Peter F. Lawrence, MD, Section Editor
From the Society for Vascular Surgery
Contrast alternatives for iodinated contrast allergy
and renal dysfunction: Options and limitations
Gregory J. Nadolski, MD, and S. William Stavropoulos, MD, Philadelphia, Pa
Diagnostic angiography and vascular interventions make routine use of iodinated contrast material (ICM). Patients with
renal disease or contrast allergy pose limitations on the use of ICM. In such cases, alternative contrast media may be used
to carry out the procedure. Current alternatives include carbon dioxide, gadolinium, and dilute ICM. Each of these
alternatives has its own unique features and limitations. In the present review article, the current alternatives to ICM are
explored, with a focus on the applications and restrictions of each. (J Vasc Surg 2013;57:593-8.)
Patients with impaired renal function or contrast allergy
pose a challenge to the safe and effective performance of
diagnostic angiography and vascular interventions using
iodinated contrast media. Despite the development of
low and iso-osmolar iodinated contrast material (ICM)
and the institution of hydration protocols, patients with
chronic kidney disease (CKD), especially those with con-
comitant diabetes, remain at risk for contrast-induced
nephropathy (CIN).1,2Contrast allergies are another po-
tential barrier to the use of iodinated contrast for vascular
interventions.3,4Although premedication with steroids
and antihistamines allows iodinated contrast to be used
safely in many allergic patients, occasionally patients pres-
ent for procedures without having taken effective prophy-
laxis or having failed premedication in the past. Given the
prevalence of the scenarios in which ICM poses potential
serious risk to the patient, a strong interest remains in
the use of alternative contrast media. Our purpose is to
briefly review ICM contrast allergies and nephrotoxicity
and then to review the applications and limitations of
alternatives to full-strength iodinated contrast, which
include carbon dioxide (CO2), gadolinium, and dilute
iodinated contrast, for patients with CKD and iodinated
Reviews devoted solely to the chemical and physical
properties of iodinated contrast have been published.5-8
In brief, all ICMs in current use are modifications of
a 2,4,6-tri-iodinated benzene ring and are classified based
on the physical and chemical properties of osmolality, ioni-
zation in solution, and chemical structure. Four classes of
contrast are commercially available: ionic monomers,
nonionic monomers, ionic dimers, and nonionic dimers.
Additionally, agents can be classified by their osmolality
relative to blood and typically are described as high, low,
or iso-osmolar. Once administered intravascularly, these
agents are rapidly distributed in the body and are excreted
largely unmetabolized in the urine.
Allergic reactions to ICM. Allergic reactions to ICM
occur. They typically are described as anaphylactoid
because they have the features of type 4 hypersensitivity
reactions but do not occur through an immunoglobulin
E-mediated pathway in most cases. In fact, the exact mech-
anism remains unknown.9Mild anaphylactic reactions to
high-osmolar ionic contrast occur between 4% and 12%,
whereas such reactions occur in only 0.7% to 3% of patients
anaphylaxis is estimated to occur between 0.1% to 0.4%
with ionic contrast material and 0.02% to 0.04% with
contrast reactions with steroid prophylaxis (classically
prednisolone 32 mg given 12 and 2 hours before the
procedure) are beneficial for mild and moderate reactions
but less so for severe anaphylaxis.13,14
breakthrough reactions occur in some patients.4
nephropathy is defined as acute kidney injury attributable
to the administration of iodinated contrast. The exact defi-
nition of acute kidney injury for diagnosing CIN and
the temporal relationship of contrast administration are
still debated. Some data support an absolute rise in serum
creatinine $0.5 within 48 hours to be a reasonable
From the Division of Interventional Radiology, Department of Radiology,
Perelman School of Medicine at the University of Pennsylvania.
Author conflict of interest: none.
Presented at 2011 Vascular Annual Meeting of the Society for Vascular
Society, Chicago, Ill, June 16-18, 2011.
Reprint requests: Dr S. William Stavropoulos, Division of Interventional
Radiology, Department of Radiology, Perelman School of Medicine at
PA 19104 (e-mail: firstname.lastname@example.org).
The editors and reviewers of this article have no relevant financial relationships
to disclose per the JVS policy that requires reviewers to decline review of any
manuscript for which they may have a conflict of interest.
