Myocardial Ischemia Secondary to Synthetic Cannabinoid (K2) Usein Pediatric Patients

Bradley C. Clark, MD1,2, Justin Georgekutty, MD1,2, and Charles I. Berul, MD1,2

K2 is a synthetic cannabinoid that has potential cardiovascular side effects, includingmyocardial ischemia,myocar-dial infarction, and arrhythmias. Cardiac testing of pediatric patients is often not performed owing to a lack of symp-tomatology. We report a series of pediatric patients with concern for myocardial ischemia temporally associatedwith K2 exposure. (J Pediatr 2015;-:---).

Although epidemiologic data are limited, the reportedprevalence of synthetic cannabinoid (K2, spice)ranges between 6.5% and 12.6% in adolescents

and adults in the US and United Kingdom.1 Syntheticcannabinoids are more attractive than cannabis, owing toease of purchase as well as increased odds of negative urineand blood testing. K2 has multiple known side effects, andserious events, including ischemic stroke, have beenreported.2 Although there are reports of adverse cardio-vascular effects secondary to cannabis or syntheticcannabinoid use, including myocardial infarction (MI),arrhythmias, and sudden death in adults,3-9 data on thecardiac effects of K2 in pediatrics is limited.10-12 We reporta series of pediatric patients who were seen at a tertiarycare center over a 2-year period with evidence of varyingdegrees of myocardial injury secondary to the use of K2.

The Children’s National Health System (CNHS) is atertiary pediatric care center in Washington, DC that seesmore than 100 000 visits to the emergency room (ER)annually. After Institutional Review Board approval wasobtained from CNHS, the electronic medical record wasqueried for a combination of K2 use, ST segment changes,and elevated troponin levels. Individual charts werethen reviewed to identify patients who used K2 andunderwent evaluation for cardiac injury, which includedelectrocardiogram (ECG), echocardiogram, and laboratorytesting. Each ECG represents an official reading from anattending pediatric cardiologist at CNHS.

Case 1

A 15-year-old previously healthy male was brought to the ERsecondary to altered mental status. On later questioning, headmitted frequent K2 smoking, including smoking beforepresentation to the ER. He denied any chest pain, shortness

CK Creatine kinase

CNHS Children’s National Health System

ECG Electrocardiogram

ER Emergency room

LVH Left ventricular hypertrophy

MI Myocardial infarction

THC Delta-9-tetrahydrocannabinol

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of breath, or palpitations. ECG on admission showed STelevation in the lateral leads, T wave inversions in the inferiorleads, and left ventricular hypertrophy (LVH) based onvoltage criteria (Figure 1, A). Laboratory testing wasnotable for an elevated troponin I level at 0.16 ng/mL(normal, <0.1 ng/mL) with normal creatine kinase (CK),CK-MB, and serum and urine drug screening. Anechocardiogram revealed normal intracardiac anatomy,normal coronary artery origins, normal biventricularfunction, no wall motion abnormalities, and no evidence ofpericardial effusion. The patient was admitted overnight forobservation, and demonstrated a return of troponin I levelto normal (0.03 ng/mL) and improved ST segments and Twave inversions (Figure 1, B). He was recently evaluated formild hypertension in the setting of an elevated body massindex. An ECG obtained during that visit was unchangedfrom his discharge study. He was advised to lose weight.

Case 2

A 16-year-old healthy male was brought to the ER withaltered mental status. He reported smoking K2 (“scooby”),but denied any other drug use. He denied chest pain,shortness of breath, palpitations, or dizziness. An ECG wasobtained which showed ST elevation in an anterolateralinjury pattern with T wave inversions in the inferior leads(Figure 2; available at www.jpeds.com). Laboratory testingwas notable for a normal troponin I level (0.03 ng/mL)and positive urine drug screen for marijuana. Anechocardiogram revealed normal intracardiac anatomy,normal coronary artery origins, normal biventricularfunction, no wall motion abnormalities, and no evidence ofa pericardial effusion. He was monitored in the ER untilhis mental status returned to baseline and was dischargedto home with a plan for outpatient cardiology follow-up.He has not followed up to date.

From the 1Division of Cardiology, Children’s National Health System; and2Department of Pediatrics, George Washington University School of Medicine,Washington, DC

The authors declare no conflicts of interest.

