BJR Received: 7 January 2016
© 2016 The Authors. Published by the British Institute of Radiology Revised: 12 May 2016
Accepted: 18 May 2016
http://dx.doi.org/10.1259/bjr.20160027
Cite this article as: Neeley C, Moritz M, Brown JJ, Zhou Y. Acute side effects of three commonly used gadolinium contrast agents in the paediatric population. Br J Radiol 2016; 89: 20160027.
FULL PAPER
Acute side effects of three commonly used gadolinium contrast agents in the paediatric population CHRIS NEELEY, MD, MICHAEL MORITZ, MD, JEFFREY J BROWN, MD and YIHUA ZHOU, MD, PhD Department of Radiology, Saint Louis University School of Medicine, Saint Louis, Missouri, USA Address correspondence to: Dr Yihua Zhou E-mail: [email protected]
Objective: To determine the incidence of acute side effects of three commonly used gadolinium contrast agents in the paediatric population. Methods: A retrospective review of medical records was performed to determine the incidence of acute adverse side effects of i.v. gadolinium contrast agents [MultiHance® (Bracco Diagnostics Inc., Princeton, NJ), Magnevist® (Bayer Healthcare Pharmaceuticals, Wayne, NJ) or Gadavist® (Bayer HealthCare Pharmaceuticals)] in paediatric patients. Results: 40 of the 2393 patients who received gadolinium contrast agents experienced acute side effects, representing an incidence of 1.7%. The majority of the acute side effects (in 30 patients) were nausea and vomiting. The incidence was significantly higher in non-sedated patients (2.37% vs 0.7%; p 5 0.0018). Furthermore, without sedation, the incidence of both nausea and vomiting was significantly higher in children receiving MultiHance, with a 4.48% incidence of nausea when compared with Magnevist (0.33%, p , 0.0001) and Gadavist (0.28%,
p , 0.0001) and a 2.36% incidence of vomiting compared with those for Magnevist (0.50%, p 5 0.0054) and Gadavist (0.28%, p 5 0.014), whereas no difference was observed between Magnevist and Gadavist within the power of the study. In addition, there was no apparent difference between any of the three contrast agents for the incidence of allergy or other acute side effects detected, given the sample size. Conclusion: The gadolinium contrast agents MultiHance, Magnevist and Gadavist have a low incidence of acute side effects in the paediatric population, a rate that is further reduced in moderately sedated patients. MultiHance demonstrated significantly increased incidence of gastrointestinal symptoms compared with Magnevist and Gadavist. Advances in knowledge: The incidence of acute side effects of three commonly used gadolinium contrast agents was determined in the paediatric population, which can have clinical implications.
While i.v. gadolinium-based MRI contrast agents are widely recognized to be safe in clinical applications, there have been reported adverse side effects associated with their use, including death.1 Nephrogenic systemic fibrosis has rightfully garnered the most attention owing to its devastating consequences; however, other adverse events associated with these contrast agents have not been as thoroughly studied in the paediatric population.
effect in the paediatric population. For example, while full prescribing information for MultiHance reports an overall side effect rate of 6.5% in the paediatric population,2 the packaging inserts of other agents, however, do not make specific comments on the observed rates of side effects in the paediatric population.
Commonly used gadolinium contrast agents at our institution include gadobenate dimeglumine [MultiHance® (Bracco Diagnostics Inc., Princeton, NJ)], gadopentetate dimeglumine [Magnevist® (Bayer Healthcare Pharmaceuticals, Wayne, NJ)] and gadobutrol [Gadavist® (Bayer HealthCare Pharmaceuticals)]. According to the product packaging inserts of non-published data as provided by the manufacturers, the reported overall side effect rates range from 3.5 to 10.4%.2–4 However, few manufacturers have offered specific information regarding the incidence of side
A recently published large prospective study of 132,252 doses of MultiHance in an adult population conducted over 7.5 years demonstrated the overall safety of this agent, with only 0.18% of patients experiencing an adverse side effect.5 Another large multicentre review of 23,553 doses of MultiHance showed similarly low rates of adverse reactions, with only 0.76% of adult patients experiencing an acute adverse effect, the most common of which were nausea and vomiting.6 A large retrospective review of 158,796 patients undergoing gadolinium contrast-enhanced MRI at two hospitals revealed a small, but statistically significant increase in the adverse side effect incidence
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associated with MultiHance when compared with gadodiamide (Omniscan) and Magnevist.7 Unfortunately, no patient age information was available in this report to determine the safety profiles in children. A retrospective review of 200 paediatric patients undergoing contrast-enhanced MRI with MultiHance demonstrated no adverse events in any of the study patients.8 A post-marketing study of 2982 adult patients and 110 paediatric patients undergoing contrast-enhanced MR with MultiHance demonstrated an adverse event incidence of 14%, similar to placebo, with no increased incidence in the paediatric population.9 Another study observed no immediate adverse event in 104 neonates and infants who received gadolinium during routine clinical utilization.10 The sample sizes of these studies were small for the paediatric population. In a retrospective study including 13,344 paediatric patients, the frequency of acute allergic-like reactions in paediatric populations using Magnevist, MultiHance and Omniscan was 0.04%.11 A similar result (0.05%, 8 of 15,706 paediatric patients) was observed more recently.12 However, only allergic-like reactions were studied in these large-scale analyses. While the acute side effects caused by gadolinium contrast administration such as nausea and vomiting are obviously undesirable in any patient population, it is the authors’ experience that these are less tolerated in the paediatric population. For example, as young children are unable to weigh the risks and benefits of an imaging examination, even a relatively minor immediate side effect may discourage the child from cooperating with future examinations despite their medical necessity. In the paediatric oncologic population, in particular, where multiple follow-up studies are the norm, a negative experience may require future examinations be performed under sedation, which carries a higher risk of serious adverse events and requires more healthcare resources. Knowledge of the incidence of such complications may be helpful in both selecting an appropriate contrast agent for specific situations and discussing the risks with the potentially anxious parents and older patients prior to the examination. To our knowledge, this is the largest retrospective study comparing the incidence of acute side effects of some of the commonly used gadolinium-based MR contrast agents in the paediatric population. The purpose of this study was to retrospectively determine the incidence of immediate adverse events associated with commonly used gadolinium contrast agents at our paediatric hospital.
