Case Report

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American Journal of Emergency Medicine

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American Journal of Emergency Medicine 35 (2017) 519.e1-519.e4

Dual cocaine and methamphetamine cardiovascular toxicity: Rapid resolution with labetalol

Abstract

Cardiovascular toxicity, including sudden hypertension, tachycardia, coronary Arterial vasoconstriction, and/or dysrhythmia, may arise from cocaine or methamphetamine use. Treatment options should be consid- ered carefully based upon the unique pharmacology of these different stimulants. We report a rare case of acute cardiovascular toxicity from concomitant use of cocaine and methamphetamine in a 24-year-old male presenting to the emergency department with chest pain. He ar- rived hypertensive, tachycardic, anxious, and diaphoretic. His initial electrocardiogram showed tachycardia, ST-depression, and prominent T-waves. He was initially administered two doses of 1 mg of intravenous lorazepam, which resulted in anxiety, agitation, and worsening vital signs suggestive of paradoxical agitation. He was then given two 5 mg doses of intravenous labetalol. This rapidly resolved his chest pain, anxiety, diaphoresis, hypertension, and tachycardia. He was later discharged without further sequelae. A second electrocardiogram dem- onstrated reversal of the prior abnormal ST-segment and T-wave find- ings. We believe clinicians should be aware of the potential for cardiovascular toxicity from concomitant cocaine and methamphet- amine use, and that labetalol represents a potential initial treatment. Unlike benzodiazepines, labetalol directly counters the pharmacologic effects of cocaine and methamphetamine and does not cause respirato- ry depression, sedation, or paradoxical agitation. Labetalol, with its mixed ?1/?2/?1-blocking properties, also may reduce concern for “un- opposed alpha stimulation.”

Cocaine and methamphetamine abuse continues to be a serious problem in the United States and worldwide [1]. Sudden cardiovascular toxicity from cocaine and/or methamphetamine use is unpredictable and may manifest as hypertension, tachycardia, dysrhythmia, tachypnea, chest pain, and acute myocardial infarction [2,3]. Benzodiaz- epines have been recommended as initial treatment to counter cocaine- induced central nervous system (CNS)-mediated hyperadrenergic symptoms [4]. However, benzodiazepines may not predictably mitigate these symptoms [2,3]. Furthermore, multiple doses are often required, which increases risk of sedation with respiratory depression. Beta- blockers have been successfully used to counter both the CNS and pe- ripheral adverse effects of cocaine and methamphetamine but have been reported to cause “unopposed alpha-stimulation” in some pa- tients, which may exacerbate vasoconstriction and/or hypertension [2-6]. In this case report, we describe concomitant cocaine and metham- phetamine cardiovascular toxicity, paradoxical effect of benzodiazepine treatment, and use of the mixed ?1/?2/?1-blocker labetalol.

A 24-year-old male drove himself to the emergency department

after experiencing chest pain and anxiety for 4 hours after snorting what he reported to be solely cocaine. He was rapidly triaged to a

treatment room and connected to continuous cardiovascular and Pulse oximetry monitoring. The patient described his chest pain as a pressure-like sensation over his left pectoral area that began 5 minutes after inhaling the powdered substance. Further questioning revealed his frequency of cocaine use was once per week, and his last use was over 7 days ago. He stated these symptoms had never happened before. He denied taking any prescribed or over-the-counter medications. There was no past medical history of cardiovascular disease, hypertension, or thyroid disorder. He smoked approximately 5 cigarettes per day. Initial vital signs were: blood pressure 165/110 mm Hg, pulse rate 151 beats/min, respiratory rate 24 breaths/min, temperature 36.6 ?C, and pulse oximetry (SpO2) 100% on room air. An electrocardiogram was performed at this time (Fig. 1) and demonstrated sinus tachycardia, upsloping ST-segment depression in leads V5 and V6, and prominent T-waves.

Physical examination revealed a mildly overweight young male who was anxious, hyperactive, and profusely diaphoretic. His cardiovascular examination revealed no murmur, gallop, or rub on auscultation, but a hyperdynamic point of maximal impulse was detected on palpation. Jugular venous distention was not present, and there was no edema noted in his extremities. His pulmonary examination was clear to aus- cultation. The remainder of his directed physical examination was normal. He was administered one mg of lorazepam intravenously (IV) 7 minutes after triage for his anxiety and suspected cocaine cardiovas- cular toxicity. Repeat vital signs were blood pressure 155/114 mm Hg, pulse rate 128 beats/min, respiratory rate 15 breaths/min, and SpO2 96%. The patient reported no change in his chest pain but experienced worsening anxiety and difficulty keeping still. Another one mg of loraz- epam was given 10 minutes after the first dose, and blood pressure and pulse rate rose to 164/120 mm Hg and 129 beats/min, respectively. The patient became even more anxious, agitated, and diaphoretic immedi- ately after the second dose of lorazepam, but his chest pain remained unchanged. The possibility of a paradoxical agitation to benzodiaze- pines was considered by his treating clinician. Based on the elapsed time, it was also suspected that he may have snorted cocaine adulterat- ed with methamphetamine.

