This document provides guidelines on the use of iodine-based and gadolinium-based contrast agents. It discusses acute and late adverse reactions to iodine-based agents and risks for patients taking metformin. It also covers use in pregnancy/lactation and measures to reduce contrast-induced nephrotoxicity and risks of nephrogenic systemic fibrosis from gadolinium agents. The EMA suspended marketing of some linear gadolinium agents but macrocyclic agents remain available given lower risks of releasing gadolinium. Healthcare professionals should use the lowest necessary doses of contrast agents only when essential for diagnosis.

1. Prof. Tarek El-Diasty
Radiology Department
Urology & Nephrology Center - Mansoura University
GUIDELINES ON IODINE-BASED
AND GADOLINIUM-BASED
CONTRAST AGENTS

2. Outline
• Acute adverse reactions
• Patients taking Metformine
• Pregnancy/Lactation
• CIN
• NSF
• GBCA - EMA

3. http://www.esur.org/

4. Acute Adverse Reactions
• Definition: An adverse reaction which
occurs within 1 hour of contrast medium
injection.
• The risk of an acute reaction to a gadolinium-
based contrast agent is significantly lower than
the risk with an iodine-based contrast agent, but
severe reactions to gadolinium-based contrast
media may occur.

5. To reduce the risk of an acute reaction
- For ALL patients:
• Use a non-ionic contrast medium.
• Keep the patient in the radiology department
for 30 min after contrast medium injection.
• Have the drugs and equipment for
resuscitation readily available.

6. Risk factors for acute reactions
- Patients-related:
• Previous moderate or severe acute reaction to an
iodine-based contrast agent.
• Asthma.
• Allergy requiring medical treatment.
- Contrast-related:
• High osmolality ionic contrast media.

7. For patients at increased risk
• Consider an alternative test not requiring
an iodine-based contrast agent.
• Use a different iodine-based agent for
previous reactors to contrast medium.

8. For patients at increased risk
• Consider the use of premedication. Clinical
evidence of the effectiveness of
premedication is limited. If used, a suitable
premedication regime is prednisolone 30 mg
(or methylprednisolone 32 mg) orally given
12 and 2 hours before contrast medium.

9. Management
• First line emergency drugs and
instruments which should be in the
examination room:
- Oxygen
- Adrenaline 1:1,000
- Atropine
- I.V. Fluids; normal saline or Ringer’s solution
- Anti-convulsive drugs (diazepam)
- Sphygmomanometer
- One-way mouth “breather” apparatus

10. Late adverse reactions
• A late adverse reaction to intravascular iodine-
based contrast medium is defined as a reaction
which occurs 1 h to 1 week after contrast medium
injection.
• Skin reactions similar in type to other drug induced
eruptions. Maculopapular rashes, erythema, swelling
and pruritus are most common. Most skin reactions
are mild to moderate and self-limiting.

11. Risk of Iodine-based CM in
Patients Taking Metformin
Lactic Acidosis
Metformin is excreted unchanged in the
urine. In the presence of renal failure,
either pre-existing or induced by iodinated
CM, metformin may accumulate in
sufficient amounts to cause lactic acidosis.
N.B. Metformin does not cause RF.

12. Risk of Iodine-based CM in
Patients Taking Metformin
- If eGFR is greater than 60 ml/min, the pt
can continue to take metformin.
- If eGFR is between 30 and 60 ml/min (or
serum creatinine is raised) stop metformin
48 hr before CM adminstration and remain
off metformin 48 hr after CM.

13. Risk of Iodine-based CM in
Patients Taking Metformin
- Restart metformin if S creatinine is
unchanged 48 hr after CM adminstration.
- If eGFR is less than 30 ml/min metformin
is not approved in most countries and
iodinated CM should be avoided if possible.

14. IBCA - PREGNANCY
• In exceptional circumstances, when
radiographic examination is essential,
iodine- based contrast media may be given
to the pregnant female.
• Following administration of iodine-based
agents to the mother during pregnancy,
thyroid function should be checked in the
neonate during the first week.

15. GBCA - PREGNANCY
• When there is a very strong indication for
enhanced MR, the smallest possible dose of
one of the most stable gadolinium contrast
agents may be given to the pregnant
female.
• Following administration of gadolinium-
based agents to the mother during
pregnancy, no neonatal tests are necessary.

