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Cocaine-Associated Chest Pain
Cardiology Grand Rounds from The University of North Carolina at Chapel Hill
Cocaine-Associated Chest Pain Editors George A. Stouffer, MD Richard G. Sheahan, MD Daniel J. Lenihan, MD
Authors Michael B. Erwin, MD Efthymios N. Deliargyris, MD
R
ecreational cocaine use dates back more than 5000 years among the Incas, and since then, its popularity has been waxing and waning. Sigmund Freud popularized the drug in Europe in the late 1800s. Cocaine reached the United States in the early 1900s and its immediate popularity led President Taft to declare it public enemy no. 1 in 1910. Cocaine became popular again in the 1980s and has since reached epidemic proportions. An estimated 23 million persons have used cocaine at least once (30% of men and 20% of women between the ages of 26 and 34 years) and 1.5 million are regular users.1,2 Cocaine produces potent euphoric effects rapidly, which probably explains its popularity; however, its actions on the central nervous and cardiovascular systems can also result in significant morbidity and occasional mortality. In fact, among all illicit drugs, cocaine is responsible for the highest number of emergency room (ER) visits. Cocaine-associated chest pain is the most frequent presenting complaint and accounts for more than 64,000 ER evaluations per year.1,3 Most cocaine users are young and otherwise at a low risk for coronary artery disease; however, there are now more than 200 reported cases of myocardial infarction associated with cocaine use. Consequently, more than 50% of patients with cocaine-associated chest pain evaluated in the ER are admitted to the hospital at a cost approximating $85 From the Cardiology Section, Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina (MBE, END); and the Division of Cardiology, University of North Carolina, Chapel Hill, North Carolina (END). Correspondence: Efthymios N. Deliargyris, M.D., Wake Forest University School of Medicine, Cardiology Section, Medical Center Boulevard, Winston-Salem, NC 27157-1045 (E-mail: [email protected]). THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
million annually.1,3 These numbers reflect cases with documented cocaine use based on toxicology testing and probably underestimate the true public health burden of cocaine abuse, because routine toxicologic screening is not part of chest pain evaluation in most ERs.3 There are distinct pathophysiologic and clinical features of cocaine-associated chest pain that can make the diagnosis and management of such patients challenging. A case recently encountered at the University of North Carolina Hospitals at Chapel Hill highlighted some of these issues. We will review this case and outline the current knowledge on the pathophysiology, clinical presentation, diagnosis, and management of cocaine-associated chest pain. Case Report A 48-year-old African American man with end-stage diabetic glomerulosclerosis requiring hemodialysis presented to an outside hospital with chest pain and dyspnea. He described his chest pain as “15/10” in intensity, substernal and “crushing” in quality. He was hemodynamically stable, but hypertensive (blood pressure, 180/100 mm Hg; heart rate, 80/min). Sublingual nitroglycerin promptly reduced his discomfort to 1/10 in intensity. The 12-lead electrocardiogram (ECG) showed normal sinus rhythm, biatrial enlargement, 1- to 1.5-mm ST-segment elevations in leads V1-V3, and increased voltage along with repolarization abnormalities in the lateral leads consistent with left ventricular hypertrophy (Figure 1). Based on the electrocardiographic findings, a diagnosis of acute myocardial infarction (MI) was made and he was treated with tissue plasminogen activator, aspirin, heparin, furosemide, and intravenous metoprolol (5 mg ⫻ 3 every 5 minutes, total of 15 mg). He rapidly became confused, markedly hypertensive, and developed worsening respiratory distress requiring intubation and ventilatory support. He was then transferred to University of North Carolina (UNC) Hospitals. His past medical history included diabetes since 1983 with retinopathy and glomerulosclerosis (hemodialysis), hypertension, and a cerebrovascular accident in 1999. He had a documented history of abuse of cocaine and intravenous drugs. His family history was significant for diabetes; both his father and his brother were on hemodialysis secondary to diabetic glomerulosclerosis. In terms of his social history, he was a former nurse anesthetist on disability leave at the time of presentation. He smoked 1 pack of cigarettes per day and used alcohol only socially; as stated earlier, he was a known cocaine and intravenous drug abuser. Review of systems was not possible because of unresponsiveness. Upon arrival to UNC Hospitals he was sedated, intubated, and markedly hypertensive. His blood pressure was 220/106 mm Hg, heart rate was 60/min, with a ventilated rate of 14 respirations/ min, and he was afebrile. His physical examination was remarkable for bilateral rales to anterior auscultation and moderate bilateral lower extremity edema. Cardiac auscultation revealed distant heart sounds with a regular rhythm and no murmurs or gallops. His laboratory values from the outside hospital were notable for: serum urea nitrogen of 36 mg/dL and serum creatinine of 6.6 mg/dL. Cardiac enzymes were negative [creatine kinase-myocardial band (CK-MB) of 4.9 ng/mL, troponin I of 0.1 ng/mL]. Upon arrival to UNC Hospitals, his ECG was essentially unchanged, still showing the anterior ST-segment elevations. A bedside transthoracic echocardiogram showed left ventricular hypertrophy with preserved left ventricular systolic function and diastolic flow limitation without any segmental wall motion abnormalities. Two sets of cardiac enzymes drawn 8 hours apart were as follows: CK, 151 and 97 U/L; CK-MB, 4.1 and 1.8 ng/mL; and troponin I, 0.5 and 1.3 ng/mL. Urine toxicology screen was positive for cocaine. For the moment, his blood pressure was controlled with intravenous nitroprusside and phentolamine. No
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Figure 1. Surface 12-lead electrocardiogram obtained at the time of initial presentation. Note the presence of 1.5- to 2-mm STsegment elevation in anterior precordial leads (V1-V3, pen marks) as well as increased voltage and repolarization abnormalities consistent with left ventricular hypertrophy in the lateral precordial leads. further -adrenergic receptor blockers (-blockers) were administered. Because of his confusion, a computed tomograph of his head was obtained but the results were unremarkable. On the fourth hospital day, he became febrile and was treated with broad-spectrum antibiotics for presumed aspiration pneumonia. On the fifth hospital day, however, he was self-extubated without consequence. His ECG remained stable with gradual resolution of the anterior ST-segment elevations. Serial cardiac enzymes remained negative and a repeat cardiac echocardiogram showed left ventricular hypertrophy with normal systolic performance and no wall motion abnormalities. He was discharged on hospital day 7.
Discussion This case underlines the importance of identifying possible cocaine use in the evaluation of patients with chest pain. As in the patient presented here, when cocaine intoxication is not suspected, otherwise appropriate medical therapies may result in significant complications. The pharmacology and mechanisms of action of cocaine have been extensively studied in both animal models and humans. This discussion will briefly review these properties but will mainly focus on the clinical presentation, diagnostic caveats, and recommended therapies for patients with cocaine-associated chest pain. Pharmacology: Mechanisms of Action Cocaine is an alkaloid extracted from the Erythroxylon coca plant and is classified within the family of local anesthetics.4 Cocaine has 2 main mechanisms of action. The first mechanism is inhibition of cellular Na⫹ transport through blockade of the fast Na⫹ channel resulting in membrane stabilization and a local anesthetic effect, which explains the pharmacologic classification. In the myocardium, this effect is similar to that produced by class I antiarrhythmic agents and can result in PR, QRS, and QT interval prolongation.5 The second pharmacologic effect of cocaine is a marked increase in 38
Figure 2. Spectrum of cardiovascular complications associated with cocaine use. CV, cardiovascular; CVA, cerebrovascular accident; HTN, hypertension; MI, myocardial infarction; PE, pulmonary embolus.
