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To assess the incidence and types of sensation of smell and taste during i.v. injection of five kinds of contrast media (CM) in CT examinations.
735 patients who underwent contrast-enhanced CT (CE-CT) between 14 March 2016 and 5 April 2016 were enrolled. Medical staff asked patients whether they felt heat sensation and sensation of smell and taste during i.v. injection of CM (one of the following: iopromide, iomeprol, iopamidol, iohexol and ioversol) after their CE-CT. If the patients stated having felt the sensation of smell or taste, they were also asked what kind of smell or taste they sensed. Next, 30ml of each CM was poured into high-purity pet cups for radiological technologists to smell directly. Radiological technologists were asked whether or not each CM had any smell.
The sensations of smell and taste incidence for iopromide were 24.3% and 18.9%, respectively, which were significantly higher than those for other CM (p<0.05). The highest incidence of the sensation of smell was medicine-ish, and the most frequently noted taste was bitterness. All radiological technologists could directly smell only iopromide, which has an ether group on a side chain and fewer hydroxyl groups.
Iopromide showed a higher incidence of sensation of smell and taste than other CM.
This was the first investigation of sensation of smell and taste during i.v. injection of CM, and a specific CM showed a higher incidence, which is suspected to be due to its chemical structure.
Non-renal acute adverse reactions to iodinated contrast media (CM) for CT are flushing, nausea, arm pain, pruritus, vomiting, headache and urticaria. They are usually mild, of short duration, self-limiting and generally require no specific treatment.1 Contrast-induced nephropathy and acute kidney injury are known as renal adverse reactions to CM.2,3 These, and anaphylactoid reactions, are potentially severe and can lead to death, albeit rarely.
Heat sensation following administration of CM is another frequent but fortunately mild acute adverse reaction. Heat sensation produced by high-concentration CM has been reported to be greater than that produced by medium-concentration CM.4 This acute adverse reaction, in addition to being uncomfortable, can startle patients who are poorly informed, making it difficult for them to co-operate with breath-hold commands, and decrease the quality of the examination.
In our institution, until January 2012, four CM were used routinely for contrast-enhanced (CE-CT). A new CM was added in February 2012. Since the introduction of the new CM, patients began asking staff about the sensation of smell and taste during i.v. injection of CM. To our knowledge, there has been no detailed report of these acute adverse reactions in CE-CT examinations. The purpose of this study was to assess the incidence and types of sensation of smell and taste during i.v. injection using five kinds of CM in CT examination.
This prospective study was approved by the ethics committee of our institution.
This study was conducted at our institution between 14 March 2016 and 5 April 2016. We enrolled 735 consecutive patients, who underwent CE-CT. We are a university hospital serving as a tertiary-care facility for our area. The vast majority of CE-CT examinations in our institution are for patients with cancer undergoing pre-operative assessment or post-operative and/or post-therapeutic follow-up.
In our hospital, all CE-CT examinations are performed using one of the five low-osmolality CM. They are iopromide (iopromide injection FRI; FUJIFILM RI Pharma Co., Ltd, Tokyo, Japan), iomeprol (Iomeron™; Eisai Co., Ltd, Tokyo, Japan), iopamidol (Iopamiron™; Bayer Yakuhin, Ltd, Osaka, Japan), iohexol (Omnipaque™; Daiichi Sankyo Co., Ltd, Tokyo, Japan) and ioversol (Optiray™; Fuji Pharma Co., Ltd, Tokyo, Japan). Table 1 summarizes each CM, and Figure 1 illustrates the molecular structures of each CM, which were downloaded from the free online source ChemSpider (http://www.chemspider.com/). CM was selected for each examination based on the purpose of the examination and patient weight. Iopromide was administered only to inpatients. Iopamidol, iohexol and ioversol were administered only to outpatients. Iomeprol was administered to both inpatients and outpatients.
A public document on research was posted in the CT waiting area. CM was injected intravenously using an 20, 22 or 24G indwelling needle with a power injector (Dual Shot GX™; Nemoto Kyorindo Co., Ltd, Tokyo, Japan), as was standard in our institution. Oral informed consent for this study was obtained from all patients after CE-CT. Age, gender and injection rate were recorded as patient and CE-CT data. After finishing the CE-CT examination, one of the medical staff asked patients whether they felt heat sensation and sensation of smell and taste during the i.v. injection of CM. If the patients felt sensations of smell or taste, they were also asked what kind of smell or taste they sensed as an open-ended question.
Five radiological technologists smelled 30ml of each CM placed in a high-purity pet cup. They were asked whether or not they noticed any smell from each CM.
The incidence of each sensation during i.v. injection for each CM was compared, and the number of hydroxyl groups in the molecular structure of each CM were assessed. Continuous variables were expressed as mean and standard deviation and compared using the one-way analysis of variance. Categorical data were compared using the Fisher's exact test (with Holm corrections for multiple comparisons), as appropriate. Differences of p<0.05 were considered to be significant. Statistical analyses were performed using statistical software (EZR v. 1.32).5
The patient characteristics and results of our study are summarized in Tables 2 and and3.3. There were significant differences in age, gender, injection rate, iodine load and fractional dose among CM. Heat sensation was felt by 98.9% of all patients.
