Equine Veterinary Journal ISSN 0425-1644

DOI: 10.1111/evj.12689

Review Article

Use of contrast media in computed tomography and magnetic

resonance imaging in horses: Techniques, adverse events and
opportunities
B. B. NELSON† , L. R. GOODRICH†, M. F. BARRETT†‡, M. W. GRINSTAFF§ and C. E. KAWCAK†*
†
Gail Holmes Equine Orthopaedic Research Center, Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado
State University, Fort Collins, Colorado, USA
‡
Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, Colorado, USA
§
Departments of Biomedical Engineering, Chemistry, Materials Science & Engineering and Medicine, Boston University, Boston, Massachusetts, USA.

*Correspondence email: christopher.kawcak@colostate.edu; Received: 12.08.16; Accepted: 04.04.17

Summary
The use of contrast media in computed tomography (CT) and magnetic resonance imaging (MRI) is increasing in horses. These contrast-enhanced
imaging techniques provide improved tissue delineation and evaluation, thereby expanding diagnostic capabilities. While generally considered safe, not
all contrast media exhibit the same safety profiles. The safety of contrast media use and descriptions of adverse events occurring in horses are sparsely
reported. This review summarises the reported evidence of contrast media use and adverse events that occur in horses, with added contribution from
other veterinary species and studies in man for comparison. This comprehensive data set empowers equine clinicians to develop use and monitoring
strategies when working with contrast media. Finally, it summarises the current state-of-the-art and highlights the potential applications of contrast-
enhanced CT and MRI for assessment of diseased or injured equine tissues, as well as (patho)physiological processes.

Keywords: horse; contrast-enhanced; contrast agent; risk; CECT; complication; joint

Introduction intensity (darken structures) on routine pulse sequences. Iron oxide

Computed tomography (CT) and magnetic resonance imaging (MRI)
provide real-time volumetric information to assess diseased or injured
tissues, as well as depict physiological processes in horses [1–3].
Conventional CT and MRI techniques are often limited in their ability to
distinguish one tissue from an adjacent one. Thus, contrast media (also
referred to as contrast agents) are administered to enable improved
identification and evaluation of tissue(s) [4–7]. After contrast media
administration, these techniques are denoted as contrast-enhanced CT and
MRI. While the contrast media used in horses are manufactured for human
use and generally considered safe, like any pharmaceutical, they are not
devoid of risk [8]. Due to widespread use in man, contrast media guidelines
have been previously published [8,9]; however, there are few detailed
descriptions in horses. Since many of the studies and resulting safety
profiles are reported in man or other veterinary species, we will draw from
these findings as they compare to horses in order to raise awareness of
potential risks that may occur. This review describes the different contrast
media available, reported techniques, adverse events and opportunities for
their use in horses and then highlights the potential advantages and
possibilities that are enabled by use of contrast-enhanced CT or MRI.
Terminology
Contrast media are classified based on their interaction with tissue and the
subsequent alteration of imaging signal. They are categorised into positive
or negative agents. While positive agents brighten the structure, negative
agents exhibit the opposite effect, darkening the structure [10]. There are
many commercially available positive agents for CT and MRI
(Supplementary Item 1), but no negative agents for CT; although air and
CO2 provide a similar effect (Fig 1). With CT, increased attenuation
(hyperattenuation) of x-rays brightens structures, while decreased
attenuation (hypoattenuation) darkens them. With regards to MRI, the T1
and T2 relaxation times are time constants describing the MRI signal decay
in the longitudinal and transverse magnetic axes, respectively, following
application of a radiofrequency pulse. Shortening T1 times increase signal
intensity (brighten structures), while shorter T2 times decrease signal
contrast media, used with MRI, are negative agents and produce
predominantly spin-spin relaxation effects with shorter T2 (and T1) times
[11]. During the vascular phase, iron oxide contrast media largely effect T1
relaxation, but this vastly decreases after macrophage phagocytosis [12].
Computed tomography contrast media
Iodinated contrast media (ICM) are the most commonly used in CT
imaging. Iodine, as an element with a high atomic number, attenuates
x-rays more than lower atomic number elements [13]. As iodine is the
critical component in ICM that imparts x-ray attenuation, solutions are
labeled in mg iodine/mL (mg I/mL) and are commercially available in
varying concentrations (Supplementary Item 1). Tissues attenuate x-rays
based on their density, thickness and photon energies applied, but
distinguishing between different tissue types with similar attenuating
properties is challenging. However, after vascular injection, ICM highlight
areas of increased vascular perfusion/permeability enabling differentiation
of these similar tissues [10,14]. Since most ICM are small molecules
(<2 kDa), they freely diffuse beyond the vascular endothelium [15] with <2%
becoming intracellular [14,16]. Elimination of ICM is predominantly through
the kidneys [17,18]. Although ICM do not undergo tubular reabsorption,
the water and salt contained in solution are reabsorbed in the proximal
renal tubules. In man, the plasma half-life is ~2 h with complete elimination
within 20 h [8] and appears similar in horses [17,18].
Composition
Iodinated contrast media typically contain a benzene ring with three iodine
atoms. The chemical structure variations include side chain modifications
and/or dimerisation [15]. The relevant physiochemical properties of ICM
include aqueous solubility, ionicity, osmolality and viscosity. The overall
charge on ICM is either negative (anionic) or positive (cationic), or the
agent is neutral (nonionic) [10]. Commercially available ionic ICM are
exclusively anionic and coordinated with meglumine or sodium. Cationic
ICM are being developed specifically for articular cartilage imaging [19,20].
After administration, ionic ICM exert substantially more osmotic pressure

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B. B. Nelson et al. Contrast media in CT and MRI: use, adverse events and opportunities

a) b) c)