catecholamine levels at the synaptic level, resulting in marked sympathetic activation. This is accomplished through both increased release and decreased reuptake of epinephrine, norepinephrine, and dopamine. This rapid and marked rise in catecholamines is responsible for the majority of cocaine’s clinical effects. In many ways, the hyperadrenergic state after cocaine intoxication resembles the pathophysiology encountered in patients with pheochromocytoma. Treatments targeting this sympathetic activation would therefore be pertinent to both conditions.3,6 Clinical Effects Cocaine can be administered through many routes, such as intravenous injection and inhalation; however, the most popular method is smoking (ie, “crack” cocaine). Cocaine has a rapid onset of action (3–5 minutes) and its effects last up to 1 hour. The effects on both the central nervous and the cardiovascular systems are primarily the result of the marked sympathetic activation. The central nervous system effects are less clearly understood but are thought to be the result of increased dopamine and serotonin levels. Most users experience a rapid and profound euphoric effect that probably accounts for its highly addictive potential. However, in some users, this sympathetic stimulation can result in confusion, agitation, hyperthermia, and even seizures.7 The effects on the cardiovascular system have been more extensively evaluated. Figure 2 summarizes the cardiovascular complications that have been associated with cocaine use.4 Increased catecholamine levels at the postsynaptic level lead to both ␣- and -adrenergic receptor activation with important systemic effects. Hypertension is common July 2002 Volume 324 Number 1
Erwin and Deliargyris Table 1. Evidence for Treatment Recommendations in Patients with Cocaine-Associated Chest Pain Recommendation Nitroglycerin Benzodiazepines Aspirin Phentolamine Heparin CCB (verapamil) -Blockers Labetalol Thrombolytics
Human Studies
Case Reports
Animal Studies
}
} }
}
⻫⻫⻫ ⻫⻫⻫ ⻫⻫ ⻫⻫ ⻫ ⻫ xx x x
}
}
} } } }
} } }
} } }
CCB, calcium channel blockers. ⻫⻫⻫, safe and effective—first-line agent; ⻫⻫, safe, probably effective; ⻫, probably safe and probably effective; xx, probably harmful, not effective; x, Possibly harmful, ⫾ effective. Adapted with permission in 2002 from Hollander JE. The management of cocaine-associated myocardial ischemia. N Engl J Med 1995;333:1267–1272. Copyright © 1995 Massachusetts Medical Society. All rights reserved.
after cocaine use and is the result of peripheral ␣-adrenergic receptor activation causing vasoconstriction. Importantly, peripheral -adrenergic receptor activation counterbalances the vasoconstrictive ␣ effects to some extent. Administration of -blockers can therefore lead to unopposed peripheral ␣ receptor activation and worsening of hypertension, as was evident in our case.8 Myocardial ischemia and infarction can also be precipitated by cocaine. In the myocardium, stimulation of -adrenergic receptors has positive chronotropic and inotropic effects, resulting in increased myocardial oxygen demand, whereas ␣-adrenergic receptor activation can lead to coronary vasoconstriction.5 Lange et al9 carefully described the acute effects of cocaine administration on systemic and coronary hemodynamics in patients undergoing cardiac catheterization. Intranasal cocaine produced significant increases in systolic blood pressure, heart rate, coronary vascular resistance, and myocardial O2 consumption compared with intranasal saline administration. In addition, cocaine also produced significant reductions in the diameter of the left anterior descending and circumflex coronary arteries assessed by quantitative coronary angiography.9 Importantly, as shown in the study by Flores et al,10 such cocaine-induced coronary vasoconstriction is especially prominent at areas of underlying coronary stenoses. Therefore, cocaine increases myocardial work and O2 demand and simultaneously jeopardizes myocardial O2 supply through coronary vasoconstriction. Although cocaine’s detrimental effects on the myocardium are particularly dangerous in patients with pre-existing heart disease, the O2 supply-demand mismatch can be very profound, producing ischemia even in the absence of underlying coronary artery disease. In fact, as demonstrated in a study by Minor et al,11 38% of patients with cocaine associated MI did not have any angiographic evidence of coronary artery disease. Cocaine can also precipitate thrombosis; there have been cases of coronary, cerebral, pulmonary, THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
mesenteric, and renal artery thrombosis reported in the setting of cocaine use.12–14 This propensity to thrombosis is believed to be a combination of acute effects on the hemostatic system and chronic effects on the vessel wall. In the short term, cocaine increases platelet aggregation primarily through elevated levels of platelet agonists, such as thromboxane A2 and adrenaline.15 Also, levels of plasminogen activator inhibitor are elevated after cocaine use.16 Long-term cocaine use has been associated with intimal hyperplasia, accelerated atherosclerosis, and endothelial dysfunction, thereby further favoring a prothrombotic tendency.17 Finally, thrombotic vasculitis has also been described in long-term cocaine users.13 Cocaine intoxication has also been associated with stroke. Although not as common as MI in the setting of cocaine use, Levine et al18 described a series of 28 patients who suffered a stroke shortly after cocaine use. These patients were young (mean age of 34 years) and stroke occurred shortly after cocaine ingestion (64% of cases within 1 hour). Cerebral hemorrhage was present in 10 of the cases; the remaining 18 were considered ischemic events. It is postulated that hemorrhage may occur in asymptomatic patients with aneurysms or arteriovenous malformations who develop marked hypertension after cocaine intoxication, whereas the ischemic events may be a combination of hypertension and in situ thrombosis. Based on these reports, the presence of severe headache or focal neurologic findings shortly after cocaine use should alert physicians to the possibility of a cerebrovascular event. Sudden death and supraventricular and ventricular arrhythmias have also been described in association with cocaine use. As stated earlier, in addition to the marked sympathetic activation, cocaine also inhibits the fast Na⫹ channel, resulting in QRS and QT interval prolongation and thereby creating a very favorable substrate for cardiac arrhythmias; concomitant myocardial ischemia can certainly contribute to the genesis of such arrhythmias.6,8,19,20 39
Cardiology Grand Rounds from the University of North Carolina at Chapel Hill
The spectrum of cardiovascular complications associated with cocaine also includes reports of aortic and coronary dissection,21 pneumopericardium22 as well as cardiomyopathy (acute and chronic)23–26 and myocarditis (hypersensitivity reaction).4 Furthermore, chronic cocaine use is also associated with left ventricular hypertrophy, which may further predispose these patients to ischemic events.27 Finally, endocarditis related to intravenous drug use is not uncommon and actually occurs more frequently in the setting of cocaine abuse compared with other illicit intravenous drugs. The propensity of cocaine users for endocarditis may be explained in part by cocaine’s cardiovascular effects, leading to accelerated valvular degeneration and damage, as well as by the immunosuppression associated with chronic cocaine use. For unclear reasons, left-sided endocarditis is more common than right.2,28 All in all, cocaine can result in a wide array of cardiovascular complications; chest pain, myocardial ischemia, and myocardial infarction, however, are clearly the most common.5,29,30 Patient Demographics and Clinical Presentation The only reliable means of identifying underlying cocaine use in patients presenting with chest pain is a high degree of clinical suspicion, routine questioning, and appropriate toxicologic screening. Unfortunately, all too frequently, questioning for cocaine use is omitted as part of the ER chest pain evaluation. In fact, according to a study by Hollander et al,31 routine questioning for cocaine use during ER evaluation was performed in only 13% of patients with chest pain admitted for rule-out MI. So when should physicians suspect cocaine use when evaluating patients with chest pain? The optimal strategy would be to question all patients presenting with chest pain regarding cocaine use, but that may be unrealistic. There are, however, certain demographic features that may identify those with the highest probability of underlying cocaine use. Gitter et al32 described the clinical characteristics of 101 consecutive patients admitted to a county hospital with cocaine-associated pain. These patients were young (mean age 31.5 years), more frequently male (⬎80%), 70% of them were minorities, and 75% of them were smokers. Despite their young age, 75% of patients had at least 2 major cardiac risk factors; smoking was the most common. In a second study of 70 cases of cocaine-related chest pain, most patients were once again young, male, minorities, and smokers.33 It is important to remember, however, that these studies provide only a helpful demographic profile and that cocaine use may also be involved in older (as in the case presented here), nonminority, and female patients. The quality of the chest pain syndrome and the associated symptoms after cocaine use is very suggestive of myocardial ischemia. Although significant 40
Figure 3. Abnormalities on the admission electrocardiogram of patients with cocaine-associated chest pain. LVH, left ventricular hypertrophy. Data is from 32.
