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Iodixanol in paediatric gastrointestinal imaging: safety and efficacy comparison with iohexol

¹Department of Paediatric Radiology, Royal Manchester & Booth Hall Children's Hospital, Manchester, UK, ²Department of Radiology, Royal Liverpool Children's Hospital, Alder Hey, Liverpool, UK, ³Department of Radiology, Sheffield Children's Hospital, Sheffield, UK, ⁴Nycomed Imaging AS, Oslo, Norway, ⁵Glostrup Amtssygehus, Copenhagen, Denmark, ⁶Skejby Sygehus, Aarhus, Denmark and ⁷Rikshospitalet, Oslo, Norway

	Abstract

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Iodixanol (Visipaque®) is a dimeric, non-ionic iodinated contrast medium that is isotonic with blood at all clinically relevant concentrations. Iodixanol was compared in a randomized, double blind, parallel group, phase III multicentre trial with a monomeric, non-ionic contrast medium, iohexol (Omnipaque®), at two concentrations assessing safety, tolerability and radiographic efficacy during contrast enhanced gastrointestinal radiography examinations of children. 154 children entered the trial; 152 formed the safety population and 147 the efficacy population. All examinations were performed following standard departmental practice. Children were assigned into either a high or low concentration group (iodixanol, 150 mgI ml^-1 and 320 mgI ml^-1 vs iohexol, 140 mgI ml^-1 and 300 mgI ml^-1). The primary outcome measure for efficacy was the overall quality of visualization, which was assessed using a 100 mm visual analogue scale (VAS). The secondary efficacy variables assessed were quality of contrast opacification, mucosal coating and overall quality of diagnostic information. Safety evaluation involved patient follow-up for at least 48 h. Taste acceptance was also assessed. There was no statistically significant difference between the two contrast media with regard to the primary and secondary efficacy variables assessed, although higher ratings were observed for iodixanol. The 100 mm VAS score overall was 86 mm for iodixanol and 82 mm for iohexol (95% confidence interval -2.56, 10.42). The frequency of adverse events was lower for patients receiving iodixanol. Adverse events, mainly diarrhoea, occurred in 12 patients (16.2%) in the iodixanol group and 28 patients (35.9%) in the iohexol group. This reached statistical significance (p=0.006). Overall, iodixanol is well suited for examinations of the gastrointestinal tract, giving good efficacy results and fewer adverse events than iohexol.

	Introduction

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Contrast enhanced fluoroscopic examinations remain the standard radiological method of imaging the gastrointestinal (GI) tract for many infants and children. Barium sulphate suspensions (both high and low osmolar) and water soluble contrast media are all currently used as positive contrast media, barium sulphate being most commonly used [1]. In some circumstances these media are either relatively or absolutely contraindicated, for instance in suspected perforation of the gut or where the risk of aspiration into the lungs is high. Barium leakage into the peritoneal cavity can lead to the formation of granulomas, since barium will not be absorbed by the peritoneum. Aspirated barium may not be coughed up, and hypertonic fluid in the lungs may lead to pneumonitis or pulmonary oedema. Hypertonic contrast media cause fluid balance disturbances, especially in infants [2]. Occasionally this can be used therapeutically, for example in the treatment of meconium ileus, but more often it is an undesirable effect, with the influx of fluid into the intestine resulting in dilution of the contrast medium and deterioration of image quality within the distal bowel [3]. Barium studies of the small bowel can also have problems, with flocculation of barium occurring in some examinations. Hypertonic, low osmolar, iodinated contrast media are generally considered inferior to barium for the evaluation of mucosal disease because of poor mucosal coating [4].

Iodixanol is a water soluble, non-ionic, hexaiodinated, dimeric radiographic contrast medium (Visipaque®) that is isotonic to blood at all clinically relevant concentrations. Theoretically, therefore, it should not cause intestinal fluid influx or reduced image quality in small bowel studies.

The object of this study was to evaluate and compare the efficacy and safety of iodixanol (150 mgI ml^-1 and 320 mgI ml^-1) with iohexol (140 mgI ml^-1 and 300 mgI ml^-1) in paediatric patients undergoing GI radiographic examinations.