patients at our institution and in the USA in general. Three general-purpose contrast agents were used at our facility during the studied period of time, including MultiHance (gadobenate dimeglumine), Magnevist (gadopentetate dimeglumine) and Gadavist (gadobutrol). The specific contrast used for a given patient was based on the availability of the agents at the time of MRI examination and the preference of one of the seven attending radiologists for the case. A standard dose of 0.1-mmol kg21 body weight was used for all gadolinium agents. The contrast agents were hand-injected by experienced MR technologists at approximately 0.5 ml s21. When patients were unable to hold still in the MR scanner for any reason, monitored anaesthesia care using propofol (i.v. infusion at 25–100 mcg/kg min) with airway protection was administered by experienced anaesthesiologists or specially trained physician assistants with supervision of an anaesthesiologist. These patients were under continuous monitoring of the cardiac and respiratory status. Patients needing monitored anaesthesia care were on Nil per os (meaning to withhold oral food and fluids) for 6 h prior to the administration of sedation medications to minimize the risk of aspiration, while non-sedated patients were generally not on Nil per os. The MR technologists at our institution were trained and required to document the incidences of acute adverse side effects to gadolinium contrast for all patients. The recorded data included the type, nature and severity of the adverse side effects, as well as the site of injection, the type of contrast agent and the treatment that the patient received for the reaction. The acute adverse side effects included any reactions either spontaneously reported by the patients or observed by the technologists, nurses or physicians during their stay in the MRI department. For sedated patients, if retching was observed, it was assumed that nausea was the cause® of the retching and the adverse event was classified as such. For this study, the medical records and the radiology log books were reviewed to collect the related data, including the patient gender and age, the use of sedation, the type of gadolinium contrast agent, the type and severity of the Figure 1. Number of sedated and non-sedated paediatric patients who received gadolinium contrast agents in the studied time frame. Gadavistâ, Bayer Healthcare Pharmaceuticals, Wayne, NJ; Magnevistâ, Bayer Healthcare Pharmaceuticals; MultiHance, Bracco Diagnostics Inc., Princeton, NJ.
METHODS AND MATERIALS This retrospective study was approved by our institutional review board and the requirement for informed consent was waived, as the patient identification information was neither collected nor disclosed. All patients under 18 years who received i.v. gadolinium contrast agents during a 2-year period between January 2013 and December 2014 at the Cardinal Glennon Children’s Medical Center in St. Louis, USA, were included in the study. This age range was used because children under 18 years were considered paediatric
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Full paper: Gadolinium side effects in children
acute adverse side effect and treatment, if any. The incidence of acute side effects was calculated by dividing the number of patients with reported side effects by the number of patients receiving each contrast agent. Each patient was counted only once, even though he/she might have had acute reactions to more than one administrations. Statistical analysis was performed using two-tailed Fisher’s exact test to compare the incidence of the various side effects observed with the different types of contrast. Fisher’s exact test was used owing to the relatively low occurrences of the side effects. RESULTS During the selected time frame of this study, a total of 2393 paediatric patients (56% males and 44% females) underwent contrast MRI using one of the three gadolinium contrast agents. Figure 1 details the number of patients receiving each type of contrast, as well as the status of sedation. Magnevist was the most commonly used contrast agent while the number of patients receiving MultiHance and Gadavist is similar. Approximately 40% of patients were sedated during the MRI scan and administration of the contrast material, and the proportion of sedated patients are similar among the three agents. Figure 2 summarizes the age distribution of all patients within each age group (,1, 1–5, 5–10 and 10–18 years). There were more patients in the 10–18-year group, whereas most patients under 5 years were sedated. Table 1 details the number of acute side effects observed for each contrast reagent in this study. The most commonly observed acute side effects included nausea, vomiting and allergic reactions. Overall, there were 40 subjects who experienced acute adverse side reactions after i.v. contrast administration, including 30 gastrointestinal (GI) side effects (26 cases of nausea and 13 cases of vomiting, including 9 cases who initially complained of nausea and eventually developed vomiting), 2 allergic reactions manifested by wheezing and hives and 8 additional reactions collectively classified as “other” reactions because of their low numbers. The reactions in the last group (“other”) included tachycardia, shortness of breath and hypoxia and cough. There was one child who had nausea after receiving
Figure 2. Age distribution of sedated and non-sedated patients.