* * *

*
* *

Fig 1: Computed tomography (CT) and CT arthrography of the metacarpophalangeal joint. Dorsal is to the top and lateral to the left in all images. All images are in the
transverse plane. Precontrast image a). Iodinated contrast media (ICM) was injected into the metacarpophalangeal joint b). Note the contrast medium in the joint space
(hyperattenuation, black asterisks) providing for observation of the articular cartilage (hypoattenuation, white arrow). Double contrast CT arthrography c). Iodinated
contrast media (40 mg I/mL) was injected into the metacarpophalangeal joint followed by air. Note the air (hypoattenuation, white asterisk) providing for contrast
between the soft tissues and articular cartilage/bone, although contrast resolution is lower between the subchondral bone and articular cartilage (white arrow) when
compared with b). The CT examination was performed with the medial aspect of the joint recumbent, thus there is excess contrast media accumulation on the medial
aspect of the joint in c).

and are more likely to interact with cell membranes and peptides than
nonionic ICM [15,21].
The osmolality (osmoles/kilogram) of an agent depends upon its
concentration, ionicity, dimerisation/oligomerisation and added solutes.
High osmolar ICM possess 5–8 times higher osmolality than normal plasma
(280–290 mOsm/kg [22]). Low osmolar ICM are 2–3 times higher than
normal plasma and iso-osmolar ICM approximate it. High osmolar ICM are
more likely to cause adverse effects compared with low and iso-osmolar
ICM (Supplementary Item 1) [23,24]. The use of ionic high osmolar ICM in
horses has largely declined due to higher complication rates and the
availability of less expensive low osmolar ICM.
In order to decrease osmolality while maintaining equivalent or
increasing iodine content per dose, ICM possessing two benzene rings and
six iodine atoms (i.e. dimers) were developed. In vitro, higher cytotoxicity is
observed with dimers than monomers [25], but in vivo, use of dimers
causes fewer acute adverse events [26]. Although overall rates of delayed
adverse events are similar for both, in man, delayed cutaneous symptoms
are more common with dimers (16.4%) than monomers (9.7%) [26].
Viscosity is determined by solution concentration, molecular shape
and interactions between the ICM molecules and water [10]. Nonionic
ICM possess higher viscosity than ionic ICM because they do not
dissociate in solution and consequently exhibit decreased osmolality [27].
High viscosity potentially leads to renal injury: resistance to renal tubular
flow results in increased intratubular pressure, altering glomerular
filtration rate (GFR) and prolonged ICM contact promotes hypoperfusion
and hypoxia [28,29].
Administration considerations
There are a number of important considerations that require attention
before and during ICM use. The American College of Radiology provides
guidelines before use in man and these standards are recommended in
horses [8]:
• Assessment of risk vs. benefit of use
• Consideration of alternative imaging strategies that would achieve the
same clinical goals and
• Valid clinical indication for administration
The ICM dose, concentration and administration route are dependent
upon the particular imaging study (angiography requires larger doses than
other applications) and is somewhat dependent upon patient size (e.g.
equine vs. other veterinary species). In man, large (>100 mL) volumes of
administered ICM can cause renal injury, but even small amounts (<30 mL)
are linked to adverse events in those with compromised renal function
[23,29–31]. A meta-analysis in man revealed intravenous (i.v.) administration
possessed less risk than intra-arterial (i.a.) administration [32].
Techniques/uses
Many of the administered doses, injection rates and scan timing after
injection in horses are extrapolated from human and canine studies
[33,34]. Although many of these adaptations are being used successfully in
horses, there are few controlled studies describing optimised and validated
techniques. In horses, ICM are administered through i.v., i.a., intrasynovial
or intrathecal routes. This section describes uses through these routes and
also includes techniques to ensure accurate quantification of CT signal (e.g.
use of density phantoms) and developing CT technology.
Intravenous: The total iodine dose administered i.v. is typically more
important for venous and parenchymal enhancement (i.e. image quality)
than injection rate [35–37]. In horses, injection of 600–880 mg I/kg bwt has
been recommended at ~2 mL/second by hand or with a power injector
[21]. Cardiac output, scan duration and the distance needed to travel to
the target organ determines the delay after injection before scanning: 1–
3 min is recommended for most equine applications [21,33,34,38].
Systemic i.v. administration of ICM with CT (usually via the jugular vein) is
used to evaluate the equine skull [39,40]. The usefulness of contrast-
enhanced CT over precontrast CT has been questioned [41]. Low case
numbers likely biased this conclusion as multiple equine reports agree that
contrast-enhanced CT provides more information about lesion aetiology
than precontrast CT [41–44]. Inflammation, sinonasal neoplasia, ethmoid
haematomas, parapharyngeal aneurysms and abscess capsules typically
enhance (Fig 2) [39–41,45–48]; although cholesterinic granulomata may
[42,43], or may not [41] contrast-enhance. Acute traumatic head injuries do
not require contrast media as haemorrhage is hyperattenuating on
precontrast images [47]. The pituitary gland enhances following i.v.
administration, but the degree of enhancement is not different between
horses with and without pituitary pars intermedia dysfunction [49]. Brain
neoplasias have variable degrees of contrast enhancement due to
variability in breakdown of the blood-brain-barrier and the tissue type of
origin [39,41,47]. Despite the added information on aetiology, not all
lesions require ICM to provide a diagnosis and precontrast images are
always indicated [41,50].
Imaging of the vasculature and determination of distal limb viability is
also accomplished after systemic i.v. administration [51,52]. The efficacy of
regional over systemic i.v. administration seems limited as ICM quickly
leave the target region, but may help outline regional venous disruption or
drainage patterns. Alternatively, the vascular distribution of ICM can be
evaluated after intraosseous administration [53] and is potentially useful
when i.v. access is limited [54–56].
Intra-arterial: Intra-arterial administration enhances arterial vasculature
and soft tissue parenchyma. As opposed to i.v., the volume administered

