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Case Report

Double jeopardy

Damien Cullington a,*, Natalie Dunford b, Stephen Beer b, Neil Hobson a,Sudipta Chattopadhyay b, Joseph John b

aCastle Hill Hospital, Castle Road, Cottingham, Kingston-Upon-Hull HU16 5JQ, UKb Scunthorpe General Hospital, UK

a r t i c l e i n f o

Article history:

Received 27 July 2012

Accepted 3 April 2013

Available online 19 April 2013

Keywords:

Methadone

Long QT

Torsades

Temporary Pacing

* Corresponding author. Tel.: þ44 (0) 1482 62E-mail address: damiencullington@hotm

0019-4832/$ e see front matter Copyright ªhttp://dx.doi.org/10.1016/j.ihj.2013.04.016

a b s t r a c t

Torsades de pointes (“twisting of points”) (TdP) is a broad complex tachyarrhythmia which

was first described in 1966 by Francois Dessertenne and usually results from prolongation

of the QT interval.1 A wide variety of drugs have been shown to prolong the QT interval in

susceptible individuals.2 We present the case of a former intravenous heroin user pre-

senting with several episodes of TdP which were caused by QT prolongation due to

methadone treatment and exacerbated by hepatitis B/C infection. Despite aggressive

medical treatment and withdrawal of methadone, he had recurrent episodes of TdP which

required continuous temporary cardiac pacing for six days. He was found to have moderate

LV dysfunction on his echocardiogram and unobstructed coronary arteries on coronary

angiography. He underwent implantation of a defibrillator due to concerns about further

episodes of ventricular arrhythmias which could recur even in the absence of further

methadone use.

Copyright ª 2013, Cardiological Society of India. All rights reserved.

1. Introduction 2. Case presentation

Prolongation of the QT interval is a known side effect of

methadone therapy. Patients with a history of hepatitis,

however, who are prescribed methadone may be at greater

risk of hazardous QT interval prolongation compared to pa-

tients with no prior history of liver disease. Patients intending

to start a methadone programme should have an ECG recor-

ded before starting methadone, after 30 days of therapy and

after a change in dosage. ECGs should then be performed on

an annual basis. The acute management of TdP will vary from

one institution to another but when transvenous pacing is not

available, a variety of therapeutic measures can usually sta-

bilize a patient.

4 073; fax: þ44 (0) 1482 62ail.com (D. Cullington).2013, Cardiological Societ

A 43-year-old man presented to his general practitioner (GP)

with a history of several “panic attacks” and paroxysms of

dyspnea occurring over the previous 24 h.While attending the

GP surgery he was syncopal in the waiting room and required

a short period of cardiopulmonary resuscitation. He had no

preceding chest pain, dyspnea or palpitations. On arrival to

the emergency department, a further episode of syncope

occurred and the cardiac monitor recorded a broad complex

tachyarrhythmia. To restore hemodynamic stability, electrical

cardioversion was required (Fig. 1).

Our patient had no previous history of cardiovascular

problems. He was a former intravenous heroin user, hepatitis

B and C positive and enrolled in a drug treatment program. He

4 071.

y of India. All rights reserved.

Fig. 1 e ECG rhythm strip showing torsades de pointes.

i n d i a n h e a r t j o u r n a l 6 5 ( 2 0 1 3 ) 3 1 5e3 1 8316

was prescribed 140 mg of methadone per day by his GP but

supplemented his prescription with illicitly bought metha-

done. His cumulative daily dose was approximately 170 mg

per day. He was not prescribed any other medications and

denied consumption of any other over-the-counter drugs.

There was no family history of sudden cardiac death or

inherited channelopathies.

Review of cardiac telemetry and rhythm strips showed that

the broad complex tachyarrhythmia was torsades de pointes

(TdP). Once cardioverted back to sinus rhythm, the corrected

QT interval (QTc), calculated using Bazett’s formula, was

654 ms (Fig. 2a).