underlying coronary artery disease may not be present in most patients, the marked hemodynamic stress of acute cocaine intoxication probably causes true myocardial ischemia in some, thereby explaining the classic symptoms. In fact, typical anginal pain is described by more than 50% of patients and is frequently accompanied by dyspnea (56%), diaphoresis (32%), nausea (28%), and palpitations (14%).32 The onset of chest pain after use is quite variable. Symptoms commonly start during or within 2 hours of use, but up to 19% of patients present after the first 24 hours.34 Mechanisms attributed to these relatively late presentations include effects produced by cocaine’s active metabolites (predominantly norcocaine),35 as well as the possibility of a withdrawal syndrome.36 Therefore the timing of cocaine use is not always helpful in predicting those who will have subsequent myocardial injury.3 Electrocardiogram In all patients presenting with chest pain, appropriate triage and management decisions are often based on the initial surface ECG. Interpretation of ECGs can be especially challenging in cocaine-associated chest pain. In the study by Gitter et al,32 a “normal” ECG was present in only 32% of patients. Figure 3 shows the breakdown of abnormalities present on the admission ECG of all 101 patients as interpreted by a blinded cardiologist. Although an acute injury pattern was diagnosed in only 8% of patients, ST-segment elevations were very frequent, mostly secondary to early repolarization and primarily present in the anterior leads. Importantly, about 40% of admission ECGs in this study met criteria for administration of thrombolytics. Despite the presence of ECG abnormalities suggestive of myocardial ischemia and/or infarction in a large portion of the study group, none of the 101 patients July 2002 Volume 324 Number 1
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actually suffered an MI.32 In our case, the admission ECG did indeed demonstrate 1- to 1.5-mm ST-segment elevations in leads V1-V3 (Figure 1), which subsequently led to the administration of thrombolytics. As in the study by Gitter et al,32 our patient also did not suffer an MI. Although it is important to identify the abnormalities present on the admission ECGs of such patients, physicians should understand that in the setting of cocaine use, these changes are usually nonspecific; they should seek further evidence for an acute infarction before the administration of thrombolytics. When available, emergent cardiac catheterization, coronary angiography, and possible primary angioplasty would be a preferable approach in patients with chest pain and abnormal ECG after cocaine use. Myocardial Enzymes Interpretation of myocardial enzyme measurements may also be challenging in these patients. Cocaine intoxication can lead to increased motor activity, hyperthermia, and occasionally to rhabdomyolysis, all of which can contribute to elevated serum CK levels.28 In fact, the initial set of CK is elevated in more than 50% of patients with cocaineassociated chest pain.1 However, as the effect of cocaine gradually wears off, 86% of patients with initially elevated CK levels will have lower values by the time of the second CK measurement (6 – 8 hours later).32 The CK-MB is more specific for cardiac damage and usually remains low in situations with CK elevations of noncardiac origin. In our patient, the initial CK was initially mildly elevated (151 U/L) and decreased on the second set (97 U/L); however, the CK-MB fraction remained low (⬍3% of total CK) on both measurements. Once again, physicians should be aware of the low specificity of CK elevations for myocardial damage after cocaine use and wait for the most specific CK-MB fraction and the second set of enzymes before making the diagnosis of MI. Cardiac troponins are the most sensitive, but also highly specific, markers for myocardial damage. Unfortunately, at the time when most studies evaluating cocaine-associated chest pain were performed, these assays were not widely used. There is, however, 1 small study by McLaurin et al37 examining the utility of cardiac troponins in patients with chest pain after cocaine use. Troponin I, troponin T, and CK measurements were taken in 19 patients presenting with cocaine-associated chest pain. Elevated CK levels were present in 14 of 19 patients (74%); however, none of the patients had elevated troponins (either I or T). Importantly, based on subsequent serial measurements, none of the 19 patients was diagnosed with MI.37 It seems that the high sensitivity and specificity of serum troponins for the detection of myocardial damage is also applicable in patients with cocaine-associated chest pain; thereTHE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
fore, when available, these assays should be included in the initial evaluation.2 Management The determination or suspicion that cocaine is involved in patients with chest pain has significant treatment implications. In fact, treatments that are proven to reduce mortality in the setting of MI (thrombolytics, -blockers) may be harmful in the setting of cocaine intoxication. In addition, attention should be given to the central nervous system effects after cocaine use because they may precipitate or worsen myocardial ischemia.7 The following discussion will outline what is currently considered the most appropriate management of patients with cocaine-associated chest pain; however, it is important to recognize that these recommendations are based on animal studies, case reports, and small observational human studies rather than large randomized clinical trials. Nitroglycerin. As in all patients with chest pain, prompt pain relief is of primary importance. Sublingual or intravenous nitroglycerin is very effective in relieving cocaine-associated chest pain, as was evident in the case presented here. Chest pain in these patients is caused primarily by the potent vasoconstriction produced by cocaine, which can produce myocardial ischemia even in the absence of underlying coronary disease. Nitroglycerin can reverse cocaine-induced vasoconstriction, an effect demonstrated in both diseased and nondiseased coronary arteries.38 Administration of nitroglycerin is also very safe because these patients are consistently hypertensive at the time of presentation; therefore, the risk of nitroglycerin-induced hypotension is minimal.39 Based on its efficacy and safety, nitroglycerin should be considered a first-line agent for the treatment of cocaine-associated chest pain. Benzodiazepines. Animal studies have clearly demonstrated that benzodiazepines have beneficial effects in reducing the cardiovascular and central nervous system toxicity associated with cocaine intoxication and should therefore be also considered as first-line therapy. By relieving agitation, these agents also alleviate the hyperthermia, tachycardia, and hypertension that are part of the hyperadrenergic state that accompanies cocaine intoxication. In addition, benzodiazepines may prevent seizures because they increase the seizure threshold.1,40 Note that in contrast to benzodiazepines, phenothiazines (eg, haloperidol) should be avoided because they may lower the seizure threshold, potentiate dysrhythmias, and impair cooling (inhibition of sweating by anticholinergic effects and dopamine receptor antagonism).7 Aspirin and Heparin. Although there are no studies that specifically evaluate the efficacy of these agents in this patient population, their use is generally accepted given the pathological effects of 41
Cardiology Grand Rounds from the University of North Carolina at Chapel Hill
cocaine on platelet aggregation and coagulability. Nevertheless, they should be used with some caution given the increased risk of central nervous system hemorrhage related to seizures, trauma, and hypertension in these patients.7 -Blockers. As mentioned earlier, the use of -blockers is generally contraindicated in the management of patients with cocaine-associated chest pain. This recommendation is based on the pathophysiologic model in which peripheral -receptor activation during ␣-adrenergic stimulation actually counterbalances in part the vasoconstriction and attenuates the hypertensive response. Therefore, based on this model, -blockade after cocaine use would produce “unopposed” ␣-activity, resulting in worsening systemic hypertension and coronary vasoconstriction. There is at least 1 randomized study in human subjects evaluating the effect of -blockers in the setting of cocaine use. Lange et al41 randomized 20 patients to intranasal cocaine or placebo (saline) followed by intracoronary propranolol during cardiac catheterization. Patients that received cocaine did indeed experience decreased coronary sinus flow and increased coronary vascular resistance compared with those receiving placebo. Sand et al42 reported a case series of 7 patients with cocaine intoxication who received intravenous esmolol and showed an adverse outcome in 4 of them (profound hypertension in 2, hypotension requiring vasopressors in 1, and 1 with worsening agitation leading to aspiration). Animal studies have also demonstrated that -blockade potentiates the lethality of cocaine intoxication. In fact, there has never been a study in animals or humans to demonstrate a beneficial effect of these agents. Therefore, based on existing data, the use of -blockers in the setting of cocaine intoxication is contraindicated. Labetalol. Given the combined effect on both ␣and -adrenergic receptors, this agent was initially theorized to be of potential benefit in patients with cocaine-associated chest pain. However, a recent study evaluated the effect of labetalol on coronary artery dimensions after cocaine administration in 10 patients undergoing cardiac catheterization and did not show any significant benefit.43 The routine use of labetalol for the treatment of patients with cocaine-associated chest pain is therefore not recommended. Furthermore, labetalol has also been shown to be of no benefit in pheochromocytoma, a disease state resembling acute cocaine intoxication. This lack of efficacy may be explained by the fact that its -blocking effects are more potent than its ␣ effects at therapeutic doses.1 Calcium Channel Blockers. Verapamil is the only agent in this class that has been shown to have a beneficial effect in humans after cocaine administration. In that study, Negus et al44 treated 10 patients with intravenous verapamil after cocaine 42
administration and showed a return to baseline of mean arterial pressure and coronary arterial area. Earlier animal studies had conflicting results when pretreatment with different calcium channel blockers before cocaine administration resulted in both positive and negative outcomes, depending on the study.7 Based on the beneficial effect demonstrated in the study by Negus et al,44 verapamil is now considered second-line therapy after nitroglycerin, benzodiazepines, and aspirin. Although some extend this recommendation to all calcium channel blockers, verapamil is the only one supported by human data. Phentolamine. In another study by Lange et al,9 phentolamine administration was very effective in reversing the vasoconstrictive effects of cocaine. Furthermore, a case report described its beneficial effects in a patient after initial first line therapy failed, with a resolution in both chest pain and ST segment elevation.45 Not surprisingly, it is also useful in pheochromocytoma patients. Experts recommend an intravenous dose of 1 mg initially with slow upward titration to avoid potential hypotension. Based on these data, phentolamine is also considered a second-line agent for the treatment of patients with cocaine-associated chest pain. Thrombolytics. Despite the frequent electrocardiographic findings suggestive of acute MI in patients with cocaine-associated chest pain, physicians should be very cautious before administering thrombolytics: first, ECG changes in this patient population are nonspecific and are not associated with an acute MI in the vast majority. Second, severe systemic hypertension is commonly present in these patients; therefore, the risk for intracranial hemorrhage may be increased. Finally, and probably most importantly, the prognosis of these persons is excellent, with a mortality rate approaching 0%.34,46 Nevertheless, the safety of thrombolytic administration was demonstrated in a retrospective study of 66 patients with cocaine-associated MI who met ECG criteria for lytics. Only 25 of these patients actually received lytic therapy, and within that group, there were no major complications or deaths. Interestingly, no benefit was observed for the patients who received thrombolytics.47 Therefore, the use of thrombolytics is not recommended unless there are multiple lines of objective evidence of an acute transmural MI (ECG and positive CPK-MB and/or troponin) and facilities for emergent cardiac catheterization are not available. Complications and Prognosis Although ER evaluations of patients experiencing chest pain after cocaine use are fairly common, the actual rate of myocardial infarction in these patients is very low at about 6%. Furthermore, even in the patients suffering a myocardial infarction, the mortality is extremely low and very close to 0%.34,46 July 2002 Volume 324 Number 1
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Figure 4. Timing of complications in cocaine-associated myocardial infarction. Brady, bradyarrhythmias; CHF, congestive heart failure; SVT, supraventricular tachycardia; VT, ventricular tachycardia. Data is from 48.
