Gadolinium-DTPA as X-ray contrast medium in clinical studies

					The British Journal of Radiology, 73 (2000), 878±882   E   2000 The British Institute of Radiology



Short communication
Gadolinium-DTPA as X-ray contrast medium in clinical
studies
1,2
      T ALBRECHT, MD, FRCR and 3P DAWSON, PhD, FRCR
1
                                                         È                                            È
 Department of Radiology and Nuclear Medicine, Universitatsklinikum Benjamin Franklin, Freie Universitat
Berlin, Hindenburgdamm 30, D-12200 Berlin, Germany, 2Department of Imaging, Hammersmith Hospital,
Imperial College School of Medicine, Du Cane Road, London W12 OHS, UK and 3Department of Radiology,
The Middlesex Hospital, University College London, Mortimer Street, London W1N 8AA, UK


       Abstract. The aim of this study was to investigate the contrast effects of gadolinium (Gd) in
       patients undergoing digital subtraction angiography (DSA), intravenous urography (IVU) and
       CT. 15 patients attending for coeliac axis DSA (n55), abdominal CT (n55) and IVU (n55) were
       injected with 0.3 mmol kg21 Gd-DTPA, the maximum approved dose. For DSA and IVU,
       images were categorized as being of diagnostic or non-diagnostic quality. For CT, enhancement
       was measured in Houns®eld Units (HU). On CT, enhancement with Gd was reproducible in all
       cases; average peak aortic enhancement was 75 HU but duration was short. On IVU, four of ®ve
       studies yielded positive pyelograms but all nephrograms were relatively poor. On DSA, all ®ve
       patients had diagnostic arteriograms and four of ®ve indirect portograms were of diagnostic
       quality. In all 15 cases, enhancement was weaker than that achieved with routine dosage of
       iodinated agents. In conclusion, Gd chelates may be clinically useful in X-ray studies under
       certain circumstances on patients with contraindications to iodinated agents. Higher doses than
       currently approved would be potentially useful.


   Gadolinium (Gd) has a relatively high atomic              Gd chelates should be ideally suited to serve as
mass of 124 and a k-edge at 52 keV. These                    radiographic contrast media.
properties make it a potent X-ray absorber in the               There are, however, several limitations of Gd
diagnostic spectrum. In vitro and animal studies             chelates as X-ray contrast agents in their current
using CT at 80 kV and 120 kV have demonstrated               formulations and under the current product
that Gd provides approximately 50% more X-ray                licences. All commercially available Gd prepara-
attenuation than iodine when compared on an                  tions have relatively low concentrations of
equimolar basis [1, 2]. Iodinated contrast media,            0.5 mmol Gd ml21, while a 300 mg ml21 radio-
while safe in most patients, are associated with a           graphic contrast medium has an iodine concen-
signi®cant incidence of life threatening adverse             tration of 2.4 mmol ml21. The maximum licensed
events, particularly in high risk patients [3]. Gd           dose for Gd chelates is 0.3 mmol kg21 body
chelates, on the other hand, have been safely used           weight, which compares unfavourably with
in MRI for several years, with virtually no                  3.4 mmol I kg21 for a typical dose of 100 ml of
documented serious adverse events [4, 5]. Unlike             300 mg ml21 strength iodinated contrast medium
iodinated contrast media, Gd chelates are not                in a 70 kg individual.
nephrotoxic [6]. Furthermore, iodinated contrast                Scattered case reports on the use of Gd chelates
media are contraindicated prior to radio-iodine              as radiographic contrast media in CT and
treatment and thyroid scintigraphy, while Gd                 angiography have appeared in the literature
chelates are not a problem in this respect. Unlike           [7±9]. Two previous studies have formally inves-
iodinated media, Gd does not carry the risk of               tigated Gd as a contrast medium in digital
                                                             subtraction angiography (DSA). Schild et al [10]
thyrotoxicosis in hyperthyroid patients. In view of
                                                             performed DSA of the abdominal aorta and lower
these physical and pharmacolocigal properties,
                                                             limb vessels with Gd-DTPA in 16 patients and
                                                             found that Gd provided images of diagnostic
Received 22 December 1998 and in revised form 27
March 2000, accepted 20 April 2000.                          quality in 14. Fobbe et al [11] injected Gd-DTPA
                                                             during DSA of the aorta and its branches in 15
Address correspondence to Dr Thomas Albrecht,
Department of Radiology and Nuclear Medicine,                patients. They used specially adapted angio-
Universitatsklinikum Benjamin Franklin, Hinden-
         È                                                   graphic equipment that provided a higher tube
burgdamm 30, D-12200 Berlin, Germany.                        potential than normal to allow for the relatively