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MultiHance in two separate administrations 3 months apart, but only counted as one patient in the calculation of the incidence rate. We observed retching reaction in three sedated patients after contrast administration, all of which were seen after injection of MultiHance. We assumed that retching was an indication of nausea and included these patients in the nausea category of adverse reactions. The overall incidence of acute side effects for all contrast agents was 1.7% in this cohort. There was, however, significantly more adverse side reactions in the nonsedated patients than in the sedated group, with an incidence of 2.37% (33 out of 1392 cases) and 0.7% (7 out of 1001 cases), respectively [odds ratio 5 3.39, 95% confidence interval (CI) 1.47–9.11; p 5 0.0018]. There was no apparent difference in the incidence of acute side effects among all gadolinium contrast agents in sedated patients. However, statistical analysis was not performed owing to the low frequency of acute side effects in sedated patients and the relatively small sample size, which limits the power of statistical analysis. Figure 3 summarizes the incidence of acute side effects among different contrast agents using the data from only the nonsedated patients. MultiHance had the highest incidence of acute side effects in non-sedated patients, the majority of which were GI, including 19 cases of nausea and 10 cases of vomiting. The incidence of nausea after MultiHance administration was 4.48%, which was significantly higher than that for Magnevist (0.33%, odds ratio 5 9.0, 95% CI 2.63–47.75; p , 0.0001) and Gadavist (0.28%, odds ratio 5 16.28, 95% CI 2.56–677.53; p 5 0.00012). The incidence of vomiting after MultiHance administration was 2.36%, also significantly higher than that for Magnevist (0.50%, odds ratio 5 7.11, 95% CI 1.50–67.16; p 5 0.0054) and Gadavist (0.28%, odds ratio 5 8.57, 95% CI 1.21–372.96; p 5 0.014). There was no apparent difference between Magnevist and Gadavist for both nausea and vomiting. There was no apparent difference in the incidence of allergic reaction or other acute side effects among the three contrast agents. However, the low frequency of acute side effects in these groups and the relatively small sample limit the power of statistical analyses. DISCUSSION Our results confirm that gadolinium-based MRI contrast agents are safe in the paediatric population judged by acute adverse reactions. The overall incidence of acute adverse reactions was 1.7% for the three studied gadolinium contrast agents. There were no serious or life-threatening acute adverse reactions in any of the 2393 patients in our paediatric institution over the 2-year study period, and the observed acute adverse side effects including nausea, vomiting, allergy, tachycardia, cough, shortness of breath and hypoxia were generally mild and self-limited. The GI side effects, namely nausea and vomiting, were the most commonly observed/reported adverse reactions, with rates comparable with those previously reported for adult patients.6,9 However, the incidence of acute adverse side effects observed in this study is higher in paediatric patients than previously reported,8 in which no adverse events were recorded during the first 24 h following administration of gadobenate dimeglumine (MultiHance) in 200 children. The discrepancy may be due to the relatively small sample size in the previous report.8
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Table 1. Acute side effects in paediatric patients receiving gadolinium contrast
Contrast Gadavist® (Bayer Healthcare Pharmaceuticals, Wayne, NJ) Magnevist® (Bayer Healthcare Pharmaceuticals) MultiHance® (Bracco Diagnostics Inc., Princeton, NJ)
Sedation
Subjects
Nausea
Vomitinga
Allergy
Othersb
Multiple side effectsc
No
364
1
1
0
1
1
Yes
260
0
0
0
2
0
No
604
3
2
1
2
1
Yes
420
0
0
0
1
0
No
424
19
10
1
1
7
Yes
321
3
0
0
1
0
a
Nine patients who initially complained of nausea and eventually developed vomiting were included in both nausea and vomiting groups. Other reactions included tachycardia, shortness of breath and hypoxia and cough. c These patients had both nausea and vomiting. b
Sedation is commonly employed in younger patients undergoing MRI to reduce motion artefacts and to improve diagnostic values. The incidence of acute side effects was significantly lower in patients receiving conscious sedation (0.7%) than in those who underwent MRI without sedation (2.37%) (p 5 0.0018). To our knowledge, the effect of sedation on the incidence of the acute side effects of the gadolinium contrast agents has not been previously reported. During the period of our study, MR technologists observed retching reaction in three sedated patients after contrast administration. The retching reactions were assumed to be indications of nausea and included these patients in the nausea category of adverse reactions. Although these patients
Figure 3. Incidence (%) of immediate side effects of MultiHanceâ (Bracco Diagnostics Inc., Princeton, NJ) (gadobenate dimeglumine), Magnevistâ (Bayer Healthcare Pharmaceuticals, Wayne, NJ) (gadopentetate dimeglumine) and Gadavistâ (Bayer Healthcare Pharmaceuticals) (gadobutrol) in nonsedated patients: gastrointestinal (GI) side effects are those of nausea or vomiting. In non-sedated paediatric patients, MultiHance had the highest rates of immediate GI side effects (nausea and vomiting) when compared with Magnevist and Gadavist (p , 0.0001). There was no apparent difference between Magnevist and Gadavist. The three contrast agents showed no obvious difference in allergic reactions and other immediate side effects, although no statistical analyses were performed for these comparisons owing to the relatively small sample size and low frequency of these side effects.
