Contrast Agents

Contrast agents are substances used to enhance the appearance of bodily structures in medical imaging studies. This page describes the use of contrast agents and the risks associated with them.

• Iodinated contrast for CT scans
  • Allergy-like reactions
  • Contrast extravasation
  • Contrast induced nephropathy
  • Contrast induced thyrotoxicosis
  • Use in pregnancy
• Gadolinium contrast for MRI scans
  • Nephrogenic systemic fibrosis
• Ultrasound contrast media

Iodinated Contrast for CT Scans

In Australia, intravascular contrast media for radiographic procedures are almost exclusively non-ionic (as opposed to ionic) contrast agents. Non-ionic agents are thought to be up to 10 times safer than ionic contrast media. Uses of contrast include intravenous urography, contrast-enhanced CT scans, venography and angiography.

Allergy-Like Reactions

The vast majority of patients tolerate intravascular non-ionic contrast injection well. Severe reactions including shock from anaphylactoid reactions do occur very rarely in about 1 in every 25,000 injections. The risk of a fatal reaction is estimated at 1 in 170,000. These reactions are not dose-dependent and do not involve antibody formation to contrast media. The clinical features of anaphylactoid reactions usually manifest within 60 minutes, with the majority developing in the first 5 minutes. Delayed reactions occur up to one week post-injection and generally involve skin rashes without bronchospasm or laryngeal oedema. Symptoms vary between patients and can be classified into system-based categories:

• Cutaneous
  • Generalised pruritus, flushing
  • Urticaria (hives) or angioedema
• Respiratory
  • Laryngeal oedema (hoarseness, stridor)
  • Bronchospasm (shortness of breath, wheezing)
  • Respiratory failure
• Cardiovascular
  • Arrhythmias
  • Conduction disturbances
  • Vasodilatation, increased vascular permeability
  • Hypotension, anaphylactic shock
• Neurological
  • Syncope, dizziness
  • Seizures
• Gastrointestinal
  • Nausea, vomiting, diarrhoea
  • Abdominal cramps

While the risk of severe reaction is largely unpredictable, factors that predispose to a reaction include: a history of a previous generalized contrast reaction, an atopic history and a history of asthma. B-blockers have also been shown to increase the risk of anaphylactoid reactions and bronchospasm (This population may be resistant to adrenaline used in resuscitation and IM glucagon should be used if adrenaline is ineffective). Patients at risk should receive non-ionic contrast agents if iodinated contrast material is needed. Use of pre-medication is variable and opinion is divided. Corticosteroids ± antihistamines (eg. prednisolone 50mg orally taken 13 and 1 hour(s) before contrast administration ± diphenhydramine 50mg 1 hour before contrast) have been the most widely recommended agents but are not effective if commenced less than 6 hours before the procedure. 1,7 There is also insufficient evidence to show that pre-medication decreases the incidence of life-threatening reactions. 2
The feeling of warmth and a metallic taste is relatively common with administration of intravenous contrast and does not indicate that an allergic reaction has occurred. Patients should be made aware of the potential risks of contrast media prior to the procedure. 3

Contrast Extravasation

Contrast extravasation is an uncommon and generally benign complication of iodinated contrast injection. It occurs when there is leakage of iodinated contrast material out of the vein and into the surrounding subcutaneous tissues. Because iodinated contrast is cytotoxic (harmful to tissues), it can cause a range of complications. However, it is uncommon, occurring in less than 1 in 100 scans requiring contrast.

The majority of patients who have contrast extravasation will only exhibit mild symptoms. These manifest as an acute local inflammatory response, including tissue oedema, erythema, stinging and tenderness. Some patients may not experience any discomfort. More severe symptoms may also occur such as compartment syndromes, skin ulceration and tissue necrosis. Compartment syndromes occur when there is mechanical compression of the nerves, blood vessels and muscles within a closed compartment within the body. If the compression is not relieved, it can lead to tissue death. It can occur in contrast extravasation after extravasation of large volumes of contrast, or when the extravasation occurs in smaller tissue compartments (such as the back of the wrist). This may require surgery to relieve the pressure.

Contrast extravasation and severe sequelae from them are very rare. Wang et al. found only 475 incidences of contrast extravasation out of nearly 70 000 contrast injections (0.7% incidence). Of the 475, only 12 patients developed moderate or severe injuries as a result of extravasation. Only one patient required surgery to relieve a compartment syndrome involving the dorsum of her hand. The patient had no residual functional impairment on follow-up.