878                                                                   The British Journal of Radiology, August 2000
Short communication: Gadolinium-DTPA as X-ray contrast medium in clinical studies

high k-edge of Gd. The authors obtained images            Erlangen, Germany). Gd-DTPA was injected
of diagnostic quality in 14 cases.                        intravenously via a 21 G cannula in the ante-
  The purpose of this study was to investigate the        cubital fossa with a pump injector (Medrad Mark
use of Gd-DTPA as a contrast medium in patients           IV, Wolverson Medrad, Willenhall, UK or
undergoing CT, intravenous urography (IVU)                Angiomat CT, Liebel-Flarshein, Cincinnati,
and visceral angiography (including indirect              USA) at 5 ml s21. Regions of interest were
portography), observing current dose limitations          placed over the abdominal aorta and time±
and using standard equipment.                             signal curves were generated and assessed for
                                                          the peak enhancement and the duration of signal
                                                          enhancement .20 Houns®eld units (HU). Images
Patients and methods                                      were also subjectively assessed for the presence of
   15 patients (4 females and 11 males, mean age          visually appreciable enhancement of the aorta, the
53 years (range 29±76 years), mean body weight            renal cortex and a renal vein. In addition, a single
74.5 kg (range 54±100 kg)) were studied. Five             late image was obtained approximately 5 min
patients underwent abdominal CT, ®ve visceral             after the injection and assessed for the presence of
angiography and ®ve IVU. The study was                    contrast in the renal collecting system. For the
approved by the Ethics Committee of the                   routine clinical studies, 100±150 ml of Iohexol
Hammersmith Hospital and all patients gave                (300 mgI ml21) was given using the same pump
written informed consent.                                 injectors. A minimum period of 10 min was
   All patients had a limited Gd enhanced study           allowed between the Gd and the clinical study.
(for details see below) and a routine clinical study
with iodinated contrast media. In the CT and
                                                          IVU
IVU group, the Gd study was performed prior to
the clinical study, while the Gd enhanced                    Gd-DTPA was hand-injected intravenously
angiograms were obtained after the clinical               over 30 s via a 19 G ``Butter¯y''. Immediate
study. Gd-DTPA was given undiluted at ``bottle            (nephrogram) and 10 min (pyelogram) radio-
strength'' of 0.5 mmol ml21 and the maximum               graphs were obtained using digital radiography
permissible dose of 0.3 mmol kg21 body weight in          (Fuji AC1, Tokyo, Japan). Abdominal compres-
the CT and IVU group. Patients in the angiog-             sion was applied. One or two additional conven-
raphy group usually had a slightly lower total            tional tomograms were obtained in four cases.
dose in line with our standard angiographic               The left and right kidneys of all patients were
injection protocols (see below). The average              analysed separately. One obstructed kidney was
total dose of Gd-DTPA per patient was 41.8 ml             excluded since no late radiographs after Gd only
(range 24±60 ml). The contrast injection and              were obtained, leaving nine for analysis. Each
imaging protocols of the routine clinical studies         kidney was assessed for the presence of a visually
with iodinated contrast material were not stan-           appreciable nephrogram and pyelogram. In addi-
dardized but varied between patients according to         tion, the observers were asked whether they felt
the clinical situation and indication.                    con®dent (a) to assess the pelvicaliceal anatomy
   Hard copy images of all studies were reviewed          and to diagnose/exclude dilatation, and (b) to
by two experienced radiologists (PD and TA,               detect/exclude ®lling defects such as tumours or
consensus opinion). First, Gd enhanced images             blood clot. For the routine clinical studies,
were assessed for image quality and diagnostic            50±100 ml of Iohexol or Iopromide (300 and
information using different criteria for the three        350 mlI ml21) were given. All these studies
imaging modalities. Second, the Gd enhanced               included an immediate and a 10 min radiograph
images were compared with the routine studies             with abdominal compression. A minimum of
using iodinated contrast medium to determine              20 min elapsed between the Gd and the clinical
whether the image quality was equal or inferior.          studies.
Gd enhanced CT images were also quantitatively
evaluated.
                                                          Visceral angiography
   The procedures for the three different imaging
modalities are described below.                             Single selective injections of Gd-DTPA using a
                                                          7 F Sidewinder catheter were made into the
                                                          coeliac axis (n53) or the superior mesenteric
CT
                                                          artery (n52). 24±32 ml of undiluted Gd-DTPA
   9±12 single level dynamic images of the abdo-          were injected at 6 ml s21 using a pump injector
men were obtained at the level of the renal hila          (Medrad Mark IV, Wolverson Medrad,
over 24±33 s, starting between 9 and 12 s after the       Willenhall, UK). Digitally subtracted images
start of the Gd-DTPA injection, using a Somatom           were obtained using an Integris V 3000
Plus or Somatom Plus 4S scanner (Siemens AG,              angiography unit (Philips, Eindhoven, The

