A pilot study to investigate the effect of a hydration regime upon immediate and 24 h delayed MRI...

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Radiography (2007) 13, e90ee98

A pilot study to investigate the effect of a hydrationregime upon immediate and 24 h delayedMRI contrast agent reactions

William Bailey a,c,*, Gill Marshall b, Jacqui Coals a,c

a Medical Imaging, Leighton Hospital, Mid Cheshire Hospital Trust, Middlewich Road, Crewe, Cheshire CW1 4QJ, UKb Chair of Faculty Academic Standards International Projects Leader, Faculty of Health and Social Care,St. Martin’s College, Lancaster LA1 3JD, UK

Received 4 December 2006; accepted 6 February 2007Available online 15 May 2007

KEYWORDSMagnetic resonanceimaging;Contrast agent;Dotarem�;Adverse reactions;Contrast inducednephropathy

Abstract Purpose: Adverse reaction rates to gadolinium based magnetic resonance imaging(MRI) contrast agents which occur immediately post-injection are well documented. Howeverlittle research has investigated delayed reaction rates (i.e. 30 mine24 h). This study evaluatedthe rate of immediate and delayed adverse reaction rates to a gadolinium based MRI contrastagent (Dotarem�) and investigated the effect of a hydration regime on the rate of adverseevents.Method: Fifty-eight patients received no preparation, prior to administration of the contrastagent, whilst another 58 underwent a hydration protocol. The patients had their answers toa questionnaire recorded immediately after the scanning procedure and also via a follow-uptelephone call 24 h later.Results: In the unprepared group 9 patients (15.5%) experienced immediate adverse events,i.e. within 0e30 min, whereas 24 (41.4%) experienced delayed reactions (30 mine24 h) afteradministration of the contrast agent. In the hydrated patient group 6 (10.3%) experiencedan immediate adverse event, whilst 8 (13.7%) experienced delayed events post-injection.The difference in the total reaction rates for the unprepared and hydrated groups was statis-tically significant for immediate and delayed reactions. The difference in the rates of delayedheadache, nausea, dizziness and problems with the injection site, for the unprepared andhydrated groups was statistically significant.

* Corresponding author. Tel.: þ44 1270 612505.E-mail address: [email protected] (W. Bailey).

c Present address: Cross Section Imaging, Manchester Royal Infirmary, Oxford Road, Manchester, UK.

1078-8174/$ - see front matter Crown Copyright ª 2007 Published by Elsevier Ltd on behalf of The College of Radiographers. All rights reserved.doi:10.1016/j.radi.2007.02.005

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The effect of hydration regime on MRI contrast agent reactions e91

Conclusion: An oral hydration regime administered to patients, both before and after MRI con-trast agent administration significantly reduced the total number of immediate and delayedreactions. It also significantly reduced delayed headache, nausea, dizziness and problems atthe injection site. Whilst this pilot study had methodological shortcomings, the strength ofthe relationship demonstrated are worthy of further investigation.Crown Copyright ª 2007 Published by Elsevier Ltd on behalf of The College of Radiographers.All rights reserved.

Introduction

The use of magnetic resonance imaging (MRI) as a diagnostictool has risen dramatically based upon the number ofprocedures performed annually.1 In conjunction with theincreasing use of this speciality is the ever-increasing appli-cation of MRI contrast agents that aid lesion detection andcharacterisation during the scanning of patients.2 World-wide, the majority of MRI contrast enhanced proceduresare performed with contrast agents based on chelates ofthe paramagnetic ion gadolinium (Gd).3 There are severalgadolinium based contrast agents in current use, the firstof which gadopentetate dimeglumine (Magnevist�) was ap-proved for clinical use in 1988.4 For this pilot study gadoter-ate meglumine (Gd-DOTA, Dotarem�) was investigated asthis agent is used routinely within the trust.

Gadolinium is highly toxic and contrast agents utilizea chelating molecule to hold the gadolinium ion tightly andsecurely, and ensure rapid excretion via the kidney.Dotarem� is an ionic agent (net charge �1) and this nega-tive charge is counterbalanced by the presence of methylglucamine, carrying a charge of þ1.

