Long QT Syndrome Unmasked by Dexmedetomidine:A Case Report

Kristin M. Burns, MD, and E. Anne Greene, MD

Children’s National Medical Center, Washington, DC, USA

A B S T R A C T

Dexmedetomidine is a selective alpha-2 adrenergic agonist that is used frequently for short-term sedation inchildren. It has been noted to cause hypertension, hypotension, bradycardia, and sinus pauses; however, QTcprolongation has not been reported with dexmedetomidine administration. We describe a case of marked QTprolongation with use of dexmedetomidine in a pediatric critical care setting. Clinicians should be vigilantabout potential QT prolongation in patients on dexmedetomidine, particularly in those receiving multiple othermedications.

Key Words. Pediatric Cardiology; Dexmedetomidine; QT Prolongation; Pediatric Critical Care

Introduction

Dexmedetomidine is an alpha-2 adrenergicagonist that has been gaining popularity for

sedation in pediatric intensive care unit settings.1–3

It is currently not approved by the Food and DrugAdministration for use in children but is beingused off-label. By purportedly maintaining venti-lation and airway patency, it is thought to have anadvantage over other types of sedatives. Thereported cardiovascular effects of dexmedetomi-dine are hypertension, hypotension, bradycardia,and sinus pauses. Although dexmedetomidine hasactivity on the cardiac conduction system at thelevels of the sinus and atrioventricular (AV) nodes,excessive QTc prolongation has not been previ-ously well-recognized.4–9

Case Presentation

The patient’s mother and the local InstitutionalReview Board gave written permission for theauthors to publish this report.

A 22-month-old male with a history of repairedleft-sided congenital diaphragmatic hernia, leftlung hypoplasia, and severe asthma was admittedto the pediatric intensive care unit with compli-cated pneumonia.

His medical history is significant for persistentpulmonary hypertension of the newborn related tocongenital diaphragmatic hernia. In the neonatalperiod, he required extracorporeal membraneoxygenation (ECMO) support. He has severeasthma and has been hospitalized multiple timesfor pneumonia. He also has a distant history ofsupraventricular tachycardia (without manifestpreexcitation) and was treated with digoxin forseveral months after birth, with no recurrence ofarrhythmia. His family history is negative forsudden death. The patient’s mother has had severalepisodes of syncope.

On admission to the pediatric intensive careunit, he was placed on supplemental oxygen andunderwent thoracostomy for a significant leftpleural effusion. Two days after admission, hedeveloped respiratory failure and required intuba-tion. He initially received morphine and mida-zolam infusions for sedation; however, after 66hours, he was transitioned to morphine (0.12 mg/kg/h) and dexmedetomidine infusions (1 mcg/kgloading dose followed by a titrated infusion rate of0.3–0.7 mcg/kg/h) in preparation for extubation.Four hours after starting the dexmedetomidineinfusion, he developed sinus bradycardia but hadno significant fluctuations in blood pressure. Eighthours later, he was noted to have giant T waves onthe cardiac monitor. An electrocardiogram (MAC5500 Resting ECG Analysis System, GE Health-

Funding: There were no external sources of funding forthis case report.

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care, Milwaukee, WI, USA) revealed profoundQTc prolongation (700 milliseconds) with T-wavealternans, a precursor to torsades de pointes.10

(Figure 1)At the time of this marked change in his elec-

trocardiogram, he had not received an albuteroltreatment for 3 days, and he was not receiving anyother medications known to prolong the QT

interval (Table 1). Laboratory analysis at the timewas notable for mild hypocalcemia, thereforecalcium gluconate was given for repletion. (Capil-lary blood gas: pH 7.55, pCO2 45 mm Hg, pO2

59 mm Hg, base excess 15; ionized calcium1.01 mmol/L, magnesium 1.8 mg/dL, and potas-sium 3.7 mmol/L). Trends in blood gases and elec-trolytes revealed a transient respiratory acidosis 21

Figure 1. Electrocardiogram on dexmedetomidine infusion. This electrocardiogram demonstrates a QTc interval of 700milliseconds with large T waves and an alternating T-wave morphology stereotypical of T-wave alternans.

Table 1. Medications and Time Intervals of Administration

HomeMedications

Intubation toDexmedetomidine(66 hours)

Dexmedetomidine(20 hours)

QTcProlongation

Discontinuation ofDexmedetomidine toExtubation (10 hours)

Extubation toQTc Normalization(64 hours)

Albuterol X XBudesonide X X X X X XHydrochlorothiazide-

spironolactoneX X X X X X

Ipratropium X X X X X XLansoprazole X X X X X XFentanyl XRocuronium XVecuronium XMidazolam X X XMorphine X X X X XDexmedetomidine X XVancomycin X X XCeftriaxone X X X X XFurosemide X X X X XMethylprednisolone X X X XAcetaminophen X X X X XDocusate X X X X XGlycerin XPolyethylene glycol X XCalcium gluconate XMagnesium sulfate X

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to 26 hours prior to the event. The lowest potas-sium level was 3.3 mmol/L 14 hours earlier(Figure 2).

The dexmedetomidine infusion was discontin-ued, and he was extubated without difficulty 10hours later. Five hours after discontinuation ofdexmedetomidine, his QTc interval decreasedfrom 700 milliseconds to 473 milliseconds, and theQTc interval normalized to 439 milliseconds overthe next 3 days (Figure 3). He did not developtorsades de pointes or other arrhythmias.