16. IBCA - LACTATION
• Breast feeding may be continued
normally when iodine-based agents
are given to the mother.

17. GBCA - LACTATION
• Breast feeding should be avoided for 24
hours after contrast medium particularly
if high risk agents are used.

18. PREGNANT OR LACTATING
MOTHER WITH RENAL
IMPAIRMENT
• Do not administer iodine-based or
gadolinium-based contrast agents.

19. Gadolinium-Based Contrast Agents
(GBCA)
GBCA were for many years considered safe.
• Nephrotoxicity
• Nephrogenic Systemic Fibrosis

20. GBCA - Nephrotoxicity
• The risk of Gd-induced nephrotoxicity is very low
when GBCAs are used in approved doses.
• GBCA should not be used for radiographic
examinations.
• GBCAs are more nephrotoxic than iodinated CAs in
equivalent x-ray attenuation doses.

21. Non-contrast C-enhanced
Potthast & Maki. Magn Reson Imaging Clin N Am 16 (2008) 573–584

22. Non-contrast MRA
Breath-hold Steady State Free percission (SSFP
MRA) can be performed as the first line MRA
technique to rule out RAS in any patient felt to be
at risk of NSF or having any other
contraindication to gadolinium contrast.
SSFP MRA is not yet recommended for
pretransplant evaluation,as the limited acquired
imaging volume may miss important accessory
renal arteries.

23. Contrast Induced
Nephrotoxicity (CIN)
Definition
CIN is a condition in which an impairment in
renal function (an increase in serum
creatinine by more than 25% ”0.5 mg/dl”)
occurs within 3 days following
intravascular administration of CM in the
absence of an alternative etiology.

24. Contrast Induced
Nephrotoxicity (CIN)
Patients at high risk
The patients at highest risk for developing
CIN are those with pre-existing renal
impairment (>132 mmol/l) particularly when
the reduction in renal function is secondary
to diabetic nephropathy

25. Measures to Reduce CIN
Volume expansion, hydration with intravenous
administration of normal saline solution (NaCl
0.9%) or half strength saline solution (NaCl
0.45%), infusion of mannitol, administration
of atrial na triuretic peptide, loop diuretics,
calcium antagonists, theophylline, dopamine,
the dopamine-1 receptor antagonist
fenoldopam, acetylcysteine.

26. Measures to Reduce CIN
Iodinated CM
No pharmacological manipulation
(renal vasodilators, receptor
antagonists of endogenous vasoactive
mediators or cytoprotective drugs)
has yet been shown to offer
consistent protection against CIN.

27. Measures to Reduce CIN
Iodinated CM
rapidly after contrastHaemodialysis
administration, haemofiltration during and
after contrast administration, an injection
of a small volume of CM, and avoiding short
intervals (<48 h) between procedures
requiring intravascular administration of
CM.

28. Measures to Reduce CIN
Iodinated CM
- Use of low osmolar non-ionic contrast
media instead of high osmolar ionic CM.
- Use of iso-osmolar CM instead of low
osmolar CM.
- ? gadolinium-based CM instead of
iodine-based CM for radiography ,
angiography and CT

29. Of all these measures, extracellular
volume expansion and use of low or iso-
osmolar CM have been found
systematically to be most effective.

30. Measures to Reduce CIN
Gd CM
• MR examinations:
The risk of CIN is very low when Gd CM are
used in approved doses.
• Radiographic examinations:
GBCA should NOT be used for radiographic
examinations in pts with renal impairment.

31. Measures to Reduce CIN
Gd CM
All CM can be removed by hemodialysis and
peritoneal dialysis.
There is NO evidence that hemodialysis
protects pts with impaired renal function
from CIN or NSF.

32. Recommendation
In patients with risk factors, one
should not (i) give high osmolar CM;
(ii) administer large doses of
contrast media;
(iii) administer mannitol and
diuretics, particularly loop diuretics;
and (iv) perform multiple studies with
CM within a short period of time.

33. Recommendation
It is of importance that (i) one makes
sure that the patient is well hydrated [give
at least 100 ml, orally (e.g. soft drinks) or
intravenously (normal saline) depending on
the clinical situation, per hour starting 4 h
before to 24 h after contrast
administration; in warm areas increase the
fluid volume];

34. Recommendation
(ii) low or iso-osmolar CM are used;
(iii) administration of nephrotoxic
drugs is stopped for at least 24 h;
(iv) alternative imaging techniques,
which do not require the administration
of iodinated CM, are considered.