The chemical structure of Dotarem� is that of a rigidmacro-cyclic ligand that binds the gadolinium tightly(Fig. 1). Cyclic gadolinium chelates are considered to bethe most stable, with the best thermodynamic and condi-tional stability characteristics within the gadoliniumcomplexes3 (Table 1). Some linear compounds, e.g. gado-diamide (Omniscan�) and gadoversetamide (Optimark�)are more susceptible to the breakdown of the chemicalbonds that bind the gadolinium ions. This results in the re-lease of free gadolinium into the body.5

Studies regarding the safety of using gadolinium contrastagents in humans have been carried out since 1984 when

Figure 1 Ligand structure for Dotarem� (Gd-DOTA).5,8,9

Laniado investigated how 20 patients tolerated an injectionof Magnevist�.7 Reactions to such agents have been shownto occur including minor adverse reactions9 (see Table 2).Articles also report serious anaphylactic events connectedwith the administration of MRI contrast agents.9e11 Onestudy reported 10 such reactions in an estimated 150,000injections10 with one published study reporting a gadoliniumcontrast related fatality.11 It is important in the context ofsafety to note that all of the clinically approved gadoliniumchelates have been shown to have the same incidence ofminor and the more serious anaphylactic type reactions.9

A large study performed on 15,496 patients12 concludedthat less than half (49.7%) of the adverse events were notedto occur between 1 and 24 h after administration of thecontrast agent. Indeed delayed reactions have subse-quently been reported, typically appearing 24e96 h afterintravenous administration.13 In the majority of clinicalMRI departments, patients will leave the imaging depart-ment shortly after completion of their examination, whichis a cause for concern given that it has been shown11 thata proportion of adverse events may occur after the patientshave left the hospital premises.

Despite gadolinium based contrast agents having one ofthe safest exogenously administered characteristics inclinical use today,5 minor adverse reactions do occur.

As roles extend for MRI radiographers, practice is rapidlyexpanding especially in the areas of administration, report-ing, prescribing and establishing departmental policies forthe safe use and administration of contrast agents as perthe Patient Group Directions.20 These extended roles aresupported by the Society and College of Radiographers21

and endorsed by the Department of Health.22 There arenow 12 beacon MRI sites with advanced practitioner MRIradiographers undertaking these tasks.23 With these newresponsibilities it is paramount that prescribing radiogra-phers understand the safety characteristics of the pharma-ceuticals they administer.

Aim

The first aim of this work was to carry out a pilot study toexamine what (if any) adverse reactions were experiencedby patients, undergoing MRI contrast enhanced scanningprocedures, and establish if these effects occurred imme-diately (i.e. 0e30 min) after injection of the gadoliniumbased contrast agents or whether patients experienced de-layed reactions (i.e. between 30 min and 24 h).

The second aim was to investigate whether an oralhydration protocol, to aid volume expansion and increasediuresis, could help reduce any adverse events experiencedby patients.

e92 W. Bailey et al.

Table 1 Stability characteristics and molecular structures of MRI gadolinium contrast agents6

Contrast agent Molecularstructure

Thermodynamic stabilityconstant log Keq

Conditional stabilityconstant pH 7.4

Gadoterate meglumineMagnevist� (0.5 mol/l)

Linear/ionic 22.1 18.1

Gadoterate meglumineDotarem� (0.5 mol/l)

Cyclic/ionic 25.8 18.8

GadoteridolProHance� (0.5 mol/l)

Cyclic/non-ionic 23.8 17.1

GadodiamideOmniscan� (0.5 mol/l)

Linear/non-ionic 16.9 14.9

Gadobenate dimeglumineMultiHance� (0.5 mol/l)


GadobutrolGadovist� (1.0 mol/l)

Cyclic/non-ionic 21.8 N/A

GadoversetOptiMark� (0.5 mol/l)


Table 2 Reported incidence of the most frequent adverse events in clinical trials after the administration of gadolinium con-trast agent

Contrast agent Number of patients Headache (%) Nausea (%) Taste perversion (%)

Magnevist� (0.5 mol/l)12 1068 3.6 1.5 0.3Dotarem� (0.5 mol/l)14 149 4 4 N/AProhance� (0.5 mol/l)15 1709 0.4 1.1 1.2Omniscan� (0.5 mol/l)16,17 439/700 1.8/4.4 0.9/3.6 0.9/2.1Multihance� (0.5 mol/l)18 2367 1.9 1.3 1.1OptiMark� (0.5 mol/l)19 1663 7.5 2.6 5.7

This protocol was performed after gaining appropriateapproval from the trust for this intervention. The hydrationstrategy was based on a protocol from the European Societyof Urogenital Radiology24 designed to minimize contrast in-duced nephropathy following the administration of iodin-ated contrast agents. It is acknowledged that there is noevidence that this would be valuable post-injection of ga-dolinium chelates. The use of this protocol was based onthe rationale that increasing diuresis and thus more rapidlyeliminating the contrast agent would be beneficial in thereduction of contrast induced reactions. The protocolwould result in no deleterious effects given the volumesof water proposed to achieve hydration. This would be pro-vided that patients in whom fluid loading could prove prob-lematic were excluded.