Given his history of neonatal supraventriculartachycardia, 14 previous electrocardiograms wereavailable for review. The most recent electrocar-diogram 15 months prior to this incident hada QTc interval of 427 milliseconds. At thattime, the patient was receiving albuterol, digoxin,hydrochlorothiazide-spironolactone, ipratropium,metoclopramide, prednisolone, and ranitidine. Allother prior QTc intervals were normal (356–442milliseconds) except on one electrocardiogramperformed on day of life 3 while on ECMO thathad a prolonged QTc interval of 490 milliseconds.A 24-hour Holter monitor placed during this hos-pitalization after normalization of the QTc intervaldid not reveal any heart block or significant ectopybut did show variable T-wave morphology atlower heart rates, suggesting abnormal repolariza-tion. Genetic testing was negative for gross dele-tions or duplications of the 12 genes analyzed forlong QT syndrome by targeted comparativegenomic hybridization analysis with exon-levelresolution. (The 12 genes tested account for atleast 75% of long QT syndrome cases.)

Clinical suspicion for long QT syndrome type 2remained quite high; therefore, he was maintainedon a potassium-sparing diuretic and started onmagnesium supplementation.

However, due to a history of severe asthma, thepatient was not started on beta-blocker therapy.

Discussion

The cardiovascular effects of dexmedetomidinehave been studied in children with and withoutcongenital heart disease. In large doses, dexme-detomidine causes peripheral vasoconstriction andsubsequent transient hypertension. Low doseshave a sympatholytic effect, leading to hypoten-sion. This effect can be attenuated by omission ofthe loading dose or by infusing the loading doseslowly.9,11 Despite its ability to increase systemicvascular resistance, dexmedetomidine has notbeen found to increase pulmonary artery pres-sures in children after congenital heart diseasesurgery.12

The effects of dexmedetomidine on the con-duction system have been studied in childrenundergoing electrophysiology study and catheterablation. Dexmedetomidine was found to depressboth sinus and AV-nodal function. QTc intervalssignificantly increased in the study, but no patientdeveloped an abnormally prolonged QTc.6 Onecase report described QTc prolongation in the

Figure 2. Trends in blood gases and electrolytes. Thesegraphs illustrate changes in capillary blood gas pH, potas-sium, and ionized calcium levels during the time from res-piratory failure to initiation of dexmedetomidine, duringdexmedetomidine infusion, from discontinuation of dexme-detomidine to extubation, and from extubation to normaliza-tion of QTc interval. Time is expressed in hours relative tothe time of QTc prolongation.

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context of anesthesia reversal with neostigmine.The patient described also received dexmedetomi-dine during the case.13

The effects of dexmedetomidine on patientswith congenital heart disease have been notable forbradycardia, but normal QTc intervals.8 Althoughthere has been evidence of delayed conductionthrough the sinus and AV nodes, abnormalities inthe QTc interval have not been reported.

To our knowledge, this is a unique case of likelycongenital long QT syndrome unmasked by theuse of dexmedetomidine. The clinical constella-tion is suggestive of type 2 long QT syndrome,caused by a defect in the human ether-a-go-go-related gene (HERG), which encodes a potassiumchannel protein. This protein regulates the rapidlyactivated component of the delayed rectifier potas-sium current (IKr) that stabilizes the repolarizationprocess. Mutations that reduce the IKr currentprolong the action potential. The same IKr currentis blocked by most drugs that prolong the QTinterval. Silent genetic defects in potassiumchannel genes may lead to “reduced repolarizationreserve,” whereby repolarization currents aregenetically reduced. In such genetically suscep-tible individuals, environmental factors such ashypokalemia or medications may then unmask thedefect and cause torsades de pointes.14,15

Studies in rats have demonstrated that dexme-detomidine is capable of blocking adenosine

triphosphate-sensitive potassium channels incardiac tissue.16,17 Further research into whetherdexmedetomidine also blocks cardiac IKr channelsmay help to clarify the cardiac effects of thisimportant medication.

Although this patient had reentrant supraven-tricular tachycardia as an infant and now likely haslong QT syndrome, we are unaware of any knownassociation of these two disease entities.

Most likely, the additive or synergistic effects ofmetabolic factors, dexmedetomidine and otherconcomitant medication use, and genetic predispo-sition likely led to this patient’s dramatic presenta-tion. He illustrates a particular challenge formanagement, as his asthma precludes use of betablocker therapy for treatment of long QT syn-drome, and his predilection for pneumonias andasthma exacerbations has necessitated treatmentwith agents such as albuterol and macrolide antibi-otics, which are known to prolong the QT interval.

With increasing use of dexmedetomidine in thepediatric critical care setting, providers should bevigilant about the potential for QT prolongationin susceptible patients on dexmedetomidine.

Author Contributions

Kristin M. Burns: concept/design, data collection, dataanalysis/interpretation, drafting of the article, and criticalrevision of the article; E. Anne Greene: concept/design,

Figure 3. Electrocardiogram 3 days after cessation of dexmedetomidine use. This electrocardiogram reveals a QTc intervalof 439 milliseconds and is completely normal for age.

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data analysis/interpretation, and critical revision of thearticle.

Corresponding Author: Kristin M. Burns, MD, Divi-sion of Cardiology, Children’s National MedicalCenter, 111 Michigan Avenue, NW, WW3-200, Wash-ington, DC 20010, USA. Tel: 202-476-2020; Fax: 202-476-5700; E-mail: kburns@childrensnational.org

Conflict of interest: None.

Accepted in final form: January 24, 2013.

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