Complications during a cocaine-associated MI occur in 36% of patients and consist of: bradyarrhythmias (19%), ventricular tachycardia (17%), congestive heart failure (7%), and supraventricular tachycardia (4%). These usually occur within 12 hours of presentation, although there may be late peak in complications (⬎24 hours) possibly associated with cocaine’s active metabolites (primarily norcocaine) as well as withdrawal phenomena (Figure 4). These overall low rates of morbidity and mortality can probably be attributed primarily to the young age of this patient population.48 Conclusions Cocaine use is still widely practiced resulting, in a large number of ER evaluations for a variety of presenting complaints, with chest pain being the most common. Identifying underlying cocaine use is very important because it carries significant treatment implications. The most important strategy in the management of these patients is a high level of suspicion leading to early recognition. This can be accomplished through routine questioning and appropriate toxicologic screening in most patients with chest pain; however, there should be special attention to younger patients (Figure 5).49 Although most patients with cocaine-associated chest pain will not progress to MI, their symptoms may still be related to myocardial ischemia because of the O2 supply-demand mismatch produced by cocaine. Diagnosis of an acute MI in these patients is very challenging, primarily because of the very nonspecific ECG changes and the frequently “false-positive” CK measurements. Cardiac troponins seem to be a more reliable means of identifying the very few patients that may actually progress to suffer an MI. In patients in whom the constellation of symptoms, ECG, and cardiac enzymes is suggestive for an acute MI and pain relief is not rapidly achieved, then THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Figure 5. Age distribution of patients with cocaine-associated chest pain. Note that ⬎75% of patients are under 40 years of age. Data is from 49.
emergent cardiac catheterization and possible primary angioplasty, when available, should be performed. With regard to appropriate medical management, first-line therapies include nitroglycerin and benzodiazepines; aspirin, heparin, phentolamine, and verapamil can also be very valuable in the treatment of these patients. -blockers are contraindicated, labetalol is generally not recommended, and the administration of thrombolytics should be reserved for the instances in which facilities for emergent cardiac catheterization are not available. With early recognition and appropriate therapies the complication and mortality rates for these patients are exceedingly low. References 1. Hollander JE. The management of cocaine-associated myocardial ischemia. N Engl J Med 1995;333:1267–72. 2. Lange RA, Hillis LD. Cardiovascular complications of cocaine use. N Engl J Med 2001;345:351– 8. 3. Hoffman RS, Hollander JE. Evaluation of patients with chest pain after cocaine use. Crit Care Clin 1997;13:809 –28. 4. Cregler LL. Cocaine: the newest risk factor for cardiovascular disease. Clin Cardiol 1991;14:449 –56. 5. Beckman KJ, Parker RB, Hariman RJ, et al. Hemodynamic and electrophysiological actions of cocaine. Circulation 1991;83:1799 – 807. 6. Kloner RA, Hale S, Alker K, et al. The effects of acute and chronic cocaine use on the heart. Circulation 1992;85:407–19. 7. Hahn I, Hoffman RS. Cocaine use and acute myocardial infarction. Emerg Med Clinics 2001;19:493–511. 8. Chakko S, Myerburge RJ. Cardiac complications of cocaine abuse. Clin Cardiol 1995;18:67–72. 9. Lange RA, Cigarroa RG, Yancy CW, et al. Cocaine-induced coronary-artery vasoconstriction. N Engl J Med 1989; 321:1557– 62. 10. Flores ED, Lange RA, Cigarroa RG, et al. Effect of cocaine on coronary artery dimensions in atherosclerotic coronary artery disease: Enhanced vasoconstriction at sites of significant stenoses. J Am Coll Cardiol 1990;16:74 –9.
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11. Minor RL, Brook DS, Brown DD, et al. Cocaine-induced myocardial infarction in patients with normal coronary arteries. Ann Intern Med 1991;115:797– 806. 12. Stenberg RG, Winniford MD, Hillis LD, et al. Simultaneous acute thrombosis of two major coronary arteries following intravenous cocaine use. Arch Pathol Lab Med 1989;113:521– 4. 13. Rezkalla SH, Mazza JJ, Klomer RA, et al. Effects of cocaine on human platelets in healthy subjects. Am J Cardiol 1993;72:243– 6. 14. Dressler FA, Malekzadeh S, Roberts WC. Quantitative analysis of amounts of coronary arterial narrowing in cocaine addicts. Am J Cardiol 1990;65:303– 8. 15. Kugelmass AD, Oda A, Monahan K, et al. Activation of human platelets by cocaine. Circulation 1993;88:876 – 83. 16. Moliterno DJ, Lange RA, Gerard RD, et al. Influence of intranasal cocaine on plasma constituents associated with endogenous thrombosis and thrombolysis. Am J Med 1994;96:492–6. 17. Kolodgie FD, Virmani R, Cornhill JF, et al. Increase in atherosclerosis and adventitial mast cells in cocaine abusers: an alternative mechanism of cocaine-associated coronary vasospasm and thrombosis. J Am Coll Cardiol 1991;17:1553– 60. 18. Levine SR, Brust JC, Futrell N, et al. Cerebrovascular complications of the use of the ‘crack’ form of alkaloidal cocaine. N Engl J Med 1990;323:699 –704. 19. Kimura S, Bassett AL, Xi H, et al. Early afterdepolarizations and triggered activity induced by cocaine. Circulation 1992;85:2227–35. 20. Daniel WC, Pirwitz MJ, Horton RP, et al. Electrophysiologic effects of intranasal cocaine. Am J Cardiol 1995;76:398–400. 21. Jaffe BD, Broderick TM, Leier CV. Cocaine induced coronary artery dissection. N Engl J Med 1994;330:510 –1. 22. Albrecht CA, Jafri A, Linville L, et al. Cocaine-Induced Pneumopericardium. Circulation 2000;102:2792– 4. 23. Wiener RS, Lockhart JT, Schwartz RG. Dilated cardiomyopathy and cocaine abuse. Am J Med 1986;81:699 –701. 24. Chokshi SK, Moore R, Pandian NG, et al. Reversible cardiomyopathy associated with cocaine intoxication. Ann Intern Med 1989;111:1039 – 40. 25. Bertolet BD, Freund G, Martin CA, et al. Unrecognized left ventricular dysfunction in an apparently healthy cocaine abuse population. Clin Cardiol 1990;13:323– 8. 26. Pitts WR, Vongpatanasin W, Cigarroa JE, et al. Effects of the intracoronary infusion of cocaine on left ventricular systolic and diastolic function in humans. Circulation 1998;97:1270–3. 27. Brickner ME, Willard JE, Eichhorn EJ, et al. Left ventricular hypertrophy associated with chronic cocaine abuse. Circulation 1991;84:1130 –5. 28. Om A, Ellahham S, DiSciascio G. Management of cocaineinduced cardiovascular complications. Am Heart J 1993;125: 469 –75. 29. Isner JM, Estes M, Thompson PD, et al. Acute cardiac events temporally related to cocaine abuse. N Engl J Med 1986;315:1438 – 43. 30. Schneider DJ. Cardiac ramifications of cocaine abuse. Coron Artery Dis 1991;2:267–73. 31. Hollander JE, Brooks DE, Valentine SM. Assessment of cocaine use in patients with chest pain syndromes. Arch Intern Med 1998;158:62– 6.