Table 3 Percentage distribution by area for investigationfor patients administered with gadolinium contrast in theunprepared patient group

Area for investigation Percentage distribution

Oncology (head and neck) 59 (n Z 34)Central nervous system 36 (n Z 21)Musculoskeletal 2 (n Z 1)ENT 3 (n Z 2)

The hypothesis was that the hydration regime of theEuropean Society of Urogenital Radiology would signifi-cantly reduce adverse events post-injection of MRI contrastagents.

Method

A pilot study was performed, with all patient data anony-mised, to establish the adverse reaction rates to thegadolinium based contrast agent Dotarem� 0e30 min afteradministration and again at 24 h post-injection. Patientsundergoing MRI requiring the use of this contrast agentwere included over a four month period (SeptembereDecember 2005). All patients who were over 18 years of

Table 4 Percentage distribution by area for investigationfor patients administered with gadolinium contrast in theoral hydration patient group

Area for investigation Percentage distribution

Oncology (head and neck) 52 (n Z 30)Central nervous system 40 (n Z 23)Musculoskeletal 3 (n Z 2)ENT 5 (n Z 3)


Table 5 Comparison of the immediate (0e30 min) adverse reactions of unprepared and oral hydration studies

Headache Numbness(legs)

Nausea Dizziness Tasteperversion

Injectionsite

Other Number of patientssuffering reactionsa

Unprepared 4 0 3 3 2 1 2 9 (15.5%)Hydrated 0 0 2 0 3 0 1 6 (10.3%)

a It must be noted that several patients suffered several reactions.

age and who gave consent to participate in the pilot studywere included. No patient declined to take part in the pilotstudy. The data collected included oncology (head andneck), central nervous system, musculoskeletal and ear,nose and throat (ENT) patients. In total 58 patients were in-jected with Dotarem�. The patients received no prepara-tion prior to the examination as per existing departmentalpolicy. No patient was injected with the gadolinium basedcontrast agent if they had any contra-indications to MRIcontrast agents (e.g. previous allergic reactions to anyform of contrast agents, severe asthma or any known renalimpairment). Age, gender and clinical indication for MRIcontrast procedure were recorded.

All 58 patients were administered Dotarem� via a handinjection over approximately 20 s. All patients to bescanned received a dose of 0.1 mmol/kg of body weightup to a maximum dose of 20 ml. Two members of the MRIradiographic staff undertook the contrast administration.Individual patient doses were recorded, as were the expirydate and batch numbers.

Two MRI staff members collected the data related to theimmediate adverse reactions via a list of pre-set questions.The patient was asked these questions 30 min post-injec-tion. The questions asked were to investigate the commonminor reactions to MRI contrast agents9 (see Appendix A). Afinal section consisted of an open question to investigatewhether the patients had other comments not covered inthe closed questionnaire. Retaining the patients in the de-partment 30 min post-contrast agent administration is asper departmental policy and as advised by the productmanufacturers.20 Once this time period had elapsed theimaging staff assessed all the subjects and if no seriousadverse events had occurred they were free to leave thedepartment. Patients were contacted 24 h after the scan-ning procedure and had their answers to the same question-naire recorded.

Having established reaction rates of patients with nopreparation, the appropriate approval was obtained toallow the effect of an intervention, namely hydration tobe assessed. This second sample also consisted of 58patients. Data were collected over another four monthperiod (JanuaryeApril 2006) and the method was identical

to that described above, to ensure consistency. Patientsincluded in the second study were adult patients attendingfor a gadolinium based MRI contrast procedure; the needfor contrast enhancement was identified before the pa-tient’s arrival in the department. These patients werecontacted by telephone, prior to arrival in the department,and were sent an information leaflet informing them of thecontrast agent procedure, the hydration guidelines andadvising them of any contra-indications to this procedure.Pathological exclusions to the oral hydration preparationincluded congestive heart failure and any potential contra-indications resulting from increased oral intake of fluids.25

The preparation of the patient for the second sampleconsisted of a minimum of 2000 ml of clear fluids takenorally by the patient 24 h preceding the MRI contrast studyand another 2000 ml of clear fluids taken in the 24 h follow-ing the examination.