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Contrast media in CT and MRI: use, adverse events and opportunities
a) b)
Fig 2: Computed tomography a) and contrast-enhanced computed tomography
b) images of a horse with an ethmoid haematoma in the right conchofrontal
sinus. Dorsal is to the top and right to the left of both images. The arrow points
to a mass originating from the ethmoidal labyrinth in both images that contrast
enhances following intravenous administration of iodinated contrast media. The
diagnosis was confirmed with histopathology.
i.a. is less important than injection rate [35,36,57]. In horses, approximately
half of the i.v. dose is used i.a. with no scanning delay and power injectors
are recommended for uniformity [21]. Scanning a smaller region or faster
scan times further reduces the amount of ICM needed. Catheter size is
important as high flow rates through small gauge catheters can lead to
vascular trauma or catheter rupture. In man, rates are kept <5 mL/s for 20
gauge catheters and most equine studies use 18 gauge catheters at 2 mL/s
without complication [21,57,58].
Two studies described contrast-enhanced CT of the equine skull and
similarly reported that low dose i.a. administration is a suitable alternative
to i.v. [59,60], although risks of common carotid artery catheterisation
warrant consideration. For distal limb studies, i.a. catheterisation is
performed in the median or medial palmar arteries (thoracic limb), or in the
cranial tibial or dorsal metatarsal arteries (pelvic limb) [21]. More distal
placement potentially results in incomplete contrast media delivery to the
foot [21].
Contrast-enhanced CT studies of normal and pathological soft tissues
(e.g. tendons, ligaments) in the distal limb are reported [57,58,61–65].
Contrast enhancement in tendon/ligament injury results from increased
blood flow and vascular permeability during the healing process [66,67].
Rim enhancement (around a nonenhancing core) is usually present in
acute phases followed by organisation and enhancement of the central
portion over time [67]. Lack of contrast enhancement is also valuable,
suggesting a degenerative process or lack of healing [58,68,69]. Normal
regional vascular patterns should be recognised to prevent being
mistaken for pathological injury [67,70]. Intra-arterial techniques are also
used to measure normal laminar blood flow and vascular permeability
[71]. These factors are expected to be altered in laminitis [72,73], although
this has yet to be shown in clinical cases. Deep digital flexor tendon
(DDFT) lesions identified by contrast-enhanced CT have high true positive
(93%) and true negative (88%) detection rates as confirmed by macroscopic
examination, with lesions at the level of the navicular bone most likely to
be missed [58]. Although this was a validation study [58], there was no
comment on whether graders were blinded to histological results.
Comparison studies between contrast-enhanced CT and low field MRI for
distal limb evaluation are described [74,75]. The first study revealed that
anatomic visibility scores of the DDFT and distal sesamoidean impar
ligament (i.e. conspicuity and clarity of the structure itself) are decreased
in contrast-enhanced CT compared with low field MRI [74]. However, the
next study revealed that more DDFT lesions are detected with contrast-
enhanced CT than with low field MRI [75]. Despite blinded assessments,
case selection was biased towards horses that had DDFT injury on MRI
and the use of consensus grading precluded determining repeatability of
the contrast-enhanced CT technique [74,75]. These studies also point out
the challenge of comparing different imaging modalities with differing
imaging acquisition parameters (e.g. slice thickness, pixel matrix, field of
view) and spatial and contrast resolution that imparts variability in
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B. B. Nelson et al.
assessments. These data demonstrate the capability of contrast-enhanced
CT as an alternative modality for equine distal limb evaluation [74,75], but
also highlight the need for future comparative studies using other
techniques including high field MRI.
Intrasynovial: Radiographic arthrography/tenography is beneficial in that
it outlines some intrasynovial soft tissue structures (e.g. manica flexoria,
articular cartilage, fistulous tracts) [76–78], although lacks sensitivity, has
false negative results and some lesions are obscured by summation effects
[79]. Computed tomography arthrography/tenography using ICM may be
preferable to systemic administration for improved local structure
evaluation and to decrease agent doses. Aseptic preparation and
technique are crucial to prevent infection.
Computed tomography arthrography/tenography is described in normal
[80–87] and damaged equine structures [82,88–90]. Since CT arthrography
only highlights surfaces in contact with ICM, extra-articular structures will
not be outlined [89]. High density objects including concentrated ICM
potentially cause streaking or blooming artifacts [21] that decrease
diagnostic quality. While the concentration injected is lower than in
systemic studies with 30–40 mg I/mL preferred by some investigators
[87,89,91], others use 100–150 mg I/mL successfully [81,88]. The injected
volume varies depending upon joint size, but should continue until full joint
distention occurs followed by a passive range of motion to disperse the
agent. Without maximal distention, gravity dependence influenced by the
horse’s recumbency may cause some articular structures to not be in
contact with the ICM [89]. To prolong agent retention, the use of dimers or
epinephrine is described [92,93], but is unnecessary if the scan is
performed promptly following injection (B. Nelson; unpublished
observations 2016).
Computed tomography arthrography is used for articular cartilage or
intra-articular (e.g. cruciate) ligament evaluation [89,94–96]. One study
reported that equine articular cartilage lesions are better detected on CT
arthrography than on high field MRI, though differences in voxel
dimensions could have biased this result [82]. Anionic agents diffuse into
cartilage inversely to the fixed charge density in the extracellular matrix as
determined with microCT. The resulting contrast-enhanced CT attenuation
reflect the mechanical and biochemical properties of the tissue [20,97–99]
and the technique can be translated to a clinical scanner [100]. Recently
developed cationic agents diffuse into cartilage in direct proportion to
glycosaminoglycan content and strongly correlate with cartilage properties
[19,101,102]. Investigations of cationic ICM in clinical scanners is ongoing
but appears promising [103].
Intrathecal: Radiographic myelography is considered the best technique
to confirm specific sites of compressive spinal cord lesions in horses
[104–106]. While noncontrast radiography enables a suggested diagnosis
of cervical vertebral malformation, it does not reveal the accurate site of
compression [104,106]. A multi-institutional retrospective study revealed
that 71/116 (61%) of horses with suspected compression were confirmed
at post-mortem using plain radiography, while 46/68 (68%) were
confirmed using myelography. However, selection bias (inclusion criteria
included horses with suspected myelopathy and only 25% underwent
myelography) and the specific site of compression were not taken into
account [105].
In horses, CT myelography has been performed [107,108]. Ex vivo [108],
compressive spinal cord lesions were identified on CT myelography with
more false positives detected on radiographs when lesions were confirmed
histologically. Minimum sagittal diameter measurements of the cervical
vertebral column on CT myelography also strongly correlated with
necropsy findings [108]. The diameter and/or design of the gantry will
impact how much of the cervical spine can be imaged. Some CT scanners
are only capable of accommodating enough of the horse to image the mid-
cervical vertebrae, while others permit scanning more caudally to the
thoracic vertebrae. One benefit of CT myelography over radiography is that