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32. Gitter MJ, Goldsmith SR, Dunbar DN. Cocaine and chest pain: Clinical features and outcome of patients hospitalized to rule out myocardial Infarction. Ann Int Med 1991;115:277–82. 33. Hollander JE, Shih RD, Hoffman RS, et al. Predictors of coronary artery disease in patients with cocaine-associated myocardial infarction. Am J Med 1997;102:158 – 63. 34. Hollander JE, Hoffman RS, Gennis P, et al. Prospective multicenter evaluation of cocaine associated chest pain. Cocaine Associated Chest Pain(COCHPA) Study Group. Acad Emerg Med 1994;1:330 –9. 35. Brogan WC, Lange RA, Glamann B, et al. Recurrent coronary vasoconstriction caused by intranasal cocaine: Possible role for metabolites. Ann Intern Med 1992;116:556 – 61. 36. Nademanee K, Gorelick DA, Josephson MA, et al. Myocardial ischemia during cocaine withdrawal. Ann Intern Med 1989;111:876 – 80. 37. McLaurin M, Apple FS, Henry TD, et al. Cardiac troponin I and T concentrations in patients with cocaine-associated chest pain. Ann Clin Biochem 1996;33:183– 6. 38. Brogan WC, Lange RA, Kim AS, et al. Alleviation of cocaine-induced coronary vasoconstriction by nitroglycerin. J Am Coll Cardiol 1991;18:581– 6. 39. Hollander JE, Hoffman RS, Gennis P, et al. Nitroglycerin in the treatment of cocaine associated chest pain-Clinical safety and efficacy. Clin Toxicol 1994;32:243–56. 40. Nelson L, Hoffman RS. How to manage acute MI when cocaine is the cause. J Crit Illness 1995;10:39 – 43. 41. Lange RA, Cigarroa RG, Flores ED, et al. Potentiation of Cocaine-induced coronary vasoconstriction by beta-adrenergic blockade. Ann Intern Med 1990;112:897–903. 42. Sand IC, Brody SL, Wrenn KD, et al. Experience with esmolol for the treatment of cocaine-associated cardiovascular complications. Am J Emerg Med 1991;9:161–3. 43. Boehrer JD, Moliterno DJ, Willard JE, et al. Influence of labetalol on cocaine-induced coronary vasoconstriction in humans. Am J Med 1993;94:608 –10. 44. Negus BH, Willard JE, Hillis LD, et al. Alleviation of cocaine-induced coronary vasoconstriction with intravenous verapamil. Am J Cardiol 1994;73:510 –3. 45. Hollander JE, Carter WA, Hoffman RS. Use of phentolamine for cocaine induced myocardial ischemia [letter]. N Engl J Med 1992;327:361. 46. Boniface KS, Feldman JA. Thrombolytic therapy and cocaine-associated acute myocardial infarction. Am J Emerg Med 2000;18:612–5. 47. Hollander JE, Burnstein JL, Hoffman RS, et al. Cocaine associated myocardial infarction: Clinical safety of thrombolytic therapy. Chest 1995;107:1237– 41. 48. Hollander JE, Hoffman RS, Burstein JL, et al. Cocaineassociated myocardial infarction. Arch Intern Med 1995;155: 1081– 6. 49. Hollander JE, Todd KH, Green G, et al. Chest pain associated with cocaine: an assessment of prevalence in suburban and urban emergency departments. Ann Emerg Med 1995;26:671– 6.
July 2002 Volume 324 Number 1
Cocaine-Associated Chest Pain Editors George A. Stouffer, MD Richard G. Sheahan, MD Daniel J. Lenihan, MD
Authors Michael B. Erwin, MD Efthymios N. Deliargyris, MD
R
ecreational cocaine use dates back more than 5000 years among the Incas, and since then, its popularity has been waxing and waning. Sigmund Freud popularized the drug in Europe in the late 1800s. Cocaine reached the United States in the early 1900s and its immediate popularity led President Taft to declare it public enemy no. 1 in 1910. Cocaine became popular again in the 1980s and has since reached epidemic proportions. An estimated 23 million persons have used cocaine at least once (30% of men and 20% of women between the ages of 26 and 34 years) and 1.5 million are regular users.1,2 Cocaine produces potent euphoric effects rapidly, which probably explains its popularity; however, its actions on the central nervous and cardiovascular systems can also result in significant morbidity and occasional mortality. In fact, among all illicit drugs, cocaine is responsible for the highest number of emergency room (ER) visits. Cocaine-associated chest pain is the most frequent presenting complaint and accounts for more than 64,000 ER evaluations per year.1,3 Most cocaine users are young and otherwise at a low risk for coronary artery disease; however, there are now more than 200 reported cases of myocardial infarction associated with cocaine use. Consequently, more than 50% of patients with cocaine-associated chest pain evaluated in the ER are admitted to the hospital at a cost approximating $85 From the Cardiology Section, Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina (MBE, END); and the Division of Cardiology, University of North Carolina, Chapel Hill, North Carolina (END). Correspondence: Efthymios N. Deliargyris, M.D., Wake Forest University School of Medicine, Cardiology Section, Medical Center Boulevard, Winston-Salem, NC 27157-1045 (E-mail: [email protected]). THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
million annually.1,3 These numbers reflect cases with documented cocaine use based on toxicology testing and probably underestimate the true public health burden of cocaine abuse, because routine toxicologic screening is not part of chest pain evaluation in most ERs.3 There are distinct pathophysiologic and clinical features of cocaine-associated chest pain that can make the diagnosis and management of such patients challenging. A case recently encountered at the University of North Carolina Hospitals at Chapel Hill highlighted some of these issues. We will review this case and outline the current knowledge on the pathophysiology, clinical presentation, diagnosis, and management of cocaine-associated chest pain. Case Report A 48-year-old African American man with end-stage diabetic glomerulosclerosis requiring hemodialysis presented to an outside hospital with chest pain and dyspnea. He described his chest pain as “15/10” in intensity, substernal and “crushing” in quality. He was hemodynamically stable, but hypertensive (blood pressure, 180/100 mm Hg; heart rate, 80/min). Sublingual nitroglycerin promptly reduced his discomfort to 1/10 in intensity. The 12-lead electrocardiogram (ECG) showed normal sinus rhythm, biatrial enlargement, 1- to 1.5-mm ST-segment elevations in leads V1-V3, and increased voltage along with repolarization abnormalities in the lateral leads consistent with left ventricular hypertrophy (Figure 1). Based on the electrocardiographic findings, a diagnosis of acute myocardial infarction (MI) was made and he was treated with tissue plasminogen activator, aspirin, heparin, furosemide, and intravenous metoprolol (5 mg ⫻ 3 every 5 minutes, total of 15 mg). He rapidly became confused, markedly hypertensive, and developed worsening respiratory distress requiring intubation and ventilatory support. He was then transferred to University of North Carolina (UNC) Hospitals. His past medical history included diabetes since 1983 with retinopathy and glomerulosclerosis (hemodialysis), hypertension, and a cerebrovascular accident in 1999. He had a documented history of abuse of cocaine and intravenous drugs. His family history was significant for diabetes; both his father and his brother were on hemodialysis secondary to diabetic glomerulosclerosis. In terms of his social history, he was a former nurse anesthetist on disability leave at the time of presentation. He smoked 1 pack of cigarettes per day and used alcohol only socially; as stated earlier, he was a known cocaine and intravenous drug abuser. Review of systems was not possible because of unresponsiveness. Upon arrival to UNC Hospitals he was sedated, intubated, and markedly hypertensive. His blood pressure was 220/106 mm Hg, heart rate was 60/min, with a ventilated rate of 14 respirations/ min, and he was afebrile. His physical examination was remarkable for bilateral rales to anterior auscultation and moderate bilateral lower extremity edema. Cardiac auscultation revealed distant heart sounds with a regular rhythm and no murmurs or gallops. His laboratory values from the outside hospital were notable for: serum urea nitrogen of 36 mg/dL and serum creatinine of 6.6 mg/dL. Cardiac enzymes were negative [creatine kinase-myocardial band (CK-MB) of 4.9 ng/mL, troponin I of 0.1 ng/mL]. Upon arrival to UNC Hospitals, his ECG was essentially unchanged, still showing the anterior ST-segment elevations. A bedside transthoracic echocardiogram showed left ventricular hypertrophy with preserved left ventricular systolic function and diastolic flow limitation without any segmental wall motion abnormalities. Two sets of cardiac enzymes drawn 8 hours apart were as follows: CK, 151 and 97 U/L; CK-MB, 4.1 and 1.8 ng/mL; and troponin I, 0.5 and 1.3 ng/mL. Urine toxicology screen was positive for cocaine. For the moment, his blood pressure was controlled with intravenous nitroprusside and phentolamine. No
37
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Figure 1. Surface 12-lead electrocardiogram obtained at the time of initial presentation. Note the presence of 1.5- to 2-mm STsegment elevation in anterior precordial leads (V1-V3, pen marks) as well as increased voltage and repolarization abnormalities consistent with left ventricular hypertrophy in the lateral precordial leads. further -adrenergic receptor blockers (-blockers) were administered. Because of his confusion, a computed tomograph of his head was obtained but the results were unremarkable. On the fourth hospital day, he became febrile and was treated with broad-spectrum antibiotics for presumed aspiration pneumonia. On the fifth hospital day, however, he was self-extubated without consequence. His ECG remained stable with gradual resolution of the anterior ST-segment elevations. Serial cardiac enzymes remained negative and a repeat cardiac echocardiogram showed left ventricular hypertrophy with normal systolic performance and no wall motion abnormalities. He was discharged on hospital day 7.