The questionnaire had one question regarding numbnessin the legs, which is not a documented side effect ofgadolinium based contrast agent injection. This was placedon the questionnaire to see whether patients exhibitedacquiescence bias,26 demonstrating a psychosomatic re-sponse due to questionnaire construction27 which couldjeopardise the validity of the data. The OptiMark trial sub-jects also exhibited acquiescence bias to a dummyquestion�.19

As well as descriptive statistics, inferential statisticswere performed on the data. The chi squared test was usedto investigate the statistical significance of the differencein the adverse reaction rates experienced between theprepared and unprepared groups. In addition the powerbase of the two sample proportions (unprepared and pre-pared) was calculated using an alpha value of 0.05.

Results

Unprepared patient group

This patient group comprised of 32 females and 26 males(55%:45%). The age range of these patients was between 18e88 years with a mean of 47 years. Although 5 patients (9%)

Table 6 Comparison of the delayed (<24 h) adverse reactions of unprepared and oral hydration studies

Headache Numbness(legs)

Nausea Dizziness Tasteperversion

Injectionsite

Other Number of patientssuffering reactionsa

Unprepared 17 1 11 8 6 4 0 24 (41.4%)Hydrated 4 0 3 1 3 1 1 8 (13.7%)

a It must be noted that several patients suffered several reactions.


Table 7 The differences in the immediate and delayed total reaction rates between the prepared and the unprepared groups

Total reaction rates Unprepared Prepared P value Delayed Unprepared Prepared P value

Immediate

No reaction 43 52 0.0000 No reaction 11 48 0.0000Reaction 15 6 Reaction 47 10

The data demonstrate that there is a statistically significant difference in the total immediate and delayed reaction rates between theunprepared and prepared groups.

had a history of mild allergy all 58 patients were adminis-tered intravenous gadolinium, as they fulfilled the inclusioncriteria (Table 3).

All the patients were retained within the imagingdepartment for 30 min post-contrast administration. Twopatients (3%) underwent moderate adverse contrast reac-tions; one suffered severe chest pain and urticaria whilstthe other experienced violent vomiting. These patientswere kept for further 30 min supervision. No interventionwas deemed necessary and both patients were fit enoughto leave the department after 1 h.

Several patients underwent multiple adverse reactionsduring the administration of contrast agent, the mostcommon being nausea and headache. Nine patients(15.5%) experienced immediate adverse reactions within0e30 min post-injection and 24 patients (41.4%) experi-enced an adverse reaction 24 h post-injection. The distribu-tion of adverse reaction rates between male and femalepatients in this group is 41%:59%.

Oral hydration patient group

This patient group comprised of 26 females and 32 males(45%:55%). The age range of these patients was between19e80 years of age with a mean of 53 years. Seven patients(12%) of this sample had a history of mild allergy (Table 4).

Table 8 The delayed differences in the headache ratesbetween the prepared and the unprepared groups

Headache rate Unprepared Prepared P value

Delayed

No reaction 41 54 0.0000Reaction 17 4

The data demonstrate that there is a statistically significant dif-ference in the delayed headache rate between the unpreparedand prepared groups.

Table 9 The delayed differences in the nausea ratesbetween the prepared and unprepared groups

Nausea rate Unprepared Prepared P value

Delayed

No reaction 47 55Reaction 11 3 0.0000

The data demonstrate that there is a statistically significant dif-ference in the delayed nausea rate between the unpreparedand prepared groups.

In this group neither moderate nor severe reactions wererecorded. One patient suffered light-headedness andsweating 5 min post-contrast administration; however,these effects passed after 3 or 4 min. The patient left thedepartment once the MRI staff were reassured of his well-being; this occurred after a 30 min delay.

The study in which the patients were hydrated recorded6 patients (10.3%) who experienced adverse reaction rates0e30 min post-contrast administration and 8 patients(13.7%) in the subsequent 24 h period. No male patient ex-perienced any form of reaction to the MRI contrast agentduring this second study.