spinal cord compression is examined volumetrically (rather than planarly)
enabling diagnosis of articular facet impingement from other stenoses
(Fig 3) [108,109]. Flexing the neck to maintain the target region in the CT
gantry isocentre is challenging. The significance of performing a full
dynamic examination (neutral, flexed and extended neck positions) in CT
myelography is unknown, although canine studies have documented
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a)
* standard pressure and temperature. The scale ranges from 1000
C2 C3 C4
b)
* with a multi-detector array. Recently, two cone beam CT systems have
C2 C3 C4
c)
*
C2 C3 C4
Fig 3: Computed tomographic myelography images of the equine cervical
vertebral column in vivo acquired with cone beam computed tomography with
reconstructions in the sagittal a), dorsal b) and oblique dorsal c) planes. Cranial is
to the left and dorsal to the top in all images. The second cervical vertebrae (C2)
through the fourth cervical vertebrae (C4) are outlined in all images. The spinal
cord (hypoattenuation, white asterisk) is outlined by the iodinated contrast media
revealing that there are no dorsal or ventral sites of compression. Image b)
highlights the C2–C3 and C3–C4 articulations allowing for observation of both
lateral aspects of the spinal cord. Image c) highlights the right articular facet joint
of C2–C3 (hypoattenuation, white arrow).
vertebral canal size changes during dynamic examination on MRI [110].
Future studies should compare dynamic CT myelography with post-
mortem evaluation and radiographic and MRI techniques to investigate this
in horses.
Other/future uses: Other reported contrast-enhanced CT techniques
include dacryocystography of the nasolacrimal apparatus [111] and
fistulograms to outline draining tracts [39]. Deposition into the paranasal
sinuses also distinguishes inspissated purulent material from mucosal
inflammation/soft tissue thickening. There are numerous other applications
performed in small animals and man (e.g. CT enterography, urography,
lymphangiography, neuroimaging) that have yet to be explored in horses
[15,21,36,112]. The main reasons these techniques are not performed is
that the target organ/region is not able to fit within the isocentre of the CT
gantry. As CT technology evolves with larger gantry diameters and
increased resolution there is significant potential for future applications in
horses.
Standing CT systems are useful as they are done without general
anaesthesia [113] and may drive use in future contrast-enhanced CT
applications. With description of ultrasound-guided centesis of CSF in
standing horses [114] and updated CT technology, standing CT
myelography is a potential future application. Also, with standing
fluoroscopic angiography of the guttural pouch region [115,116], the
variation in carotid artery branches [117] and the potential for inadvertent
coil embolisation [118], standing contrast-enhanced CT offers improved
evaluation of guttural pouch mycosis without risking fatal haemorrhage
that could occur after the horse is anaesthetised.
Equine Veterinary Journal 49 (2017) 410–424 © 2017 EVJ Ltd
Contrast media in CT and MRI: use, adverse events and opportunities
Signal quantification: Quantifiable changes in x-ray attenuation reported
as CT numbers or Hounsfield units (HUs) are measurable in the pre- and
post-contrast images [57]. The HU scale is an arbitrary assignment of CT
attenuation based upon the x-ray attenuation of water (HU = 0) at a
(complete transmission of x-rays [air]) to 3000 (complete attenuation of
x-rays [dense bone]). There is an inherent variability in HUs between CT
manufacturers, between different acquisitions on the same scanners over
time and varying kilovoltage peak (kVp) used [119–121]. To counteract this
problem, density phantoms are imaged concurrently to standardise and
improve HU accuracy across multiple scans while also providing
biologically meaningful data (e.g. bone mineral density) [122,123].
Therefore, imaging studies that report HUs but do not contain a density
phantom should be interpreted as a relative change and not as absolute
values reliably replicated.
Cone beam CT: Most commercial CT scanners have fan beam geometry
been marketed for use in the horse (Pegaso Epicaa; Helios/Zeus, 4DDIb).
Despite improved spatial resolution and isotropic voxel dimensions, cone-
beam CTs possess disadvantages compared with multi-detector systems
including increased motion susceptibility, scatter, decreased contrast
resolution and HU variability [124]. Although a promising technology, this
variability and ICM use with cone beam CT [125,126] requires further
investigation to optimise use in the horse.
Adverse events
Adverse events are unintentional occurrences during or after contrast
media administration varying from minor reactions requiring no medical
intervention to severe and life threatening [127]. In horses, adverse events
are uncommon with rates comparable to man (Supplementary Item 2).
However, the reduced use and decreased ability to identify specific clinical
signs that cannot be voiced (e.g. headache, itching) inhibit assessments
and comparisons of adverse event rates between species. Based upon
high adverse event rates compared with low osmolar ICM, use of high
osmolar ICM in horses should be avoided.
Potential complications during administration include air injection and
extravasation. Clinically significant intravascular air injection (air embolism)
is rare [128,129], but potentially fatal in horses [130] and should be
avoided. Extravasation causes swelling, erythema and/or burning pain,
although some humans report no discomfort [131]. Extravasation causes a
local inflammatory response related to altered tissue osmolality,
sometimes peaking after 48 h [131]. Skin ulceration and necrosis are rare
but can develop. Extra-articular extravasation of iohexol is rarely observed
in horses, but swelling resolves within 24 h without observable pain (B.
Nelson; unpublished observations 2016).
Adverse events are categorised based upon the duration of onset
(acute, delayed), those specific to particular organ systems, or by the route
of administration.
Acute adverse events: Acute adverse events are described as allergic-
like (anaphylactoid, idiosyncratic) or physiological responses. Allergic-like
reactions are not dose-dependent [132,133], develop within 20 min due to
mast cell and basophil degranulation and with no IgE antibody involvement
are not hypersensitivity (anaphylactic) reactions [8,134]. Physiological
reactions, related to ICM chemotoxicity, or osmolality are acute (<30 min)
or delayed (>30 min to 1 week) affecting many organ systems.
In man, most adverse events are mild (77%) and do not require
treatment, while 2% are severe [135] and this appears comparable to
horses (Supplementary Item 2). In man, acute adverse events are reduced
~80% by using low osmolar instead of high osmolar ICM [8,136,137].
Severe events are unpredictable in man and occur at similar rates with
ionic and nonionic ICM [136,138]. In man, severe events are typically
allergic-like with ionic ICM, while cardiopulmonary with nonionic ICM [136].
Severe adverse events in horses include anaphylactoid reactions, seizure,
hypo/hypertension and bronchospasm [139–142]. Self-limiting hypertension
in horses is likely due to peripheral vasoconstriction and systemic pain
responses [143], while in man, tachycardia develops with hypotension due
to intravascular fluid shifts and is usually classified as at least a moderate
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Contrast media in CT and MRI: use, adverse events and opportunities
reaction [144]. Although considered rare in horses, severe adverse events
can be fatal [142,145].
Delayed adverse events: In one equine study, nonspecific hyperthermia
occurred in 25/92 (27%) cases which self-resolved without treatment [142].
Another study using ionic ICM revealed 4/97 (4%) horses developed
cutaneous signs (urticaria or facial oedema) that all self-resolved [143]. In
man, the lack of follow-up in outpatient procedures likely underestimates
true prevalence of delayed adverse events [8,137,146,147] and this is