Table 4 and Figure 2 show the results of the comparisons in the incidence of sensations of smell and taste between CM. Iopromide showed a higher incidence of sensation of smell compared with all other CM (p=0.040 for iopamidol and p<0.001 for other CM). Iopromide also showed a higher incidence of sensation of taste compared with all other CM (p=0.009 for iomeprol and p<0.001 for other CM). Iopamidol showed the second highest incidence of sensation of smell, but there were no differences in the sensation of taste among the four CM excluding iopromide. The types of sensations of smell during i.v. injection of all CM were varied: alcoholic and medicine-ish were most frequent, although statistical analysis was not appropriate. Types of sensations of taste during i.v. injection of all CM were bitterness, medicinal and alcoholic in the descending order of incidence.
Other acute adverse reactions, such as nausea and urticaria, were observed in 15/735 (2.0%) patients, but there was no difference in the incidence between CM (p=0.343): in 5.4% (4/74) patients for iopromide, in 2.3% (3/132) patients for iomeprol, in 1.7% (4/237) patients for Iopamiron, in 1.5% (3/203) patients for iohexol and in 1.1% (1/89) patients for ioversol. Among the patients with acute adverse reactions, one patient with iopromide and one patient with iopamidol reported sensation of smell, and one patient with iomeprol reported sensation of taste. The differences of these incidences were not significant between CM (p=1.000 for sensation of smell and p=0.467 for sensation of taste).
All radiological technologists felt smell directly only from iopromide.
Comparison of these incidences between the number of hydroxyl groups in the molecular structure of each CM is shown in Table 5. There were significant differences between the number of hydroxyl groups of 4 and 5, 5 and 6, and 4 and 6 for the sensation of smell (p<0.001, 0.001 and <0.001, respectively) and for that of taste (p<0.001, 0.017 and <0.001, respectively) (Figure 3). There was a negative correlation between the number of hydroxyl groups in a CM and the percentage of patients feeling smell and/or taste when it was administered.
Incidences of sensation of smell and taste during i.v. injection of iopromide were significantly higher than that for other CM, and iopromide was the only CM which could be smelled directly.
The reason for this specific feature of iopromide was not totally clear to us. There were significant differences in iodine load among CM, but that of iopromide was neither particularly high nor low. Rather, this feature is suspected to be due to its chemical structure. First, the basic chemical structure of any CM is a tri-iodinated ring and one or more hydroxyl groups for heightening hydrophilicity. Only iopromide has an ether group (R–O–R′; R and R′ are alkane) on a side chain. CM compounds containing functional groups, including the ether group, tend to have scent. This ether group may be increasing the incidence of the sensation of smell. An i.v. olfactory test (Alinamin® test; Takeda Pharmaceutical Co. Ltd, Osaka, Japan) is the most commonly performed olfactory examination in Japan.6 The mechanism of the sensation of smell after i.v. infusion of Alinamin® occurs via exhalation, because metabolites of the drug are discharged from the blood into the alveoli, and these odorous substances reach the nasal cavity through exhalation.7 Iopromide might stimulate the olfactory sense through a mechanism similar to Alinamin®. Second, the number of hydroxyl groups (–OH) for iopromide is smaller than that of other CM. The smaller number of hydroxyl groups in a compound makes it more hydrophobic. Generally, highly hydrophobic compounds can easily move from the blood to cells, allowing CM to reach smell or taste receptors more easily. In this regard, there was a significant difference between iopamidol and iomeprol in incidences of sensation of smell, even though they have the same number of hydroxyl groups. Thirdly, the additives which are added to each CM may contribute to the sensation of smell and taste. However, the additives for CM are almost the same for each CM we employed, and are thus less likely to be the cause of differences between CM.
The types of smell during i.v. injection of CM varied among individuals. Alcoholic and medicine-ish tastes were most frequent. There was no relationship between the incidences of acute adverse reaction and sensation of smell and taste, although the number of patients in the present study was too small to make a concrete conclusion.
The study had a major limitation. CM selection was based on the patient weight and the purpose of the CE-CT examination, and inpatients were administered only iopromide because of financial issues. Thus, there must be some bias introduced into CM selection. For example, diseases such as diabetes may be more frequent in patients who are overweight and obese, possibly causing neurological symptoms. Inpatients are likely to be sicker than outpatients, which may alter perceptions of smell and taste. Additional studies with randomization of administered CM may be necessary to confirm our results.
In conclusion, iopromide showed a higher incidence of sensation of smell and taste than other CM. The incidence of sensation of smell by iopamidol was also relatively high. The chemical structure of CM may contribute to these minor acute adverse reactions. Our findings may provide more information for patients receiving CM for CE-CT, enabling them to better tolerate the examination, improving imaging quality.
The authors thank Junya Fukuda, RT, Hitomi Miyazawa, RT, Keisuke Arai, RT, Eri Ono, RT, Kyoko Hashizume, RT, Junpei Nakamura, RT, and nurses in the CT Section, Department of Radiology, Gunma University Hospital, for obtaining data for this study.