	Materials and methods

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Study design
The study was a multicentre, randomized, parallel group, double-blind, phase III clinical trial in paediatric patients referred for conventional radiographic examination of the GI tract. It compared iodixanol (Visipaque®; Nycomed Amersham Imaging AS, Oslo, Norway) at two concentrations (150 mgI ml^-1 and 320 mgI ml^-1) with a comparative contrast medium, iohexol (Omnipaque®; Nycomed Amersham Imaging AS, Oslo, Norway) at two concentrations (140 mgI ml^-1 and 300 mgI ml^-1).

Ethical approval was obtained at each centre involved according to the relevant national regulations, and the study was conducted in accordance with the EEC guidelines on good clinical practice for trials on medicinal products in the European Community and with the Declaration of Helsinki. Written, informed consent was obtained from parents/guardians and where appropriate assent was obtained from the child. The study formed part of the international paediatric documentation programme for iodixanol.

Subjects
Paediatric (<16 years old) patients referred for upper or lower GI contrast enhanced radiographic examinations were eligible for inclusion into the study. Subjects were excluded if they were unconscious, had previously been included in this or another clinical trial with an unregistered investigational drug, had previously experienced serious reactions to iodinated contrast media, were clinically unstable or were pregnant or breast-feeding.

For each patient, demographic and clinical data, including age, weight, height, gender, medical history including risk factors and indication, were recorded. A drug history was obtained that included all medications given within 24 h of contrast medium administration, during the examination and within 48 h after the examination.

Procedure
Prior to the examination, patients followed the instructions regarding restrictions to food and fluid intake in accordance with the hospital's routine for the particular examination depending on the patient's medical condition. The examination procedure was the same as that routinely used in each individual hospital. Pre-medication was usually not given. Consecutive patients were randomly assigned to receive either iodixanol or iohexol. Either high or low concentration was selected at the discretion of the attending radiologist, depending on their own routine practice. The contrast media were delivered in vials of identical appearance to ensure blinding. The contrast medium was warmed to 37°C and administered orally either by drinking, by a syringe, by a catheter binky, through a nasogastric tube, through a stoma, or rectally as appropriate. Following common paediatric practice, a small amount of fruit juice (1 ml 50 ml^-1 of contrast medium) was sometimes added for flavouring oral administrations. The examination procedures, including images obtained, were performed using conventional radiological Siemens or Philips equipment, in accordance with each attending radiologist's routine practice.

Efficacy assessment
Contrast medium efficacy was evaluated by reviewing the images obtained from each examination. Depending upon the examination performed, the following areas were individually assessed: oesophagus, stomach, duodenum, jejunum, ileum, ascending colon, transverse colon, descending colon and rectum. The quality of radiographic visualization for individual anatomical regions was scored, assessing the degree of opacification and the coating of the mucosa. An overall evaluation of the radiographic visualization and of the quality of diagnostic information was obtained, based on the radiographic examination and all clinical data available at the time of the examination.

The quality of radiographic visualization provided in the contrast enhanced images was rated according to the following four categories:

1. No visualization: no visualization of contrast medium in the region of interest;
   
2. Poor: insufficient radiographic visualization, inferior radiographic delineation;
   
3. Good: sufficient radiographic visualization, adequate radiographic delineation; and
   
4. Excellent: superior radiographic visualization, very detailed radiographic delineation.
   

The overall evaluations (of radiographic visualization and diagnostic information) were obtained using a 100 mm visual analogue scale (VAS). This meant scoring the parameter in question out of 100 by marking a point along a fixed linear scale (0–100 mm).

The degree of contrast density was evaluated as too high, optimal, too low or none. Coating of the mucosa was scored in categories as poor, good and excellent. Only one appointed investigator in each trial centre performed the efficacy evaluations. As multiple centres were involved in this trial, it was considered important to establish a common baseline for assessing quality in efficacy evaluations between the centres. Meetings were arranged between the appointed investigators on two occasions, during the early part of the trial, where images were evaluated and quality was discussed. These persons also recorded the radiological diagnosis and made the necessary arrangements to obtain the final diagnosis for the patient within 3–4 days after the examination if additional clinical data or results from additional examinations were available to make a new diagnosis. In this case, the radiological and clinical diagnoses were compared for consistency. It was also evaluated how much the radiographic examination contributed in making the final diagnosis (scale 0–100%).