35. Nephrogenic Systemic Fibrosis
- The link between NSF and Gd based contrast
agents was only recognized in 2006.
- Onst: from day of exposure up to 2-3 months.
-Thickened skin and S.C. tissues ‘woody texture’ ;
fibrosis of internal organs (ms.diaphragm, heart,
liver, lung).
- Results: contractures, cachexia, death in a
proportion of patients.

36. NSF - Skin lesions
Prince et al., RadioGraphics 2009; 29:1565–1574

37. Prince et al., RadioGraphics 2009; 29:1565–1574

38. Nephrogenic Systemic Fibrosis
• Although many cases are mild and limited
to dermatologic manifestations, an
estimated 5% of cases have a more
fulminant course resulting in death.

39. Nephrogenic Systemic Fibrosis
-The least stable agents may trigger
the development of nephrogenic
systemic fibrosis (NSF) in renal
failure patients.

40. Nephrogenic Systemic Fibrosis
Patients
At higher Risk:
- Pts with CKD 4 and 5 (GFR < 30 ml / min).
- Pts on dialysis.
- Pts with reduced renal function who have had or
are waiting liver transplantation.

41. Nephrogenic Systemic Fibrosis
Patients
At lower Risk:
- Pts with CKD 3 (GFR = 30 - 59 ml / min).
Children under 1 year, because their immature
kidneys.
Not at Risk:
Pts with normal renal function.

42. Nephrogenic Systemic Fibrosis - GBCA
• The least stable agents may trigger
the development of nephrogenic
systemic fibrosis (NSF) in renal
failure patients.

44. Information for patients
• Gadolinium contrast agents are essential for
diagnosing a wide range of life-threatening and
debilitating diseases.
• If you need a scan with a gadolinium contrast
agent to help in your treatment, your doctor will
use the lowest dose required for a clear image.
• If you have any questions about your scan, speak
to your doctor.

45. Information for patients
• It is known that small amounts of gadolinium
may remain in the brain after a scan with
these agents, although there is currently
no evidence that these small amounts cause
any harm.

46. Information for healthcare
professionals
•
has beendeposition in the brainGadolinium•
confirmed by mass spectrometry and
increases in signal intensity in brain tissue.
-in vitro and non, as well asstability• Data on
clinical studies, show that linear gadolinium
agents release gadolinium from to a greater
extent than macrocyclic agents.

47. Information for healthcare
professionals
• No adverse neurological effects, such as
cognitive or movement disorders, have
been attributed to gadolinium deposition in
the brain with any gadolinium agents.

48. Unenhanced T1-weighted MR images of the typical finding of
hyperintensities in the Dentate Nucleus “DN” (arrows).
Images were acquired (a) before and (b) after six administrations of
macrocyclic GBCA and (c) before and (d) after six administrations of
linear GBCA.
Radbruch et al. Radiology: 2015; Volume 275: Number 3

49. Information for healthcare
professionals
• The marketing authorisations for the
intravenous linear agents gadodiamide and
gadoversetamide, as well as the
intravenous formulation of the linear agent
gadopentetic acid, are being suspended in
EU.

50. EMA
Final Opinion

51. acidgadoxetic–Two intravenous linear agents•
(Primovist) and gadobenic acid (MultiHance) – will
remain available as these agents undergo hepatic
uptake, and can be used for imaging poorly
vascularised hepatic lesions, especially in delayed
phase imaging, that cannot be adequately studied with
other agents.
• Intra-articular formulations of the linear agent
gadopentetic acid (Magnevist) will continue to be
available because the dose of gadolinium that is
required for these scans is very low.

52. EMA
Final Opinion

53. Information for healthcare
professionals
• All macrocyclic agents reviewed –
gadobutrol (Gadovist), gadoteric acid
(Dotarem) and gadoteridol (ProHance) –
will also remain available.

54. Information for healthcare
professionals
• Healthcare professionals should use
gadolinium contrast agents only when
essential diagnostic information
cannot be obtained with unenhanced
scans.
• Healthcare professionals should always
use the lowest dose that provides
sufficient enhancement for diagnosis.

55. thank you very much