6) ANIMAL POISON CONTROL CENTERS
    a) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
    b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
    c) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.
    7) Due to lack of reports of large animal intoxication with this substance, the following sections address small animals (dogs and cats) only. In the case of a poisoning involving large animals, consult a veterinary poison control center.
    11.4.2) DECONTAMINATION
    11.4.2.2) GASTRIC DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) GENERAL TREATMENT
    a) DECONTAMINATION
    1) DECONTAMINATE AS QUICKLY AS POSSIBLE, before clinical signs appear. Emesis may be indicated; however, sedation followed by enterogastric lavage may be the safer route of gastric decontamination (Dumonceaux & Beasley, 1990).
    b) EMESIS AND LAVAGE
    1) If within 2 hours of exposure, induce emesis with 1 to 2 mL/kg syrup of ipecac by mouth. Dogs may vomit more readily with 1 tablet (6 mg) apomorphine diluted in 3 to 5 mL water and instilled into the conjunctival sac or by mouth.
    a) Dogs may also be given apomorphine IV at 40 mcg/kg, although this route may not be as effective. Do not use an emetic if the animal is hypoxic.
    b) In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage. Pass large bore stomach tube and instill 5 to 10 mL/kg water or lavage solution, then aspirate. Repeat 10 times (Kirk, 1986).
    c) EMESIS AT HOME
    1) Advise owner to induce emesis at home using 5 mL hydrogen peroxide orally; dose can be repeated every 10 minutes for 3 doses. Alternatively, owner can try 1 to 2 mL/kg syrup of ipecac by mouth.
    a) CAUTION: Carefully examine patients with chemical exposure before inducing emesis. If signs of oral, pharyngeal, or esophageal irritation, a depressed gag reflex, or central nervous system excitation or depression are present, EMESIS SHOULD NOT BE INDUCED.
    d) WHOLE BOWEL IRRIGATION
    1) Whole bowel irrigation or full enterogastric lavage may help pass packets of cocaine or whole crack rocks. This will not be effective for chewed rocks or open bags.
    e) ACTIVATED CHARCOAL
    1) Administer activated charcoal. Dose: 2 g/kg orally or via stomach tube. Avoid aspiration by proper restraint, careful technique, and if necessary, tracheal intubation.
    f) CATHARTIC
    1) Administer a dose of a saline cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 g/kg). If access to these agents is limited, give 5 to 15 mL magnesium oxide (Milk of Magnesia) orally for dilution.
    g) OCULAR
    1) Rinse eyes with copious amounts of tepid water for 15 minutes. See veterinarian as soon as possible.
    h) INHALATION
    1) Move patient to fresh air. Monitor patient for respiratory distress. Emergency airway support and supplemental oxygen with assisted ventilation may be needed. If a cough or difficulty in breathing develops, evaluate for respiratory tract irritation or bronchitis.
    i) DERMAL
    1) In case of dermatologic exposure, bathe in mild detergent (animal shampoo or Ivory liquid). Wear gloves to avoid human exposure. Clip hair as necessary to facilitate removal.

Kinetics

    11.5.1) ABSORPTION
    A) SPECIFIC TOXIN
    1) Cocaine is very rapidly absorbed from the mucous membranes; slightly delayed after oral ingestion.
    11.5.3) METABOLISM
    A) SPECIFIC TOXIN
    1) Poorly understood; involves plasma pseudocholinesterase.

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