The frequency and type of delayed and immediatereactions experienced are shown in Tables 5 and 6.

Inferential statistics presented for statistically signifi-cant results in (Tables 7e13).

Discussion

The data show that a 32% reduction in MRI contrastreactions was achieved using hydration in the immediate(0e30 min) category. Patients who received oral hydrationrevealed a decrease in immediate reaction rates; 10.3%compared to 15.5% in the unprepared group (Table 5).

Table 10 The delayed differences in the dizziness ratesbetween the prepared and unprepared groups

Dizziness rate Unprepared Prepared P value

Delayed


The data demonstrate that there is a statistically significant dif-ference in the delayed dizziness rate between the unpreparedand prepared groups.

Table 11 The delayed differences in the injection site(pain, swelling, redness) between the prepared and unpre-pared groups

Injection site Unprepared Prepared P value

Delayed


The data demonstrate that there is a statistically significant dif-ference in delayed problems at the injection site between theunprepared and prepared groups.


More significantly was the three-fold reduction in delayedadverse events in patients who had been subjected to thehydration protocol; 13.7% in comparison to 41.4% (Table 6).

Table 7 demonstrates that when all immediate and de-layed reaction rates are considered globally there is a statis-tically different rate of reaction between the two groups.Tables 8e11 demonstrate that there is a statistically differ-ent rate of certain specific delayed reactions namely head-ache, nausea, dizziness and problems at the injection sitebetween the two groups.

Based on the proportion of immediate adverse reactionsfor the prepared and the unprepared groups using an alphavalue of 0.05 a power of 0.49 (49%) was estimated,indicating a marginally significant difference in reactionrates Table 12. However for all delayed adverse reactionsfor the prepared and the unprepared groups, again usingan alpha value of 0.05 a power of 1 was estimated (100%)(Table 13), and thus a highly significant difference. Conse-quently these data demonstrate that the hydration protocolused brings about a significant reduction in reactions, whichis particularly marked in the delayed reactions.

It is worth noting that the delayed ‘reactions’ or postacute effects could in fact be contrast induced toxicityrather than reactions but nevertheless the hydration re-gime is shown to be valuable.

This dramatic decrease in adverse events was simplyachieved by oral intake of clear fluids; both 24 h prior and

Table 12 The estimated power for two-sample compari-son of proportions e immediate reactions

Test Ho: p1 Z p2, where p1 is the proportion in population1 and p2 is the proportion in population 2

Assumptions alpha 0.0500 (two-sided)p1 0.2590p2 0.1030

Sample size n1 58n2 58n2/n1 1.00

Estimated power 0.4922

The data demonstrate a marginally significant difference in im-mediate reaction rates between the unprepared and the pre-pared groups.

Table 13 The estimated power for two-sample compari-son of proportions e all delayed reactions

Test Ho: p1 Z p2, where p1 is the proportion in population1 and p2 is the proportion in population 2

Assumptions alpha 0.0500 (two-sided)p1 0.81000p2 0.2240

Sample size n1 58n2 58n2/n1 1.00

Estimated power 1.0000

The data demonstrate a highly significant difference in delayedreaction rates between the unprepared and the preparedgroups.

post-administration of MRI contrast agents. Interestinglytwo patients, in the unprepared group who suffered mildadverse reactions (headache and nausea) experienced noadverse reactions when undergoing routine MRI contrastfollow-up scans with the hydration regime. These couldbe an indication that oral hydration helps to reduce con-trast agent reactions but more research is needed in thisarea to claim this.

The hydration protocol used was based on volumeexpansion and hydration strategies for high dose x-raycontrast agent procedures (i.e. cardiac angiography) and‘at risk’ renally impaired patients from the guidelines ofthe European Society of Urogenital Radiology to reducecontrast agent induced nephropathy.23 As mentioned in theaim the rationale for this was increasing diuresis and thusmore rapidly eliminating the contrast agent would be ben-eficial in the reduction of contrast induced reactions. Fur-thermore there would be no deleterious effects given thevolumes of water proposed to achieve hydration, providedthat patients in whom fluid loading could prove problematicwere excluded.25 The protocol used would have the effectof increasing renal function and ensuring the fast clearanceof any excess chelate and, it was believed, reducing ad-verse immediate and delayed reaction rates.24 Such find-ings have been observed in studies of iodinated x-raycontrast agents used in tandem with a hydration protocol.The European Society of Urogenital Radiology recommendsincreasing renal output to reduce contrast agent inducednephrotoxicity, particularly when using high dose highosmolar contrast agents.22 The mechanisms that produceadverse events, particularly delayed reactions, when in-jecting MRI gadolinum contrast agents are unknown but itwas speculated that they could be similar to that of x-raycontrast agents.