0022-3476/$ - see front matter. Copyright ª 2015 Elsevier Inc. All rights reserved.

http://dx.doi.org/10.1016/j.jpeds.2015.06.001

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Figure 1. Case 1 ECG on A, presentation and B, discharge. A, Normal sinus rhythm, LVH, ST flattening in the lateral leads, Twave inversion in inferior leads.B,Marked sinus bradycardia, possible LVH, ST-T wave elevation in precordial leads, and T waveinversion in lead III.

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Case 3

A 17-year-old male with a past medical history of impulsecontrol disorder, depression, developmental delay, andattention deficit hyperactivity disorder presented to the ERwith altered mental status and homicidal ideation. He re-ported smoking 4 cigarettes containing unknown substances,but there was a strong suspicion for K2 ingestion. He had re-ported a history of chest pain, which had resolved at the timeof presentation. His ECG revealed sinus tachycardia, with STelevation more pronounced in V2 and V3 (Figure 3, A;available at www.jpeds.com); there was evidence of RSR’(right ventricular conduction delay) in lead V1 initiallyconcerning for possible Brugada syndrome, but no furtherworkup was done in the absence of previous symptoms andfamily history. Troponin I level was elevated at 0.39 ng/mL,but normalized within 24 hours. A urine drug screen atadmission was negative. An echocardiogram showednormal intracardiac anatomy, normal coronary arteryorigins, normal biventricular function, no wall motion

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abnormalities, and no evidence of pericardial effusion. Thepatient was discharged from the medical service at 36 hoursafter presentation with an ECG showing ST elevation,though decreased from that seen at presentation (Figure 3,B). One month later, the patient presented to the ER for anunrelated complaint, at which time a repeat ECG showedno evidence of ST changes.

Additional Cases

Five patients in addition to the 3 case report patients whopresented for evaluation after using K2 had ECG changesconcerning for ischemia with normal serum markers(Table). All of the patients were adolescent malesexhibiting a variety of symptoms at presentation, includingchest pain, shortness of breath, syncope, and/orpalpitations. Evaluation included ECG, echocardiogram,and laboratory testing. The majority were observedovernight and discharged home the next day. In 1 patient,acute appendicitis was found incidentally on presentation,

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Table. Clinical information, ECG findings, laboratory and echocardiogram results for all patients with ECG abnormalities in the setting of K2 usage, both with andwithout abnormal serum markers

Age, y SexSigns andsymptoms

Timing ofK2 use ECG findings

Laboratorytest results

Echocardiographyfindings

Clinicalcourse

Case reports15 M AMS Day of presentation Initial: NSR, LVH, ST flattening in the

lateral leads, T wave inversion ininferior leads

Discharge: marked sinusbradycardia, possible LVH, ST-Twave elevation in precordialleads, T wave inversion in lead III

Troponin I 0.16 ng/mL on admission,negative at discharge

UDS: negative

Normal Observed inpatient; dischargedhome next day

16 M AMS Day of presentation Initial: NSR, ST elevation consideranterolateral injury or acuteinfarct, T wave inversion moreevident in inferior leads

Discharge: NA

Troponin I negative � 1UDS: positive for MJ

Normal Observed in ER until returned tobaseline mental status; did notattend outpatient cardiologyfollow-up

17 M AMS, homicidal ideation,chest pain

Day of presentation Initial: sinus tachycardia, possibleleft atrial enlargement, STelevation; consider anterolateralinjury or infarct, ST more elevatedin V2-V3

Discharge: NSR, possible left atrialenlargement, LVH, ST elevation;consider early repolarization,pericarditis, or injury

Troponin I 0.39 ng/mL on admission,negative at discharge

UDS: negative

Normal Observed inpatient for 36 hours andtransferred to psychiatry

Additional cases17 M Shortness of breath, labored

respirationsDay of presentation Initial: NSR, T wave inversion in lead

III, ST elevation in septal leadsDischarge: NSR, T wave flattening inlead III

Troponin I negative � 3UDS: negativeBNP: normal

Normal Observed inpatient; dischargedhome next day

15 M Palpitations, dizziness,weakness

Day of presentation Initial: intermittent ectopic atrialrhythm, ST elevation in leads II, III,and aVF