Safety assessment
The patients were observed for adverse events during the examination and up to at least 48 h after the last administration of contrast medium. Any change in medication after the procedure was also noted at this point. If a child was referred for surgery prior to the 48 h check, the follow-up period ceased at the time of surgery. The following information regarding each adverse event was obtained: date and time of onset and resolution (duration), severity, treatment required, outcome, relationship to study drug, and whether the adverse event caused withdrawal from the study. In addition to the investigators own description of the adverse events, each adverse event was coded according to the WHO code list. The severity of all adverse events was graded as mild, moderate or severe by the investigator, who was asked to grade the actual symptom in relation to their previous clinical experience with similar symptoms. The intensity was rated on a scale from 1 to 10 (mild=1–3, moderate=4–7, severe=8–10). Each subject experiencing adverse events, whether ascribed to the study drug or not, was followed until the outcome had been determined. Bronchial aspiration was recorded where appropriate. Taste acceptance was evaluated where appropriate using the categories "good", "acceptable", "unpleasant" and "bad". Safety follow-up was performed by a visit to the ward for inpatients or by telephone contact for outpatients.

Statistical analysis
The overall quality of radiographic visualization (100 mm VAS) was analysed to reveal whether a difference was present between iodixanol and iohexol. An analysis of variance (ANOVA) was performed to compare the mean scores, evaluating the potential effects of age (<2 years vs 2 years), centre and pathological findings (yes vs no). Possible interaction effects were also investigated. In addition, subgroup analyses were performed, comparing iodixanol and iohexol per concentration group (high or low). The associated 95% confidence interval for the difference in mean score was calculated both across groups and per concentration group.

Administrations both with and without fruit juice additive were included in the analysis. A Fisher's exact test was used to test whether a difference in taste acceptance was present between the two contrast medium groups. The ² test was used to determine whether there was any significant difference between the incidence of adverse events. The level of significance was 5% in all analyses.

	Results

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Demographic and procedural details
154 patients were entered into the trial. The overall demographic data are displayed in Table 1. Only small differences were observed between the high and low concentration groups. Children in the higher concentration groups were older on average (8.2 years and 7.3 years for iodixanol and iohexol, respectively vs 4.6 years and 5.8 years), with weight and height differing appropriately. In addition, the groups were not homogeneous with respect to gender. While the number of males/females was nearly equal in the higher concentration groups, more males were enrolled in the low concentration groups. However, since these differences were balanced between the treatment groups it was assumed that they would not influence the overall results.

70 children were receiving medication before the examination for treatment of asthma, allergy, pain, infections, gastro-oesophageal reflux (GOR) and other GI conditions. These were not expected to have any influence on variables recorded in this trial. Only one patient was given pre-medication for relaxation.

One patient was given medication during the examination. This patient was also given barium sulphate owing to poor contrast with the trial drug, which was iohexol at 140 mgI ml^-1. In addition, four children completed the examination with barium sulphate after iodinated contrast medium had confirmed that there was no risk to the administration of barium (2 children in the iohexol at 140 mgI ml^-1 group and 2 patients in the iodixanol at 150 mgI ml^-1 group). Images taken after the administration of barium were not included in the efficacy evaluations for this trial.

17 children received medication within 48 h of completing the examination. Most agents were for treating GOR, pain or infection. However, one patient was given paracetamol for treatment of rash and itching following an upper GI study using iodixanol at 320 mgI ml^-1.

Fruit juice was added to the trial drug in 91 patients. Additions ranged from 1–63% fruit juice in the safety population. Patients with very high amounts (>3%) of fruit juice mixed with the trial drug in error were excluded from the efficacy evaluation group. There was no difference between the treatment groups with regard to the amount of fruit juice added (mean concentration in the efficacy population 1.98% with iodixanol and 1.91% with iohexol).