The clinical reasons for MRI imaging of the patients inthe pilot studies were varied and covered several special-ities including oncology (head and neck), central nervoussystem, musculoskeletal and ENT. As the patient numberswithin these sub-categories were very small specific statis-tical trends were not established in relation to contrastadverse events per sub-category.

The recorded adverse reaction in the first study (nopatient preparation) shows that 15.5% of patients expe-rienced contrast reactions within 0e30 min and 41.4%experienced delayed contrast reactions (i.e. up to 24 hpost-injection). This establishes that nearly three quar-ters (73%) of the adverse reactions would have occurredafter the patient had left the direct supervision of thehospital. Interestingly in the first double-blind randomisedclinical trial, comparing two gadolinium complexes (Gd-DOTA and Gd-DTPA), similar results were recorded after24 h with 71% of all the adverse reactions after thisperiod.14

The results from the unprepared sample revealed thatthe majority of adverse reactions were typically mild (e.g.headache, nausea). If approximately three quarters (73%)of the adverse reactions are recorded after 30 min, but be-fore 24 h, the possibility of more serious life-threateninganaphylactic type reactions occurring may exist. These re-actions would occur later than most MRI departments maycurrently appreciate and certainly after the patient hasleft the hospital premises, if they were outpatients.


Although the rate of severe reactions from the pilotstudy is minor, there is always the possibility that they mayarise. Estimates of these life-threatening adverse eventsrange from 0.0003%28 to 0.017%.29 Although little is knownabout serious delayed MRI contrast reactions, Sahniet al.30 report an anaphylactic reaction in a 21-year-oldwoman following an intravenous injection of gadolinium di-meglumine (Magnevist�). This reaction occurred approxi-mately 20 min after administration of the MRI contrastagents. In the unprepared patient group two patients(3.4%) experienced moderate reactions including severechest pain, urticaria and violent vomiting.

The aetiology of delayed reaction rates is unclear butmajor safety concerns about residual chelate and/or thepossible release of free gadolinium within the body havebeen made.5,31 Gadolinium is a heavy metal and extremelytoxic to humans. The dissociation of the chelate from thegadolinium ion is determined partly by concentration ofcompeting ions and the amount of time it is allowed to re-main in solution. In humans both these conditions are of po-tential concern, i.e. increased concentration of competingmoieties and/or increased time during which the gadoli-nium chelate remains within the body are situations thatwould increase concerns about the safe use of administra-tion of these drugs.31

The safety of gadolinium chelates is mainly based ontheir stability in vivo. Gadolinium contrast agents areeliminated mainly by glomerular excretion. After 6 h ap-proximately 87% would be eliminated13 with less than 1%of the injected dose remaining the week following adminis-tration.3 Although there is no known research into delayedMRI contrast agent reactions, a possible hypothesis could bethat the immediate and delayed contrast reactions mayhave different aetiologies. The gadolinium contrast agentitself could initiate the immediate reactions, while the de-layed reactions could be caused by the dissociation of freegadolinium and/or excess chelate. Further research is sug-gested in this area and is beyond the scope of this study.Also as mentioned delayed ‘reactions’ could in fact notbe reactions at all but manifestations of contrast inducedtoxicity.

In evaluating the data from this pilot study in the light ofthe published literature it is acknowledged that directquantitative comparisons based on overall numbers ofadverse events from clinical trials are misleading sinceclinical trials vary in study designs, phase of development,location and size of study and crucially the subjective ofdifferent investigators.3 In this way, adverse reaction ratesfor the same MRI contrast agent can show significant varia-tions. Clinical evaluations using Magnevist� in the centralnervous system have reported adverse reaction ratesbetween 6% and 19.9%.12,32 Kirchin and Runge6 concludethat although it is difficult to compare adverse reactionrates between clinical trials and studies, the most directapproach is through the use of controlled trials. In this pilotstudy the contrast agent (Dotarem�) was compared directlyagainst itself.