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did not actually vomit, we believe this was an important observation because of the high risk of aspiration if retching were to progress to frank vomiting in sedated patients. We cannot prove that these reactions are not caused by medications for sedation; however, given the fact that the reactions happened right after contrast administration, they are more likely to be related to contrast injection. In non-sedated patients, MultiHance had the highest overall incidence of adverse reactions (4.48% for nausea), which was significantly higher than that in patients who received Magnevist (0.33%) or Gadavist (0.28%). A similar phenomenon was reported in adult patients also.7 This knowledge may be helpful in both selecting an appropriate contrast agent for specific situations and discussing the risks with the potentially anxious parents and older patients prior to the examination. There was no apparent difference in the rates of adverse reactions with Magnevist and Gadavist in non-sedated patients, although the low frequency of the side effects prevents us from a meaningful statistical test. Similarly, the incidence of non-GI adverse reactions was too low to allow for an accurate statistical analysis to determine if the rates of these differed among the contrast agents. Limitations of this study include the inherent difficult in assessing the acute adverse side effects after contrast administration in sedated patients and young children. While our data suggested significantly lower immediate side effects in sedated patients (p , 0.0001), it is conceivable that our data underestimated the true incidence for two reasons. First, sedated patients may be less likely or unable to report nausea. Second, sedation is more often necessary for younger children, who may also be unable to report nausea. In non-sedated patients, the incidence may also be underestimated owing to the retrospective nature of this study. For example, a patient who experienced nausea without vomiting may not have reported the side effect to the technologist and thus the reaction would not have been recorded. Future studies of acute adverse reactions would benefit from prospective data collection with more formal, comprehensive screening of patients for adverse side effects, although subjectively assessing the experienced symptoms will always prove difficult in young or sedated patients.
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Another potential limitation of our study is that the technologists were not blinded to which contrast agent they were administering, creating the possibility of biased data collection. However, we feel that because the only data included in our study involved either symptoms spontaneously reported by the patients or objective reactions such as vomiting or retching directly observed by the technologists, such bias is likely low. Blinded contrast administration would be logistically difficult, as the technologists are responsible for both the administration of the contrast agent and for patient monitoring. The lack of a placebo control owing to the retrospective nature of our study is an additional limitation, although the observed statistical
differences in the rates of adverse reactions among the various agents remain valid. In conclusion, the incidence of acute adverse side effects of i.v. gadolinium contrast agents including MultiHance, Magnevist and Gadavist is low, confirming the general safety of these agents in the paediatric population. The most common side effects were GI side effects including nausea and vomiting. Non-sedated patients had a significantly higher incidence of GI side effects than sedated patients, while MultiHance demonstrated a small but significantly increased incidence of nausea and vomiting compared with Magnevist and Gadavist.
REFERENCES 1.
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5.
Abujudeh HH, Kosaraju VK, Kaewlai R. Acute adverse reactions to gadopentetate dimeglumine and gadobenate dimeglumine: experience with 32,659 injections. AJR Am J Roentgenol 2010; 194: 430–4. doi: http://dx. doi.org/10.2214/AJR.09.3099 Package Insert. Princeton, NJ: Bracco Diagnostics. MultiHance® (gadobenate dimeglumine injection). Package Insert, Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc. Magnevist® (Gadopentetate dimeglumine injection). Package Insert, Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc. Gadavist® (Gadobutrol injection). Fakhran S, Alhilali L, Kale H, Kanal E. Assessment of rates of acute adverse reactions to gadobenate dimeglumine: review of more than 130,000 administrations in 7.5 years. AJR Am J Roentgenol 2015; 204: 703–6. doi: http://dx.doi.org/ 10.2214/AJR.14.13430
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6.