Table 4 shows the variation in volume of administered contrast medium and iodine dose. Bronchial aspiration occurred in one patient in each of the two main contrast medium groups. Four patients (all in the iohexol group) had an obstruction in the GI tract found during the examination, none of which resolved during the procedure.

Efficacy
147 patients were included in the efficacy population. One child received an insufficient amount of contrast medium and four had too high concentration of fruit juice administered and these were excluded from the efficacy evaluations.

Overall quality of visualization (100 mm VAS)
The overall quality of visualization is shown in Table 5 and Figure 1. Although the mean VAS score was higher for iodixanol in both the low and high dose subgroups, this did not reach statistical significance (Table 6).

View larger version (18K): [in this window] [in a new window]   Figure 1. Overall quality of radiographic visualization scored on a 100 mm visual analogue scale.

In the subgroup analysis for high concentration groups, comparing iodixanol 320 mgI ml^-1 and iohexol 300 mgI ml^-1, no adjustments were made, as none of the possible effects were significant at the 5% level. No interaction effect was present in any of the analyses.

Quality of visualization per area
Quality of radiographic visualization. Efficacy was evaluated for each anatomical area of examination. Overall, there was no major difference between the two contrast medium groups. Most evaluations in both groups were excellent or good for those areas applicable to the examination. More patients with a poor rating were observed in the iohexol groups, particularly for the oesophagus. In general, the area with the best visualization was the stomach, followed by the oesophagus and the duodenum. These were also the main areas examined.

The reasons for poor or no visualization of areas were related to contrast opacification in a total of 17 areas, with other causes (movement, technical or non-contrast related events) recorded in 53 additional areas. Poor visualization due to inadequate contrast opacification did not occur in the iodixanol 320 mgI ml^-1 subgroup, but occurred on four occasions in the iodixanol 150 mgI ml^-1 group. This compares with 2 episodes in the iohexol 300 mgI ml^-1 group and 11 episodes in the iohexol 140 mgI ml^-1 group.

Contrast density. Most of the scores showed optimal densities for the areas under examination. There were six occasions when the density was scored as too high. These were distributed in the jejunum/ileum in all groups except the iohexol at 140 mgI ml^-1 group. Too low density was scored for many areas, even in the high concentration groups. Figure 2 shows the percentage of optimal scores by area and by contrast medium. No enhancement was recorded on eight occasions across the iohexol groups.

View larger version (43K): [in this window] [in a new window]   Figure 2. Optimal contrast density score by area (n=number of patients in each group).

View larger version (34K): [in this window] [in a new window]   Figure 3. Mucosal coating evaluation by area (n=number of patients in each group).

Radiological and final diagnosis
In keeping with the indications and examination requests, the radiological diagnoses were varied. GOR and constipation were common diagnoses and many children had assessments of known conditions. The final diagnoses were very similar to the initial radiological diagnoses. Many patients did not have additional clinical data available to help make a final diagnosis. 51 cases in each of the two contrast medium groups showed consistency between radiological and final diagnosis. None was scored as inconsistent. The contribution that the examination was felt to make to the final diagnosis was 96.0% in the iodixanol group and 96.4% in the iohexol group (mean values). For the different concentration groups, the percentage contribution was higher for the high concentration groups (both groups 98.5%) compared with the low concentration groups (94.8% and 95.5%, iodixanol and iohexol groups, respectively).

A total of five patients, three in the iodixanol group and two in the iohexol group, underwent surgery within the follow-up period.

Safety evaluation
152 patients provided data for the safety evaluation, one child did not receive any trial contrast medium and one was withdrawn since there were no safety or efficacy data recorded.

