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A. General adverse reactions

A.1. Acute Adverse Reactions

A.1.1. Acute Adverse Reactions to Iodine-based Contrast Media

A.1.2. Acute Adverse Reactions to Gadolinium-based Contrast Media (non-organ specific)

A.1.3. Management of Acute Adverse Reactions

A.1.4. Recording Acute Adverse Reactions

A.1.5. Review of Treatment Protocols

A.2. Late Adverse Reactions

A.3. Very Late Adverse Reactions

A.3.1. Thyrotoxicosis

A.3.2. Nephrogenic Systemic Fibrosis

 


A. GENERAL ADVERSE REACTIONS

 

A.1. Acute Adverse Reactions

Definition: An adverse reaction which occurs within 1 hour of contrast medium injection.

 

The same acute adverse reactions are seen after iodine- and gadolinium-based contrast agents and after ultrasound contrast agents. The incidence is highest after iodine-based contrast agents and lowest after ultrasound agents.

 

Classification

 

Acute reactions are either allergy-like, hypersensitivity reactions or chemotoxic responses. Allergy-like reactions may or may not be true IgE-mediated allergy.

 

 

Allergy-like/

Hypersensitivity

Chemotoxic

Mild

Mild urticaria

Mild itching

Erythema

Nausea/mild vomiting

Warmth/chills

Anxiety

Vasovagal reaction which resolves spontaneously

Moderate    

Marked urticaria

Mild bronchospasm

Facial/laryngeal edema

Vomiting

Severe vomiting

Vasovagal attack

Severe

Hypotensive shock

Respiratory arrest

Cardiac arrest

Arrythmia

Convulsion

 

 

Note:

  • Not all symptoms experienced by patients in the hour after contrast medium injection are adverse reactions to the contrast agent.
  • Patient anxiety may cause symptoms after contrast medium administration (Lalli effect).
  • When a new contrast medium is first introduced, adverse effects tend to be over-reported (Weber effect).

 

 

 

A.1.1. Acute Adverse Reactions to Iodine-based Contrast Media

 

Risk factors for acute reactions

Patient-related

Patients with a history of

  • Previous moderate or severe acute reaction (see classification above) to an iodine-based contrast agent.
  • Unstable asthma.
  • Atopy requiring medical treatment.

Contrast medium-related

  • High-osmolality ionic contrast media.

Note:

  • There is no difference in the incidence of acute reactions between the non-ionic low-osmolar contrast agents and the non-ionic iso-osmolar contrast agents.
  • There is no difference in the incidence of acute adverse events among the non-ionic low-osmolar agents.

To reduce the risk of an acute reaction

For all patients

  • Use a non-ionic contrast medium.

 

For patients at increased risk of reaction (see risk factors above)

  • Consider an alternative test not requiring an iodine-based contrast agent.
  • Use a different iodine-based agent for previous reactors to contrast medium.
  • Consider the use of premedication. Clinical evidence of the effectiveness of premedication is limited and premedication may not prevent anaphylaxis. If used, a suitable premedication regime is prednisolone 30 mg (or methylprednisolone 32 mg) orally given 12 and 2 hours before contrast medium.
Be prepared for an acute reaction in all patients
  • Have the drugs and equipment for resuscitation readily available (see A.1.3.).
  • Keep the patient in a medical environment for 30 minutes after contrast medium injection.
Warming iodine-based contrast medium before administration
  • Appears to make the patient more comfortable, based on clinical observation.
  • May reduce the rate of general adverse events, but data on this is limited.
  • Is widely regarded as best practice
Extravascular administration of iodine-based contrast medium
When absorption or leakage into the circulation is possible, take the same precautions as for intravascular administration.

 

A.1.2. Acute Adverse Reactions to Gadolinium-based Contrast Media (non-organ specific)

 

Note:

The risk of an acute reaction to a gadolinium-based contrast agent is lower than the risk with an iodine-based contrast agent, but severe reactions to gadolinium-based contrast media may occur.

 

Risk factors for acute reactions

Patient-related

Patients with a history of

  • Previous moderate or severe acute reaction to a gadolinium-based contrast agent.
  • Unstable asthma.
  • Atopy requiring medical treatment.

Contrast medium-related

  • The risk of reaction is not related to the osmolality of the contrast agent: the low doses used make the osmolar load very small.
  • There is no difference in the incidence of acute adverse reactions among the gadolinium-based extracellular agents.