Discussion This case underlines the importance of identifying possible cocaine use in the evaluation of patients with chest pain. As in the patient presented here, when cocaine intoxication is not suspected, otherwise appropriate medical therapies may result in significant complications. The pharmacology and mechanisms of action of cocaine have been extensively studied in both animal models and humans. This discussion will briefly review these properties but will mainly focus on the clinical presentation, diagnostic caveats, and recommended therapies for patients with cocaine-associated chest pain. Pharmacology: Mechanisms of Action Cocaine is an alkaloid extracted from the Erythroxylon coca plant and is classified within the family of local anesthetics.4 Cocaine has 2 main mechanisms of action. The first mechanism is inhibition of cellular Na⫹ transport through blockade of the fast Na⫹ channel resulting in membrane stabilization and a local anesthetic effect, which explains the pharmacologic classification. In the myocardium, this effect is similar to that produced by class I antiarrhythmic agents and can result in PR, QRS, and QT interval prolongation.5 The second pharmacologic effect of cocaine is a marked increase in 38
Figure 2. Spectrum of cardiovascular complications associated with cocaine use. CV, cardiovascular; CVA, cerebrovascular accident; HTN, hypertension; MI, myocardial infarction; PE, pulmonary embolus.
catecholamine levels at the synaptic level, resulting in marked sympathetic activation. This is accomplished through both increased release and decreased reuptake of epinephrine, norepinephrine, and dopamine. This rapid and marked rise in catecholamines is responsible for the majority of cocaine’s clinical effects. In many ways, the hyperadrenergic state after cocaine intoxication resembles the pathophysiology encountered in patients with pheochromocytoma. Treatments targeting this sympathetic activation would therefore be pertinent to both conditions.3,6 Clinical Effects Cocaine can be administered through many routes, such as intravenous injection and inhalation; however, the most popular method is smoking (ie, “crack” cocaine). Cocaine has a rapid onset of action (3–5 minutes) and its effects last up to 1 hour. The effects on both the central nervous and the cardiovascular systems are primarily the result of the marked sympathetic activation. The central nervous system effects are less clearly understood but are thought to be the result of increased dopamine and serotonin levels. Most users experience a rapid and profound euphoric effect that probably accounts for its highly addictive potential. However, in some users, this sympathetic stimulation can result in confusion, agitation, hyperthermia, and even seizures.7 The effects on the cardiovascular system have been more extensively evaluated. Figure 2 summarizes the cardiovascular complications that have been associated with cocaine use.4 Increased catecholamine levels at the postsynaptic level lead to both ␣- and -adrenergic receptor activation with important systemic effects. Hypertension is common July 2002 Volume 324 Number 1
Erwin and Deliargyris Table 1. Evidence for Treatment Recommendations in Patients with Cocaine-Associated Chest Pain Recommendation Nitroglycerin Benzodiazepines Aspirin Phentolamine Heparin CCB (verapamil) -Blockers Labetalol Thrombolytics
Human Studies
Case Reports
Animal Studies
}
} }
}
⻫⻫⻫ ⻫⻫⻫ ⻫⻫ ⻫⻫ ⻫ ⻫ xx x x
}
}
} } } }
} } }
} } }
CCB, calcium channel blockers. ⻫⻫⻫, safe and effective—first-line agent; ⻫⻫, safe, probably effective; ⻫, probably safe and probably effective; xx, probably harmful, not effective; x, Possibly harmful, ⫾ effective. Adapted with permission in 2002 from Hollander JE. The management of cocaine-associated myocardial ischemia. N Engl J Med 1995;333:1267–1272. Copyright © 1995 Massachusetts Medical Society. All rights reserved.
after cocaine use and is the result of peripheral ␣-adrenergic receptor activation causing vasoconstriction. Importantly, peripheral -adrenergic receptor activation counterbalances the vasoconstrictive ␣ effects to some extent. Administration of -blockers can therefore lead to unopposed peripheral ␣ receptor activation and worsening of hypertension, as was evident in our case.8 Myocardial ischemia and infarction can also be precipitated by cocaine. In the myocardium, stimulation of -adrenergic receptors has positive chronotropic and inotropic effects, resulting in increased myocardial oxygen demand, whereas ␣-adrenergic receptor activation can lead to coronary vasoconstriction.5 Lange et al9 carefully described the acute effects of cocaine administration on systemic and coronary hemodynamics in patients undergoing cardiac catheterization. Intranasal cocaine produced significant increases in systolic blood pressure, heart rate, coronary vascular resistance, and myocardial O2 consumption compared with intranasal saline administration. In addition, cocaine also produced significant reductions in the diameter of the left anterior descending and circumflex coronary arteries assessed by quantitative coronary angiography.9 Importantly, as shown in the study by Flores et al,10 such cocaine-induced coronary vasoconstriction is especially prominent at areas of underlying coronary stenoses. Therefore, cocaine increases myocardial work and O2 demand and simultaneously jeopardizes myocardial O2 supply through coronary vasoconstriction. Although cocaine’s detrimental effects on the myocardium are particularly dangerous in patients with pre-existing heart disease, the O2 supply-demand mismatch can be very profound, producing ischemia even in the absence of underlying coronary artery disease. In fact, as demonstrated in a study by Minor et al,11 38% of patients with cocaine associated MI did not have any angiographic evidence of coronary artery disease. Cocaine can also precipitate thrombosis; there have been cases of coronary, cerebral, pulmonary, THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
mesenteric, and renal artery thrombosis reported in the setting of cocaine use.12–14 This propensity to thrombosis is believed to be a combination of acute effects on the hemostatic system and chronic effects on the vessel wall. In the short term, cocaine increases platelet aggregation primarily through elevated levels of platelet agonists, such as thromboxane A2 and adrenaline.15 Also, levels of plasminogen activator inhibitor are elevated after cocaine use.16 Long-term cocaine use has been associated with intimal hyperplasia, accelerated atherosclerosis, and endothelial dysfunction, thereby further favoring a prothrombotic tendency.17 Finally, thrombotic vasculitis has also been described in long-term cocaine users.13 Cocaine intoxication has also been associated with stroke. Although not as common as MI in the setting of cocaine use, Levine et al18 described a series of 28 patients who suffered a stroke shortly after cocaine use. These patients were young (mean age of 34 years) and stroke occurred shortly after cocaine ingestion (64% of cases within 1 hour). Cerebral hemorrhage was present in 10 of the cases; the remaining 18 were considered ischemic events. It is postulated that hemorrhage may occur in asymptomatic patients with aneurysms or arteriovenous malformations who develop marked hypertension after cocaine intoxication, whereas the ischemic events may be a combination of hypertension and in situ thrombosis. Based on these reports, the presence of severe headache or focal neurologic findings shortly after cocaine use should alert physicians to the possibility of a cerebrovascular event. Sudden death and supraventricular and ventricular arrhythmias have also been described in association with cocaine use. As stated earlier, in addition to the marked sympathetic activation, cocaine also inhibits the fast Na⫹ channel, resulting in QRS and QT interval prolongation and thereby creating a very favorable substrate for cardiac arrhythmias; concomitant myocardial ischemia can certainly contribute to the genesis of such arrhythmias.6,8,19,20 39
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The spectrum of cardiovascular complications associated with cocaine also includes reports of aortic and coronary dissection,21 pneumopericardium22 as well as cardiomyopathy (acute and chronic)23–26 and myocarditis (hypersensitivity reaction).4 Furthermore, chronic cocaine use is also associated with left ventricular hypertrophy, which may further predispose these patients to ischemic events.27 Finally, endocarditis related to intravenous drug use is not uncommon and actually occurs more frequently in the setting of cocaine abuse compared with other illicit intravenous drugs. The propensity of cocaine users for endocarditis may be explained in part by cocaine’s cardiovascular effects, leading to accelerated valvular degeneration and damage, as well as by the immunosuppression associated with chronic cocaine use. For unclear reasons, left-sided endocarditis is more common than right.2,28 All in all, cocaine can result in a wide array of cardiovascular complications; chest pain, myocardial ischemia, and myocardial infarction, however, are clearly the most common.5,29,30 Patient Demographics and Clinical Presentation The only reliable means of identifying underlying cocaine use in patients presenting with chest pain is a high degree of clinical suspicion, routine questioning, and appropriate toxicologic screening. Unfortunately, all too frequently, questioning for cocaine use is omitted as part of the ER chest pain evaluation. In fact, according to a study by Hollander et al,31 routine questioning for cocaine use during ER evaluation was performed in only 13% of patients with chest pain admitted for rule-out MI. So when should physicians suspect cocaine use when evaluating patients with chest pain? The optimal strategy would be to question all patients presenting with chest pain regarding cocaine use, but that may be unrealistic. There are, however, certain demographic features that may identify those with the highest probability of underlying cocaine use. Gitter et al32 described the clinical characteristics of 101 consecutive patients admitted to a county hospital with cocaine-associated pain. These patients were young (mean age 31.5 years), more frequently male (⬎80%), 70% of them were minorities, and 75% of them were smokers. Despite their young age, 75% of patients had at least 2 major cardiac risk factors; smoking was the most common. In a second study of 70 cases of cocaine-related chest pain, most patients were once again young, male, minorities, and smokers.33 It is important to remember, however, that these studies provide only a helpful demographic profile and that cocaine use may also be involved in older (as in the case presented here), nonminority, and female patients. The quality of the chest pain syndrome and the associated symptoms after cocaine use is very suggestive of myocardial ischemia. Although significant 40
Figure 3. Abnormalities on the admission electrocardiogram of patients with cocaine-associated chest pain. LVH, left ventricular hypertrophy. Data is from 32.