Copyright ? 2013 by the Society for Vascular Surgery.
definition.15,16Contrast-induced nephropathy likely is the
result of direct tubule toxicity and hypoxia caused by
reduced blood flow and subsequent generation of reactive
oxygen species.17The incidence of CIN is related to the
dose of ICM, the route of administration (intra-arterial >
intravenous), and patient factors, of which CKD with an
estimated glomerular filtration rate (eGFR) <60 mL/min
is the most important.17,18Studies have tried to identify
the maximum amount of CM that can safely be injected
during percutaneous coronary interventions, suggesting
possible limits of ICM dose in grams of iodine equal to the
clearance <3.7. However, a safe dose of ICM has not been
established for patients with CKD.19Multiple meta-analyses
regarding prevention of CIN have been conducted using
hydration protocols and various oral medications thought to
be renal protective. Most authors conclude that intravenous
hydration is of some benefit. Comparison of hydration
protocols and oral agents is beyond the scope of this review.
For a more detailed review, see van der Molen et al.2,19
ALTERNATIVE CONTRAST AGENTS
Principles of carbon dioxide and its advantages.
Carbon dioxide (CO2) is a highly soluble, invisible gas.
When injected into vessels, it briefly displaces the blood
before it is rapidly dissolved and eliminated through exha-
lation.20The unique properties of CO2 give it several
advantages over other contrast media. Foremost, CO2is
nonallergenic and nonnephrotoxic, making it safe for use in
patients with either contrast allergy or kidney disease.21-25
Essentially unlimited volumes of CO2 can be used,
assuming sufficient time is allowed for the gas to be elim-
inated from the body. Carbon dioxide even is safe in
patients with chronic lung disease with CO2retention, as
long as additional time is taken between injections to allow
for the gas to be cleared by the lungs.26Further benefits
include its low viscosity relative to blood, which can aid in
the detection of subtle bleeding.27Carbon dioxide’s low
viscosity additionally can improve visualization of small
collateral vessels and aid in identifying distal reconstitution
in patients with peripheral arterial disease.21
medical-grade CO2 is very inexpensive compared with
iodinated contrast and is readily available.
Limitations and complications of CO2. However,
CO2is not without limitations. Given the possibility of
neurotoxicity, CO2cannot be injected or allowed to enter
the cerebral circulation.28Thus, CO2should be used only
for infradiaphragmatic arteriography. Central venography
above the diaphragm is still permissible with CO2and, in
fact, may be more sensitive for detecting central venous
stenosis.26The rare complication of air trapping, or vapor
lock, is another limitation. If an excessive volume of CO2is
injected at once or the blood–gas interface is reduced,
normal dissolution of CO2 into the bloodstream may
not occur. The undissolved bolus of gas may then im-
pede blood flow and produce ischemia.29Nondependent
locations such as aortic aneurysms, the pulmonary outflow
tract, and the mesenteric vessels are most at risk.30Typi-
cally, vapor lock can be broken by changing the patient’s
position or by aspiration of the CO2. If CO2arteriography
is being used near or in a vessel at risk for vapor lock,
periodic fluoroscopy between injections is advisable. If
residual gas is seen between injections, the patient’s posi-
tion should briefly be changed to move the CO2bolus into
a different vessel to allow dissolution.31The theoretical risk
of air trapping increases with introduction of less soluble
gases from room air contamination and the use of nitrous
oxide as an inhaled anesthetic. Nitrous oxide may dissolve
out of the soft tissues and into the intravascular CO2bolus,
rapidly increasing its volume and its potential to create
a vapor lock.29
Another barrier is ease of use. Because a dedicated CO2
injector or bag delivery system is not available in the
United States, practitioners may be unfamiliar with admin-
istration of CO2. Most physicians use a system of tandem
three-way stopcocks or a three-way stopcock and a flow
switch (Fig 1). Contamination with less soluble room air
could occur if a stopcock or flow switch is left open.26
Because both gases are invisible, contamination of CO2
with room air is impossible to detect. Special attention
must be given to purging syringes of air and, once filled
with CO2, not allowing valves to be left open. Carbon
dioxide has been shown to accurately measure vessel diam-
eter (Fig 2). However, improper injection of CO2can lead
to errors in measurement.21,32CO2is buoyant relative to
blood and therefore rises to the nondependent portion of
the vessel. If insufficient volumes of CO2 are injected
into large vessels, the operator may underestimate the
true size of the vessel (Fig 3). Alternatively, if the bolus is
delivered in an explosive manner, the operator may overes-
timate vessel diameter.33
Optimizing image quality with CO2. Unfamiliar
users may be uncertain of how to optimize image quality
for their procedures. With the development of digital
subtraction angiography and image stacking software, use
of CO2as a contrast agent has became a viable option.