Unfortunately, there is no clear consensus as to the most effective treatment for contrast extravasation. Generally, conservative treatments such as limb elevation, cold compresses & application of lanolin are adequate in most cases. The patient should be reviewed by a doctor and remain in hospital for observation for at least 2-4 hours. If the doctor is satisfied that the initial signs & symptoms have improved, or if no new symptoms have developed, then the patient may discharged. They should be given clear instructions to re-present to ED if there is any worsening or development of new symptoms. If the patient’s symptoms worsen or new neurological/vascular symptoms develop during the observation period, they should be referred to the plastic surgery team for urgent review.

Contrast Induced Nephropathy

Click here for a risk assessment and management protocol for contrast induced nephropathy.

The use of intravenous contrast medium in radiological examinations carries an overall risk of contrast-induced nephropathy of approximately 1.2-2.7%. Contrast-induced nephropathy is defined as impairment of renal function indicated by a rise in serum creatinine by more than 25% occuring within 3 days of IV contrast administration in the absence of another aetiology. Most cases recover spontaneously within 14 days although a minority can progress to chronic renal failure and dialysis. The factors that increase the risk of intravascular contrast media-induced nephropathy with a marked decline in renal function include:

• Underlying renal impairment (plasma creatinine >132 mmol/L) or renal disease
• Diabetes Mellitus
• Age > 70 years
• Use of nephrotoxic medications (eg NSAIDS, diuretics, ACE inhibitors, aminoglycosides, amphotericin, antineoplastics, cyclosporin, lithium, methotrexate, vancomycin)
• Cardiac failure
• Hypertension
• Gout
• Dehydration
• Previous renal surgery
• Cirrhosis of the liver
• Intra-arterial contrast administration, large doses of contrast and repeated doses of contrast

Renal function can be assessed by using the plasma/serum creatinine and estimating creatine clearance using the Cockcroft-Gault equation (shown below). The Modified Diet in Renal Disease (MDRD) derived eGFR commonly reported in association with serum creatinine in laboratory reports does not take into account patient weight and is unreliable for those who are extremely overweight or underweight. 10

The Cockcroft-Gault formula is: 4

Creatinine Clearance [mL/min] =	(140 - age [yrs]) x weight [kg]	[x 0.85 (for women)]
	serum creatinine [µmol/L] x 814

Note: Normal creatinine clearance is 95±20 mL/min in women and 120±25 mL/min in men.

The probability of developing contrast induced nephropathy requiring dialysis varies according to the pre-existing renal impairment. 5

Creatinine Clearance (mL/min)	Risk in Non-Diabetics (%)	Risk in Diabetics (%)
50	0.04	0.2
40	0.3	2
30	2	10
20	12	43
10	48	84

Evidence suggests that a small, transient rise in plasma creatinine is relatively common following administration of intravenous contrast media. Patients with normal or borderline-normal renal function generally do not require precautionary measures. In patients with a plasma/serum creatinine of >250-300µmol/L, iodinated contrast is contraindicated and should be avoided. For patients with a plasma/serum creatinine >150mmol/L, strategies to reduce the risk of contrast nephropathy include: 3,6

• Considering alternatives to the use of IV iodinated contrast, such as non-contrast CT, ultrasound, or MRI.
• Use of low osmolality or iso-osmolar contrast media.
• Hydration: intravenous hydration with normal saline is preferable to oral hydration at a rate of at least 1-2 mL/hr/per kg body weight and should be commenced at least 4 hours prior to the procedure and continued for 4-24 hours post procedure. This may not be appropriate in certain clinical situations (eg. congestive heart failure) and caution must be applied.
• Nephrotoxic medications should be ceased for at least 24 hours before and after where possible.
• N-Acetyl Cysteine: its use is controversial and there is variable evidence regarding its reno-protective effect. A renal physician should be consulted regarding its use.

Patients with Type II diabetes mellitus may be taking the oral hypoglycaemic medication metformin. It is renally excreted in its active form, but with increasing renal impairment, there is a risk of lactic acidosis (a form of metabolic acidosis) due to metformin accumulation. Lactic acidosis is a medical emergency and requires urgent treatment. The risk increases with the degree of renal dysfunction and the patient’s age. After receiving iodinated contrast media, some patients may experience an acute renal impairment. This may also result in metformin accumulation and lactic acidosis. The absolute risk remains low, however there are guidelines to prevent this from occurring. 7

In patients with renal impairment who require iodinated contrast:

• Metformin should ideally be ceased 48 hours prior to the procedure.
• The patient should be kept well hydrated.
• Re-check renal function and serum creatinine after the procedure and recommence patient on metformin 48 hours post-procedure if their renal function is unchanged.