It must be noted that due to anatomical and pathologicalvariations it is often impossible to predict which patientswill benefit from the administration of an MRI contrastagents prior to the scanning procedure. Thus it is not alwayspossible for radiographic staff to ‘prep’ patients with oral

fluids prior to the examination, unless the protocol used inthis study were, subject to further research to justify it,used routinely irrespective of the need for contrast agentenhancement. Further research could also usefully investi-gate whether post-injection hydration only demonstratedreduction in contrast induced delayed reactions.

There are several methodological shortcomings of thisexploratory work. Consequently the results should beviewed with caution e.g. the questionnaire was not piloted,the patient groups were not randomised, the two arms ofthe trial were not conducted in parallel, there was nostandardisation of the patients who had no preparation e.g.they could have drunk hugely variable amounts of waterpre- and post-procedure and the sample size is small giventhe prevalence of the side effects. Further there arepotentially confounding variables e.g. all the patients didnot receive contrast agents with the same batch number,which could have affected the rate and severity of re-actions. Indeed the only standardisation of the patients waswith respect to hydration in the prepared group. There wasno control group to establish the incidence of reporting ofside effects such as headache etc. in the population.However the strength of the relationships demonstratedin this pilot study are such that this work should beinvestigated further by a randomised study (a powercalculation would be necessary to ensure the sample sizewas representative in such a study).

The data gathered are apparently valid based on thefact that only one patient complained of numbness in thelegs. Thus it seems the responses documented are genu-inely experienced sensations. Numbness in the legs is nota documented side effect of gadolinium based contrastagent injection but as this occurred 24 h after the injectionit is possible that the patient was reporting a real effect notrelated to the injection of contrast agent. Another possibil-ity is that this is potentially a previously unreporteddelayed effect. There are many reasons why effects re-ported after 24 h may be due to other than the contrastagent investigation, and they could also be manifestationsof contrast induced toxicity rather than delayed contrastagent reactions.

Conclusion

The results of this pilot study should be viewed with cautionas there are several methodological flaws in the work.However this work should not be dismissed because of thestrength and importance of the findings. The work demon-strated a rate of immediate and delayed reactions toa gadolinium chelate of 15.5% and 41.4%, respectively, inunprepared patients. Furthermore the study demonstratesthat the rate of all immediate and delayed reactions isreduced significantly with the hydration regime used.Similarly a significant reduction was demonstrated incertain categories of delayed reactions, namely headache,nausea, dizziness and injection site events. The findingswarrant the undertaking of a randomised control trial.

Little is known as to why delayed adverse events takeplace and more research is needed to assess the causes.The limited data provided by this study suggest thatincreasing the renal output by adequately hydrating


patients, via increased oral intake, may substantially re-duce the frequency of adverse events. This appears to bean important step to improving the patient’s treatmentwithin the MRI environment and minimizing potential risksfrom the administration of the gadolinium contrast agents.

The oral hydration guidelines recommended by theEuropean Society of Urogenital Radiology have prompteda change in local clinical practice. Oral hydration is nowincorporated into the departmental framework and poli-cies20 and is implemented for all MRI gadolinium contrastexaminations (excluding patients with contra-indications).

It has been concluded that delayed reactions do occurand perhaps more frequently than currently realized. Byadopting a simple oral hydration scheme, similar to thatused to reduce x-ray contrast induced nephrotoxicity, itappears these delayed MR contrast reactions could bedramatically reduced. While it is not practical, due toresources, to supervise patients within the hospital envi-ronment for any extensive period of time (i.e. >1 h) it is im-portant to minimize the risks for patients within our care.However it is acknowledged that further work is requiredto validate these findings.

Acknowledgements

Sassithorn Willmott for statistical guidance regarding thepower calculations. Leslie Robinson for all her hard workand the staff who helped within the MRI department and ofcourse the patients.

Appendix AMR contrast adverse events questionnaire(initial and 24 h prospective study)

Magnetic Resonance Contrast Injection Questionnaire

During the injection did you feel any of the following? (Tickas appropriate)HeadacheNumbness in your legsNauseaDizzinessStrange tasteInjection site painful (swelling, redness)Any other comments?

In the 24 h after the injection did you feel any of the follow-ing? (Tick as appropriate)HeadacheNumbness in your legsNauseaDizzinessStrange tasteInjection site painful (swelling, redness)Any other comments?

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