The British Journal of Radiology, August 2000                                                             879
                                                                                    T Albrecht and P Dawson

Netherlands) at 2 frames s21 during the arterial         these diagnostic pyelograms had a larger body
phase and at 1 frame s21 during the portal venous        weight than the other three and were therefore
phase. Both arteriograms and indirect portograms         injected with a larger dose (average 57 ml vs
were assessed for their diagnostic quality. For the      46 ml). None of the seven positive pyelograms
arterial phase images, the criteria for ``diagnostic''   were considered of suf®cient quality to exclude
images were the ability to demonstrate the arterial      ®lling defects. Iodinated contrast medium pro-
anatomy and to detect or exclude luminal                 vided considerably stronger enhancement and
irregularities con®dently. The branching order to        good quality diagnostic studies in all cases
which this was possible was recorded in all cases.       (Figure 2b).
Portograms were considered ``diagnostic'' when
they demonstrated the main, left and right portal
veins as well as the splenic vein or superior            Visceral angiography
mesenteric vein, and allowed con®dent diagnosis
                                                            Arterial phase images were diagnostic in all ®ve
or exclusion of obstruction or occlusion of these
                                                         patients. Con®dent assessment was possible up to
vessels. For the routine clinical studies, 24 ml of
                                                         third order branches of the injected vessels in four
Iohexol (200 mgI ml21) were selectively injected
                                                         cases and up to fourth order branches in one
at 6 ml s21 into one of the above vessels. A
                                                         (Figure 3a). Arterial images obtained with iodi-
minimum period of 5 min was allowed between
                                                         nated contrast medium were of better quality,
the clinical and the Gd study.
                                                         with fourth order branches being well demon-
                                                         strated in all cases (Figure 3b).
Results                                                     Indirect portograms were diagnostic in four of
                                                         ®ve patients (Figure 3a). In one case of a
  No adverse events other than a mild sensation
                                                         pancreatic carcinoma, Gd-DTPA demonstrated
of heat were observed with Gd-DTPA and
                                                         splenic vein obstruction but failed to show
iodinated contrast medium. A sensation of heat
                                                         splenorenal collaterals, which were well demon-
during the injection was reported by the patients
                                                         strated with iodinated contrast medium. This case
at a similar frequency with both contrast media.
                                                         was therefore classi®ed as partially diagnostic.
All the clinical studies enhanced with iodinated
                                                         Among the four cases with diagnostic indirect
contrast medium provided adequate diagnostic
                                                         portograms, enhancement was slightly better with
images.
                                                         iodinated contrast medium in three cases
                                                         (Figure 3b), and both media provided the same
CT                                                       degree of good enhancement in one case.
   Quantitative evaluation showed a mean aortic
peak enhancement with Gd-DTPA of 78.6 HU
                                                         Discussion
(range 63±112 HU), the mean duration of
enhancement of more than 20 HU being 20.8 s                 The results of this pilot study demonstrate that
(range 16±33 s). Subjective analysis showed              contrast enhancement of X-ray studies with Gd-
visually appreciable enhancement of the aorta,           DTPA in patients is feasible and can provide
the renal cortex and a renal vein in all ®ve cases       diagnostic images under appropriate circum-
(Figure 1a). However, the enhancement of all             stances. However, the current restrictions of a
these structures was considerably weaker than            comparatively low maximum permissible dose
that achieved with iodinated contrast medium             and low Gd concentration, even at ``bottle
(Figure 1b). Delayed scans showed contrast               strength'', limit the clinical usefulness of this
medium within the renal pelvis in four of the            new application of Gd-DTPA. The current high
®ve cases. The one patient with no contrast              price of Gd-DTPA is an additional limiting
medium detectable in the collecting system at            factor.
5 min had mild chronic renal failure.                       In clinical situations where contrast enhanced
                                                         X-ray imaging is crucial but iodinated agents are
                                                         contraindicated, for example in renal failure or
IVU
                                                         prior to radio-iodine treatment, Gd can serve as a
  Nephrographic enhancement was weak in four             useful, albeit limited, alternative to iodinated
of the nine kidneys, and absent in the remaining         media. This may also apply to patients with a
®ve. Pyelograms were positive in seven kidneys           history of anaphylactoid reactions to iodinated
and negative in two (Figure 2a). Only two of the         media, since the incidence of such reactions is
seven positive pyelograms were considered diag-          8-fold lower for Gd-DTPA than for iodinated
nostic with regard to con®dent assessment of             agents and only one fatal reaction has been
pelvicalyceal anatomy and the diagnosis or               reported after more than 5 million administra-
exclusion of dilatation. The two patients with           tions [6].