To reduce the risk of an acute reaction

For patients at increased risk of reaction (see risk factors above)

  • Consider an alternative test not requiring a gadolinium-based contrast agent.
  • Use a different gadolinium-based agent for previous reactors to contrast medium.
  • Consider the use of premedication. There is no clinical evidence of the effectiveness of premedication and premedication may not prevent anaphylaxis. If used, a suitable premedication regime is prednisolone 30 mg (or methylprednisolone 32 mg) orally given 12 and 2 hours before contrast medium.
Be prepared for an acute reaction in all patients
  • Have the drugs and equipment for resuscitation readily available (see A.1.3).
  • Keep the patient in a medical environment for 30 minutes after contrast medium injection.

 

 

 

A.1.3. Management of Acute Adverse Reactions

 

The management is the same for acute adverse reactions after iodine- and gadolinium-based and ultrasound contrast agents.

 

First-line emergency drugs and equipment which should be in the examination room

  • Oxygen
  • Adrenaline 1:1,000
  • Antihistamine H1 – suitable for injection
  • Atropine
  • ß2-agonist metered dose inhaler
  • I.V. Fluids – normal saline or Ringer’s solution
  • Anti-convulsive drugs (diazepam)
  • Sphygmomanometer
  • One-way mouth “breather” apparatus

Simple guidelines for first-line treatment of acute reactions to all contrast media

When an acute reaction occurs, check for the following:

  • Skin erythema, urticaria
  • Nausea, vomiting
  • Decreased blood pressure, abnormal heart rate
  • Dyspnea, bronchospasm

 

 

Nausea/Vomiting

Transient: Supportive treatment.

Severe, protracted:  Appropriate antiemetic drugs should be considered.

Note: Severe vomiting may occur during anaphylaxis.

 

Urticaria

Scattered, transient: Supportive treatment including observation.

Scattered, protracted: Appropriate H1-antihistamine intramuscularly or intravenously should be considered. Drowsiness and/or hypotension may occur.

Generalized: Appropriate H1-antihistamine intramuscularly or intravenously should be given. Drowsiness and/or hypotension may occur. Consider adrenaline 1:1,000, 0.1-0.3 ml (0.1-0.3 mg) intramuscularly in adults, 50% of adult dose to pediatric patients between 6 and 12 years old and 25% of adult dose to pediatric patients below 6 years old. Repeat as needed.

Note: Urticaria may precede anaphylaxis, so the patient should be observed carefully.

 

Bronchospasm

1.  Oxygen by mask (6-10 l/min).

2.  ß-2-agonist metered dose inhaler (2-3 deep inhalations).

3.  Adrenaline.

3.a. Normal blood pressure

Intramuscular: 1:1,000, 0.1-0.3 ml (0.1-0.3 mg) [use smaller dose in a patient with coronary artery disease or elderly patient]. In pediatric patients: 50% of adult dose to pediatric patients between 6 and 12 years old and 25% of adult dose to pediatric patients below 6 years old. Repeat as needed.

3.b Decreased blood pressure

Intramuscular: 1:1,000, 0.5 ml (0.5 mg), In pediatric patients:

6-12 years: 0.3 ml (0.3 mg) intramuscularly. 

< 6 years: 0.15 ml (0.15 mg) intramuscularly.                                                 

 

Laryngeal edema

1.  Oxygen by mask (6-10 l/min).
2. Intramuscular adrenaline (1:1,000), 0.5 ml (0.5 mg) for adults, repeat as needed. In pediatric patients:

6-12 years: 0.3 ml (0.3 mg) intramuscularly. 

< 6 years: 0.15 ml (0.15 mg) intramuscularly   

 

Hypotension

Isolated hypotension

1.

Elevate patient’s legs.

2.

Oxygen by mask (6-10 l/min).

3.

Intravenous fluid: rapidly, normal saline or Ringer’s solution.

4.

If unresponsive:  adrenaline: 1:1,000, 0.5 ml (0.5 mg) intramuscularly, repeat as needed. In pediatric patients:

6-12 years: 0.3 ml (0.3 mg) intramuscularly. 

< 6 years: 0.15 ml (0.15 mg) intramuscularly.

 

Vagal reaction (hypotension and bradycardia)

1.

Elevate patient’s legs.

2.

Oxygen by mask (6-10 l/min).

3.

Atropine 0.6-1.0 mg intravenously, repeat if necessary after 3-5 min, to 3 mg total (0.04 mg/kg) in adults. In pediatric patients give 0.02 mg/kg intravenously (max. 0.6 mg per dose), repeat if necessary to 2 mg total.