Ten minutes of observation passed during which time lorazepam failed to ameliorate the patient’s objective and subjective symptoms. Oral aspirin (325 mg) was given. Sublingual nitroglycerin was considered at this point, but as there was concern for reflex tachycardia, 5 mg of labetalol IV was given instead. Vital signs were taken 5 minutes later and revealed blood pressure 149/93 and pulse rate 108 beats/min. His chest pain, anxiety, and diaphoresis immediately resolved. A second elec- trocardiogram was obtained at this time and demonstrated resolution of the earlier ST-segment depression and prominent T-waves (Fig. 2). To achieve normalization of his vital signs, a second 5 mg dose of labetalol

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Fig. 1. Initial electrocardiogram demonstrates sinus tachycardia, prominent T-waves, and upsloping ST-depression in leads V5-6.

was given 30 minutes later. Subsequent vital signs were recorded as blood pressure 129/87 mm Hg, pulse rate 97 beats/min, and respiratory rate 13 breaths/min. His chest radiograph was normal, and laboratory re- sults revealed normal complete blood count. His chemistry panel was no- table for a potassium of 2.9 mEq/L (reference range, 3.3-5.0 mEq/L), carbon dioxide 20 mEq/L (normal range, 24-32 mEq/L), and creatinine

1.49 mg/dL (normal range, 0.44-1.27 mg/dL). Troponin I obtained initial- ly and 3 hours later were reported as 0.01 ng/mL (normal range 0-0.04 ng/mL) and 0.04 ng/dL, respectively. A qualitative urine drug screen was positive for cocaine and methamphetamine.

He was treated with 2 L of normal saline for his elevated creatinine and received 50 mEq of potassium bicarbonate/citrate orally for his hy- pokalemia. When presented with the results of his toxicology screen and chemistry panel, the patient admitted to snorting methamphet- amine with cocaine in an attempt to augment the subjective and tempo- ral effects of cocaine. He also stated he had not drunk any liquid since the prior evening. The remainder of his 7-hour emergency department stay was uneventful, and he declined admission for further monitoring. As such, a third troponin I level could not be obtained. His vital signs at discharge were normal. His family arrived to escort him home as he was

Fig. 2. Repeat electrocardiogram after first dose of labetalol shows resolution of sinus tachycardia and normalization of T-wave and ST-segment abnormalities.

J.R. Richards et al. / American Journal of Emergency Medicine 35 (2017) 519.e1–519.e4 519.e3

not allowed to drive, and he was counseled on illicit drug use and given outpatient resources for drug cessation and rehabilitation.

This case report is unique and worthy of discussion for several rea- sons. It involves rarely-encountered dual cocaine and methamphet- amine acute cardiovascular toxicity and acute treatment in the emergency department. Another reason is the unexpected adverse ef- fects of a benzodiazepine for treatment of anxiety and hyperadrenergic symptoms, possibly representing paradoxical agitation. Yet another dis- tinctive aspect of this case is the use of labetalol for rapid resolution of hypertension, tachycardia, anxiety, and chest pain induced by cocaine and methamphetamine.

Cocaine inhibits of the re-uptake of the monoamines dopamine, nor- epinephrine, and serotonin at preganglionic sympathetic nerve endings, resulting in ? – and ? –adrenergic stimulation with resultant hyperten- sion, tachycardia, and vasoconstriction [7]. Cocaine also inhibits sodium influx into cells, increasing risk of dysrhythmia. Cocaine results in platelet activation, ? -granule release, and microaggregate formation which increase the potential for coronary arterial thrombosis [8]. Methamphetamine blocks plasmalemmal and vesicular transporters, resulting in elevated levels of monoamines in the cytoplasm and synap- se, respectively [9]. It also causes reverse transport of cytoplasmic monoamines across the cell membrane of the presynaptic neuron into the synaptic space. Methamphetamine also disrupts vesicular storage of monoamines and inhibits the degradative enzymes mono- amine oxidase A and B [9]. The serum half-life of methamphetamine can range up to 12 hours, compared to approximately one hour for cocaine [7,9]. This may explain the patient’s Persistent symptoms 4 hours after reported use.