An urgent biochemical profile showed that he was nor-

mokalaemic, normomagnesemic and marginally hypo-

calcaemic: Na 136mmol/L; K 3.5mmol/L; Ur 5.5 mmol/L; Creat

93 mmol/L; Mg 0.87 mmol/L; Adj Ca 2.15 mmol/L. His liver

function tests were mildly deranged: ALT ¼ 60 u/L;

GGT ¼ 202 u/L; Bili 9 mmol/L; ALT 60 u/L; Alb 38 g/L. He was

given 2 g of intravenous magnesium sulphate (8 mmol) and IV

potassium supplementation (80 mmol potassium chloride

over 24 h). Three further episodes of sustained TdP occurred

which required cardioversion and a magnesium infusion was

commenced (72 mmol magnesium sulphate mixed with

100 ml 0.9% saline infused at 2.5 mmol/h).

Initial medical therapy was unsuccessful therefore a tem-

porary pacing wire was inserted via the right femoral vein and

positioned at the RV apex. He was “overdrive” paced at a rate

of 90 bpm. Several attempts were made to withdraw tempo-

rary pacing but due to recurrent episodes of TdP, this needed

continuation for the following six days. His QTc shortened to

533ms and no further episodes of TdP occurred (Fig. 2b). Daily

ECGs were performed and the QTc normalized (340 ms) 3

weeks after stopping methadone (Fig. 2c). Transthoracic

echocardiography showed that he had moderate left ventric-

ular dysfunction. Coronary angiography showed no obstruc-

tive coronary artery disease. He was commenced on

bisoprolol, ramipril and spironolactone.

His methadone was stopped on admission and replaced

withmorphine sulphate tablets, titrated up to a dose of 150mg

bd. He was transferred to the regional cardiology center and

after discussion with electrophysiology specialists underwent

implantation of a cardiac defibrillator. Since implantation, he

has not had any therapies or shocks from his defibrillator and

remains well.

3. Discussion

Methadone is an opioid receptor antagonist and is extensively

prescribed to treat opioid dependence. Prolongation of the QT

interval in methadone users is common and may be seen in

up to 30% but TdP is relatively rare and seen in less than

0.5%.3,4 Patients prescribed higher doses of methadone are at

greater risk of significant lengthening of the QTc (�500 ms)

and TdP.4,5 There is no specific methadone dose which is

associated with hazardous prolongation of the QTc. However,

methadone doses <40 ml per day are unlikely to cause haz-

ardous prolongation of the QTc (i.e. >500 ms), and <70 ml per

day are unlikely to cause TdP.4 Neither the methadone dose

nor baseline QTc can accurately predict the development of

significant lengthening of the QTc resulting in TdP, hence

periodic ECG monitoring is essential. Similar unpredictable

patterns of QTc lengthening tomedicationswhich prolong the

QT interval occur in healthy subjects and those with a history

of TdP.6,7

Methadone causes lengthening of the QTc as it blocks the

delayed rectifier potassium ion channel IKr. It is metabolized

by the liver, mostly by the cytochrome P450 3A4 enzymes.

Hepatitis C co-infection in patients with HIV is a significant

independent risk factor associated with a prolongation of the

QTc interval.8 The mechanism by which this is mediated is

not fully understood. Previous hepatitis may cause chronic

hepatic dysfunction which slowsmethadonemetabolism and

results in supranormal serum levels of methadone.

It is advisable that patients who are prescribed methadone

have a baseline ECG tomeasure theQTc interval and then have

annual ECGs toensure that this isnot significantly lengthening.

Additional drugs which prolong the QT interval should be

avoided if at all possible. The Bazett formula is used to calcu-

lated theQTc ðmsÞ ¼ QT interval ðmsÞ=OR-R interval ðmsÞ.9We

would suggest that if the QTcmeasures � 490 ms, reduction of

the methadone dose or substitution for buprenorphine should

be considered.