Patients with normal renal function do not need to cease their metformin pre-procedure or re-check renal function post-procedure. 7

Contrast Induced Thyrotoxicosis

Thyrotoxicosis secondary to iodinated contrast material is rare but may occur in patients with abnormal thyroid function. Patients whom manifest hyperthyroidism should not be given iodinated contrast material. Patients with Graves’ disease, multinodular goiter or other forms of thyroid autonomy, especially if they are elderly and/or live in areas of dietary iodine deficiency are at risk of iodinated contrast induced thyrotoxicosis. 8 These patients should be monitored by an endocrinologist after administration of iodinated contrast medium and in selected high-risk patients, prophylaxis prescribed by an endocrinologist may be warranted. Intravenous cholangiographic contrast media should not be given to patients at risk. 8

Iodinated Contrast Use in Pregnancy and Lactation

In exceptional circumstances, when contrast use is deemed necessary, iodinated contrast media may be given to the pregnant mother. The theoretical risk of contrast induced hypothyroidism within the foetus has not been validated and foetal exposure to iodinated contrast media and any associated free iodide is likely to be small and relatively short-lived. Although no adverse foetal effects due to contrast administration during pregnancy have been proven, current guidelines recommend that all neonates should receive thyroid function testing in the first week of life where the mother has received iodinated contrast material in accordance with current standard paediatric care. 9

European guidelines have stated that cessation of breast feeding following iodinated contrast material is not required. 9 The amount of contrast media excreted in breast milk is very small and the absorbed dose to the foetus even smaller. The likelihood of either direct toxicity or allergic reaction is therefore extremely low. However, as with other drugs and foodstuffs, the taste of milk may be altered.

Gadolinium for MRI Scans

Gadolinium is a rare earth metal which has special paramagnetic properties, making it useful as a contrast agent for MRI scans. They can be administered intravenously or orally, and are often used for the enhancement of blood vessels or pathology (eg. brain tumours).

Nephrogenic Systemic Fibrosis (NSF)

Gadolinium containing contrast agents have recently been associated with the development of Nephrogenic Systemic Fibrosis (NSF) and should be used with caution in patients with renal failure pending further study.6,7,13,14

NSF, formerly known as Nephrogenic Fibrosing Dermopathy (NFD), is a rare scleroderma-like disease characterised by thickening, induration and hardening of the skin with predilection for the distal extremities and occurs only in patients with renal failure (receiving dialysis, particularly peritoneal dialysis or creatinine clearance <20mL/min). Over 200 cases have been recorded since it was originally described in 1997. Proximal involvement of the trunk and abdomen, including internal organs may occur. 1,2 Sparing of the head and face in NSF is a distinguishing feature of NSF along with the absence of typical serological markers associated with scleroderma.

Diagnosis is confirmed by deep skin biopsy which demonstrates thickened collagen bundles with surrounding clefts, mucin deposition and proliferation of fibroblasts and elastic fibres. Signs of inflammation are absent histologically. 3 Disability due to limited mobility may occur in up to 58% of patients 4 and NSF has been associated with at least one patient death. 1

The US Food and Drug Administration (FDA) issued a Public Health Advisory warning in June 2006 following a notification by the Danish Health Authority of 25 cases of NSF following gadodiamide exposure. 5 The European Society of Urogenital Radiology (ESUR) reports that 57 cases of NSF following gadolinium exposure have been referred to regulatory authorities with 49 cases associated with gadodiamide, 6 with gadopentetate and 2 with gadoversetamide. 6 In addition, gadolinium has been found to be present in affected tissue specimens of patients with NSF. 7,8

Gadolinium exposure has preceded the onset of NSF symptoms by 2-77 days. 3,4,9 Acidosis was implicated in one study of 9 dialysis patients exposed to gadodiamide 3 but was not confirmed in another study of 13 patients with NSF. 9 Cessation of gadolinium administration to patients with renal failure by this group resulted in no new cases of NSF. 9

