Download magnesium sulfate

THERAPY AND PREVENTION
Treatment of torsade de pointes with
magnesium sulfate
DAN TzIvONI, M.D., SHMUEL BANAI, M.D., CLAUDIO SCHUGER, M.D., JESAIA BENHORIN, M.D.,
ANDRE KEREN, M.D., SHMUEL GOTTLIEB, M.D., AND SHLOMO STERN, M.D.
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ABSTRACT Twelve consecutive patients who developed torsade de pointes (polymorphous ventricular tachycardia with marked QT prolongation, TdP) over a 4 year period were treated with intravenous
injections of magnesium sulfate. In nine of the patients a single bolus of 2 g completely abolished the
TdP within 1 to 5 min, and in three others complete abolition of the TdP was achieved after a second
bolus was given 5 to 15 min later. Nine of the patients also received continuous infusion of MgSO4
(3 to 20 mg/min) for 7 to 48 hr until the QT interval was below 0.50 sec. In nine of the 12 patients
the TdP was induced by antiarrhythmic agents. The QT interval preceding TdP ranged from 0.54 to
0.72 sec. After the MgSO4 bolus, which prevented the recurrence of TdP, no significant changes were
observed in the QT interval. There were no side effects of this treatment. In eight of the 12 patients
potassium levels before the TdP were below 3.5 meq/liter; magnesium levels were available in eight
patients before TdP, and were normal in all. Five additional patients with polymorphous ventricular
tachycardia but normal QT intervals (non-TdP patients) received two to three boluses of MgSO4. This
treatment was ineffective in all, but they responded to conventional antiarrhythmic therapy. Thus,
MgSO4 is a very effective and safe treatment for TdP, and its application is rapid and simple. Its use
is therefore recommended as the first line of therapy for TdP.
Circulation 77, No. 2, 392-397, 1988.
TORSADE DE POINTES (TdP) is a distinct form of
ventricular tachycardia occurring in patients with
marked QT prolongation. The conventional treatment
is aimed at shortening the QT interval by accelerating
the heart rate with isoproterenol infusion or by cardiac
pacing.
Three years ago we first reported our experience with
magnesium sulfate as a treatment for TdP in three
patients. Now with extended experience the role of
magnesium sulfate seems to be well established in the
treatment of patients with TdP.
Patients and methods
Twelve consecutive patients who developed TdP with QT
prolongation between March 1982 and December 1986 were
treated with magnesium sulfate. There were 10 women and two
men. Their ages ranged from 46 to 87 years (mean, 69 years).
Six patients had chronic ischemic heart disease, two had valvular
rheumatic heart disease, two had atrial arrhythmia, and two had
no signs of organic heart disease. Of the 12 patients nine were
on antiarrhythmic therapy: six received type 1 antiarrhythmic
drug only (quinidine, three patients; procainamide, three
patients), one received amiodarone alone, and two received a
From the Heiden Department of Cardiology, Bikur Cholim Hospital
and The Hebrew University Hadassah Medical School, Jerusalem.
Address for correspondence: Dan Tzivoni, M.D., Department of
Cardiology, Bikur Cholim Hospital, P.O. Box 492, Jerusalem, Israel.
Received Aug. 24, 1987; accepted Sept. 24, 1987.
392
combination of quinidine or procainamide with amiodarone. Of
the remaining three patients, one tried to commit suicide with
imipramine and thioridazine, one received furosemide alone,
and one had psychogenic polydipsia. Eight of the 12 patients
were on diuretic therapy.
Five additional patients with chronic ischemic heart disease
(two had acute myocardial infarction and three chronic congestive heart failure) developed polymorphous ventricular
tachycardia with normal QT interval and received magnesium
sulfate therapy, and their response was compared with that in the
TdP group.
TdP was diagnosed as a recurrent polymorphous ventricular
tachycardia in which the peaks of the QRS complexes twisted
around the isolectric line in a set up of marked QT interval
prolongation (figure 1). The QT intervals were measured in the
limb leads of the electrocardiogram when possible, from the
sinus beat immediately preceding the TdP. The corrected QT
interval (QTc) was calculated according to Bazett's formula.
Solutions of 25% or 50% MgSO4 were used. The magnesium
was given as an intravenous bolus of 2 g within 1 to 2 mn and
in most patients this was followed by a continuous infusion (3
to 20 mg/min).