Hawkins21first reported his pioneering use of CO2as an
intravascular contrast agent in the early 1980s. Most
modern angiography suites come with preinstalled settings
to optimize image quality for CO2angiography. Typically,
inversion opacification software is used with a frame rate of
three to six per second using a 60-ms exposure time.26To
prevent explosive delivery of CO2, blood should be purged
from the catheter with CO2 before subtraction angiog-
raphy is performed. A less explosive injection will reduce
patient discomfort and thus motion artifact. Proper injec-
tion rate also reduces fragmentation of the CO2 bolus,
which, when combined with the buoyancy of CO2, can
give the illusion of a stenosis.34If fragmentation occurs,
image stacking may be used to improve image quality. If
stacking is unavailable or does not resolve the problem,
a repeat angiogram with a longer injection (and larger
volume of CO2) can be performed.26Vessel-specific
protocols for CO2arteriography are beyond the scope of
JOURNAL OF VASCULAR SURGERY
594 Nadolski and Stavropoulos
this review. A detailed protocol for aortogram with runoff
can be found in Hawkins et al.26
Dilute iodinated contrast
Advantages and use of angiography in patients with
CKD. Another alternative for patients with CKD under-
going vascular interventions is dilute ICM. The principal
advantage of using diluted ICM is the operator’s familiarity
with administration during diagnostic angiography and
endovascular procedures. Its use has primarily been studied
in dialysis fistulography and venous mapping. In 28 patients
undergoing venous mapping, Won et al35demonstrated no
significant difference in eGFR at baseline and 4 days after
receiving 10 to 15 mL of iodinated contrast diluted 1:1 with
Fig 2. Diagnosis of May-Thurner syndrome and treatment using carbon dioxide (CO2). Cavogram and bilateral iliac
venogram demonstrate normal right iliac vein (A) and extrinsically compressed left common iliac vein (B). Accurate
estimation of vessel size for stent placement can be obtained with CO2. Poststent venogram demonstrates brisk flow
into the inferior vena cava with appropriately sized and properly apposed stent in the left common iliac (C).
Fig 1. A, Tandem three-way stopcocks with extension tubing and 60-mL syringe used to administer carbon dioxide
(CO2) for angiography. B, Filling the syringe with CO2. C, Disconnect syringe from tubing that is connected to the
CO2canister. Close three-way stopcock. The syringe is not ready to connect to the diagnostic catheter.
JOURNAL OF VASCULAR SURGERY
Volume 57, Number 2
Nadolski and Stavropoulos 595
saline. In this study, only one patient developed CIN,
which resolved within 1 week.35Similarly, patients with
stage 4 kidney disease (eGFR <30 mL/min) undergoing
fistulography and intervention who are hydrated with
a weight-basedbicarbonate protocol and receive <20mL of
ICM diluted 1:2 with normal saline have a reported CIN
incidence of 5.5%.36
Limitations of dilute contrast. Several limitations of
dilute ICM exist. First, it cannot be used as an alternative
in patients with anaphylactic allergy to ICM. Second, the
operator is still limited with regard to the total volume of
contrast that can safely be used without putting patients
at risk for CIN. Lastly, if overly dilute, the contrast may
not be rendered optimal image quality in large vessels
within the abdomen or thorax. Given the limited advan-
tages of diluteICM, we typically reserveits use for extremity
angiography, fistulography, and selective arteriography as
a supplemental tool for use with CO2(Figs 4 and 5).37
Nephrogenic systemic sclerosis and the limited role
of gadolinium. Gadoliniumoncewasheraldedasanalterna-
tivecontrastagent inpatientswithCKD. Sinceits association
its use as an angiographic agent in patients with CKD has
appropriately declined rapidly.38
Nephrogenic systemic fibrosis is an illness that presents
with firm, erythematous, and indurated plaques of the skin
associated with subcutaneous edema involving the extrem-
ities.39It can progress to flexion contractures with limited
range of motion, pain, paresthesias, and/or severe pruritus.