4.

Intravenous fluids: rapidly, normal saline or Ringer’s solution.

 

 

Generalized anaphylactoid reaction

1.

Call for the resuscitation team.

2.

Suction airway as needed.

3.

Elevate patient’s legs if hypotensive.

4.

Oxygen by mask (6-10 l/min).

5.

Intramuscular adrenaline (1:1,000), 0.5 ml (0.5 mg) in adults. Repeat as needed. In pediatric patients: 6-12 years: 0.3 ml (0.3 mg) intramuscularly. < 6 years: 0.15 ml (0.15 mg) intramuscularly.

6.

Intravenous fluids (e.g. normal saline, Ringer’s solution).

7.

H1-blocker e.g. diphenhydramine 25-50 mg intravenously.

 

A.1.4. Recording Acute Adverse Reactions

  • Acute adverse reactions must be properly documented in the patient’s records, so that appropriate precautions can be taken before any future examination.
  • All reactions requiring medical treatment should be recorded.
  • Mild symptoms after contrast medium not requiring treatment should not be recorded.  They may be unrelated to the contrast medium and caused by anxiety or by the patient’s disease. If such minor symptoms are recorded, the patient may in future be denied a clinically important enhanced examination.
  • Full documentation of acute allergy-like reactions includes (a) measuring serum tryptase, preferably immediately after and 2 hours after the reaction, and (b) skin testing one month after the reaction to check for evidence of true allergy to the triggering contrast agent and for evidence of cross-reactivity to other agents.

 

A.1.5. Review of Treatment Protocols

Radiologists and their staff should review treatment protocols regularly (e.g. at 12 monthly intervals), so that each can accomplish their role efficiently. Knowledge, training, and preparation are crucial for guaranteeing appropriate and effective treatment if there is an adverse contrast-related event.

 

A.2. Late Adverse Reactions

 

Definition:

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.

Reactions:

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.

 

A variety of late symptoms (e.g., nausea, vomiting, headache, musculoskeletal pains, fever) have been described following contrast medium, but many are not related to the contrast medium.

Risk factors for skin reactions:

  • Previous late contrast medium reaction.
  • Interleukin-2 treatment.
  • Use of non-ionic dimers.

Management:

Symptomatic and similar to the management of other drug-induced skin reactions e.g. antihistamines, topical steroids and emollients.

Recommendations:

Patients who have had a previous contrast medium reaction, or who are on interleukin-2 treatment should be advised that a late skin reaction is possible and that they should contact a doctor if they have a problem.

 

Patch and delayed reading intradermal tests may be useful to confirm a late skin reaction to contrast medium and to study cross-reactivity patterns with other agents.

 

To reduce the risk of repeat reaction, use another contrast agent than the agent precipitating the first reaction. Avoid agents which have shown cross-reactivity on skin testing.

 

Drug prophylaxis is generally not recommended.

 

 

Note: Late skin reactions of the type which occur after iodine-based contrast media have not been described after gadolinium-based and ultrasound contrast media.

 

A.3. Very Late Adverse Reactions

 

Definition: An adverse reaction which usually occurs more than 1 week after contrast medium injection.

 

Type of reaction

Iodine-based contrast media

Thyrotoxicosis.

Gadolinium-based contrast media

Nephrogenic systemic fibrosis.

 

A.3.1. Thyrotoxicosis

Thyrotoxicosis

At risk

  • Patients with untreated Graves’ disease.
  • Patients with multinodular goiter and thyroid autonomy, especially if they are elderly and/or live in an area of dietary iodine deficiency.

Not at risk

Patients with normal thyroid function.

Recommendations

  • Iodine-based contrast media should not be given to patients with manifest hyperthyroidism.
  • In patients suspected of being at risk of thyrotoxicosis, TSH measurement may be helpful.
  • In selected high-risk patients, prophylactic treatment may be given by an endocrinologist.
  • Patients at risk should be closely monitored by endocrinologists after iodine-based contrast medium injection.
  • Intravenous cholangiographic contrast media should not be given to patients at risk.

 

A.3.2. Nephrogenic Systemic Fibrosis

 

A diagnosis of nephrogenic systemic fibrosis (NSF) should only be made if the Yale NSF Registry clinical and histopathological criteria are met (J Am Acad Dermatol 2011; 65: 1095-1106). The link between nephrogenic systemic fibrosis (NSF) and gadolinium-based contrast agents was recognized in 2006.