Fig. 2 e a: 12 Lead ECG performed following DC cardioversion showing prolongation of the QTc interval. Using Bazett’s

formula the QTc measured 654 ms. b: 12 Lead ECG performed during RV overdrive pacing showing shortening of the QTc

interval. Using Bazett’s formula, the QTc measured 533 ms. c: 12 Lead ECG performed after 3 weeks following withdrawal of

methadone showing normalization of the QTc interval. Using Bazzet’s formula, the QTc measured 340 ms.

i n d i a n h e a r t j o u rn a l 6 5 ( 2 0 1 3 ) 3 1 5e3 1 8 317

i n d i a n h e a r t j o u r n a l 6 5 ( 2 0 1 3 ) 3 1 5e3 1 8318

The key aspects of clinical management to treat TdP are i)

correct electrolyte disturbances (Kþ, Mg2þ, Ca2þ); ii) cease any

medications which prolong the QTc; iii) administer 2 g IV

magnesium over 1e2 min, repeated if necessary after

5e15min iv) increase the heart rate to reciprocally shorten the

QTc.10 Patients with episodes of TdP, which recur despite

intravenous magnesium sulphate and during correction of

electrolytes, should ideally be transvenously paced at rates

�90 per minute.11,12 Although amiodarone commonly in-

creases the QTc interval, it is safe and rarely causes TdP when

used chronically.13 However, in the acutemanagement of TdP,

amiodarone should be avoided since it may be pro-

arrhythmic. Intravenous isoprenaline or atropine infusions

can increase heart rate and shorten the QTc and repeated

administration of IV magnesium boluses or a magnesium

infusion (3e20 mg/min) can successfully treat TdP but these

measures should be used viewed as bridging measures until

temporary pacing is organized.11,14

Up to 20%of subjectswith drug inducedTdPmayhave forme

fruste varieties of the LQTS which may be ‘unmasked’ by QT

prolonging drugs or electrolyte disturbances.15 Genetic testing

for longQTsyndromemutationsmaybe considered for the index

case and recording a 12 lead ECG is recommended for first-

degree relatives.16 It is possible that our patient had exces-

sively high serum levels ofmethadone due to impaired hepatic

metabolism, changing the predicted pharmacokinetic profile,

but we were unable to confirm this. Although the pharmaco-

logical trigger for QT prolongation was stopped on admission,

our patient underwent elective implantation of a defibrillator.

In some patients who have experienced drug induced TdP, the

recurrence risk of TdP may remain elevated despite cessation

of offending medications.17 Patients with an opiate addiction

are at high risk of recidivism, and for some patients with

intractable methadone dependence, implantation of a defi-

brillator may be necessary as a precautionary measure.18

4. Learning points

1. The normal QTc interval in men <430 ms and in women

<450 ms. A baseline ECG should be performed before pre-

scription of methadone, annually thereafter and if the dose

is uptitrated >100 mg/day.

2. Risk of QT prolongation is increased for females, electrolyte

disturbance (hypokalemia, hypomagnesemia, hypocalce-

mia), CYP3A4 inhibiting drugs, hepatic dysfunction,

concomitant prescription of QT prolonging drugs, left

ventricular dysfunction and high doses of methadone.

3. Consensus guidelines have suggested that if the QTc in-

creases between 450 and 500 ms, discussion of pros and

cons of continued methadone treatment, avoidance of QTc

prolongingmedications andmore frequent ECGmonitoring

should occur. If the QTc increases above 500 ms, with-

drawal of other exacerbating drugs/electrolyte disturbance,

reducing the methadone dose or substitution with an

alternative is advisory.19

4. Initial medical management of TdP includes IVmagnesium

and correction of electrolytes. Early institution of overdrive

pacing is an effective remedy for drug induced TdP in cases

which are refractory to medical therapy. Where temporary

pacing is not immediately available, isoprenaline or atro-

pine can be used as bridging therapy.

5. An excellent reference regarding what drugs prolong the

QT interval can be found at www.qtdrugs.org.

Conflicts of interest

All authors have none to declare.

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