Cocaine Toxicity

Etiology

The leaves of the coca plant Erythroxylon coca have been used as a stimulant in South America for over 4000 years. Cocaine was first isolated from the leaves in the mid-1800s. It was considered safe and used in toothache drops, nausea pills, energy tonics, and, of course, the original “Coca-Cola” beverage. Since 1961 the International Single Convention on Narcotic Drugs has made recreational use of cocaine a crime internationally. The resurgence of cocaine’s popularity occurred in the 1970s during the disco era and then in the 1980s with the advent of crack cocaine. Cocaine is listed as a DEA schedule II controlled substance because it has a medical use (see StatPearls chapter “Cocaine”), but it also has a high potential for abuse.[4]

Epidemiology

Cocaine abuse is a major public health problem, with an estimated 20 million users worldwide, based on the most recent United Nations World Drug Report. The number of frequent cocaine users, which had been declining since 2006 in North America, has experienced a recent increase, with an estimated 1% of the population reporting use. The Drug Enforcement Agency estimated that in 2012, 639,000 persons aged 12 or older had used cocaine for the first time within the previous 12 months in the United States (US), averaging approximately 1,800 initiates per day. In the US, cocaine was the most common drug of abuse resulting in hospital treatment, with 505,224 ED visits (40.3% of drug reported visits) in 2011 based on data from the Substance Abuse and Mental Health Services Administration. This translates to a rate of 162 ED visits per 100,000 population.[5][6]

Pathophysiology

Patients who abuse cocaine risk life-threatening consequences, including tachydysrhythmia, severe hypertension, acute coronary syndrome, stroke, acute myocardial and renal failure, seizure, hyperthermia, cocaine-induced rhabdomyolysis, and fetal/maternal morbidity and mortality.[7]

The adverse effects on the heart are due to the direct actions of cocaine by inhibiting the reuptake of catecholamines into the nerve endings. The increased catecholamine levels can induce life-threatening arrhythmias, and at the same time, the local anesthetic properties of cocaine further impair impulse conduction, leading to re-entry ventricular arrhythmias.

Long-term use of cocaine can also alter cardiac histology leading to fibrosis, myocarditis, and contraction band necrosis. Cocaine significantly increases myocardial oxygen requirements, heart rate, and cardiac output. In patients with even mild coronary disease, these hemodynamic changes, plus its vasoconstriction ability, can trigger an acute coronary syndrome.

Asides from the myocardium, cocaine can also increase the risk of ischemic stroke. Cocaine can also cause seizures by lowering the threshold for seizure initiation. Chronic use of cocaine can lower the density of dopamine receptors leading to extrapyramidal symptoms, dystonia, bradykinesia, akinesia, and akathisia.

A high risk of death is the ability of cocaine to induce delirium. These patients are often at risk for sudden death. Excited delirium is often associated with aggression, hyperactivity, extreme paranoia, hyperthermia, incoherent screaming, and unusual strength. Individuals who develop excited delirium tend to be more sensitive to the elevated levels of catecholamines.

Another feature of cocaine toxicity is hyperthermia, which may be as high as 45 C. Hyperthermia is a marker for poor prognosis and is often associated with muscle breakdown, renal and liver injury, encephalopathy, disseminated intravascular coagulation (DIC), and metabolic acidosis.

Toxicokinetics

Cocaine can be snorted, swallowed, injected, or smoked. Its pharmacodynamics involves multiple complex mechanisms, although its half-life is short at about 1 hour. This drug binds and blocks monoamine (dopamine, norepinephrine, and serotonin) reuptake transporters with equal affinity. Monoamines accumulate in the synaptic cleft resulting in enhanced and prolonged sympathetic effects. The principal actions of cocaine on the cardiovascular system are from alpha- and beta-1-adrenoceptor stimulation resulting in increased heart rate, systemic arterial pressure, and myocardial contractility, which are major determinants of myocardial oxygen demand. Cocaine and its metabolites may cause arterial vasoconstriction hours after use.[7] Epicardial coronary arteries are especially vulnerable to these effects, leading to decreased myocardial oxygen supply. Cocaine-induced platelet activation and thrombus formation are another deleterious effects caused by alpha-adrenergic- and adenosine diphosphate-mediated increase in platelet aggregation. Plasminogen activator inhibitor is also increased following cocaine use, thereby promoting thrombosis. Similar to local anesthetics such as lidocaine, cocaine blocks sodium channels and interferes with action potential propagation. This Vaughn-Williams class IC effect increases the risk of conduction disturbance and tachyarrhythmias. Adding to its complex toxicity, cocaine targets muscarinic acetylcholine, N-methyl-D-aspartate (NMDA), sigma, and kappa-opioid receptors.[8]

History and Physical

These patients present to the hospital with agitation, chest pain, anxiety, psychosis, and blunt and penetrating traumatic injuries. They are frequently hypertensive and tachycardic. They may be unwilling to disclose their cocaine use, and clinicians must consider a wide spectrum of diagnoses during the initial evaluation, such as withdrawal syndromes, thyrotoxicosis, acute psychosis, sepsis, pheochromocytoma, anticholinergic toxicity, serotonin and neuroleptic malignant syndromes, and intracranial hemorrhage.

A thorough history of drug abuse should be sought, including past admissions.

