14. Water-Soluble Contrast Media

Authors: Dahnert, Wolfgang

Title: Radiology Review Manual, 6th Edition

Copyright 2007 Lippincott Williams & Wilkins

> Table of Contents > Water-Soluble Contrast Media

Water-Soluble Contrast Media

• Ionic = dissociation in water

• Nonionic = soluble in water (hydrophilic); no dissociation in solution

• Iodine-to-particle ratio:

  • = quotient of iodine atoms (attenuation of rays) and number of particles (osmotoxic effect)

  • ratio 1.5 agents = high-osmolar contrast media (HOCM)

  • ratio 3.0 agents = low-osmolar contrast media (LOCM)

  • ratio 6.0 agents = isotonic contrast media (IOCM)

Ionic Monomers

• = monoacidic salts composed of benzoic acid derivatives, with 3 hydrogen atoms replaced by iodine atoms + 3 hydrogen atoms replaced by simple amide chains

• in solution: strong organic acid completely dissociated (ionized) into negatively charged ions / anions

• Conjugated cations:

  • sodium

  • methylglucamine (meglumine)

  • combination of above

• Iodine concentration: up to 400 mg/mL

• Iodine-to-particle ratio: 3:2 or 1.5:1

• Osmolality: 1,400-2,100 mOsm/kg = HOCM

Ionic Dimers

• Construction:

  • 2 iodinated benzene rings containing 6 iodine atoms, one of which contains an ionizing carboxyl group; benzene rings are connected by a common amide side chain

Acetrizoate

The parent triiodinated contrast medium in first clinical use; the benzene ring is attached to a carboxyl (COO-) group at the 1-carbon position and conjugated with sodium / meglumine

Diatrizoate

The unsubstituted hydrogen of acetrizoate has been exchanged for another acetamido unit leading to higher biologic tolerance through higher degree of protein binding Iodine concentration: up to 350 mg/mL Iodine-to-particle ratio: 3:1 Compounds: iohexol, iopamidol, ioversol, iopental,

Ioxaglate (Hexabrix )

Sodium + meglumine are conjugated with the carboxyl group

• Conjugation with: sodium + meglumine

• Compound: ioxaglate (the only available)

• Iodine concentration: 320 mg/mL

• Iodine-to-particle ratio: 6:2 or 3:1

• Osmolality: 600 mOsm/kg = LOCM

Nonionic Monomers

• Construction:

• benzoic acid carboxyl group replaced by amide; side chains have been modi.ed by adding 4-6 hydroxyl (OH) groups, which allows solubility in water

Metrizamide

The first compound with 4 hydroxyl groups positioned at one end of the molecule on the glucosamide moiety

Iohexol (Omnipaque )

contains 6 hydroxyl (OH) groups more evenly distributed around the molecule improving subarachnoid toxicity

Iopamidol (Isovue )

This nonionic monomer contains 5 hydroxyl (OH) groups

Ioversol (Optiray )

This nonionic monomer contains 6 hydroxyl (OH) groups

P.1131

• Iodine concentration: up to 350 mg/mL

• Iodine-to-particle ratio: 3:1

• Compounds: iohexol, iopamidol, ioversol, iopental, iopromide (Ultravist ), iobitridol (Xenetix ), ioxilan (Oxilan )

• Osmolality: 616-796 mOsm/kg

Nonionic Dimers

• Construction:

  • contain up to 12 hydroxyl groups to eliminate ionicity, increase hydrophilicity, lower osmotoxicity, and increase iodine atoms per molecule

  • Iodecol, iotrolan (Isovist ), iodixanol (Visipaque )

  • Iodine-to-particle ratio: 6:1

  • Osmolality: hypo- / isoosmolar

Excretory Urography

• Clearance:>99% of contrast material eliminated through kidney (<1% through liver, bile, small and large intestines, sweat, tears, saliva); vicarious excretion with renal insult / failure (may be unilateral as in obstructive uropathy)

Iotrolan (Iotrol )

This noniomic dimer contains 12 hydroxyl (OH) groups

Physicochemical Properties of Commonly Used Radiographic Contrast Media

Contrast Media	Compound	mOsm/kg H2O	Viscosity (cps) at 37	Iodine mg/mL
Ionic monomers
Uroradiological
Cysto-Conray II (Mallinckrodt)	Meglumine-iothalamate	1,300	4	202
gastrointestinal
Hypaque Sodium Oral Solution (Nycomed Amersham)	Na diatrizoate	1,300	4	249
Gastrografin (Bracco)	Na-meglumine diatrizoate	1,940	8.4	370
Intravascular
Renovue -DIP (Bracco)	Meglumine	iodamide	433	1.8	111
Conray-60 (Mallinckrodt)	Meglumine iothalamate	1,400	4	282
Renografin -60 (Bracco)	Na-meglumine diatrizoate	1,450	4	292
Ionic dimers
Hexabrix (Mallinckrodt)	Na-meglumine ioxaglate	600	7.5	320
nonionic monomers
Oxilan 300 (Cook)	ioxilan	585	5.1	300
Ultravist 300 (Berlex)	iopromide	607	4.9	300
Isovue 300 (Bracco)	iopamidol	616	4.7	300
Optiray 300 (Mallinckrodt)	ioversol	651	5.5	300
Omnipaque 300 (Nycomed Amersham)	iohexol	672	6.3	300
Omnipaque 140 (Nycomed Amersham)	iohexol	322	1.5	140
Omnipaque 240 (Nycomed Amersham)	iohexol	520	3.4	240
Omnipaque 350 (Nycomed Amersham)	iohexol	844	10.4	350
Nonionic dimers
Iotrol 300 (Schering AG)	iotrolan	~310	9.1	300
Visipaque -320 (Nycomed Amersham)	iodixanol	290	11.8	320
Osmolality of human serum is 290 mOsm/kg!
The higher the number of hydroxyl groups, the larger the size + the higher the viscosity + the higher the hydrophilicity! This decreases protein- and tissue-binding properties making the compound biologically more !