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Bleicher AG, Kanal E. Assessment of adverse reaction rates to a newly approved MRI contrast agent: review of 23,553 administrations of gadobenate dimeglumine. AJR Am J Roentgenol 2008; 191: W307–11. doi: http:// dx.doi.org/10.2214/AJR.07.3951 Prince MR, Zhang H, Zou Z, Staron RB, Brill PW. Incidence of immediate gadolinium contrast media reactions. AJR Am J Roentgenol 2011; 196: W138–43. doi: http://dx.doi. org/10.2214/AJR.10.4885 Schneider G, Sch¨urholz H, Kirchin MA, B¨ucker A, Fries P. Safety and adverse effects during 24 hours after contrast-enhanced MRI with gadobenate dimeglumine (MultiHance) in children. Pediatr Radiol 2013; 43: 202–11. doi: http://dx.doi.org/10.1007/s00247-0122498-8 Shellock FG, Parker JR, Venetianer C, Pirovano G, Spinazzi A. Safety of gadobenate dimeglumine (MultiHance): summary of findings from clinical studies and
postmarketing surveillance. Invest Radiol 2006; 41: 500–9. doi: http://dx.doi.org/ 10.1097/01.rli.0000209661.99225.c2 10. Emond S, Brunelle F. Gd-DOTA administration at MRI in children younger than 18 months of age: immediate adverse reactions. Pediatr Radiol 2011; 41: 1401–6. doi: http://dx.doi.org/10.1007/s00247-011-2167-3 11. Dillman JR, Ellis JH, Cohan RH, Strouse PJ, Jan SC. Frequency and severity of acute allergic-like reactions to gadoliniumcontaining i.v. contrast media in children and adults. AJR Am J Roentgenol 2007; 189: 1533–8. doi: http://dx.doi.org/10.2214/ AJR.07.2554 12. Davenport MS, Dillman JR, Cohan RH, Hussain HK, Khalatbari S, McHugh JB, et al. Effect of abrupt substitution of gadobenate dimeglumine for gadopentetate dimeglumine on rate of allergic-like reactions. Radiology 2013; 266: 773–82. doi: http://dx.doi.org/ 10.1148/radiol.12120253
Br J Radiol;89:20160027
© 2016 The Authors. Published by the British Institute of Radiology Revised: 12 May 2016
Accepted: 18 May 2016
http://dx.doi.org/10.1259/bjr.20160027
Cite this article as: Neeley C, Moritz M, Brown JJ, Zhou Y. Acute side effects of three commonly used gadolinium contrast agents in the paediatric population. Br J Radiol 2016; 89: 20160027.
FULL PAPER
Acute side effects of three commonly used gadolinium contrast agents in the paediatric population CHRIS NEELEY, MD, MICHAEL MORITZ, MD, JEFFREY J BROWN, MD and YIHUA ZHOU, MD, PhD Department of Radiology, Saint Louis University School of Medicine, Saint Louis, Missouri, USA Address correspondence to: Dr Yihua Zhou E-mail: [email protected]
Objective: To determine the incidence of acute side effects of three commonly used gadolinium contrast agents in the paediatric population. Methods: A retrospective review of medical records was performed to determine the incidence of acute adverse side effects of i.v. gadolinium contrast agents [MultiHance® (Bracco Diagnostics Inc., Princeton, NJ), Magnevist® (Bayer Healthcare Pharmaceuticals, Wayne, NJ) or Gadavist® (Bayer HealthCare Pharmaceuticals)] in paediatric patients. Results: 40 of the 2393 patients who received gadolinium contrast agents experienced acute side effects, representing an incidence of 1.7%. The majority of the acute side effects (in 30 patients) were nausea and vomiting. The incidence was significantly higher in non-sedated patients (2.37% vs 0.7%; p 5 0.0018). Furthermore, without sedation, the incidence of both nausea and vomiting was significantly higher in children receiving MultiHance, with a 4.48% incidence of nausea when compared with Magnevist (0.33%, p , 0.0001) and Gadavist (0.28%,
p , 0.0001) and a 2.36% incidence of vomiting compared with those for Magnevist (0.50%, p 5 0.0054) and Gadavist (0.28%, p 5 0.014), whereas no difference was observed between Magnevist and Gadavist within the power of the study. In addition, there was no apparent difference between any of the three contrast agents for the incidence of allergy or other acute side effects detected, given the sample size. Conclusion: The gadolinium contrast agents MultiHance, Magnevist and Gadavist have a low incidence of acute side effects in the paediatric population, a rate that is further reduced in moderately sedated patients. MultiHance demonstrated significantly increased incidence of gastrointestinal symptoms compared with Magnevist and Gadavist. Advances in knowledge: The incidence of acute side effects of three commonly used gadolinium contrast agents was determined in the paediatric population, which can have clinical implications.
While i.v. gadolinium-based MRI contrast agents are widely recognized to be safe in clinical applications, there have been reported adverse side effects associated with their use, including death.1 Nephrogenic systemic fibrosis has rightfully garnered the most attention owing to its devastating consequences; however, other adverse events associated with these contrast agents have not been as thoroughly studied in the paediatric population.
effect in the paediatric population. For example, while full prescribing information for MultiHance reports an overall side effect rate of 6.5% in the paediatric population,2 the packaging inserts of other agents, however, do not make specific comments on the observed rates of side effects in the paediatric population.