underlying coronary artery disease may not be present in most patients, the marked hemodynamic stress of acute cocaine intoxication probably causes true myocardial ischemia in some, thereby explaining the classic symptoms. In fact, typical anginal pain is described by more than 50% of patients and is frequently accompanied by dyspnea (56%), diaphoresis (32%), nausea (28%), and palpitations (14%).32 The onset of chest pain after use is quite variable. Symptoms commonly start during or within 2 hours of use, but up to 19% of patients present after the first 24 hours.34 Mechanisms attributed to these relatively late presentations include effects produced by cocaine’s active metabolites (predominantly norcocaine),35 as well as the possibility of a withdrawal syndrome.36 Therefore the timing of cocaine use is not always helpful in predicting those who will have subsequent myocardial injury.3 Electrocardiogram In all patients presenting with chest pain, appropriate triage and management decisions are often based on the initial surface ECG. Interpretation of ECGs can be especially challenging in cocaine-associated chest pain. In the study by Gitter et al,32 a “normal” ECG was present in only 32% of patients. Figure 3 shows the breakdown of abnormalities present on the admission ECG of all 101 patients as interpreted by a blinded cardiologist. Although an acute injury pattern was diagnosed in only 8% of patients, ST-segment elevations were very frequent, mostly secondary to early repolarization and primarily present in the anterior leads. Importantly, about 40% of admission ECGs in this study met criteria for administration of thrombolytics. Despite the presence of ECG abnormalities suggestive of myocardial ischemia and/or infarction in a large portion of the study group, none of the 101 patients July 2002 Volume 324 Number 1
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actually suffered an MI.32 In our case, the admission ECG did indeed demonstrate 1- to 1.5-mm ST-segment elevations in leads V1-V3 (Figure 1), which subsequently led to the administration of thrombolytics. As in the study by Gitter et al,32 our patient also did not suffer an MI. Although it is important to identify the abnormalities present on the admission ECGs of such patients, physicians should understand that in the setting of cocaine use, these changes are usually nonspecific; they should seek further evidence for an acute infarction before the administration of thrombolytics. When available, emergent cardiac catheterization, coronary angiography, and possible primary angioplasty would be a preferable approach in patients with chest pain and abnormal ECG after cocaine use. Myocardial Enzymes Interpretation of myocardial enzyme measurements may also be challenging in these patients. Cocaine intoxication can lead to increased motor activity, hyperthermia, and occasionally to rhabdomyolysis, all of which can contribute to elevated serum CK levels.28 In fact, the initial set of CK is elevated in more than 50% of patients with cocaineassociated chest pain.1 However, as the effect of cocaine gradually wears off, 86% of patients with initially elevated CK levels will have lower values by the time of the second CK measurement (6 – 8 hours later).32 The CK-MB is more specific for cardiac damage and usually remains low in situations with CK elevations of noncardiac origin. In our patient, the initial CK was initially mildly elevated (151 U/L) and decreased on the second set (97 U/L); however, the CK-MB fraction remained low (⬍3% of total CK) on both measurements. Once again, physicians should be aware of the low specificity of CK elevations for myocardial damage after cocaine use and wait for the most specific CK-MB fraction and the second set of enzymes before making the diagnosis of MI. Cardiac troponins are the most sensitive, but also highly specific, markers for myocardial damage. Unfortunately, at the time when most studies evaluating cocaine-associated chest pain were performed, these assays were not widely used. There is, however, 1 small study by McLaurin et al37 examining the utility of cardiac troponins in patients with chest pain after cocaine use. Troponin I, troponin T, and CK measurements were taken in 19 patients presenting with cocaine-associated chest pain. Elevated CK levels were present in 14 of 19 patients (74%); however, none of the patients had elevated troponins (either I or T). Importantly, based on subsequent serial measurements, none of the 19 patients was diagnosed with MI.37 It seems that the high sensitivity and specificity of serum troponins for the detection of myocardial damage is also applicable in patients with cocaine-associated chest pain; thereTHE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
fore, when available, these assays should be included in the initial evaluation.2 Management The determination or suspicion that cocaine is involved in patients with chest pain has significant treatment implications. In fact, treatments that are proven to reduce mortality in the setting of MI (thrombolytics, -blockers) may be harmful in the setting of cocaine intoxication. In addition, attention should be given to the central nervous system effects after cocaine use because they may precipitate or worsen myocardial ischemia.7 The following discussion will outline what is currently considered the most appropriate management of patients with cocaine-associated chest pain; however, it is important to recognize that these recommendations are based on animal studies, case reports, and small observational human studies rather than large randomized clinical trials. Nitroglycerin. As in all patients with chest pain, prompt pain relief is of primary importance. Sublingual or intravenous nitroglycerin is very effective in relieving cocaine-associated chest pain, as was evident in the case presented here. Chest pain in these patients is caused primarily by the potent vasoconstriction produced by cocaine, which can produce myocardial ischemia even in the absence of underlying coronary disease. Nitroglycerin can reverse cocaine-induced vasoconstriction, an effect demonstrated in both diseased and nondiseased coronary arteries.38 Administration of nitroglycerin is also very safe because these patients are consistently hypertensive at the time of presentation; therefore, the risk of nitroglycerin-induced hypotension is minimal.39 Based on its efficacy and safety, nitroglycerin should be considered a first-line agent for the treatment of cocaine-associated chest pain. Benzodiazepines. Animal studies have clearly demonstrated that benzodiazepines have beneficial effects in reducing the cardiovascular and central nervous system toxicity associated with cocaine intoxication and should therefore be also considered as first-line therapy. By relieving agitation, these agents also alleviate the hyperthermia, tachycardia, and hypertension that are part of the hyperadrenergic state that accompanies cocaine intoxication. In addition, benzodiazepines may prevent seizures because they increase the seizure threshold.1,40 Note that in contrast to benzodiazepines, phenothiazines (eg, haloperidol) should be avoided because they may lower the seizure threshold, potentiate dysrhythmias, and impair cooling (inhibition of sweating by anticholinergic effects and dopamine receptor antagonism).7 Aspirin and Heparin. Although there are no studies that specifically evaluate the efficacy of these agents in this patient population, their use is generally accepted given the pathological effects of 41
Cardiology Grand Rounds from the University of North Carolina at Chapel Hill