equally probable in equine studies [142]. Although usually self-limiting in
horses, anti-inflammatory, or anti-histamine treatments may be beneficial.
Different mechanisms between acute and delayed events and the rarity of
severe events downplays the recommendation of corticosteroid
premedication [8,26]. In man, test injections do not consistently predict
subsequent reactions [148]. Premedication does not reliably prevent a
reaction or reduce its severity [144,149–152], although is potentially
beneficial in those with previously mild events or asthma [153].
Premedication is not indicated for those with prior physiological adverse
events [154]. Although no premedication data exists in horses, these
human recommendations are a valid reference point until definitive data
become available.
Organ-specific adverse events: Renal adverse events, although not
reported in horses, are reported in dogs, cats and man [155,156]. Thus, the
renal status of the horse warrants consideration prior to ICM
administration. In man, using low osmolar instead of high osmolar ICM
reduces the risk of renal injury [138,157], but not in those with normal GFR
[23,24,32,158,159]. Generally, iso-osmolar ICM are not safer than low
osmolar ICM [160] except in humans with renal insufficiency or with i.a.
(supra-renal) administration [8,30,32]. Dehydration leads to prerenal
azotaemia, decreasing renal blood flow and GFR and would prolong renal
tubular exposure to ICM [161]. Concurrent use of nephrotoxic drugs also
exacerbates underlying renal disease. Therefore, prophylactic volume
expansion is important, although oral routes may not be sufficient as has
been shown in man [162].
Pulmonary adverse events (decreased PO2, increased PaCO2) are
observed with ICM administration in man and diatrizoate possesses the
highest risk [163]. Meglumine is a potent histamine releaser and that or
diatrizoate may have caused bronchospasm in one horse [141,164].
Monitoring of cardiovascular and pulmonary parameters is important to
detect potential alterations during and after administration.
Intra-arterial: In horses, partial venous thrombosis (typically subclinical)
has been observed following regional i.a. catheterisation [165,166].
Another study showed severe arterial thrombosis following tourniquet
application and i.a. delivery of mesenchymal stem cells that caused severe
lameness and dermal necrosis [167]. Tourniquet use was thought to be the
cause and more recent studies without the tourniquet report no severe
complications [165,166,168]. Other potential complications of i.a.
catheterisation (haematoma and spasm) should also be considered
[21,60,169].
Intrasynovial: The few equine studies discussing arthrography
complications report it to be safe [88,89]. In man, sterile chemical synovitis
is the most common adverse event (0.1%), while vagal reactions, cellulitis
and pain are rarer [170]. In vitro, exposure to iohexol (592 mOsm/kg)
decreased bovine chondrocyte viability to 86%, although this increased
with dilution [171]. In vivo effects of ICM on articular cartilage are
unknown.
Intrathecal: In man, iohexol ≤140 and ≥350 mg I/mL are contraindicated
for intrathecal use (in-between concentrations are acceptable) with
cerebral haemorrhage, seizures and death potentially occurring [172].
These concentrations are also adhered to in canine studies [21,173,174]. A
comparison study in horses evaluating two iohexol doses (300 and 350 mg
I/mL) showed slightly less irritation with 300 mg I/mL [175]. Both
concentrations exhibited slight extradural oedema and increased
(mononuclear) white blood cell counts and specific gravity in cerebrospinal
fluid (CSF) [175]. Similar changes occur with iopamidol and both are less
damaging than metrizamide [145,175–181] analogous to other species
414
B. B. Nelson et al.
[182–185]. Despite the lack of reports confirming use of 350 mg I/mL to be
detrimental, most equine clinicians still adhere to human guidelines
[104,142,186,187].
In horses, adverse events during and after myelography (12.9% cases)
include generalised and focal seizures, worsening neurological signs,
muscle fasciculations, central nervous depression, hyperesthesia, star
gazing and prolonged anaesthetic recovery [142,176,178–181]. The risk of
adverse events increased with larger ICM volumes and longer anaesthetic
periods and in 5% of cases resulted in euthanasia [142]. However,
complications of ICM are difficult to distinguish from the primary
neurological disease. In man, adverse events also occur from increased
volume in the subarachnoid space, leakage after puncture, or neurotoxicity
due to ICM osmolality, sodium ions or lipid solubility [188,189]. In horses,
man and dogs, high osmolar ICM are contraindicated for intrathecal use
due to severe adverse events and high fatality [190–192].
Barium sulfate preparations
Barium-based agents are generally used for evaluation (including transport)
of the oesophageal/gastrointestinal tracts [193–195]. They are insoluble,
provide improved mucosa delineation and are less susceptible to dilution
than ICM [196]. There are many barium agents available and compositional
differences are minor [10]. Due to CT/MRI size constraints, use in adult
horses is limited, but is potentially beneficial in foals. Contraindications for
use of barium agents include oesophageal/gastrointestinal perforations, as
these lead to cellulitis, mediastinitis or peritonitis. Conversely, ICM used in
these instances are readily absorbed without permanent adverse effects
[197], although high osmolar ICM may cause hypovolaemia and
dehydration due to osmotic draw [198]. Aspiration causes severe
pulmonary oedema [199]. Following oral administration of ICM, <2% is
absorbed, although mucosal disruption increases absorption [154]. Allergic-
like and physiological adverse events after barium agent use are similar to
ICM, but are far less common [10]. Allergic-like events are more related to
the additives and not the barium itself [200]. Most studies report no
complications, but include rectal or colonic rupture (rectal administration),
submucosal granuloma, intravasation, obstipation, disseminated
intravascular coagulation, or hypersensitivity reactions [201,202].
Other compounds in CT contrast media
Gadolinium, gold and bismuth all have higher atomic numbers than iodine
and are being investigated for use in contrast-enhanced CT. Compared
with iodine, gadolinium has a higher k-edge (or binding energy needed to
eject a K shell electron) and is more attenuating at x-ray photon energies
>50 keV. This is approximately the average x-ray energy used on standard
CT acquisitions and reflects the potential benefit of gadolinium use in CT
examinations [203]. However, ICM possess more iodine atoms per
molecule than gadolinium in gadolinium contrast media (GCM). To achieve
comparable CT attenuation using commercial concentrations, the volume
of GCM needed is ~5 times that of ICM [204]. The toxic dose (LD50) for GCM
is 6–20 mmol/kg (high osmolar ICM = 10 mmol/kg, nonionic low osmolar
ICM = 30 mmol/kg) [204]. Early use of GCM in contrast-enhanced CT in
man seemed to reduce the prevalence of renal adverse events [205], but
has since been refuted [206,207]. Therefore, the use of GCM for contrast-
enhanced CT is reserved for those with prior severe adverse reactions to
ICM. With high chemical stability and x-ray attenuation, long circulation
times and low toxicity, gold is promising for use in contrast-enhanced CT
[15,208]. Despite high x-ray attenuation, bismuth is plagued with toxicity
problems [15]. Iodinated agents encapsulated in liposomes, gold
nanoparticles and other compounds are being evaluated in small animal
models [15,208,209]. However, the high costs and lack of fast renal
elimination of these agents are precluding clinical use [209].
MRI contrast media
Composition
Gadolinium complexes are used for contrast-enhanced MRI since
gadolinium is a paramagnetic metal [203]. Free gadolinium is toxic partly
due to calcium competition, but chelating the gadolinium within a stable
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B. B. Nelson et al. Contrast media in CT and MRI: use, adverse events and opportunities

