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British Journal of Radiology (2006) 79, 368-371
© 2006 British Institute of Radiology
doi: 10.1259/bjr/88469693
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Full paper

Acute adverse reactions to magnetic resonance contrast media – gadolinium chelates

A Li, MBChB, FRCR 1 C S Wong, MBChB 2 M K Wong, MBBS, FRCR, FHKCR 2 C M Lee, MBBS, FRCR, FHKCR 2 and M C Au Yeung, MBBS, FRCR, FHKCR 2

1 Department of Radiology and Organ Imaging, United Christian Hospital, 130 Hip Wo Street, Kwun Tong, Hong Kong, SAR, 2 Department of Radiology, Princess Margaret Hospital, Hong Kong, SAR


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
The objective of this study was to evaluate the clinical safety of intravenous gadolinium-based contrast media used in patients who underwent MRI at a single institution. Acute adverse reactions to intravenous gadolinium-based contrast media used for MRI at the Princess Margaret Hospital, Hong Kong, SAR, from January 1999 to November 2004 were recorded in an incidence log book. The medical records of patients' demographics were retrospectively reviewed and the nature, frequency and severity of the adverse reactions were investigated and documented. The incidence of acute adverse reactions to intravenous gadolinium-based contrast media was 0.48% (45 patients with 46 adverse reactions). The severity of these adverse reactions were 96% mild, 2% moderate (one patient developed shortness of breath that required oxygen supplementation and intravenous steroidal management) and 2% severe (one patient developed an anaphylactoid reaction, but successfully recovered through timely resuscitation). No patients were recorded as having contrast extravasation and none died as a result of any adverse reaction. Among the 45 patients who developed adverse reactions, three patients (6.7%) had prior adverse reactions to iodinated contrast media, three (6.7%) had prior reactions to a different gadolinium-based contrast agent, one (2%) had asthma and nine (20%) had a history of drug/food allergy. Overall, 41% of the adverse reactions were not documented in the final MRI report or the clinical medical records. Gadolinium-based contrast media are safe and well tolerated by the vast majority of patients. In our study, the adverse reaction rate (0.48%) and the incidence of severe anaphylactoid reaction (0.01%) concur with those reported in the literature. Although most of the symptoms are mild and transient, these adverse reactions must be accurately documented and managed.


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
MRI is often considered a safer alternative to CT for patients who cannot tolerate iodinated contrast media.

The intravenous gadolinium-based contrast media is widely used in MRI for a number of reasons: it improves sensitivity of lesion detection, and provides better diagnostic specificity and more accurate depiction of the extent of the disease involvement. Although the total adverse reaction rates are in the range of 0.17% to 2.40%, many of the problems that lead to concerns about the use of iodinated contrast agents also exist in the use of gadolinium-based contrast media [1–3]. The purpose of this report is to quantify the frequency and manifestations of adverse reactions associated with the use of gadolinium-based contrast media in our regional hospital.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
From January 1999 to November 2004, 18 142 MRI examinations were performed at the Princess Margaret Hospital, Hong Kong, SAR (including those performed on patients referred from Yan Chi Hospital and Caritas Medical Center, Hong Kong, SAR). Gadolinium-based contrast media was used in 9528 (52.8%) examinations. All adverse reactions that occurred in patients within 1 h of intravenous administration of the gadolinium-based contrast media were documented in an incidence log book by the nursing staff or the responsible radiologist. This information was either provided voluntarily by the patients or observed by the MRI radiographers, nurses or radiologists. The following details were recorded in the incidence log book: demographic data of the patients (name, medical record number, sex and age); medical history (e.g. asthma, or previous allergic reactions such as allergies to iodinated or gadolinium-based contrast media); severity and nature of adverse reactions; treatments given and actions taken; the name and signature of the reporter and responsible radiologists. This information, the medical records and the MRI radiology reports relevant to the patients were reviewed.

An adverse reaction was defined to be any unfavourable or unintended alteration in the clinical status that was temporally associated with the use of contrast media, even if it was not considered to be related to administration of the drug. The sensations of hot or cold, transient sensations of taste or mild pain at the injection site were excluded as adverse reactions. The severity of the reaction was subdivided into mild, moderate and severe. Mild reactions were defined as symptoms that were transient, or that required minimal or no therapy. Moderate reactions were more severe in nature or occurred for a longer duration than mild reactions; therapy was required but the patient was not considered critical. Patients who had severe reactions required resuscitation and their condition was considered to be possibly life-threatening.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
A total of 45 (0.48%) of the 9528 patients were recorded as having adverse reactions to the gadolinium-based media. One patient developed repeated mild contrast reactions in two separate MRI studies (counted as one patient in our study). The mean age of the study population was 42 years (median 42 years, range 12–79 years). Five patients (11%) were in the paediatric age group (16 years or younger). 58% of the patients were female (n = 26).