Results
Magnesium sulfate was given intravenously to all 12
patients. Four of the patients received other modes of
therapy before the administration of magnesium sulfate. Two of them had received lidocaine because the
ventricular tachycardia was not diagnosed initially as
TdP, and the drug was ineffective in both. Three
CIRCULATION
THERAPY AND PREVENTION-ARRHYTHMIA
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FIGURE 1. A rhythm strip of TdP induced by quinidine. Note the marked QT prolongation before the ventricular arrhythmia,
the twisting of the QRS axis, and the spontaneous termination.
patients were treated with intravenous isoproterenol (1
to 5 g.g/min), which was effective in only one, and
because of intolerable palpitations had to be stopped.
Cardiac pacing was tried in one patient and was not
effective. In the other eight patients magnesium sulfate
was the only treatment given. A bolus of 2 g of MgSO4
was given intravenously to all 12 patients (table 1). In
nine of the patients the TdP was completely abolished
after this initial treatment. Three other patients who did
TABLE 1
Magnesium therapy for TdP
MgSo administration
Patient
No.
Bolus 1
(g)
1
2
3
4
5
6
7
8
9
10
11
12
2
2
2
2
2
2
2
2
2
2
2
2
Vol. 77, No. 2, February 1988
Bolus 2
Infusion
(g)
(mg/ml)
4
2
2
5
7.5
3
15
5
15
20
5
5
not respond completely to the first MgSO4 bolus
received a second bolus within 5 to 15 min. In nine
patients MgSO4 infusion was given at rates of 3 to 20
mg/min. In three of these patients the infusion was
given after a second bolus of MgSO4 was required,
while in the other six, it was given preventively. In two
patients the TdP recurred 1 to 6 hr after the intravenous
infusion of magnesium was begun; therefore another
bolus was given that was effective in both. Intravenous
infusion of MgSO4 was continued in nine of the
patients until the QT interval was shortened below 0.50
sec (7 to 48 hr).
Table 2 details the QT, QTc, potassium, and mag-
nesium levels in all patients before and after administration of magnesium. The QT intervals ranged from
0. 54 to 0.72 sec (mean, 0.61 sec) and the QTc intervals
ranged from 0.53 to 0.80 sec (mean, 0.64 sec). No
significant changes in the QT or QTc intervals were
observed in most patients immediately after magnesium therapy (table 2, figure 2). Serum potassium levels
before the development of TdP were below 3.5 meq/
liter in eight of 12 patients. These patients received oral
and intravenous potassium supplements after magnesium therapy was given. Magnesium levels were within
normal limits (1.6 to 2.5 meq/liter) at the time of the
arrhythmia in all eight patients in whom magnesium
levels were available.
393
TZIVONI et al.
TABLE 2
QT, QTc, potassium, and magnesium levels before and after magnesium therapy of TdP
After MgSO4 therapy
Before MgSO, therapy
Patient
No.
QT
(sec)
QTc
(see)
K+
(meq/1)
Mg+ +
(meq/1)
l
2
3
4
5
6
7
8
9
10
11
12
Mean
0U60
0.69
0.80
0.63
0.62
0.55
0.56
0.53
0.73
0.69
0.63
0.57
0.66
0.64
3.4
4.2
3.6
3.1
2.9
3.2
1.7
2.1
2.0
1.6
0.68
0.72
0.56
0.60
0.54
0.64
0.60
0.60
0.60
0.56
0.60
0.61
2.9
2.9
1.7
3.4
3.5
3.3
4.2
3.8
1.8
2.0
2.1
1.9
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patients suffering from ischemic heart disease developed recurrent polymorphous ventricular tachycardia
with normal QT intervals (figure 3). Four patients had
recurrent nonsustained polymorphous ventricular
.24
- -
---
4
QTc
(sec)
K+
(meq/1)
0.56
0.50
0.66
0.52
0.58
0.52
0.64
0.60
0.56
0.58
0.54
0.64
0.57
0.64
0.52
0.62
0.57
0.51
0.56
0.54
0.68
0.64
0.62
0.63
0.61
0.59
4.0
4.2
3.6
3.5
3.3
3.7
4.7
3.9
3.6
4.5
4.0
4.5
4.06
Mg+ +
(meq/1)
2.5
5
2.3
2.3
3.5
3.1
tachycardia and one had sustained polymorphous ventricular tachycardia (more than 30 sec) requiring several direct-current shocks. Three of the patients were
on antiarrhythmic therapy; one received ajmaline, one
disopyramide, and one lidocaine. The QT intervals
ranged from 0.38 to 0.49 sec (mean, 0.46). The potas-
Magnesium sulfate in patients with polymorphous ventricular tachycardia and normal QT interval. Five other
Vl
QT
(see)
V4
1
4
K
W4
Ww
Alttr-K>
4
-
4
o.lr4>X4 4- ';i; ~ ~ --~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~.....