small molecule cage prevents its release and cellular uptake [210]. Although Techniques/uses
other lanthanide metals form stable compounds and have potential uses
Reported administration routes for GCM in horses include i.v. and
as MRI contrast media, GCM are the most commonly used [211].
intrasynovial, while intrathecal and i.a. administration are also reported in
Since GCM are paramagnetic, they cause shortening of both T1 and T2
man [223–225]. The advantages of GCM use in horses include improved
relaxation times on MRI. Although changes in T1 times are dominant, T2
lesion conspicuity and delineation, and assessment of vascularised regions
times are also affected influencing the appearance of tissues on other
and chronicity [210].
pulse sequences (e.g. T2-weighted and inversion recovery) and this should
be recognised when these sequences are acquired after GCM
Intravenous: Extrapolated from human guidelines, 0.1 mmol/kg bwt is
administration [203]. Gadolinium contrast media are classified as
used for contrast-enhanced MRI in horses (gadoxetate and gadofosveset
extracellular fluid, blood pool, or liver agents (Supplementary Item 1).
doses are lower by one quarter) [210]. A lower dose (0.05 mmol/kg) shows
Extracellular fluid GCM (majority of commercial agents) quickly diffuse
subjectively similar lesion conspicuity, but 0.025 mmol/kg was deemed
through the vascular endothelium, while blood pool agents remain in the
suboptimal [210]. However, other studies report a dose of 0.02–
intravascular space for longer periods (<1 h) and the liver agents are taken
0.04 mmol/kg bwt as providing diagnostic quality images [226–228].
up into hepatocytes. While extracellular GCM eliminate via the kidneys,
Regardless, using objective MRI measurements shows a difference
blood pool and liver GCM bind proteins and exhibit additional elimination
between pre- and post-contrast images at all doses [210]. Digital
pathways (Supplementary Item 1).
subtraction techniques increase the perceived magnitude of change
The chelate structure is an important feature for GCM safety, while
(Figs 4–6); however, further validation and analysis of potential artifacts are
ionicity, osmolality and viscosity are less critical. Despite alterations in
required in horses [210].
chelate structure, the pharmacokinetics and pharmacodynamics are similar
A multi-centre MRI study evaluating the equine skull showed contrast
between different GCM formulations [203]. Linear chelates are less stable,
enhancement with cerebral inflammation and masses, sinonasal disease
releasing 10-fold more gadolinium ions than macrocyclic compounds thus
and neoplasia, ocular masses, pituitary adenomas and abscessation
exhibiting poorer safety profiles [209,212]. In humans with normal renal
(Fig 4), while cerebral infarcts and ethmoid haematomata (hyperintense
function, GCM are quickly excreted (90% in 24 h), but are delayed in
on precontrast images) did not enhance after GCM administration [227].
chronic severe disease (80% in 7 days) [203,213,214]. Ionic GCM are all
The results from a subsequent study are in agreement, revealing
anionic and coordinated with sodium or meglumine. Due to lower doses of
contrast enhancement in cases of pituitary adenomas and abscessation
GCM administered (compared with ICM), the osmolality and viscosity of the
[226]. Enhancement of head tumours depends upon the tumor type, but
GCM solution affects vascular homeostasis to a lesser magnitude [203,209].
rim enhancement is also common similar to paranasal sinus cysts
Excluding cases with renal complications, ionicity is not a concern in GCM
[11,226–228]. Low field contrast-enhanced MRI also enables observation
safety in man or dogs [212,215–217]. In studies on anaesthetised dogs
of vessel morphology of the laryngopharynx [229]. Though similar results
[217,218] and rats [219,220] administered GCM with different levels of
are found between studies regardless of dose, higher GCM doses
osmolality did not demonstrate a difference in observed cardiovascular or
provide greater contrast enhancement [11,226,227,230]. Not all disease
haemodynamic effects.
processes require GCM to detect, but pathological conditions causing
increased extracellular fluid, increased vascularity, or breakdown of the
Administration considerations blood brain barrier will be detected using contrast-enhanced MRI
Recommendations for GCM use are similar as previously described for ICM. [11,227].
In man, clinical signs of GCM extravasation are similar to ICM, but are more Contrast-enhanced MRI evaluation of equine orthopaedic soft tissues
related to intrinsic GCM toxicity rather than osmolality [131,203]. provides information on structural morphology, lesion chronicity and
In man, significant reductions in serum calcium concentrations after temporal assessment of tissue healing [11,210,231], although further
using gadoversetamide and gadodiamide (but not other GCM) occur in validation studies using postmortem confirmation are required. Uninjured
patients with renal impairment [203,221]. However, this is a spurious result tendons and ligaments do not contrast enhance, but regional
as these GCM directly interfere with the calcium assay [222]. Usually this angiogenesis, increased vascular permeability and/or in granulation tissue
effect diminishes after GCM leaves the vasculature (24 h), but may take enhance following injury [230]. Synovitis (including septic) results in
longer in patients with renal dysfunction [222]. This finding is not contrast enhancement (Fig 5); although, noninflamed synovium normally
documented in animals. shows minor enhancement [11,232].