Currently, no effective treatment of NSF is available.39
acquiring it, and its exact relationship to gadolinium is still
not completely elucidated.39,40Studies suggest that slow
excretion of gadolinium-based contrast media in patients
with severe renal impairment allows lower-stability gadoli-
nium chelates to dissociate, releasing free gadolinium,
which incites the disease.41
The overall incidence of NSF is difficult to assess but
may be as high as 3% to 7% in patients with severe CKD.42
In a study of 33 patients presenting with NSF, all patients
had eGFR <15 mL/min at the time of gadolinium admin-
istration. Four of these patients had received gadolinium
during arteriography.40Although the incidence is low
and the exact relationship between gadolinium and NSF
is not fully known, its use in patients with severe CKD
(eGFR <15 mL/min) is not recommended by the United
States Food and Drug Administration and the American
College of Radiology.43Furthermore, studies have shown
gadolinium chelates to be nephrotoxic in patients with stage
3 and 4 CKD (eGFR <60 mL/min) when used in equiva-
lent X-ray attenuating doses with a reported incidence of
gadolinium CIN of 1.9%.1,44,45In fact, the use of gadoli-
nium as an alternative contrast agent in patients with any
risk factors for
Fig 3. Leg arteriogram demonstrating pseudostenosis. A, Left leg
arteriogram depicting stenosis in left common femoral artery and
proximal left superficial femoral artery (arrows). B, Repeat arte-
riogram with the patient’s leg elevated and with more forceful
injection showing the suspected lesion in the common femoral
artery was a pseudostenosis, while the stenosis of the superficial
femoral artery was overestimated. Both occurred due to poor
injection technique and underfilling of the vessel.
Fig 4. Use of carbon dioxide (CO2) in conjunction with dilute
contrast. Aortogram with CO2identifies single left renal artery
(white arrow) and large hypervascular left renal mass (black arrow).
Dilute contrast was used for selective renal arteriogram before
embolization of the mass (image not shown).
JOURNAL OF VASCULAR SURGERY
596 Nadolski and Stavropoulos
degree of renal impairment is not advised by several
consensus groups.1,44In summary, the application of gado-
linium as an ICM alternative for angiography is essentially
limited to patients with normal renal function who have
anaphylactic reaction to ICM.
Limitations of gadolinium in patients with normal
renal function. Eveninthisscenario,gadoliniumhasseveral
challenges and limitations. The physical properties of gadoli-
nium are different from those of iodine, and the contrast
produced by gadolinium chelates using standard angio-
graphic settings is similar to that of dilute contrast. Adjust-
ments to the peak voltage of the X-ray source can result in
contrast similar to that of full-strength ICM.46Gadolinium
chelates thatit cannotbevisualizedunder fluoroscopy. Thus,
all test injections must be performed using digital subtraction
istypically limited to0.3 mmol/kg toprevent nephrotoxicity
(approximately between 42 and 56 mL for a 70-kg man
depending on the chelate used).1,47
Impaired renal function and allergic reactions can limit
the typical use of ICM for diagnostic arteriography and
vascular interventions. Several alternatives, each with its
unique benefits and limitations, exist for use in these
scenarios. Patients with normal renal function but contrast
allergy ideally should receive appropriate prophylaxis, and
ICM can be used. If prophylaxis cannot be administered
or has been ineffective in the past, CO2is our preferred
alternative contrast, with gadolinium being reserved for
arteriography of the arch vessels. In the setting of CKD,
our preferred alternative contrast is CO2, which may be
supplemented with a limited volume of ICM, which can
be diluted to provide a greater volume. We do not recom-
mend the use of gadolinium in patients with CKD.
Conception and design: SS, GN
Analysis and interpretation: SS, GN
Data collection: SS, GN
Writing the article: SS, GN
Critical revision of the article: SS, GN
Final approval of the article: SS, GN
Statistical analysis: SS, GN
Obtained funding: Not applicable
Overall responsibility: SS
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Submitted Jul 11, 2012; accepted Oct 2, 2012.
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598 Nadolski and Stavropoulos