FULL PAPER Surgery

The Risk of Contrast Media-Induced Ventricular Fibrillation is Low in Canine Coronary Arteriography with Ioxilan

Kazuhiro MISUMI, Oki TATENO, Makoto FUJIKI, Naoki MIURA and Hiroshi SAKAMOTO Department of Veterinary Medicine, Kagoshima University, 21Ð24 Korimoto 1-chome, Kagoshima 890Ð0065, Japan

(Received 5 August 1999/Accepted 28 December 1999)

ABSTRACT. Previous studies have proposed that sodium supplement to nonionic contrast media (CM) can decrease the risk of ventricular fibrillation (VF). This study was designed to compare the occurence of VF induced by ioxilan (containing 9 mmol/LNa+) with other nonionic CMs. After wedging a catheter in the right coronary artery, test solutions including ioxilan, ioversol, iomeprol, and iopromide were infused for 30 sec at the rate of 0.4 ml/sec or until VF occurred. Then, incidence of VF, contact time (i.e. the time required to produce VF), and QTc were measured. Also, the CMs other than ioxilan were investigated at sodium levels adjusted to 9 and 20 mmol/L Na+. The incidence of VF with ioxilan (0% ) was the lowest of all. In the other CMs, the incidence decreased in accordance with increase of sodium. Iomeprol and iopromide showed significant reduction of VF incidence at the sodium level of 20 mmol/L. The higher sodium supplements also prolonged the contact times. The increase of QTc was the greatest in ioxilan. Ioxilan has the least arrythmogenic property among the current low-osmolality nonionic CMs. This property might be attributable to an optimal sodium concentration of 9 mmol/L in the CM.—KEY WORDS: contrast media, coronary arteriography, ioxilan, ventricular fibrillation. J. Vet. Med. Sci. 62(4): 421Ð426, 2000

The addition of balanced electrolytes, including sodium, the themes left for further research, and designed to compare calcium, potassium, and magnesium, to conventional the incidence of VF induced by ioxilan with those induced nonionic contrast media (CM) has been effective in reducing by other low-osmolality nonionic CMs with or without the risk of cardiovascular complications during selective sodium supplement. injection into the coronary circulation [5, 11, 20]. In particular, the sodium level of CM can be responsible for a MATERIALS AND METHODS risk of ventricular fibrillation (VF) [2, 3, 10, 18], which is well known as a dangerous complication during coronary Animals: Seven healthy adult beagles with weights from arteriography in humans [1, 14]. The CMs containing no 9 to 15 kg (12 ± 2.1 kg), of both sexes, were the subjects. sodium may affect cardiac excitability and impulse They had been bred for cardiovascular experiments, and conduction, and induce VF. The addition of sodium close before use in this study, the dogs were judged to be free of to the physiologic concentration (150 mmol/L sodium) had disease on the basis of physical and hematological analysis, been expected optimal to lower the incidence of VF, whereas radiography, electrocardiography, and echocardiography. the sodium concentration actually caused a negative Test solutions: The following ten solutions were tested. inotropic effect [4, 12]. Current studies have proposed that Four low-osmolality nonionic CMs consisting of ioxilan the addition of 10 to 30 mmol/L of sodium to nonionic CM (Imagenil¨, 350 mgI/ml, citrate buffer; containing 9 mmol/ can effectively decrease the incidence of the VF [4, 10, 17]. L Na+, Japan Tabacco Inc., Japan), ioversol (Optiray¨, 350 Despite the publication of these data, however, a nonionic mgI/ml, Yamanouchi Pharmaceutical Co., Japan), iomeprol CM which does not involve the risk of VF has yet to be (Iomeron¨, 350 mgI/ml, Eisai Co., Japan), and iopromide developed. To our knowledge, iotrolan, which is a CM (Proscope¨, 370 mgI/ml, Tanabe Pharmaceutical Co., containing 8 mmol/L of sodium ions, presents the lowest Japan). The remaining six solutions were prepared 9 and incidence of VF in experimental canine coronary 20 mmol/L Na+ with sodium supplements of the three CMs arteriography [7], but its clinical safety for infusion into the other than ioxilan. They are expressed as CM+9 mmol/ coronary circulation has not yet been determined. LNa+ and CM+20 mmol/LNa+, respectively. Ioxilan is a low-osmolality nonionic CM designed by Experimental procedure and design: The beagles were Sovak [25]. We reported that, in canine experimental right anesthetized with inhalation of oxygen-enflurane after the coronary arteriography, ioxilan (350 mg of iodine per induction of intravenous sodium thiopental (25 mg/kg). Six milliliter; mgI/ml, citrate buffer, 9 mmol/L Na+) can French sheath catheters (Catheter Sheath Introducer System, obviously lower the incidence of VF compared with iohexol Cordic Co., U.S.A.) were placed into the left carotid and and iopamidole [24]. Ioxilan is now commercially available femoral arteries. Polyethylene tubing (PE160) introduced under the name ‘Imagenil’, however, it has yet to be through the femoral sheath catheter, was used to monitor determined whether the least arrythmogenic property of the arterial pressure, blood pH and gases. ioxilan depends on the sodium level of 9 mmol/L or not. The present study was designed according to the protocol, The present study was undertaken in order to demonstrate reported by Morris et al. [19]. A 6 Fr angiographic catheter 422 K. MISUMI ET AL.

