Iohexol contrast medium induces QT prolongation in amiodarone patients

Abstract

Aims

Amiodarone is widely used in ventricular tachyarrhythmias and atrial fibrillation, known to prolong QT-intervals. Concurrent administration of drugs prolonging QT- time can induce life-threatening ventricular tachyarrhythmia.

Methods

QT-interval changes following use of Iohexol contrast-medium for coronarangiography were observed comparing 21 patients taking long-term amiodarone therapy with 21 controls not taking amiodarone or QT-prolonging drugs retrospectively.

Results

Concurrent use of Iohexol and amiodarone was associated with significant prolongation of QTc-interval (433, 95%CI: 419–448 ms vs. 480, 95%CI: 422–483 ms, P < 0.001) the day after coronarangiograpgy. 6/21 patients showed severe prolonged QTc-interval of >500 ms.

Conclusion

Caution is advised until more is known about pro-arrhythmic effects of Iohexol.

Introduction

Amiodarone is a class lIl anti-arrhythmic agent, which is widely used in the treatment of life-threatening ventricular tachyarrhythmias [1–3] and atrial fibrillation [4]. Amiodarone has generally been classified as a Vaughan Williams class III agent, prolonging repolarization by inhibition of outward potassium channels. Its class III activity results in prolongation of the QT interval. Combined use with other drugs prolonging repolarization may cause serious arrhythmogenic side effects. These effects are known for instance for antibiotics, antipsychotics, and antidepressants [5].

It is also well established that contrast media affect cardiac physiology when injected into the coronary arteries and can induce electrophysiological effects involving regional disturbances of depolarization and repolarization [6]. Iohexol, a low-osmolality and nonionic compound, causes an increase in resting potential, amplitude and action potential duration, and decreases refractory period of the myocardium [7, 7]. Clinically, Iohexol can induce a slowing of heart rate and prolongation of the QT interval, which, however, is more pronounced in other contrast media [8].

In the rabbit model Iohexol induces polymorphic ventricular tachycardia in the presence of QT interval lengthening induced by class III antiarryhthmic agents [9]. Patient data on the interaction of amiodarone and Iohexol contrast medium are not available. Therefore we retrospectively analyse ECG findings in amiodarone patients having undergone cardiac catheterization with Iohexol contrast medium.

Methods

We retrospectively screened a database of patients having undergone cardiac catheterization at the University Hospital of Jena during the past four years (1999–2002). 36 of those patients were found to have had amiodarone pretreatment. Routine ECG recordings on the day of cardiac catheterization and on the day after were available in 21 amiodarone patients (AMIO). A control group (CON) was established by randomly selecting 21 age-matched patients who had received cardiac catheterization without prior amiodarone nor other QT prolonging treatment. In each case, Iohexol (Accupaque 350^®, Amersham Health AS, Oslo, Norway) was used as contrast medium, and the serum potassium levels were normal. Left ventricular ejection fraction was 0.458, 95%CI: 0.378–0.539 in AMIO and 0.609, 95%CI: 0.509–0.708 in CON.

The heart rate (HR) and the QT intervals (QT) of AMIO and CON were derived from the ECG prior to catheterization and the day after catheterization. ECGs were read blind with a 12-channel electrocardiograph (Cardioscript CU 12, Picker GmbH, Munich, Germany) using bipolar limb leads introduced by Einthoven and unipolar precordial leads introduced by Wilson. Bazett's correction for heart rate was applied () where RR is the interbeat interval). QTc intervals in excess of 500 ms were considered severely prolonged. QT% was determed by QT-normograms of Lepeschkin [10].

The unpaired samples t-test and 95% confidence intervals (95%CI) for changes were performed to compare HF, QT% and QTc before and after catheterization. The study was approved by the ethics board of the Friedrich Schiller University of Jena.

Results

In the AMIO group, the uncorrected QT interval as well as the QT interval corrected for heart rate (QTc), were significantly increased after catheterization. QTc increased on average by 10% from 433 (95%CI: 419–448) to 480 (95%CI: 422–483 ms) (P< 0.001). The results are shown in. Table 1. An example of QT prolongation due to Iohexol and with subsequent return to normal after 48 h is shown in Figure 1. QTc prolongation > 500 ms had been observed in none of the AMIO patients before catheterization, however, 6/21 [28%] of AMIO patients had a severely lenghthened QTc interval after catheterization. No significant change was seen in the CON group.

Table 1. Repolarization interval measurements in AMIO and CON.

	Parameter	Prior to angiography	Day after angiography	t-test
AMIO	HR	67.8, 95%CI:60.5–75.1 min−1	70.9, 95%CI:63.9–78.5 min−1	0.23
	QT%	115.0, 95%CI:111.4–118.7	131.9, 95%CI:124.4–139.3	<0.001
	QTc	433.3, 95%CI:418.6–448.0 ms	480.2, 95%CI:422.4–483.1 ms	<0.001
	KM	89.7, 95%CI:68.7–110.7 ml
	Crea	109.1, 95%CI:92.6–125.6 µmol/(l*s)
CON	HR	65.5, 95%CI:58.5–72.5 min−1	69.0, 95%CI:60.2–77.7 min−1	0.16
	QT%	107.5, 95%CI:99.2–115.8	109.0, 95%CI:100.2–117.8	0.68
	QTc	401.9, 95%CI:389.2–414.6 ms	398.8, 95%CI:385.2–412.5 ms	0.51
	KM	83.1, 95%CI:70.9–95.3 ml
	Crea	93.6, 95%CI:82.8–104.4 µmol/(l*s)

HR: Heart rate; Kmml: Volume of contrast medium; Crea: Creatinine serum level, 95%CI: 95% confidence interval for changes, reference range: 44–96 mmol/l.

Figure 1.

QT prolongation 24 h after cardiac catheterization in a 70y old male suffering from anterior myocardial infarction. QTc interval increased from 480 to 660 ms after catheterization, and returned to normal (460 ms) at 48 h

Discussion

Iohexol is a nonionic X-ray contrast medium of low osmolality, extensively used in clinical radiology and considered essentially free from side effects [11–13]. Like other iodine-containing contrast media, it is eliminated from the body by excretion in the urine. 97–99% of the intravenously injected Iohexol is excreted unchanged through the kidneys within 24 h in patients with normal renal function. The maximum urinary concentration appears within approximately 1 h after injection. The elimination half-life is 120–150 min in healthy subjects [14]. Significant metabolism does not occur, and protein binding is less than 2%.

The time course of the QT-prolongation effect of Iohexol is not known. Our routine ECG measurements were taken randomly from 12 to 24 h after cardiac catheterization. Assuming that Iohexol induced QT prolongation relates proportional to the course of Iohexol level in serum, a peak effect can be expected to occur at about two hours after application given a normal glomerular filtration rate. Supplementary studies which prospectively sampled ECGs within the first hours after angiography are necessary to support this assumption.

Our findings are especially of relevance in outpatient angiographies, where the patients are under less surveillance having left the diagnostic facilities. Iohexol should be used cautiously in patients on antiarrythmics which prolong QT interval such as amiodarone.

We conclude that systematic study of the interaction of amiodarone and iodine containing contrast media is required. Until this is done we propose to increase watchfullness in patients under amiodarone pretreatment who receive iohexol contrast medium.