The FDA has recently revised its recommendations on the safe use of Gadolinium Based Contrast Agents (GBCAs) stating that: 15

• “Use of the three GBCA drugs - Magnevist (gadopentetate), Omniscan (gadodiamide), and Optimark (gadoversetamide) - is contraindicated in patients with acute kidney injury (AKI) or with chronic, severe kidney disease (with glomerular filtration rates under 30 mL/min).”
• Screen patients prior to administration of a GBCA to identify those with AKI or chronic, severe kidney disease. These patients appear to be at highest risk for NSF.
• Use the clinical history to screen patients for features of AKI or risk factors for chronically reduced kidney function.
  • Features of AKI consist of rapid (over hours to days) and usually reversible decrease in kidney function, commonly in the setting of surgery, severe infection, injury, or drug-induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess kidney function in the setting of AKI.
  • For patients at risk for chronically reduced kidney function (such as patients over age 60 years, patients with high blood pressure, or patients with diabetes), estimate the kidney function (GFR) through laboratory testing.
• Avoid use of GBCAs in patients suspected or known to have impaired drug elimination unless the need for the diagnostic information is essential and not available with non-contrasted MRI or other alternative imaging modalities.
• Monitor for signs and symptoms of NSF after a GBCA is administered to a patient suspected or known to have impaired elimination of the drug.
• Do not repeat administration of any GBCA during a single imaging session.

The FDA has recommended instituting prompt dialysis in patients with renal failure who receive gadolinium due to previous studies demonstrating accelerated excretion of gadolinium during dialysis. 10 However, anecdotal evidence so far does not seem to support this strategy as being effective. 3

RANZCR Guidelines on the use of Gadolinium containing MRI Contrast Agents

These are as follows: 12

1. MRI contrast agents should be used only when the benefits from their use will exceed the (usually very small) risk.
2. Consideration to be given to other imaging modalities like a non-contrast MRI, CT, or ultrasound that will provide the desired diagnostic information at a lesser risk.
3. The least amount of dose, that is diagnostically adequate, should be used.
4. All patients should have screening for kidney disease. The following set of questions can be asked:
   • Is the patient's age >60?
   • Is the patient hypertensive?
   • Does the patient have diabetes mellitus?
   • Does the patient have a history of renal disease (including renal transplant, solitary kidney)?
   • Is the patient in the immediate (within 1 month or less) pre or post-operative period of a liver transplant?
   • Is the patient currently experiencing an acute deterioration in renal function? Note that serum creatinine may not stabilise until 7-10 days after an acute insult.

   A serum creatinine or eGFR should be obtained in most cases. Previous blood results <3 months for stable outpatients or <7 days for stable inpatients, is acceptable.

   Based on eGFR, patients can be grouped into six main categories:
   • Normal renal function: no evidence of increased risk from any of the marketed agents.
   • Impaired renal function (eGFR 30-60 ml/min/1.73 m²) (excluding patients with any degree of acute renal impairment, and those with mild-moderate renal impairment in the peri-operative liver transplant period): To date no NSF case has been reported in this group. However, because of the potential risk of gadolinium accumulation and later complications, caution should be taken with the use of less stable chelates : gadodiamide, gadoversetamide, and gadopentetate. Use of cyclic agents, like gadoterate (Dotarem), gadobutrol (Gadovist) and gadoteridol (ProHance), may be appropriate in this group.
   • Severely impaired renal function (eGFR <30 ml/min/1.73 m²): These patients are at significant risk for NSF (in the order of 1% per dose). Less stable chelates (gadodiamide, gadoversetamide, gadopentetate) are contra-indicated in this group.To date, it is not known whether early haemodialysis reduces the risk of NSF.
   • Unstable renal function (including all peri-operative liver transplant patients with any renal function abnormality, and patients with hepato-renal syndrome): These patients are at significant risk for NSF, but the size of this risk remains poorly quantified at this time. Less stable chelates (gadodiamide, gadoversetamide, gadopentetate) are contra-indicated in this group.
   • Patients on haemodialysis: These patients are at high risk for NSF (in the order of 1% per dose). The risk of CT with iodinated contrast agents may well be less than that of a gadolinium-enhanced MRI examination, since there is no longer any material risk of nephrotoxicity. If the benefit of a contrast-enhanced MRI examination is felt to outweigh the risk, and CT cannot be effectively substituted, use the minimum necessary dose of a cyclic agent. The MRI examination should be scheduled immediately before a dialysis session, to maximise clearance of the agent, and the possibilities of a second session within 24 hours, and perhaps a third additional session, should be considered. To date, it is not known whether early haemodialysis reduces the risk of NSF.
   • Patients on peritoneal dialysis: These patients are at the highest risk for NSF. Avoid all gadolinium-based MRI contrast agents (clearance of the agent in these patients is very slow; in one study, their measured risk of NSF was seven times higher than that of haemodialysis patients).
5. Choices which may reduce the risk from gadolinium-containing contrast agents include the following:
   • Use of the theoretically most stable chelates (ionic cyclic group) minimising the risk of gadolinium retention. Example of such agents are gadoterate (Dotarem), gadobutrol (Gadovist) and gadoteridol (ProHance).
   • Use of agents with higher relaxivity, allowing smaller doses of gadolinium for the same T1 shortening effect e.g. gadoxetate (Primovist).
   • Use of agents which have significant biliary excretion, as well as (or instead of) renal excretion e.g. gadoxetate (Primovist). However, there is little reported experience with this strategy.