Table 1Go displays the adverse reactions that occurred in patients with a history of potentially predisposing conditions. Among the 45 patients who developed adverse reactions to gadolinium-based contrast media, 8 patients (18%) had previous exposure to an iodinated contrast media (one patient had a prior adverse reaction to the iodinated contrast media); 34 patients (75%) had no previous exposure; status was unknown in 3 patients (7%). Nine of the 45 patients (20%) who developed adverse reactions had prior exposure to gadolinium-based contrast media (three patients had prior adverse reactions to the gadolinium-based contrast media); 33 patients (73%) had no prior exposure; the contrast history was unknown in three patients (7%). Nine of the 45 patients (20%) had a history of allergies (eczema, to drugs, alcohol, etc.) and one patient (2%) had a history of asthma.


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  		Table 1. The medical history of patients who had adverse reactions

 
Table 2Go displays the type, number, and severity of adverse reactions that occurred after the use of intravenous gadolinium-based contrast media. Gadoterate meglumine (Dotarem; Guerbet, France) was used in three patients, Gadodiamide (Omniscan; Nycomed, New York, NY) in 23 patients and Gadopentetate dimeglumine (Magnevist; Berlex, Schering AG, Germany) in 19 patients. The dose was administered according to the manufacturers' instructions. Two of the patients who developed adverse reactions underwent MR angiography, which involved the use of power injectors to administer the contrast agent at a rate of 2 ml per second. In all other cases, the contrast media was manually administered by injection.


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  		Table 2. The type and severity of the adverse reactions

 
None of the patients in our study with a history of adverse reactions to gadolinium-based (three patients) or iodinated contrast media (one patient) had pre-medication to prevent recurrence of such adverse reactions.

Among these 45 patients, the majority of adverse reactions to gadolinium-based contrast media were mild and transient (96%) (Table 2Go). The most frequent mild reaction was nausea and vomiting (40%) and 33% of patients were affected by urticaria and a rash. All patients with nausea, vomiting and urticaria responded to conservative management, and the seven patients who developed a rash were treated with a stat dose of oral diphenhydramine. One patient developed dyspnoea that was treated with oxygen supplementation, intravenous steroids and fluids, and further inpatient management. The patient was subsequently discharged uneventfully. This patient did not have a history of respiratory disorders such as asthma or chronic obstructive airway disease—bronchospasm was the presumed cause of the dyspnoea. Among the 9528 patients who underwent contrast MRI, one patient (0.01%) developed an anaphylactoid reaction. This 77-year-old patient was referred for outpatient MRI for follow up of a known malignant melanoma of the nostril that had intracranial extension. The patient had undergone a contrast enhanced MRI study using gadodiamide without complications, but developed anaphylactoid shock shortly after injection of gadopentate dimeglumine. The patient did not have a history of asthma, allergies, or previous sensitivities to drugs including iodinated contrast media. The patient was successfully resuscitated (by securing the airways, use of oxygen, and intravenous diphenhydramine, steroids, adrenaline and fluids) and was hospitalized for intensive care and later discharged uneventfully. No contrast extravasation was recorded for any patient and none died as a result of an adverse reaction.


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
Gadolinium-based contrast agents constitute the largest group of MRI contrast media and are considered to be very safe and well tolerated. Gadopentetate dimeglumine, the first agent approved by the Food and Drug Administration (FDA) for clinical use in the USA (1988), has a total adverse reaction rate in the range of 0.17–2.40% [1–3]. Nelson et al [1] reported the adverse reaction rate in a patient population of 15 496 given gadopentetate dimeglumine was 2.4%. The overall adverse reaction rate was 1.2% if patients voluntarily reported their symptoms instead of being directly questioned.