Commonly used gadolinium contrast agents at our institution include gadobenate dimeglumine [MultiHance® (Bracco Diagnostics Inc., Princeton, NJ)], gadopentetate dimeglumine [Magnevist® (Bayer Healthcare Pharmaceuticals, Wayne, NJ)] and gadobutrol [Gadavist® (Bayer HealthCare Pharmaceuticals)]. According to the product packaging inserts of non-published data as provided by the manufacturers, the reported overall side effect rates range from 3.5 to 10.4%.2–4 However, few manufacturers have offered specific information regarding the incidence of side
A recently published large prospective study of 132,252 doses of MultiHance in an adult population conducted over 7.5 years demonstrated the overall safety of this agent, with only 0.18% of patients experiencing an adverse side effect.5 Another large multicentre review of 23,553 doses of MultiHance showed similarly low rates of adverse reactions, with only 0.76% of adult patients experiencing an acute adverse effect, the most common of which were nausea and vomiting.6 A large retrospective review of 158,796 patients undergoing gadolinium contrast-enhanced MRI at two hospitals revealed a small, but statistically significant increase in the adverse side effect incidence
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Neeley et al
associated with MultiHance when compared with gadodiamide (Omniscan) and Magnevist.7 Unfortunately, no patient age information was available in this report to determine the safety profiles in children. A retrospective review of 200 paediatric patients undergoing contrast-enhanced MRI with MultiHance demonstrated no adverse events in any of the study patients.8 A post-marketing study of 2982 adult patients and 110 paediatric patients undergoing contrast-enhanced MR with MultiHance demonstrated an adverse event incidence of 14%, similar to placebo, with no increased incidence in the paediatric population.9 Another study observed no immediate adverse event in 104 neonates and infants who received gadolinium during routine clinical utilization.10 The sample sizes of these studies were small for the paediatric population. In a retrospective study including 13,344 paediatric patients, the frequency of acute allergic-like reactions in paediatric populations using Magnevist, MultiHance and Omniscan was 0.04%.11 A similar result (0.05%, 8 of 15,706 paediatric patients) was observed more recently.12 However, only allergic-like reactions were studied in these large-scale analyses. While the acute side effects caused by gadolinium contrast administration such as nausea and vomiting are obviously undesirable in any patient population, it is the authors’ experience that these are less tolerated in the paediatric population. For example, as young children are unable to weigh the risks and benefits of an imaging examination, even a relatively minor immediate side effect may discourage the child from cooperating with future examinations despite their medical necessity. In the paediatric oncologic population, in particular, where multiple follow-up studies are the norm, a negative experience may require future examinations be performed under sedation, which carries a higher risk of serious adverse events and requires more healthcare resources. Knowledge of the incidence of such complications may be helpful in both selecting an appropriate contrast agent for specific situations and discussing the risks with the potentially anxious parents and older patients prior to the examination. To our knowledge, this is the largest retrospective study comparing the incidence of acute side effects of some of the commonly used gadolinium-based MR contrast agents in the paediatric population. The purpose of this study was to retrospectively determine the incidence of immediate adverse events associated with commonly used gadolinium contrast agents at our paediatric hospital.
patients at our institution and in the USA in general. Three general-purpose contrast agents were used at our facility during the studied period of time, including MultiHance (gadobenate dimeglumine), Magnevist (gadopentetate dimeglumine) and Gadavist (gadobutrol). The specific contrast used for a given patient was based on the availability of the agents at the time of MRI examination and the preference of one of the seven attending radiologists for the case. A standard dose of 0.1-mmol kg21 body weight was used for all gadolinium agents. The contrast agents were hand-injected by experienced MR technologists at approximately 0.5 ml s21. When patients were unable to hold still in the MR scanner for any reason, monitored anaesthesia care using propofol (i.v. infusion at 25–100 mcg/kg min) with airway protection was administered by experienced anaesthesiologists or specially trained physician assistants with supervision of an anaesthesiologist. These patients were under continuous monitoring of the cardiac and respiratory status. Patients needing monitored anaesthesia care were on Nil per os (meaning to withhold oral food and fluids) for 6 h prior to the administration of sedation medications to minimize the risk of aspiration, while non-sedated patients were generally not on Nil per os. The MR technologists at our institution were trained and required to document the incidences of acute adverse side effects to gadolinium contrast for all patients. The recorded data included the type, nature and severity of the adverse side effects, as well as the site of injection, the type of contrast agent and the treatment that the patient received for the reaction. The acute adverse side effects included any reactions either spontaneously reported by the patients or observed by the technologists, nurses or physicians during their stay in the MRI department. For sedated patients, if retching was observed, it was assumed that nausea was the cause® of the retching and the adverse event was classified as such. For this study, the medical records and the radiology log books were reviewed to collect the related data, including the patient gender and age, the use of sedation, the type of gadolinium contrast agent, the type and severity of the Figure 1. Number of sedated and non-sedated paediatric patients who received gadolinium contrast agents in the studied time frame. Gadavistâ, Bayer Healthcare Pharmaceuticals, Wayne, NJ; Magnevistâ, Bayer Healthcare Pharmaceuticals; MultiHance, Bracco Diagnostics Inc., Princeton, NJ.