Patients suspected of cocaine toxicity may have the following features:

• Hypertension
• Altered mental status
• Seizure
• Chest pain, dyspnea
• Epistaxis
• Headache
• Paranoia
• Neurological deficits
• Hyperthermia
• Vascular spasm and loss of distal pulses
• Extreme diaphoresis
• Severe agitation, restlessness, confusion
• Pruritus
• Blurring of vision
• Corneal ulceration, vision loss
• Diarrhea, vomiting, abdominal pain (think mesenteric ischemia)
• Excited delirium

Stages of Acute Cocaine Toxicity

Three stages of acute cocaine toxicity have been described and include the following:

Stage 1

• CNS: Headache, nausea, mydriasis, vertigo, twitching, pseudohallucinations, and preconvulsive movements
• Vascular: Increased BP, ectopic beats
• Pulmonary: Tachypnea
• Skin: Hyperthermia
• Psychiatric: Paranoia, euphoria, confusion, aggression, agitation, emotional lability, restlessness

Stage 2

• CNS: Encephalopathy, seizures, increased deep tendon reflexes, incontinence
• Cardiac: Hypertension, arrhythmias,  peripheral cyanosis
• Pulmonary: Tachypnea, gasping, apnea, irregular breathing
• Skin: Hyperthermia

Stage 3

• CNS, Areflexia, coma, fixed and dilated pupils, loss of vital functions
• Cardiac: Hypotension, ventricular fibrillation, cardiac arrest
• Pulmonary: Apnea, respiratory failure, cyanosis, agonal breathing

Evaluation

Depending on the patient's presentation, laboratory testing for suspected cocaine toxicity can include a complete blood count, comprehensive chemistry panel, troponin, B-type natriuretic peptide, creatinine kinase, urinalysis, urine toxicology screen, and electrocardiogram. Imaging may also include chest x-ray, abdominal x-ray for suspected body packers or stuffers, and head CT if altered mental status suggests intracranial hemorrhage.[9][10]

Creatine kinase may be useful for the detection of rhabdomyolysis. Urinalysis may detect myoglobinuria. A urine drug screen is a must to detect other illicit substances. Most cocaine disappears from the body within 24 hours, but the metabolite, benzoylecgonine, may persist for weeks. This metabolite can also cause neurotoxicity.

A myocardial infarction should be ruled out with troponin, and if meningitis is suspected, a lumbar puncture should be done.

The chest x-ray may show signs of pulmonary edema, pneumothorax, or even aspiration pneumonia. The abdominal x-ray may reveal swallowed packets of cocaine. Because of false negatives with the plain x-rays, a contrast-enhanced study or CT scan is recommended. The risk of bag rupture increases with time, so it is important to make the diagnosis promptly.

CT scan of the head is recommended in patients with seizures to identify any other pathology. An ECG should be done if the patient has chest pain, dyspnea, irregular pulse, or hypoxia.

Treatment / Management

Patients with cocaine toxicity need to be stabilized, and attention should be paid to the ABCDEs. The patient's fever should be managed, and one should rule out hypoglycemia as a cause of the neuropsychiatric symptoms. A pregnancy test should be ruled in women of childbearing age. The treatment should be based on clinical symptoms, and one should avoid physical restraints. 

Based on a large systematic review referenced below, cardiovascular toxicity and agitation are best-treated first-line with benzodiazepines to decrease CNS sympathetic outflow.[11] However, there is a risk of over-sedation and respiratory depression with escalating and numerous doses of benzodiazepines, which is often necessary. Non-dihydropyridine calcium channel blockers such as diltiazem and verapamil have been shown to reduce hypertension reliably, but not tachycardia. Dihydropyridine agents such as nifedipine should be avoided, as reflex tachycardia may occur. The alpha-blocker phentolamine has been recommended but only treats alpha-mediated hypertension and not tachycardia. It is a rarely-used drug, and most clinicians are unfamiliar with its use and limited titratability. Nitroglycerin and nitroprusside are effective at lowering blood pressure, but the risk of reflex tachycardia should be recognized. The mixed beta/alpha blocker labetalol has been shown to be safe and effective for treating concomitant cocaine-induced hypertension and tachycardia without any “unopposed alpha-stimulation” adverse events recorded. The use of labetalol is approved by an AHA/ACC guideline for cocaine and methamphetamine patients with unstable angina/non-STEMI.[12](A1)

Agitated patients are best treated with benzodiazepines, but antipsychotics such as haloperidol and olanzapine may also be useful. Combination treatment with benzodiazepines and antipsychotics has been shown to be more efficacious than monotherapy.[13]  Diphenhydramine is often added to enhance sedation and as prophylaxis against dystonia and akathisia. A common example of this is the “B-52,” with its combination of haloperidol (5 mg), diphenhydramine (50 mg), and lorazepam (2 mg). Lidocaine and intravenous lipid emulsion have been successfully used for serious ventricular tachydysrhythmia in several case reports. Hyperthermia from cocaine toxicity is best treated with external cooling measures. Tepid water misting with convection cooling from a fan is the easiest and safest method to accomplish this in the field and all emergency departments.[11](A1)

Differential Diagnosis

• Hypoglycemia
• Anticholinergic toxicity
• CNS hemorrhage
• Delirium tremens
• Acute schizophrenia
• Phencyclidine (PCP) toxicity
• Neuroleptic malignant syndrome

Prognosis

Cocaine toxicity is associated with high mortality. Also, injection of cocaine can be associated with pneumothorax, thrombosis, endocarditis, pseudoaneurysm of the central vessels, and arteriovenous fistulas. Other sequelae include cellulitis, HIV infection, thrombophlebitis, abscess, tetanus, and necrosis. For those who develop neuropsychiatric symptoms, the recovery is often prolonged and may not be complete.

Complications

• Thrombophlebitis
• HIV
• Cellulitis
• Hepatitis
• Endocarditis
• Pulmonary emboli
• Aneurysms