880                                                              The British Journal of Radiology, August 2000
Short communication: Gadolinium-DTPA as X-ray contrast medium in clinical studies




                         (a)                                                        (b)

Figure 1. (a) Single level images of the abdomen at the level of the renal hila, before and after 18 mmol Gd-
DTPA. After 20 s there is enhancement of the aorta, the renal vessels and the renal cortex. After 4 min there is
enhancement of the renal collecting systems. (b) CT section at the same level after injection of 150 ml Iohexol
300 shows considerably more enhancement.

   According to our results and to those of               usefulness to speci®c situations. A fast spiral scan
previous investigators [10±12], angiographic              with arterial enhancement, for example to assess
image quality with Gd is usually suf®cient for            vessel patency, stenosis and dissection or to
diagnostic purposes. In our experience this               differentiate vessels from lymph nodes, could be
includes indirect portograms, although results of         a possible clinical use.
a previous study do not appear to con®rm this                IVU with Gd-DTPA was not reproducibly
[10]. The number of angiographic runs is,                 effective. Although this pilot study was not
however, limited to one to three, or occasionally         designed to assess the dose±response relationship,
four (depending on the patient's body weight, the         our results in the small number of ®ve subjects
vessels to be investigated and the local injection        gave the impression that patients with larger body
protocols), unless the maximum permissible dose           masses, and therefore higher injected Gd doses,
is exceeded.                                              yielded more favourable results than did smaller
   For CT, contrast enhancement with Gd was               patients.
usually relatively weak and short lasting. While             The dose limitations of Gd mentioned above,
vascular enhancement was readily appreciable,             namely low concentration and low permissible
parenchymal enhancement was weak. Our results             maximum dose, may not be immutable. Given the
are in keeping with those of two previous studies,        high safety of Gd chelates, doses exceeding
both of which included ®ve patients with Gd               0.3 mmol kg21 are likely to be well tolerated.
enhanced CT and showed suf®cient arterial                 This will be particularly true for the low
enhancement but insuf®cient parenchymal                   osmolality Gd agents that have recently emerged,
enhancement [13, 14]. This limits the clinical            although higher doses might potentially introduce




                         (a)                                                        (b)

Figure 2. (a) Intravenous urography images before and after 30 mmol Gd-DTPA. The immediate ®lm shows a
faint nephrogram and the 10 min ®lm shows a nephrogram that allows assessment of the normal pelvicalyceal
anatomy. (b) The comparative study performed with 100 ml Iopromide 300 in the same patient shows a stronger
nephrogram and pyelogram.


The British Journal of Radiology, August 2000                                                               881
                                                                                       T Albrecht and P Dawson




                         (a)                                                        (b)
                                                                    21
Figure 3. (a) Angiogram after 32 ml of 16 mmol Gd-DTPA at 6 ml s injected into the coeliac axis shows ar-
terial enhancement up to fourth degree branches and a diagnostic indirect portogram. (b) The comparative study
performed with 24 ml Iohexol 350 at 6 ml s21 in the same patient shows slightly stronger enhancement during
the arterial and portographic phases.

an element of nephrotoxicity. More work is                6. Niendorf HP, Alhassan A, Balzer T, Clauû W,
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                                                             extended clinical experience after more than
medium manufacturers have recently developed                 5,000,000 applications. In: Felix R, Heshiki A,
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should reduce the current limitations of Gd as            7. Bloem JL, Wondergem J. Gd-DTPA as a contrast
                                                             agent in CT. Radiology 1989;171:578±9.
an X-ray contrast medium and should make it a             8. Quinn AD, O'Hare N, Wallis FJ, Wilson GF. Gd-
more competitive alternative to the iodinated                DTPA: an alternative contrast medium for CT.
media. High cost is likely to remain a limitation            J Comput Assist Tomogr 1994;18:634±6.
for the foreseeable future but, given the small           9. Kinno Y, Odagiri K, Andoh K, Itoh Y, Tarao K.
number of patients in whom iodinated contrast                Gadopentetate dimeglumine as an alternative con-
                                                             trast material for use in angiography. AJR
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                                                             Strunk H, Duber C, et al. Gadolinium-DTPA
                                                             (Magnevist)      als   Kontrastmittel       È
                                                                                                       fur     die
                                                                                  È
                                                             arterielle DSA. Rofo Fortschr Geb Rontgenstr
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882                                                              The British Journal of Radiology, August 2000

				
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