The frequency of adverse events was lower for patients receiving iodixanol compared with those receiving iohexol. 40 patients, 12 (16.2%) in the iodixanol group and 28 (35.9%) in the iohexol group, experienced 54 adverse events. This difference between contrast media is statistically significant (p=0.006). Some children had more than one kind of event. The cause of adverse events was believed to be the contrast medium in 11 events (6 in the iodixanol group and 5 in the iohexol group). It was uncertain in 39 events (9 in the iodixanol group and 30 in the iohexol group). The number of patients with at least one adverse reaction either due to contrast medium or to an uncertain cause was 10 patients (13.5%) in the iodixanol group and 26 patients (33.3%) in the iohexol group. There were no adverse events leading to changes in dose or administration procedure, nor any events resulting in withdrawal from the trial. There were no deaths or serious adverse events, or other significant adverse events. All the adverse events that occurred were of mild or moderate intensity. The types of events that occurred were mostly different kinds of GI system disorders (40 events). The commonest adverse event was diarrhoea; 5 patients in the iodixanol group and 23 patients in the iohexol group had diarrhoea as an adverse event. Nausea was experienced by two patients (one in each group) and vomiting by three patients (all in the iohexol group). Abdominal pain was reported for two patients in the iodixanol group. Bronchial aspiration occurred in one patient in each contrast medium group. Skin reaction was reported in three patients, all in the iodixanol group. One patient had rash and itching of mild to moderate intensity lasting 72 h, who recovered after medical treatment (paracetamol). One had mild erythema of 4 h duration commencing 26 h after completing the examination. This patient recovered without treatment. One child had a rash of moderate intensity appearing 20 h after the examination and lasting for 48 h. This patient recovered without treatment.

Four patients received treatment, either medication or physiotherapy, owing to an adverse event. These were as follows: one child (iodixanol group), mentioned above, received paracetamol for rash, fever and itching, with no previous history of adverse reactions or allergy. One child (iodixanol group) with asthma as a risk factor required an increase in routine medication (Ventolin and Flixotide) for coughing and sneezing. One child (iohexol group) was given paracetamol for pyrexia. The child was pyrexial prior to the examination but received medication after completing the contrast examination. The child also was neurologically abnormal and had asthma. One neurologically abnormal child with a chest infection (iodixanol group) received physiotherapy after aspiration of contrast medium.

Taste evaluation
Taste acceptance was evaluated by 104 children. 33 patients scored the taste as good, 36 as acceptable, 19 as unpleasant and 16 as bad. No statistically significant difference between the contrast media was present (p=0.55). A few more patients scored good or acceptable in the iodixanol group (70.6%) than in the iohexol group (62.3%). The addition of fruit juice did not seem to improve taste acceptance. There was no score in the category bad from patients who drank the contrast medium without fruit juice added.

	Discussion and conclusions

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The ideal contrast medium for diagnostic paediatric examinations should be physiological in composition, should represent no risk to the child and should give perfect opacification of the part of the GI tract under investigation. The contrast medium should also taste pleasant or at least acceptable. The aim of this trial was to show how closely iodixanol could meet these requirements, comparing it with iohexol, a contrast medium in common usage in paediatric practice.

The main variable used to assess the efficacy of the contrast media was the overall quality of radiographic visualization measured on a 100 mm VAS. Overall there was no statistically significant difference between the VAS scores for the two contrast media, although the mean and median scores were higher for iodixanol at both 150 mgI ml^-1 and 320 mgI ml^-1 concentrations. Both iodixanol and iohexol produced appropriate contrast in GI examinations and resulted in high VAS scores. Not surprisingly, there was generally a higher score on the overall quality parameters (on the VAS) for patients in the higher concentration groups, but both test products also gave acceptable efficacy at the lower concentrations. The dose of iodine per kg of body weight is higher for iodixanol than iohexol and this in itself may have contributed to the better results for iodixanol.

The secondary efficacy variables obtained for each area of evaluation also had high scores and there was no statistically significant difference between the contrast media regarding the grading excellent and good. However, more patients had a poor or no visualization score in the iohexol groups attributed to a contrast opacification (13/31, 41.9%) than in the iodixanol groups (4/22, 18.1%). Iodixanol produced slightly better results for all areas assessed with regard to contrast density. The only exception was the ileum and it was not clear why this was the case.