The safety of the gadolinium chelates is largely based on their stability in vivo. The chelates are designed to bind gadolinium ions tightly, preventing the possible release of free gadolinium ions, which are extremely toxic to the body. The differences between the gadolinium chelates in terms of chemical stability and transmetallation gives rise to some theoretical concerns. Transmetallation refers to the substitution of the chelates by copper and zinc ions in the body leading to the release of free gadolinium ions. Both gadopentetate dimeglumine and gadodiamide can inhibit the zinc-dependent angiotensin-converting enzyme (ACE) in the body and may also give rise to transmetallation [4–7]. To our knowledge, no harmful effects in humans caused by free gadolinium ion deposition resulting from the clinical use of these agents have been reported. All commercially available gadolinium chelates have comparable adverse reaction profiles including mild reactions such as nausea and severe anaphylactoid reactions [4]. For reference, the incidence of urticaria in clinical trials for gadopentetate dimeglumine is 0.3% in 1068 patient [8], for gadodiamide it is 0.7% in 439 patients [9], and for gadoterate meglumine it is 0.4% in 518 patients [10]. These figures are not statistically differentiable.

Numerous cases of severe anaphylactoid reactions associated with the use of gadolinium-based contrast media have been reported [11–13]. For example, a fatal reaction to gadopentetate dimeglumine was reported in 1995. This patient did not have a history of asthma or previous allergic reactions to iodinated contrast media [14]. The incidence rate of severe anaphylactoid reaction in our series was 0.01%. This concurs with a large series by Murphy et al [3], in which two severe reactions to gadopentetate dimeglumine out of 21 000 patients were reported. For reference, in another study by Caro et al, the risk of a life-threatening event with iodinated radiographic contrast media was 0.031% for low-osmolarity contrast media, and 0.157% for conventional ionic contrast media [15]. Our results again confirm that gadolinium-based contrast media is safer than iodinated contrast media. In 1994, Witte et al reported a case of life-threatening anaphylactoid reaction that occurred after the administration of intravenous gadoteridol (Prohance; Bracco Diagnostics, Princeton, NJ) in a patient who had previously received gadopentetate dimeglumine [16]. To our knowledge, our study is the first reported case in the English language literature of a patient who developed severe anaphylactoid reaction after intravenous administration of gadodiamide without having exhibited any adverse reaction with the prior use of gadopentetate dimeglumine. Although the incidence of life-threatening reactions to gadolinium-based contrast media is low, anaphylactoid reactions are among the worst adverse reactions that might occur with the use of MRI contrast agents. Therefore, it is prudent to provide sufficient training for personnel and to have available adequate resuscitation facilities in the MRI suite if these agents are to be used.

Nelson et al reported that the likelihood of adverse reactions to gadolinium-based contrast media is about eight times higher in patients who have had previous reactions to gadolinium-based contrast media. The severity of a second adverse reaction tends to be more pronounced than the first [1]. In our series, all three patients who had prior adverse reactions to gadolinium-based contrast media developed adverse reactions after repeated use of such an agent. These three patients were not pre-medicated to reduce risk of contrast reactions. In an attempt to reduce the risk of a reaction to the contrast media, a different gadolinium-based media (gadodiamide) was administered instead of the previously used gadopentate dimeglumine. However, adverse reactions still developed despite the use of a different gadolinium-based contrast media, but these reactions were mild and transient (rash and nausea). The frequency of adverse reactions among patients who have a history of adverse reactions to gadolinium-based contrast media cannot be determined from our data. However, our observations may support the findings of the study by Nelson et al.

The role of pre-medication with corticosteroids as a preventive measure in patients with prior reactions to gadolinium-based contrast media has not been well established. In a study by Murphy et al [3], two patients were pre-medicated before the gadolinium contrast agent was administered. One patient had a single oral dose of 50 mg diphenhydramine 1 h before the procedure, and the second patient had an oral dose of 50 mg diphenhydramine 1 h before the procedure and 20 mg prednisolone every 6 h (starting 13 h before the examination). Both patients had the same adverse reaction as with the previous gadolinium exposure. The second patient returned for a further MRI study and was given the same pre-medication, but a different contrast agent from the previous one. He did not develop any complications. Murphy et al [3] recommends the use of 12–24 h pre-medication with corticosteroids and subsequent use of a different or lower osmolar MRI contrast agent as a preventative measure among this group of patients. The evidence of benefits of such pre-medication has not been well established. Until more data are available, gadolinium-based MRI contrast media should be used with caution in patients with a history of adverse reactions, in particular severe reactions.