(A)

(B)

Fig. 1. ECG (Lead II) records just before the occurrence of ventricular fibrillation (A) and after defibrillation (B). Paper speed, 50 mm/sec.

(Amplatz L-1, Asahi Intecc Co., Japan) was inserted via the The statistical differences in the contact time and QTc were sheath catheter into the carotid artery, and advanced until analyzed by factorial and repeated measures ANOVA, the tip was positioned near the entrance of the right coronary respectively, and Scheffé’s method was used for artery under fluoroscopic guidance. After wedging the simultaneous multiple comparisons. A p-value less than catheter in the right coronary artery, the prewarmed (37°C) 0.05 was considered significant. test solutions were randomly injected for 30 sec at the rate of 0.4 ml/sec, or until fibrillation occured, using a Masterflex RESULTS perfusion pump (Master Flex¨, Cole-Parmer Instrument Co., U.S.A.). To confirm that the catheter was wedged in the Incidence of VF: Figure 2 summarizes the incidences of coronary artery, we required less than 1 ml of each CM. If VF during infusion of the ten test solutions. The infusion VF occurred (Fig. 1), the catheter was immediately of ioxilan produced the lowest incidence of VF (0%) of all withdrawn into the aorta and the infusion was stopped. The the test solutions, which was significantly lower than dogs were defibrillated within one min after the start of VF ioversol (85.7%), iomeprol (85.7%), iopromide (71.4%), using a defibrillator (FC-200, Fukuda Denshi Co., Japan). ioversol+9 mmol/LNa+ (57.1%), iomeprol+9 mmol/LNa+ Before evaluating the toxicity of the test solutions, it was (71.4%), and ioversol+ 20mmol/LNa+ (57.1%), as shown confirmed that VF did not occur in all dogs during the by asterisks in Fig. 2. In the CMs other than ioxilan, the infusion of saline (37°C) for two min at the rate of 0.4 ml/ incidence of VF decreased in accordance with the increase sec. Recovery times were 30 min after VF, or 15 to 30 min of sodium supplement. This effect was more definite with after an injection without VF. The next infusion started iomeprol and iopromide, which showed significant after confirming the successful recovery of normal sinus reductions of VF incidence when the sodium level reached rhythm and blood pressure. Arterial blood pH and gases to 20 mmol/L (14.3%), as shown by # marks in Fig. 2. were controlled at pH of 7.35Ð7.45, pO2 of 100Ð150 mmHg, Contact time: Figure 3 illustrates the contact time, that is and pCO2 of 30Ð40 mmHg before each infusion. the time required to induce VF after infusing CM solutions, Measurements: Lead II of the electrocardiogram (ECG) except for ioxilan. The higher sodium supplement of was recorded continuously for 60 sec from 5 sec before an ioversol prolonged the contact time, but there were no infusion, and intermittently (10Ð20 beats every one min) significant differences. Both iomeprol and iopromide during the 10 min after completion of an infusion, using an showed the prolongation of contact time at only 9 mmol/ ECG recorder (CardioPal¨ 600, NEC, Japan). The incidence LNa+. Again no significant differences were evident in of VF (%) was determined in each of the ten test solutions. these two CMs. Contact time, that is the time (sec) required to produce VF, QTc: The changes in the QTc are summarized in Fig. 4. and QTc were obtained using the ECG records. The QTc Also, the QT and RR intervals during the coronary infusion was defined as the quotient of the QT interval divided by with CM are shown in Table 1. The values calculated before the square root of the RR interval, and was calculated before and at the maximal QT interval after infusion of each test and at the maximal QT interval after an infusion. solution, are expressed as Pre- and Max-values. The QTc Statistics: All data were expressed as mean ± SD. The values calculated before and at the maximal QT interval incidence of VF was statistically compared in accordance after infusing each test solution, are expressed as pre-QTc with the McNemar test, after analyzing the overall and max-QTc, respectively. The QTc values increased significance within the test solutions by the Cochran Q-test. significantly in all the test solutions. The increase of QTc VENTRICULAR FIBRILLATION WITH IOXILAN 423

Fig. 2. The incidence of ventricular fibrillation (VF) during right coronary infusion of contrast media (CM). The numbers at the top of the column give the number of fibrillations and the total number of infusions. Statistically significant differences from ioxilan are indicated with a asterisk. A “#” mark indicates statistical differences from the CMs (iomeprol and iopromide) not containing sodium ions.