Coating of the mucosa to define detail is not generally sought in paediatric examinations, with most studies being performed in single contrast only. It is also generally accepted that iodinated, water soluble contrast media are inferior to barium in this respect [4]. Despite this, the results suggest that adequate mucosal coating can be obtained with water soluble agents, and more often with iodixanol than iohexol. However, the number of comparable patients with similar indications and of comparable age was probably too small to assess mucosal coating adequately. In many cases the mucosal coating was not of any significance in the examination and thus was not evaluated. When evaluated, however, most scores were in the categories good or excellent.

There was no significant difference in the overall quality of the diagnostic information, although the VAS scores were slightly higher for iohexol. This is not unexpected considering the small differences in radiological image quality seen between the two contrast media. This trial was designed to obtain both the radiological and clinical diagnoses for comparison and evaluation of consistency. The clinical diagnosis was obtained some days after the radiological examination and was based on any additional data about the patient's condition. In no case was any difference observed. However, in many cases there were no additional data obtained during these following days, suggesting that the radiographic examination was diagnostic for clinical management, at least in the short term. There was also little difference between the radiological diagnosis and the final diagnosis between the two groups. In general terms, even poor or average quality examinations may yield sufficient diagnostic information to answer specific questions posed by a referring clinician, i.e. the examination may be of poor quality but can still yield diagnostic information.

The number of adverse events showed an unexpected statistically significant difference between the iodixanol and iohexol groups. The difference was mainly in the occurrence of diarrhoea, which was much more common following iohexol. Iohexol at 140 mgI ml^-1 and 300 mgI ml^-1 has osmolalities of 300 mOsm kg^-1 H₂O and 690 mOsm kg^-1 H₂O, respectively, compared with iodixanol that has an osmolality of 290 mOsm kg^-1 H₂O at both 150 mgI ml^-1 and 320 mgI ml^-1 concentrations. It seems logical that a contrast medium of lower osmolality would cause less water influx from the bowel mucosa and consequently less diarrhoea than one with high osmolality. It is unclear, however, what the mechanism of diarrhoea was in the iodixanol group. Although theoretically fluid influx should also have an influence on image quality, only small differences were observed in the efficacy results. Three cases of skin hypersensitivity reactions were reported in the iodixanol group, suggesting a slightly higher rate of these reactions with iodixanol compared with iohexol. None of them was severe and only one patient required treatment. A previous study comparing iodixanol and iohexol for intravenous urography in 72 children showed comparable safety results [5], although caution was expressed in view of the number of children involved. Diarrhoea was not an adverse event reported in that study, further supporting the proposal that diarrhoea appears to be a direct consequence of the presence of contrast medium in the bowel lumen. In a recent study comparing iodixanol and iohexol for follow-through examinations in adults, adverse events such as diarrhoea, nausea and abdominal pain again occurred less frequently with iodixanol [6].

Only two patients aspirated contrast medium during the examinations, one in each contrast media group, neither patient came to any harm.

Given the relatively small sample size, it is no surprise that there were no serious adverse events or deaths in the study population [7].

The scores for taste acceptance showed no difference between the two contrast media. Iodixanol has a slightly sweet taste, while iohexol tastes more bitter. However, the assumption that children would appreciate the sweeter taste was not proven in this trial. A small amount of fruit juice was added to the contrast medium (<3% by volume in the efficacy population) before administration in many cases to increase the child's confidence, but such additions are not able to mask the characteristic taste of the contrast medium. Interestingly, there was no score in the category bad from patients who drank the contrast without fruit juice added.

	Acknowledgments

 
This study was supported financially by Nycomed Amersham Imaging AS, Oslo, Norway. We would also like to thank the numerous radiologists, radiographers and technicians who helped in this study, especially Mrs H Stowbridge, Radiographer at Royal Liverpool Children's NHS Trust, Alder Hey, and Ms S Bastow and Mrs J Poxton, Radiographers at Booth Hall & Royal Manchester Children's Hospitals.

Received for publication January 11, 2001. Accepted for publication October 9, 2001.

	References

Top Abstract Introduction Materials and methods Results Discussion and conclusions References

 

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