The frequency of adverse reactions to gadolinium-based contrast agents is about 2.3–3.7 times higher in patients with a history of reactions to iodinated contrast material [1, 2]. In our study, three of the 45 patients who experienced adverse reactions to gadolinium-based contrast media had also had previous reactions to iodinated contrast media, but the rash and nausea symptoms were mild and transient. Again, administration of gadolinium-based contrast media among these types of patients should be made with caution, because the role of steroid pre-medication has not been well established.

Patients with asthma and various allergies are also at greater risk of adverse reactions. Nelson et al [1] reported that the frequency of adverse reactions is 1.5 and 1.9 times higher, respectively, compared with patients who have none of these allergies. Among the 45 patients in our study who had adverse reactions (Table 1Go), one patient had asthma and nine patients had a prior allergy (2 urticaria, 2 seafood, 1 eczema, 3 alcohol and 1 aspirin related).

In this study, 19 out of 46 cases of contrast adverse reactions (41%) were not documented in the final MRI report or the clinical medical records. The adverse reactions in these cases were all mild and transient. Proper documentation of the adverse reaction is not only essential for medico-legal purposes, but also more importantly for the interest and well being of the patient. If precautions could be taken before the repeated administration of gadolinium-based contrast media, then the awareness and management of adverse reactions would be more efficient. Therefore, the accurate recording of the reactions associated with gadolinium-based contrast media should be as thorough as they are for reactions associated with other drugs.

Several limitations were identified in the design of this study. The design was a retrospective review of the incidence log book, which was originally intended for documenting all acute adverse reactions to the gadolinium chelates for medical records and for departmental audit. Although clear instructions were given to staff in the department, all acute adverse reactions may not have been documented, in particular those that were trivial in nature. Voluntary reporting by patients was also likely to lead to under-reporting. Additional minor reactions might have been reported if patients were questioned directly or by way of a questionnaire. Only acute adverse reactions were recorded, occurring within 1 h between the gadolinium-based contrast media injection and the patient leaving the department after observation. In the study by Nelson et al, 44.9% of adverse reactions occurred more than 1 h after the gadolinium-based contrast media injection. Those reactions were all mild and transient, with no severe or life-threatening events recorded [1]. In such circumstances, the incidence of acute adverse reactions in our patient population still concurs with those reported in the literature.

In conclusion, gadolinium-based contrast media is safe and well tolerated by the vast majority of patients. Although most adverse reactions are mild and transient, life-threatening anaphylactoid reactions do occur. Personnel should be well trained and resuscitation facilities should be readily available in the MRI examination room. Accurate documentation and cautious management of all adverse reactions related to gadolinium-based contrast media should be made in the same manner as for other drug reactions.

Received for publication May 9, 2005. Revision received August 24, 2005. Accepted for publication October 17, 2005.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

  1. Nelson KL, Gifford LM, Lauber-Huber C, Gross CA, Lasser TA. Clinical safety of gadopentetate dimeglumine. Radiology 1995;2:439–43.
  2. Niendorf H, Dinger J, Haustein J, Cornelius I, Alhassan A, Clauss W. Tolerance data of Gd-DTPA: a review. Eur J Radiol 1991;13:15–20.[CrossRef][Medline]
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  4. Runge VM. Safety of approved MR contrast media for intravenous injection. J Magn Reson Imaging 2000;12:205–13.[CrossRef][Medline]
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  7. Corot C, Idee JM, Hentsch AM, et al. Structure-activity relationship of macrocyclic and linear gadolinium chelates; investigation of transmetallation effect on the zinc-dependent metallopeptidase angiotensin-converting enzyme. J Magn Reson Imaging 1998;8:695–702.[Medline]
  8. Goldstein HA, Kashanian FK, Blumetti RF, et al. Safety assessment of gadopentetate dimeglumine in U.S. clinical trials. Radiology 1990;174:17–23.[Abstract/Free Full Text]
  9. Sze G, Brant-Zawadzki M, Haughton VM, Maravilla KR, et al. Multicenter study of gadodiamide injection as a contrast agent in MR imaging of the brain and spine. Radiology 1991;181:693–9.[Abstract/Free Full Text]
  10. Oudkerk M, Sijens PE, Van Beek EJ, Kuijpers TJ. Safety and efficacy of dotarem (Gd-DOTA) versus Magnevist (Gd-DTPA) in magnetic resonance imaging of the central nervous system. Invest Radiol 1995;30:75–8.[CrossRef][Medline]
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This Article
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