METHODS AND MATERIALS This retrospective study was approved by our institutional review board and the requirement for informed consent was waived, as the patient identification information was neither collected nor disclosed. All patients under 18 years who received i.v. gadolinium contrast agents during a 2-year period between January 2013 and December 2014 at the Cardinal Glennon Children’s Medical Center in St. Louis, USA, were included in the study. This age range was used because children under 18 years were considered paediatric
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Br J Radiol;89:20160027
Full paper: Gadolinium side effects in children
acute adverse side effect and treatment, if any. The incidence of acute side effects was calculated by dividing the number of patients with reported side effects by the number of patients receiving each contrast agent. Each patient was counted only once, even though he/she might have had acute reactions to more than one administrations. Statistical analysis was performed using two-tailed Fisher’s exact test to compare the incidence of the various side effects observed with the different types of contrast. Fisher’s exact test was used owing to the relatively low occurrences of the side effects. RESULTS During the selected time frame of this study, a total of 2393 paediatric patients (56% males and 44% females) underwent contrast MRI using one of the three gadolinium contrast agents. Figure 1 details the number of patients receiving each type of contrast, as well as the status of sedation. Magnevist was the most commonly used contrast agent while the number of patients receiving MultiHance and Gadavist is similar. Approximately 40% of patients were sedated during the MRI scan and administration of the contrast material, and the proportion of sedated patients are similar among the three agents. Figure 2 summarizes the age distribution of all patients within each age group (,1, 1–5, 5–10 and 10–18 years). There were more patients in the 10–18-year group, whereas most patients under 5 years were sedated. Table 1 details the number of acute side effects observed for each contrast reagent in this study. The most commonly observed acute side effects included nausea, vomiting and allergic reactions. Overall, there were 40 subjects who experienced acute adverse side reactions after i.v. contrast administration, including 30 gastrointestinal (GI) side effects (26 cases of nausea and 13 cases of vomiting, including 9 cases who initially complained of nausea and eventually developed vomiting), 2 allergic reactions manifested by wheezing and hives and 8 additional reactions collectively classified as “other” reactions because of their low numbers. The reactions in the last group (“other”) included tachycardia, shortness of breath and hypoxia and cough. There was one child who had nausea after receiving
Figure 2. Age distribution of sedated and non-sedated patients.
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MultiHance in two separate administrations 3 months apart, but only counted as one patient in the calculation of the incidence rate. We observed retching reaction in three sedated patients after contrast administration, all of which were seen after injection of MultiHance. We assumed that retching was an indication of nausea and included these patients in the nausea category of adverse reactions. The overall incidence of acute side effects for all contrast agents was 1.7% in this cohort. There was, however, significantly more adverse side reactions in the nonsedated patients than in the sedated group, with an incidence of 2.37% (33 out of 1392 cases) and 0.7% (7 out of 1001 cases), respectively [odds ratio 5 3.39, 95% confidence interval (CI) 1.47–9.11; p 5 0.0018]. There was no apparent difference in the incidence of acute side effects among all gadolinium contrast agents in sedated patients. However, statistical analysis was not performed owing to the low frequency of acute side effects in sedated patients and the relatively small sample size, which limits the power of statistical analysis. Figure 3 summarizes the incidence of acute side effects among different contrast agents using the data from only the nonsedated patients. MultiHance had the highest incidence of acute side effects in non-sedated patients, the majority of which were GI, including 19 cases of nausea and 10 cases of vomiting. The incidence of nausea after MultiHance administration was 4.48%, which was significantly higher than that for Magnevist (0.33%, odds ratio 5 9.0, 95% CI 2.63–47.75; p , 0.0001) and Gadavist (0.28%, odds ratio 5 16.28, 95% CI 2.56–677.53; p 5 0.00012). The incidence of vomiting after MultiHance administration was 2.36%, also significantly higher than that for Magnevist (0.50%, odds ratio 5 7.11, 95% CI 1.50–67.16; p 5 0.0054) and Gadavist (0.28%, odds ratio 5 8.57, 95% CI 1.21–372.96; p 5 0.014). There was no apparent difference between Magnevist and Gadavist for both nausea and vomiting. There was no apparent difference in the incidence of allergic reaction or other acute side effects among the three contrast agents. However, the low frequency of acute side effects in these groups and the relatively small sample limit the power of statistical analyses. DISCUSSION Our results confirm that gadolinium-based MRI contrast agents are safe in the paediatric population judged by acute adverse reactions. The overall incidence of acute adverse reactions was 1.7% for the three studied gadolinium contrast agents. There were no serious or life-threatening acute adverse reactions in any of the 2393 patients in our paediatric institution over the 2-year study period, and the observed acute adverse side effects including nausea, vomiting, allergy, tachycardia, cough, shortness of breath and hypoxia were generally mild and self-limited. The GI side effects, namely nausea and vomiting, were the most commonly observed/reported adverse reactions, with rates comparable with those previously reported for adult patients.6,9 However, the incidence of acute adverse side effects observed in this study is higher in paediatric patients than previously reported,8 in which no adverse events were recorded during the first 24 h following administration of gadobenate dimeglumine (MultiHance) in 200 children. The discrepancy may be due to the relatively small sample size in the previous report.8