Fig. 3. The contact time (or injection duration) required to produce fibrillation during right coronary infusion of contrast media (CM). was the greatest in ioxilan (pre-QTc; 0.35 ± 0.03, max-QTc; needed. So far, angialgia, peripheral vasodilation, 0.48 ± 0.09). In ioversol, iomeprol and iopromide, QTc hypervolemia, and cardiac hyposystole, which were increased more with 20 mmol/L Na+ than with 0 and 9 suggested as being dependent on the hyperosmolality of mmol/L Na+ addition. However, significant differences ionic CM, have been almost eliminated by the use of newer were not apparent in or among any of the test solutions. low-osmolality nonionic CM [13]. Hyperosmolality of ionic CMs can also elevate the risk of VF [16], through the DISCUSSION dehydration of cardiomyocytes which can inhibit the sinoatrial automaticity and atrioventricular conductivity [9, To reduce cardiovascular complications during coronary 27], and/or reduce Purkinje fiber repolarization and angiography, studies on CM-induced toxicity have been conduction [9, 15]. Although the clinical frequency of VF 424 K. MISUMI ET AL.

Fig. 4. The changes in the QTc during right coronary infusion of contrast media (CM). The QTc values calculated before and at the maximal QT interval after infusion of each test solution, are expressed as pre-QTc and max-QTc, respectively. In any solution, the max- QTc was statistically greater than the pre-QTc (asterisks), but there were no significant differences in the prolongation of QTc among the test solutions.

Table 1. Changes in the QT and RR intervals during right coronary infusion of contrast media (CM)

Ioxilan Ioversol Iomeprol Iopromide Pre Max Pre Max Pre Max Pre Max

QT interval (sec.) CM + 0 mmol/L Na+ 0.26±0.02 0.34±0.06* 0.27±0.03 0.31±0.06 0.27±0.02 0.33±0.04* 0.27±0.03 0.30±0.04* CM + 9 mmol/L Na+ 0.28±0.03 0.33±0.06* 0.28±0.03 0.31±0.03* 0.28±0.03 0.30±0.04 Cm + 20 mmol/L Na+ 0.26±0.02 0.33±0.07* 0.26±0.03 0.34±0.05* 0.26±0.03 0.32±0.04*

RR interval (sec.) CM + 0 mmol/L Na+ 0.57±0.11 0.52±0.10* 0.55±0.07 0.59±0.08 0.58±0.04 0.60±0.06 0.58±0.07 0.52±0.13 CM + 9 mmol/L Na+ 0.55±0.10 0.57±0.12 0.57±0.04 0.55±0.15 0.57±0.07 0.51±0.07 CM + 20 mmol/L Na+ 0.52±0.06 0.57±0.15 0.50±0.05 0.52±0.07 0.53±0.05 0.53±0.09

The values calculated before and at the maximal QT interval after infusion of each test solution, are expressed as Pre- and Max-values. Asterisks mean significant differences (p<0.05) between Pre- and Max-values. has been decreased by the replacement of high-osmolality ischemia produced by the wedged catheter. ionic CM with low-osmolality nonionic CM, the risk has In consideration of the toxicity of ionic CM, a number of not been eliminated completely and it remains an essential low-osmolality nonionic CMs have been recently developed topic of research. and made available commercially. However, the absence of Animal studies comparing the cardio-electrophysiologic ions in CM is also known as another critical factor of VF effects of CMs have used two types of canine models: 1) [6, 8, 23], because the absence or only trace presence of the electric premature ventricular stimulation model [21, sodium in nonionic CM increases the risk of VF. In the 22], and 2) the spontaneous fibrillation model [17, 19]. This present study, ioxilan showed a significantly lower risk (0%) study was designed according to the latter model, as reported of VF compared with the other new nonionic CMs, which by Morris et al. [19]. While the right coronary circulation contain less or no sodium. This result was consistent with was being perfused with saline for two min at the rate of 0.4 our previous study, in which the VF incidence of ioxilan ml/sec before infusing the test solutions, none of the dogs containing 9 mmol/L Na+ (9.1%, 1 of 11 infusions) was showed VF. This observation suggested that VF in right significantly lower than iohexol (92.3%, 12 of 13 infusions) coronary angiography may be a primary attribute of CM and iopamidole (80%, 8 of 10 infusions) [24]. The least toxicity, rather than a secondary result of local myocardial arrhythmogenic property of ioxilan may be attributable to hypoxia caused by perfusing non-oxygenated solution or the sodium ions in this agent. VENTRICULAR FIBRILLATION WITH IOXILAN 425

Nine mmol/L of sodium ions in ioxilan can be derived infusions (7.6%) occurred in less than 10 sec using a from citrate used in the buffer process. Experimental ioxilan nonionic CM of meglumine sodium diatrizoate [19]. This with tris buffer, instead of citrate buffer, contained 0.5 fact may imply that nonionic CMs having the risk of VF mmol/L Na+ and produced a significantly higher (90%, 9 of may still be in use in current clinical practice. Ioxilan, 10 infusions) incidence of VF [24]. In this study, VF which has a lower arrythmogenic property than other incidences with the three CMs other than ioxilan decreased nonionic CMs, can meet clinical expectations, especially in the 9 mmol/L Na+ supplement, yet were higher than for for coronary arteriography. ioxilan. At the sodium level of 20 mmol/L, the incidence of VF was significantly decreased in iomeprol and iopromide, REFERENCES while ioversol kept the same risk as in 9 mmol/L Na+ supplement. 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