cocaine on platelet aggregation and coagulability. Nevertheless, they should be used with some caution given the increased risk of central nervous system hemorrhage related to seizures, trauma, and hypertension in these patients.7 -Blockers. As mentioned earlier, the use of -blockers is generally contraindicated in the management of patients with cocaine-associated chest pain. This recommendation is based on the pathophysiologic model in which peripheral -receptor activation during ␣-adrenergic stimulation actually counterbalances in part the vasoconstriction and attenuates the hypertensive response. Therefore, based on this model, -blockade after cocaine use would produce “unopposed” ␣-activity, resulting in worsening systemic hypertension and coronary vasoconstriction. There is at least 1 randomized study in human subjects evaluating the effect of -blockers in the setting of cocaine use. Lange et al41 randomized 20 patients to intranasal cocaine or placebo (saline) followed by intracoronary propranolol during cardiac catheterization. Patients that received cocaine did indeed experience decreased coronary sinus flow and increased coronary vascular resistance compared with those receiving placebo. Sand et al42 reported a case series of 7 patients with cocaine intoxication who received intravenous esmolol and showed an adverse outcome in 4 of them (profound hypertension in 2, hypotension requiring vasopressors in 1, and 1 with worsening agitation leading to aspiration). Animal studies have also demonstrated that -blockade potentiates the lethality of cocaine intoxication. In fact, there has never been a study in animals or humans to demonstrate a beneficial effect of these agents. Therefore, based on existing data, the use of -blockers in the setting of cocaine intoxication is contraindicated. Labetalol. Given the combined effect on both ␣and -adrenergic receptors, this agent was initially theorized to be of potential benefit in patients with cocaine-associated chest pain. However, a recent study evaluated the effect of labetalol on coronary artery dimensions after cocaine administration in 10 patients undergoing cardiac catheterization and did not show any significant benefit.43 The routine use of labetalol for the treatment of patients with cocaine-associated chest pain is therefore not recommended. Furthermore, labetalol has also been shown to be of no benefit in pheochromocytoma, a disease state resembling acute cocaine intoxication. This lack of efficacy may be explained by the fact that its -blocking effects are more potent than its ␣ effects at therapeutic doses.1 Calcium Channel Blockers. Verapamil is the only agent in this class that has been shown to have a beneficial effect in humans after cocaine administration. In that study, Negus et al44 treated 10 patients with intravenous verapamil after cocaine 42
administration and showed a return to baseline of mean arterial pressure and coronary arterial area. Earlier animal studies had conflicting results when pretreatment with different calcium channel blockers before cocaine administration resulted in both positive and negative outcomes, depending on the study.7 Based on the beneficial effect demonstrated in the study by Negus et al,44 verapamil is now considered second-line therapy after nitroglycerin, benzodiazepines, and aspirin. Although some extend this recommendation to all calcium channel blockers, verapamil is the only one supported by human data. Phentolamine. In another study by Lange et al,9 phentolamine administration was very effective in reversing the vasoconstrictive effects of cocaine. Furthermore, a case report described its beneficial effects in a patient after initial first line therapy failed, with a resolution in both chest pain and ST segment elevation.45 Not surprisingly, it is also useful in pheochromocytoma patients. Experts recommend an intravenous dose of 1 mg initially with slow upward titration to avoid potential hypotension. Based on these data, phentolamine is also considered a second-line agent for the treatment of patients with cocaine-associated chest pain. Thrombolytics. Despite the frequent electrocardiographic findings suggestive of acute MI in patients with cocaine-associated chest pain, physicians should be very cautious before administering thrombolytics: first, ECG changes in this patient population are nonspecific and are not associated with an acute MI in the vast majority. Second, severe systemic hypertension is commonly present in these patients; therefore, the risk for intracranial hemorrhage may be increased. Finally, and probably most importantly, the prognosis of these persons is excellent, with a mortality rate approaching 0%.34,46 Nevertheless, the safety of thrombolytic administration was demonstrated in a retrospective study of 66 patients with cocaine-associated MI who met ECG criteria for lytics. Only 25 of these patients actually received lytic therapy, and within that group, there were no major complications or deaths. Interestingly, no benefit was observed for the patients who received thrombolytics.47 Therefore, the use of thrombolytics is not recommended unless there are multiple lines of objective evidence of an acute transmural MI (ECG and positive CPK-MB and/or troponin) and facilities for emergent cardiac catheterization are not available. Complications and Prognosis Although ER evaluations of patients experiencing chest pain after cocaine use are fairly common, the actual rate of myocardial infarction in these patients is very low at about 6%. Furthermore, even in the patients suffering a myocardial infarction, the mortality is extremely low and very close to 0%.34,46 July 2002 Volume 324 Number 1
Erwin and Deliargyris
Figure 4. Timing of complications in cocaine-associated myocardial infarction. Brady, bradyarrhythmias; CHF, congestive heart failure; SVT, supraventricular tachycardia; VT, ventricular tachycardia. Data is from 48.
Complications during a cocaine-associated MI occur in 36% of patients and consist of: bradyarrhythmias (19%), ventricular tachycardia (17%), congestive heart failure (7%), and supraventricular tachycardia (4%). These usually occur within 12 hours of presentation, although there may be late peak in complications (⬎24 hours) possibly associated with cocaine’s active metabolites (primarily norcocaine) as well as withdrawal phenomena (Figure 4). These overall low rates of morbidity and mortality can probably be attributed primarily to the young age of this patient population.48 Conclusions Cocaine use is still widely practiced resulting, in a large number of ER evaluations for a variety of presenting complaints, with chest pain being the most common. Identifying underlying cocaine use is very important because it carries significant treatment implications. The most important strategy in the management of these patients is a high level of suspicion leading to early recognition. This can be accomplished through routine questioning and appropriate toxicologic screening in most patients with chest pain; however, there should be special attention to younger patients (Figure 5).49 Although most patients with cocaine-associated chest pain will not progress to MI, their symptoms may still be related to myocardial ischemia because of the O2 supply-demand mismatch produced by cocaine. Diagnosis of an acute MI in these patients is very challenging, primarily because of the very nonspecific ECG changes and the frequently “false-positive” CK measurements. Cardiac troponins seem to be a more reliable means of identifying the very few patients that may actually progress to suffer an MI. In patients in whom the constellation of symptoms, ECG, and cardiac enzymes is suggestive for an acute MI and pain relief is not rapidly achieved, then THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Figure 5. Age distribution of patients with cocaine-associated chest pain. Note that ⬎75% of patients are under 40 years of age. Data is from 49.
emergent cardiac catheterization and possible primary angioplasty, when available, should be performed. With regard to appropriate medical management, first-line therapies include nitroglycerin and benzodiazepines; aspirin, heparin, phentolamine, and verapamil can also be very valuable in the treatment of these patients. -blockers are contraindicated, labetalol is generally not recommended, and the administration of thrombolytics should be reserved for the instances in which facilities for emergent cardiac catheterization are not available. With early recognition and appropriate therapies the complication and mortality rates for these patients are exceedingly low. References 1. Hollander JE. The management of cocaine-associated myocardial ischemia. N Engl J Med 1995;333:1267–72. 2. Lange RA, Hillis LD. Cardiovascular complications of cocaine use. N Engl J Med 2001;345:351– 8. 3. Hoffman RS, Hollander JE. Evaluation of patients with chest pain after cocaine use. Crit Care Clin 1997;13:809 –28. 4. Cregler LL. Cocaine: the newest risk factor for cardiovascular disease. Clin Cardiol 1991;14:449 –56. 5. Beckman KJ, Parker RB, Hariman RJ, et al. Hemodynamic and electrophysiological actions of cocaine. Circulation 1991;83:1799 – 807. 6. Kloner RA, Hale S, Alker K, et al. The effects of acute and chronic cocaine use on the heart. Circulation 1992;85:407–19. 7. Hahn I, Hoffman RS. Cocaine use and acute myocardial infarction. Emerg Med Clinics 2001;19:493–511. 8. Chakko S, Myerburge RJ. Cardiac complications of cocaine abuse. Clin Cardiol 1995;18:67–72. 9. Lange RA, Cigarroa RG, Yancy CW, et al. Cocaine-induced coronary-artery vasoconstriction. N Engl J Med 1989; 321:1557– 62. 10. Flores ED, Lange RA, Cigarroa RG, et al. Effect of cocaine on coronary artery dimensions in atherosclerotic coronary artery disease: Enhanced vasoconstriction at sites of significant stenoses. J Am Coll Cardiol 1990;16:74 –9.
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Cardiology Grand Rounds from the University of North Carolina at Chapel Hill
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July 2002 Volume 324 Number 1