V 4
1.
FIGURE 2. Rhythm strip 5 min after 2 g of intravenous magnesium sulfate, which suppressed the TdP. Note the marked QT
prolongation.
394
CIRCULATION
THERAPY AND PREVENTION-ARRHYTHMIA
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QT=0.44sec
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FIGURE 3. Polymorphous ventricular tachycardia with normal QT induced by disopyramide. Three boluses of magnesium
sulfate were given intravenously but were ineffective.
sium levels at the time of the ventricular tachycardia
ranged from 3.1 to 4.3 meq/liter (mean, 3.7). Serum
magnesium levels before the ventricular tachycardia
were available in two of the patients, and were normal
in both. MgSO4 was given as a 2 g bolus to all patients
and was inelfective in all. A second bolus was therefore
given and two of the patients received a third bolus that
was also ineffective; another antiarrhythmic drug was
therefore administered. Three patients responded to
intravenous lidocaine and two to procainamide.
Discussion
Since the first description of TdP by Dessertenne,2
controversy has existed as to whether polymorphous
ventricular tachyarrhythmias associated with a normal
QT interval should also be called TdP. Our group3 and
others4-7 have expressed their opinion that the term
Torsade de pointes should be reserved only for a ventricular tachycardia with a polymorphous appearance
that is associated with marked prolongation of the QT
interval, since the presence of the QT prolongation
mandates completely different therapy.
The treatment of TdP was the subject of many
reports. The aim of the treatment has been to shorten
the delayed repolarization by increasing the heart rate
Vol. 77, No. 2, February 1988
with the infusion of isoproterenol j atrial or ventricular
pacing,9'10 or atropine. Isoproterenol is an effective
mode for accelerating the heart rate and thereby shortening the QT interval. However, this drug is contraindicated in patients with acute myocardial infarction,
angina pectoris, or hypertension. In some patients it
may cause intolerable side effects, such as severe palpitations, and in others it may be ineffective. " 8 Furthermore, use of isoproterenol may be fatal if it is given
to patients with a ventricular tachycardia that is not TdP
(without QT prolongation). Cardiac pacing is an effective and safe method for treating TdP,8 9 but its application requires certain skills and equipment and therefore it can not be applied in an ambulance or in every
emergency room, and even if skilled personnel and
equipment are available there is a considerable delay
between the time of diagnosis of TdP and the initiation
of cardiac pacing.
The role of magnesium in ventricular tachyarrhythmias has been the subject of several clinical
investigations. 1t113 Magnesium sulfate was used
empirically for many years as a treatment for atrial and
ventricular arrhythmias in patients with normal or low
magnesium levels,14-17 in patients with digitalis toxicity, and in alcoholics.
395
TZIVONI et al.
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In 1984 we reported the first three patients with TdP
who were successfully treated with MgSO4.1 In the
present report we describe our extended experience in
12 patients with TdP, all of whom responded to intravenous magnesium sulfate. In eight of the patients
magnesium was the only therapy given, while in four
others initial therapy failed and therefore magnesium
sulfate was given. The treatment with magnesium sulfate consisted of an initial bolus of 2 g, given within
1 to 2 min. In nine of the 12 patients this was associated
with complete eradication of TdP and most ventricular
premature beats. In three patients, only a partial
response was observed and therefore a second bolus
was given 5 to 15 min later. Infusion of magnesium
sulfate (3 to 20 mg/min) was given to nine of the
patients after the initial bolus. In three of them it was
given because of partial response to the initial bolus,
while in the others it was given preventively. It seems
to us that if a complete response is observed after the
first bolus of 2 g no further therapy is required, while
in patients with no or a partial response a second bolus
is indicated together with continuous infusion of 3 to
10 mg/min. In two of our patients TdP recurred after
few hours of continuous infusion of magnesium and
another bolus abolished it. In the nine patients in whom
a continuous infusion of magnesium was given, the
indication for cessation of infusion was shortening of
QT below 0.50 sec, which occurred within 7 to 48 hr.
Except for flushing sensations during the bolus injection no side effects were noted.