Discharge: Sinus bradycardia withSA, ST elevation; consider earlyrepolarization, pericarditis, orinjury

Troponin I negative � 2UDS: negative

Normal Observed inpatient; dischargedhome next day

18 M Chest and back pain 2-3 days beforepresentation

Initial: NSR; RSR’ in V1, J pointelevation in precordial leadsconsistent with earlyrepolarization

Discharge: NA

Troponin I negative � 1Abdominal ultrasound: acute

appendicitisUDS: positive for MJ

Normal Admitted for laparoscopicappendectomy; discharged homenext day

16 M Seizure Day of presentation Initial: sinus rhythm with marked SA,ST elevation in leads I and aVL

Discharge: Sinus bradycardia withsinus arrhythmia, earlyrepolarization

Troponin I: NAEtOH: positiveElevated CKUDS: positive for MJ

NA Observed inpatient; dischargedhome next day

16 M Syncope, palpitations Day of presentation Initial: sinus rhythm with SA, leftwardaxis; early repolarization;nonspecific ST-T changes

Troponin I: NAUDS: positive for TCA

NA Outpatient evaluation and discharge

M, male; AMS, altered mental status; NSR, normal sinus rhythm; UDS, urine drug screen; MJ, marijuana; BNP, brain natriuretic peptide; SA, sinus arrhythmia; EtOH, ethanol; TCA, tricyclic anti-depressant; NA, not applicable.

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and he underwent laparoscopic appendectomy withoutevent.

Discussion

Themain psychoactive component in synthetic cannabinoidsis delta-9-tetrahydrocannabinol (THC).13 The cardiac effectsof THC, both natural and synthetic, involve 2main receptors,CB1 and CB2, located in the myocardium, coronaryendothelium, and peripheral vasculature, as well as multipleother organ systems throughout the body. CB1 receptoractivity mediates negative inotropy in the myocardium viainhibition of norepinephrine release and stimulates vasodila-tion of the coronary endothelial vasculature. CB2 receptorsare located in multiple aspects of the cardiovascular system,including myocardium, coronary artery endothelium andsmooth muscle cells, myofibrolasts, and cardiomyocytes,and are thought to blunt the inflammatory response and toprotect against coronary reperfusion injury after an ischemicinsult.13 Although synthetic cannabinoids have shown somebeneficial effects via agonism of CB1 and CB2 receptors inrodent models, these effects and how they translate to humansubjects remain unclear.13

At low or moderate doses, THC causes an increase in sym-pathetic activity and inhibition of parasympathetic activity,often leading to tachycardia and increased cardiac output.14

Acutely, THC use can lead to a 20%-100% rise in heartrate, a slight increase in blood pressure, and up to a 30% in-crease in cardiac output.15 The tachycardia response andincreased catecholamine concentrations can be proarrhyth-mic, as well as increase myocardial oxygen demand. THCuse also causes an increase in carboxyhemoglobin, which de-creases the overall oxygen-carrying capacity, creating amismatch between increased oxygen demand and decreaseddelivery to the myocardium.7

At higher doses, THC can result in increased parasympa-thetic activity, leading to hypotension and bradycardia.14

The hypotension secondary to both parasympathetic activityand activation of CB1 receptors can lead to decreased coro-nary perfusion pressure, possibly further contributing tomyocardial ischemia.16 Other consequences of THC useinclude decreased atrioventricular node conduction, reducedleft ventricular ejection time, and decreased vascular resis-tance in skeletal muscle, leading to postural hypotension.15

Furthermore, the analgesic effects of THC can potentiallymask cardiac symptomatology and lead to delays in seekingmedical care. Mittelman et al8 found that in 3882 individualswith MI, 3.2% reported marijuana use in the 1 year beforepresentation. In this group, 37 patients smoked marijuanawithin 24 hours of their MI and 9 had smoked within1 hour of presentation. The risk of MI was 4.8 times higherin the latter group, and decreased to 1.7 times greaterbetween 1 and 2 hours after use.8

Mir et al11 reported 3 adolescent males who presented withchest pain in the context of smoking both K2 and marijuana.They demonstrated ST segment elevation on ECG, elevatedtroponin I levels to a maximum of 25 ng/mL, and normal