a) b) c)

Fig 4: Precontrast a), post-contrast b) and digital subtraction c) magnetic resonance images in a horse with periapical tooth root abscess in the right ventroconchal and
rostral maxillary sinuses. The arrows point to the abscess in all images. Dorsal is to the top and right is to the left. Pre- and post-contrast images are from a three-
dimensional T1 weighted rapid gradient-echo sequence (MP RAGE). The post-contrast image was acquired after intravenous injection of gadopentetate dimeglumine
(0.03 mmol/kg bwt). Note the space-occupying mass in image a). In image b), the periphery of the mass enhances (increased signal intensity), while the central portion
does not enhance. Though paranasal sinus cysts and some neoplastic lesions have similar contrast enhancement, the proximity to a maxillary tooth root and adjacent
periodontal widening (not shown) was more consistent with tooth root abscessation. The abscess was confirmed with a sinusotomy flap. Images courtesy of K.T. Selberg.

Equine Veterinary Journal 49 (2017) 410–424 © 2017 EVJ Ltd 415

Contrast media in CT and MRI: use, adverse events and opportunities B. B. Nelson et al.

a) b) c)

Fig 5: Precontrast a), post-contrast b) and digital subtraction c) magnetic resonance images in a horse with lameness localised to the foot. Dorsal is to the left and
proximal to the top in all images. Pre- and post-contrast images are from a three-dimensional T1 weighted gradient echo sequence (volumetric interpolated breath-hold
examination [VIBE]). The post-contrast image was acquired after intravenous injection of gadopentetate dimeglumine (0.03 mmol/kg bwt). The arrow points to contrast
enhancement of the synovium in the dorsal aspect of the distal interphalangeal joint (DIPJ) and the chevron points to contrast enhancement in the navicular bone
consistent with synovitis of the DIPJ and navicular bone degeneration, respectively. Images courtesy of K.T. Selberg.

a) b) c) d)

Fig 6: Magnetic resonance images of the foot in an equine cadaver. All images are in the sagittal plane with dorsal to the left and proximal to the top. Proton density
fast spin echo sequence a). The precontrast image b) was acquired using a T1 weighted spoiled gradient recalled echo (SPGR) sequence. Post-contrast image c) following
intra-articular injection of gadopentetate dimeglumine (4 mmol/L) imaged with the SPGR sequence. Window width and leveling were kept similar between b) and c).
Digital subtraction d) was created from images b) and c) to highlight contrast enhancement. The arrow points to articular cartilage on the proximal aspect of the distal
phalanx in all images. Note the increased signal (hyperintensity) within the distal interphalangeal joint cavity and in the articular cartilage in c) and d). Also note the
increased contrast resolution between the articular cartilage and synovial fluid.

Intrasynovial: Following intrasynovial injection, contrast-enhanced MRI
scans are performed immediately or after a delay to delineate structures
within the synovial cavity [233,234]. Delayed gadolinium-enhanced MRI of
cartilage (dGEMRIC) is a specific procedure where i.v. or intra-articular
GCM are administered to evaluate articular cartilage (Fig 6) [233]. Intra-
articular administration is less common due to off-label designations in
man but is generally accepted at ~2–4 mmol/L [96,235]. If
concentrations are too high, signal dropout occurs due to magnetic
susceptibility. Use of dGEMRIC includes a 90 min delay to allow sufficient
diffusion into articular cartilage, while exercise, joint loading and
cartilage thickness influence uptake [236,237]. In horses, dGEMRIC is
used [233,238–241], although thin cartilage in the metacarpophalangeal
joint reduces segmentation accuracy due to volume averaging [242] and
long acquisition times remain a challenge [233]. A recently developed
cationic agent shows better penetration at 10% the dose of an anionic
GCM and holds promise for improved dGEMRIC techniques [243].
Studies using ioxaglate/gadopentetate mixtures for concurrent CT
arthrography/dGEMRIC imaging in man show that dual modality imaging
is achievable [92,244,245], but ICM alters anticipated MR signal intensity
[246,247].