CLINICAL FEATURES OF NSF

Onset

  • From day of exposure for up to 2-3 months.
  • Sometimes years after exposure.

Early changes

  • Pain, pruritus, swelling and erythema.
  • Usually starts in legs.

Later changes

  • Fibrotic thickening of skin and subcutaneous tissues.
  • Fibrosis of internal organs, e.g. muscle, diaphragm, heart, liver, lung.

End result

  • Limb contractures.
  • Cachexia.
  • Death may occur.

Patients

 

At higher risk

  • Patients with CKD 4 and 5 (GFR < 30 ml/min).
  • Patients on dialysis.
  • Patients with acute kidney insufficiency.

At lower risk

  • Patients with CKD 3 (GFR 30-59 ml/min).

Not at risk of NSF

  • Patients with stable GFR > 60 ml/min.

Measurement of renal function

See B.1.

CONTRAST AGENTS

Risk classification (based on laboratory data) and Recommendations

Highest risk of NSF

 

  • Contrast agents

Gadodiamide (Omniscan®)

Ligand: Non-ionic linear chelate (DTPA-BMA)

Gadopentetate dimeglumine (Magnevist® plus generic products)

Ligand: Ionic linear chelate (DTPA)

Gadoversetamide (Optimark®)

Ligand: Non-ionic linear chelate (DTPA-BMEA)

 

  • Recommendations

These agents are CONTRAINDICATED in

  • patients with CKD 4 and 5 (GFR < 30 ml/min), including those on dialysis
  • acute renal insufficiency
  • pregnant women
  • neonates

 

These agents should be used with CAUTION in patients with CKD 3 (GFR 30-60 ml/min) and in children less than 1 year old. There should be at least 7 days between two injections.

Lactating women: Stop breastfeeding for 24 hours and discard the milk.

Serum creatinine (eGFR) measurement and clinical assessment of patient before administration is mandatory.

These agents should never be given in higher doses than 0.1 mmol/kg per examination in any patient.

High-risk agents should be stored separately from intermediate and low risk agents to avoid use in error of a high-risk agent in a patient with poor renal function.

Intermediate and lowest risk of NSF

 

Contrast agents:
  • Intermediate risk of NSF

Gadobenate dimeglumine (Multihance®)

Ligand: Ionic linear chelate (BOPTA)

Special feature: It is a combined extracellular and liver specific agent with 2-3% albumin binding. In man ~4% is excreted via the liver.

Gadofosveset  trisodium (Vasovist®, Ablavar®)   

Ligand: Ionic linear chelate (DTPA-DPCP)

Special feature: It is a blood pool agent with affinity to albumin (> 90%); 5% is excreted via the bile. Biological half-life is 12 times longer than for any other gadolinium-based contrast agent (18 hours compared to 1½ hours, respectively).

Gadoxetate disodium (Primovist®, Eovist®)

Ligand: Ionic linear chelate (EOB-DTPA)

Special feature: It is an organ-specific gadolinium contrast agent with 10% protein binding and 50% excretion by hepatocytes.

 

  • Lowest risk of NSF

Gadobutrol (Gadovist®, Gadavist®)

Ligand: Non-ionic cyclic chelate (BT-DO3A)

Gadoterate meglumine (Dotarem®, Magnescope®)

Ligand: Ionic cyclic chelate (DOTA)

Gadoteridol (Prohance®)

Ligand: Non-ionic cyclic chelate (HP-DO3A)

 

  • Recommendations

These agents should be used with CAUTION in patients with CKD 4 and 5 (GFR < 30 ml/min). There should be at least 7 days between two injections.

Pregnant women: These agents can be used to give essential diagnostic information.

Lactating women: Discarding the breast milk in the 24 hours after contrast medium is not considered necessary, but the patient can discuss with the doctor whether she wishes to do this.

Laboratory testing of renal function (eGFR) is not mandatory.

Patients with NSF

 

Gadolinium-based contrast media should only be used if the indication is vital and then only intermediate or low- risk agents should be used.

Recommendations for all patients

Never deny a patient a clinically well-indicated enhanced MR-examination.

In all patients use the smallest amount of contrast medium necessary for a diagnostic result.

Always record the name and dose of the contrast agent used in the patient records.

Confounded cases: If two different gadolinium-based contrast agents have been injected, it is impossible to determine with certainty which agent triggered the development of NSF and the situation is described as ‘confounded’.

Unconfounded cases: The patient has never been exposed to more than one agent.

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