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echocardiograms. Two of the 3 patients underwent cardiaccatheterization, which revealed normal coronary arteries.McKeever et al10 reported a patient who presented withsubsternal pressure after smoking K2 and had evidence ofdiffuse ST elevation, worse in the inferolateral leads. Hehad an initial elevation in troponin I that increased duringhis hospitalization (peak, 8.29 ng/mL). He was treated witha combination of nitroglycerin, morphine, aspirin, Ativan,and Reglan, followed by nitroglycerin infusion and laterverapamil because of concerns about coronary vasospasm.Both echocardiogram and cardiac catheterization revealednormal findings, including normal coronary arteries.Other pediatric case reports have addressed the

arrhythmogenic effects of THC. Singh et al12 reported a14-year-old male who presented with palpitations, dizziness,and a fall after using marijuana and was ultimately found tohave atrial fibrillation necessitating digitalis therapy. Afterthe patient stopped smoking marijuana, he was able todiscontinue digitalis therapy and experienced no furtherrecurrence of arrhythmia. Daccarett et al4 reported a19-year-old male who presented with syncope aftermarijuana use who had ST elevation in leads V1-V2concerning for Brugada pattern without right bundlebranch block. Procainamide testing was negative, andechocardiogram was normal. Pratap and Korniyenko9

reported another 19-year-old male with palpitations andsyncope after marijuana use with ST elevation in V1-V2and incomplete right bundle branch block concerning forBrugada pattern. Troponins and CK-MB were negative,and echocardiogram was normal. Procainamide challengewas negative, and ST changes resolved on repeat ECG.Our subset of patients had a history of K2 inhalation and

evidence of significant ST elevation in a coronary distributionpattern with or without elevated troponin levels.Echocardiogram was normal in all patients who underwentechocardiography, and no patient required cardiaccatheterization. Even though these patients did not meetthe definition of MI based on ECG changes and elevatedtroponin levels, they did show evidence of myocardialischemia.K2 and other synthetic cannabinoids can potentially cause

significant cardiac effects secondary to tachycardia,decreased coronary perfusion, and mismatch of increasedoxygen demand and decreased oxygen delivery. Althoughthe reported incidence of MI related to K2 use is extremelylow, there may be a higher occurrence of myocardialischemia that goes unrecognized. The significance of this isunknown, and these patients may require long-term moni-toring for the development of wall motion abnormalitiesand other signs of decreased cardiac function. Furthermore,workups including ECG and troponin levels often are notperformed, owing to the absence of specific cardiac com-plaints. This is further complicated by the decreased regula-tion of synthetic cannabinoids; there may be additionalsubstances, such as amphetamines, contained within thedrug that may increase the risk of cardiac injury, leadingto an increased risk of coronary vasospasm. Compliance

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- 2015 CLINICAL AND LABORATORY OBSERVATIONS

with medical care and concern about legal issues may hinderhonest reporting during history taking. This may beespecially pertinent in adolescents.

Although the ECG abnormalities and increased serumtroponin levels were temporally associated with K2 use, wecannot absolutely identify a direct causal relationship ineach case. All echocardiograms performed, were normal,but the long-term consequences of K2 use and myocardialischemia are unknown and require long-term follow-upstudies. The lack of specific cardiac symptoms should notdeter healthcare providers from obtaining an ECG andpossibly cardiac enzyme tests. n

Submitted for publication Mar 20, 2015; last revision received May 1, 2015;

accepted Jun 2, 2015.

Reprint requests: Bradley C. Clark, MD, Division of Cardiology, Children’s

National Health System, 111 Michigan Ave NW, WW 3.0, Washington,

DC 20010. E-mail: brclark@childrensnational.org

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se in Pediatric Patients 5

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Figure 2. Case 2 ECG on presentation. Normal sinus rhythm, ST segment elevation in the anterolateral leads, and T waveinversions more evident in inferior leads.

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Figure 3. Case 3 ECG on A, presentation and B, discharge. A, Sinus tachycardia, possible left atrial enlargement, ST elevation;consider anterolateral injury or acute infarct; STmore elevated in V2-V3.B,Normal sinus rhythm, possible left atrial enlargement,LVH, ST elevation; consider early repolarization, pericarditis, or injury.

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