416 Equine Veterinary Journal 49 (2017) 410–424 © 2017 EVJ Ltd

B. B. Nelson et al.
Adverse events
Only minor adverse events (mild and transient hypotension) are noted after
i.v. GCM use in horses [11,210]. Allergic-like reactions have been reported
in three dogs [248]. In man, headache, nausea, vomiting and hives are
reported though these events may be related to the primary disease or
MRI noise [249]. In man, adverse events with GCM are less common than
with ICM [250], but can still be fatal [136,249]. The rates of adverse events
after GCM administration in man are similar among agents [11,251–253],
although gadoteridol appears to have the lowest risk [252]. In man,
moderate and severe reactions encompass <1% of all adverse events
[254,255].
Organ-specific adverse events: Nephrogenic systemic fibrosis is a rare,
but potentially fatal complication after GCM use (usually >0.1 mmol/kg bwt)
in man [154,256,257]. It has not been reported in horses [210], but
potentially reflects the relatively lower use of GCM, the lack of long-term
follow-up, or physiological species differences compared with man. The
pathogenesis is unclear [127], although limb swelling, joint contracture,
bone pain or dysfunction of the kidneys, lungs and liver are reported
sometimes years after exposure [258–260]. Free gadolinium release from
the GCM structure is postulated as the cause [261]. No GCM are
contraindicated in the horse; nonetheless, low risk GCM are suggested for
horses with known renal insufficiency as recommended in small animals
[262]. Prior allergy/adverse events to ICM do not preclude GCM use (no
cross-reactivity), but the risk of a subsequent reaction is potentially higher
[8,263].
Intrasynovial: No abnormal clinical signs, cytological responses,
macroscopic or microscopic changes after intra-articular GCM
administration are observed in dogs [264]. Gadolinium contrast media
exposure to chondrocytes in vitro also reveals no necrosis or toxicity at
clinically used concentrations [264–266]. Adverse effects to synovial tissues
are unknown in horses.
Comparison of GCM to ICM: Because of pharmacokinetic differences
between GCM and ICM, comparisons of safety profiles are challenging,
although are reported in veterinary species. Moderate adverse events are
twice as likely with iohexol compared with gadobuterol in anaesthetised
dogs, but not in cats [267]. In another study, tachycardia in anaesthetised
cats is more common with high osmolar ICM than low osmolar ICM or
GCM while hypo/hypertensive adverse events are more common with GCM
[268]. In general, high osmolar ICM more commonly prompt concerns
during anaesthesia than low osmolar ICM or GCM [268,269].
Other contrast media
Other fluids provide contrast enhancement in synovial structures using
fluid sensitive MRI sequences. Distension of the navicular bursa with 0.9%
saline revealed adhesion formation, DDFT injury and fibrocartilaginous
damage to the navicular bone in vivo [270,271]. Distention of the distal
interphalangeal joint showed similar results [272], although further
investigation in vivo is required.
Iron oxide and manganese-based agents are used for contrast-enhanced
MRI. Manganese is a paramagnetic metal ion and due to biliary excretion is
an attractive alternative agent for patients with renal compromise [215]. As
with all metal-based contrast media, dissociation of the metal ion from the
bound complex or leakage from a nanoparticle leads to toxicity [273,274].
Iron oxide-based agents are selectively uptaken by the kupffer cells in the
reticuloendothelial system. Classified as superparamagnetic (>50 nm) and
ultrasmall superparamagnetic (<50 nm) iron oxide [215], they can also be
coated with liposomes, dextran, etc. to maintain colloidal stability [275].
Superparamagnetic nanoparticles are used to label mesenchymal stem
cells for equine DDFT lesion assessment [276]. Today, both iron oxide and
magnanese-based agents are not used in the human US market due to lack
of diagnostic utility and/or concerns of unfavourable side effects, although
an iron oxide agent nanoparticle is approved for use in man in Europe.
Finally, a number of new contrast media are under development, including
redox MRI, dendrimer-based nitroxides and multimodal liposomes encasing
both ICM and GCM [277–280], but their translation and efficacy in the
Equine Veterinary Journal 49 (2017) 410–424 © 2017 EVJ Ltd
Contrast media in CT and MRI: use, adverse events and opportunities
horse is unknown. Detailed reviews of these new systems are available and
the reader is referred to these articles [15,281–283].
Conclusion
The use of contrast media in CT and MRI enables improved tissue
evaluation and monitoring of disease progression and tissue healing in
horses. These contrast-enhanced imaging techniques are in their infancy
compared with their use in man and small animals; however, the available
data reported thus far documents their clear benefit of use. When
administered at recommended doses, ICM and GCM are well tolerated and
safe. Nonetheless, adverse events have the potential to occur and horses
should be monitored during and after the imaging examination so that
appropriate interventions can be performed when needed. Horses with
renal disease and/or dehydration must be identified and treated before
contrast media administration. In most instances, the benefits of using
contrast media vastly outweigh the, typically minor, complications that
could develop.
Today, contrast-enhanced CT and MRI examinations are typically
performed for the evaluation of intracranial or orthopaedic diseases in
horses. Importantly, there are numerous additional applications currently
being used in man and small animals that may be adapted to equine
practice. A few of the many examples of techniques/organ systems where
contrast-enhanced imaging is valuable include angiography, cystography,
nephrography and gastrointestinal and neuroimaging. As CT and MRI
technology and techniques evolve and by using contrast media in more
imaging studies, there will undoubtedly be future developments that will
greatly expand our diagnostic capabilities across organ systems in horses.
Through these advancements, new treatments, diagnostics and monitoring
strategies will emerge improving patient outcomes.
Authors’ declaration of interests
No competing interests have been declared.
Ethical animal research
None required.
Source of funding
None.
Acknowledgements
The authors acknowledge K.T. Selberg for providing images for Figures 4
and 5 and J. Daglish for assistance in acquiring the MRI images in Figure 6.
Authorship
B.B. Nelson and C.E. Kawcak developed the idea for the article and all
authors contributed to the conception and design. B.B. Nelson performed
the literature review and wrote the article with critical revisions from all
authors. All authors approved the final version of the article.
Manufacturers’ addresses
a
Pegaso, Epica Medical Innovations, San Clemente, California, USA.
b
Helios/Zeus, 4DDI, New York, USA.
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Supporting Information
Additional Supporting Information may be found in the online version
of this article at the publisher’s website:
Supplementary Item 1: Structural and physiochemical properties of
iodinated and gadolinium contrast media.
Supplementary Item 2: Summary of literature sources documenting
adverse events encountered with contrast media use in horses.
Equine Veterinary Journal 49 (2017) 410–424 © 2017 EVJ Ltd