The use of benzodiazepines as First-line treatment for cocaine cardiovascular toxicity has been established for many years [4]. Based on systematic reviews of cocaine and amphetamines, benzodiazepines may not always reliably counter hyperadrenergic symptoms from stimulant use, as illustrated by this case [2,3]. Multiple and escalating doses of benzodiazepines may be required for these patients, which in- creases risk of over-sedation and respiratory depression. Furthermore, the uncommon adverse effect of paradoxical agitation should be antici- pated by clinicians administering benzodiazepines, as illustrated by this case [10]. Other pharmaceuticals may be considered for treatment, such as calcium channel blockers, ? 1-blockers, nitric oxide mediated vasodilators, and ? 2-agonists, which more reliably mitigate hyperten- sion than tachycardia based on the aforementioned systematic reviews [2,3]. In comparison, ? -blockers, especially those with mixed ? and ? properties, were shown to be effective in treating both tachycardia and hypertension [2,3].

The use of ? -blockers for treatment of cocaine cardiovascular toxic- ity is controversial because of the rare and unpredictable phenomenon of “unopposed alpha-stimulation,” whereupon blood pressure suddenly rises and/or coronary arterial vasoconstriction occurs after ? -blockers are administered [2-6]. This Adverse drug effect is based on a small num- ber of reported cases but has led to a relative contraindication that has persisted for many years despite limited evidence [2,6]. The use of the mixed ? 1/? 2/? 1-blocker labetalol in the setting of cocaine and meth- amphetamine use has been previously described with no “unopposed alpha stimulation” events reported [2,3,11-13]. In a study by Boehrer and colleagues, 9 subjects were administered 2 mg/kg intranasal co- caine, which increased their mean arterial pressure and decreased cor- onary arterial area [13]. Intravenous labetalol lowered mean arterial pressure and had no deleterious effect on coronary arterial area.

Labetalol is accepted for use in cocaine- and methamphetamine- associated unstable angina/non-ST-elevation myocardial infarction in a recent American Heart Association/American College of Cardiology guideline, specifically: “Administration of combined alpha- and beta-blocking agents (e.g., labetalol) may be reasonable for patients after cocaine use with hypertension (systolic blood pressure greater than 150 mm Hg) or those with sinus tachycardia (pulse greater than 100 beats per min) provided that the patient has received a

vasodilator, such as nitroglycerin or a calcium channel blocker, within close temporal proximity (i.e., within the previous hour). (Level of evidence: C).” [14] It is our belief the ? -blocking property of labetalol, although less potent than its ? -effect, alleviates risk of “unopposed alpha-stimulation” and is a safe, expedient, and efficacious treatment for cocaine and/or methamphetamine cardiovascular toxicity, as sug- gested by our case.

Some limitations should be mentioned regarding this case. No quan- titative laboratory drug screen was performed to determine the blood levels of cocaine and methamphetamine. This is not routinely done in the emergency department, unless there is unknown toxicity and/or fo- rensic testing is required. Instead we relied on our qualitative urine drug screen and the patient’s candor during questioning. This patient’s pre- sentation in the emergency department may have represented subacute cocaine toxicity based on the time frame of 4 hours. We believe cocaine caused his initial chest pressure, as it occurred within minutes of inha- lation, and that his symptoms were prolonged by methamphetamine. Since lorazepam was administered prior to labetalol, this may have accounted for the resolution of this patient’s symptoms to some degree. However, we feel that in this case lorazepam failed and may have wors- ened his condition from possible paradoxical agitation. This is evidenced by the striking change in the patient’s mental state and worsening vital signs just after lorazepam was given.

The authors (JRR, RAL, TCA, BZH) certify that they have no affiliations with or involvement in any organization or entity with any financial in- terest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent licensing arrange- ments) or nonfinancial interest (such as personal or professional rela- tionships, affiliations, knowledge, or beliefs) in the subject matter or materials discussed in this article.

John R. Richards, MD Department of Emergency Medicine, University of California Davis Medical Center, Sacramento, CA

Corresponding author at: Department of Emergency Medicine PSSB 2100, U.C. Davis Medical Center, 2315 Stockton Boulevard Sacramento, CA 95817. Tel.: +916 734 1537; fax: +916 734 7950

E-mail address: jrrichards@ucdavis.edu

Richard A. Lange, MD, MBA Texas Tech University Health Sciences Center, Department of Internal Medicine, Division of Cardiology, El Paso, TX

Thomas C. Arnold, MD Department of Emergency Medicine, Louisiana State University Health Sciences Center, Louisiana Poison Center, Shreveport, LA

B. Zane Horowitz, MD Department of Emergency Medicine, Oregon Health Sciences University, Oregon Poison Center, Portland, OR

http://dx.doi.org/10.1016/j.ajem.2016.09.040

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