Br J Radiol;89:20160027
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Neeley et al
Table 1. Acute side effects in paediatric patients receiving gadolinium contrast
Contrast Gadavist® (Bayer Healthcare Pharmaceuticals, Wayne, NJ) Magnevist® (Bayer Healthcare Pharmaceuticals) MultiHance® (Bracco Diagnostics Inc., Princeton, NJ)
Sedation
Subjects
Nausea
Vomitinga
Allergy
Othersb
Multiple side effectsc
No
364
1
1
0
1
1
Yes
260
0
0
0
2
0
No
604
3
2
1
2
1
Yes
420
0
0
0
1
0
No
424
19
10
1
1
7
Yes
321
3
0
0
1
0
a
Nine patients who initially complained of nausea and eventually developed vomiting were included in both nausea and vomiting groups. Other reactions included tachycardia, shortness of breath and hypoxia and cough. c These patients had both nausea and vomiting. b
Sedation is commonly employed in younger patients undergoing MRI to reduce motion artefacts and to improve diagnostic values. The incidence of acute side effects was significantly lower in patients receiving conscious sedation (0.7%) than in those who underwent MRI without sedation (2.37%) (p 5 0.0018). To our knowledge, the effect of sedation on the incidence of the acute side effects of the gadolinium contrast agents has not been previously reported. During the period of our study, MR technologists observed retching reaction in three sedated patients after contrast administration. The retching reactions were assumed to be indications of nausea and included these patients in the nausea category of adverse reactions. Although these patients
Figure 3. Incidence (%) of immediate side effects of MultiHanceâ (Bracco Diagnostics Inc., Princeton, NJ) (gadobenate dimeglumine), Magnevistâ (Bayer Healthcare Pharmaceuticals, Wayne, NJ) (gadopentetate dimeglumine) and Gadavistâ (Bayer Healthcare Pharmaceuticals) (gadobutrol) in nonsedated patients: gastrointestinal (GI) side effects are those of nausea or vomiting. In non-sedated paediatric patients, MultiHance had the highest rates of immediate GI side effects (nausea and vomiting) when compared with Magnevist and Gadavist (p , 0.0001). There was no apparent difference between Magnevist and Gadavist. The three contrast agents showed no obvious difference in allergic reactions and other immediate side effects, although no statistical analyses were performed for these comparisons owing to the relatively small sample size and low frequency of these side effects.
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did not actually vomit, we believe this was an important observation because of the high risk of aspiration if retching were to progress to frank vomiting in sedated patients. We cannot prove that these reactions are not caused by medications for sedation; however, given the fact that the reactions happened right after contrast administration, they are more likely to be related to contrast injection. In non-sedated patients, MultiHance had the highest overall incidence of adverse reactions (4.48% for nausea), which was significantly higher than that in patients who received Magnevist (0.33%) or Gadavist (0.28%). A similar phenomenon was reported in adult patients also.7 This knowledge may be helpful in both selecting an appropriate contrast agent for specific situations and discussing the risks with the potentially anxious parents and older patients prior to the examination. There was no apparent difference in the rates of adverse reactions with Magnevist and Gadavist in non-sedated patients, although the low frequency of the side effects prevents us from a meaningful statistical test. Similarly, the incidence of non-GI adverse reactions was too low to allow for an accurate statistical analysis to determine if the rates of these differed among the contrast agents. Limitations of this study include the inherent difficult in assessing the acute adverse side effects after contrast administration in sedated patients and young children. While our data suggested significantly lower immediate side effects in sedated patients (p , 0.0001), it is conceivable that our data underestimated the true incidence for two reasons. First, sedated patients may be less likely or unable to report nausea. Second, sedation is more often necessary for younger children, who may also be unable to report nausea. In non-sedated patients, the incidence may also be underestimated owing to the retrospective nature of this study. For example, a patient who experienced nausea without vomiting may not have reported the side effect to the technologist and thus the reaction would not have been recorded. Future studies of acute adverse reactions would benefit from prospective data collection with more formal, comprehensive screening of patients for adverse side effects, although subjectively assessing the experienced symptoms will always prove difficult in young or sedated patients.
Br J Radiol;89:20160027
Full paper: Gadolinium side effects in children
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Another potential limitation of our study is that the technologists were not blinded to which contrast agent they were administering, creating the possibility of biased data collection. However, we feel that because the only data included in our study involved either symptoms spontaneously reported by the patients or objective reactions such as vomiting or retching directly observed by the technologists, such bias is likely low. Blinded contrast administration would be logistically difficult, as the technologists are responsible for both the administration of the contrast agent and for patient monitoring. The lack of a placebo control owing to the retrospective nature of our study is an additional limitation, although the observed statistical
differences in the rates of adverse reactions among the various agents remain valid. In conclusion, the incidence of acute adverse side effects of i.v. gadolinium contrast agents including MultiHance, Magnevist and Gadavist is low, confirming the general safety of these agents in the paediatric population. The most common side effects were GI side effects including nausea and vomiting. Non-sedated patients had a significantly higher incidence of GI side effects than sedated patients, while MultiHance demonstrated a small but significantly increased incidence of nausea and vomiting compared with Magnevist and Gadavist.
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