   At milder levels of renal impairment, the risk of NSF appears extremely small, with no documented case in a patient with stable eGFR >30 ml/min/1.73 m². There remains a theoretical possibility of late and/or cumulative effects from gadolinium-based agents, perhaps related to persistence of small amounts of de-chelated gadolinium in tissues. The risk of iodinated contrast-induced nephropathy also appears low in these patients, but may outweigh the largely theoretical risks from gadolinium-based agents.

   For any contrast-enhanced MRI examination, the name of the agent used, and the dose, must be recorded in the patient record and/or the report of the examination.

6. MRI contrast agents should not be used in lieu of CT or conventional angiography in an attempt to avoid nephrotoxicity.

Ultrasound Contrast Media

US contrast agents (UCA) consist of microscopic bubbles of gas enclosed in thin flexible shell. The types of gas and shell material used differ depending on the brand of contrast agent. The microbubbles are generally 1-4 micrometers in size (smaller than a red blood cell) making them small enough to flow easily through the circulation, but large enough so they remain inside the blood vessels. When high frequency sound waves from an ultrasound probe hit them, they oscillate and reflect a non-characteristic echo. The ultrasound probe is directed to send a special pulse inversion signal which enhances the echoes from the UCA, while reducing the echoes from the surround tissuing. This results in an enhanced image of the tissue vasculature.  1

The UCA may continue to oscillate for a short time before it bursts. The gas diffuses into the bloodstream, and the shell material is metabolised. Generally the UCA is given as an injection and only lasts a short time in the body. If longer times are required, UCA may be given through a drip to maintain a steady infusion of contrast. 1

Safety

Ultrasound contrast agents are generally tolerated very well and have a very good safety record. They are among the safest contrast agents used in radiology. 1, 2 The main serious adverse reaction is an anaphylactoid hypersensitivity reaction, which may occur in 1 in 7000 patients. This reaction is non-IgE mediated and may occur even if the patient has not been previously exposed to UCA. 2 However the overall rate of fatal events is quite low (approximately 1 in 500000). Less serious adverse reactions may include itching, moderate hypotension, headache, erythema, sensation of warmth and nausea & vomiting. 3 UCAs do not cause any renal impairment, and can be used in patients with any level of renal function.

A retrospective review of over 23000 injections of UCA in Italian centres found only 2 serious adverse reactions and no deaths (< 1 in 10000 serious adverse reactions). 3 There were 27 minor adverse reactions recorded (1 in 850). Another retrospective review compared the mortality & morbidity of 42000 patients who had UCA during rest & stress echocardiograms and compared with a matched cohort of 16000 patients who did not have UCA. 4 They found that there were no significant differences in the rates of death of AMI. A smaller retrospective study looked for differences in adverse reaction rates in patients undergoing dobutamine stress echocardiography with & without UCA. 5 Two different types of UCA were used in a total of 1486 patients. The control group contained 1012 patients. They did not find any significant differences in the incidence of adverse events among the three groups.

It is recommended that any UCA administration should take place in the presence of an experienced clinician who is experienced in managing severe hypersensitivity reactions. Additionally, patients with pulmonary hypertension or unstable cardiopulmonary conditions should have continuous monitoring of their ECG & vital signs for at least 30 minutes.

Last updated December 2011.

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