As in many previously reported cases of TdP, eight
of our 12 patients suffered from hypokalemia (K level
below 3.5 meq/liter). Therefore, in addition to the
administration of MgSO4, these patients received intravenous and oral potassium supplements. Serum magnesium levels were available in eight of the 12 patients
and in all it was within normal range. Thus, the TdP
could not be attributed to serum hypomagnesemia.
Intracellular magnesium levels were not available in
our study.
The effect of magnesium sulfate was assessed in five
additional patients with polymorphous ventricular
tachycardia and a normal QT interval. Two to three
boluses of magnesium sulfate were given (4 to 6 g) to
these patients without any response. Subsequent conventional therapy for ventricular tachycardia with lidocaine or procainamide was given with satisfactory
results. Thus, MgSO4 is not effective in the treatment
of patients with polymorphous ventricular tachycardia
without QT prolongation.
The mechanism of action of MgSO4 is not understood. Unlike isoproterenol infusion and cardiac pac396
ing, MgSO4 prevented the recurrence of TdP without
shortening the QT interval. The fact that the QT interval
remained unchanged despite the suppression of the
ventricular arrhythmia suggests that the salutary effect
of magnesium is not related to shortening of repolarization. Since magnesium is a cofactor in the sodiumpotassium ATPase activity, it may have prevented the
TdP by facilitating influx of potassium into the cells,
thereby stabilizing membrane potential, correcting the
dispersed repolarization process without shortening it.
It is well known that various drugs that cause QT
interval prolongation are capable of inducing
TdP.4 7, 18, 19 It has been suggested that asynchronous
recovery of excitability is a predisposing factor for
reentrant ventricular arrhythmias.20 Dispersion of
refractoriness has been demonstrated in a number of
conditions, such as left stellate ganglion stimulations,
myocardial ischemia, hypothermia,21 and also after premature stimulation or pacing at a long cycle length. The
recently described observation that the last supraventricular beat (before the initiation of TdP) is almost always
preceded by a long cycle length (either postextrasystolic
pause or bradycardia) favors this hypothesis. On the
other hand, the inability to induce TdP in the laboratory
by premature electrical stimulation22 is a serious argument against a reentrant mechanism for TdP.
Dessertenne,2 in his original description of TdP,
suggested that this arrhythmia may be a result of the
activity of two automatic foci. Naumann et al.,23 who
succeeded in building a model of TdP-like arrhythmia
in isolated pig hearts by simultaneous pacing from both
ventricles, also suggested that the tachycardia is a result
of the interference of two separate foci acting at two
different rates. On the other hand, Bhargava et al.24
presented evidence against the multiple focal cause for
TdP, based on their results of spectral-analysis data of
the electrocardiograms of three patients with TdP; they
suggested that the origin of the tachycardia is in a single
ectopic center, migrating around the ventricles in a
periodic way. Triggered activity and afterdepolarization may play a role in the initiation and/or perpetuation
of TdP.22 Jackman et al.25 succeeded in inducing TdP
in dogs with cessium cloride, which in vitro prolongs
repolarization and induces bradycardia-dependent
early afterdepolarization and triggered activity. The
ionic mechanism responsible for afterdepolarization is
not clear. Intracellular calcium may play a role as an
oscillatory modulator of inward currents that are not
specific and are probably responsible for the
afterdepolarization.26
Kass et al.27 suggested that the phasic movement of
calcium in and out the sarcoplasmic reticulum as a
CIRCULATION
THERAPY AND PREVENTION-ARRHYTHMIA
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result of intracellular gain of sodium and loss of potassium might cause transient inward currents and transient depolarization and that high magnesium levels
block, and low magnesium levels potentiate, the phasic
movement. It is possible also that magnesium deficiency may lead to influx of calcium and may be the
primary cause of intracellular potassium loss.28' 29
Because of the properties of magnesium as a modulator
of calcium ions it has been called "nature's physiologic
calcium blocker."30 In the light of the above discussion
it seems to us that the effectiveness of intravenous
magnesium therapy in patients with TdP might be
related to suppression of oscillatory currents responsible for afterdepolarization.
From our experience with the above-described 12
patients with TdP who were effectively treated with
MgSO4, it is our recommendation that this treatment
should be used as the first line of therapy for patients
suffering from this disorder. This treatment is not only
very effective, but is also safe and easily applied, and
the response is very rapid.
References
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397
Treatment of torsade de pointes with magnesium sulfate.
D Tzivoni, S Banai, C Schuger, J Benhorin, A Keren, S Gottlieb and S Stern
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Circulation. 1988;77:392-397
doi: 10.1161/01.CIR.77.2.392
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