P.1132

• Halftime: 1-2 hours (doubled in dialysis patients)

• Concentration: 60% by weight

  • Sodium-containing HOCM

    • less distension of collecting system

  • Meglumine-only HOCM

    • improved distension of collecting system (due to decreased tubular resorption of water)

  • LOCM

    • denser nephrogram + slightly denser pyelogram than HOCM (due to higher tubular concentration)

Angiography

• Burning sensation:

  • intense with concentration of 60-76% HOCM

  • reduced with concentration of 30% HOCM / LOCM

    • Overall incidence of adverse allergic-type reactions is (for unknown reasons) much less with intra-arterial than with intravenous use of contrast media!

Venography

• Foot / calf discomfort or pressure or burning

  • ~24% with 60% HOCM

  • ~5% with 40% HOCM / 300 mg iodine/mL LOCM

    • The addition of 10-40 mg lidocaine/50 mL of contrast media decreases patient discomfort!

• Postphlebography deep vein thrombosis

  • 26-48% with 60% HOCM

  • 0-9% with dilute HOCM / LOCM

    • Infusion of 150-200 mL of 5% dextrose in water / 5% dextrose in 0.45% saline / heparinized saline through injection site immediately after examination reduces likelihood of DVT!

Contrast Material in Pediatrics

• Conventional dose: 1 mL / pound up to 150 mL

• Maximum dose: 280-300 mg I/mL

Adverse Contrast Reactions

• Nonidiosyncratic (= dose-related) reactions

  • Cause: direct chemotoxic / hyperosmolar effect

    • nausea, vomiting

    • cardiac arrhythmia

    • renal failure

    • pulmonary edema

    • cardiovascular collapse

• Idiosyncratic (= anaphylactoid) reactions

  • = reactions occurring unpredictably + independently of dose / concentration = not a true antigen-IgE antibody-mediated reaction nor a reaction to iodine / iodide

  • Cause: unknown

    • hives, itching

    • facial / laryngeal edema

    • bronchospasm, respiratory collapse

    • circulatory collapse

• Delayed reactions

  • erythematous rashes, pruritus

  • fever, chills, ulike symptoms

  • joint pain

  • loss of appetite, taste disturbance

  • headache, fatigue, depression

    Prevalence of Adverse Contrast reactions

    	High-osmolar Ionic	Low-osmolar Nonionic
    Non-life-threatening reaction	1-2%	0.2-0.4%
    Life-threatening reaction	0.2%	0.04%
    Mortality	1:100,000	1:100,000
    Late reaction		6%

  • abdominal pain, constipation, diarrhea

Signi.cant underlying medical conditions:

• renal disease

• cardiac disease

• blood dyscrasias

• pheochromocytoma

• increased symptoms with COPD plus pulmonary hypertension

• increased sickling in patients with sickle-cell disease

  • Approximately 20-40% of population are at increased risk for adverse reaction to contrast media!

  • In patients with adverse reactions to HOCM repeated reactions will be lowered to 5% by using LOCM

  • No direct correlation / association to povidone-iodine skin cleansing solution (Betadine )

Nephrotoxicity

Nonoliguric Transient Renal Dysfunction

• = transient decline of renal function

  • serum creatinine level peaks on days 3-5

  • serum creatinine returns to baseline values within 14-21 days

  • fractional excretion of sodium < 0.01 (DISTINCTIVE CHARACTERISTIC compared with other causes)

Acute Renal Failure

• = sudden + rapid deterioration of renal function

• = increase in serum creatinine of > 25% or to > 2 mg/dL within 2 days of receiving contrast material

Risk Factors and Incidence of Adverse reactions for High- and Low-Osmolality Contrast Media

Type of Reaction	HOCM	LOCM [%]
Overall incidence
Australia (Palmer et al.)	3.80	1.20
United States (Wolf et al.)	4.20	0.70
Japan (Katayama et al.)	12.70	3.10
Severe adverse reactions	0.22	0.04
Severe allergies to drugs, foods, etc.	23.40	6.90
Asthma	19.70	7.80
Repeat reaction to contrast media	16-44	4.1-11.2

P.1133

• Frequency:1-30%; 3rd most common cause of in-hospital renal failure after hypotension and surgery

• Risk factors:

  • Preexisting renal insuf.ciency (serum creatinine <1.5 mg/dL)

  • Diabetes mellitus with renal insuf. ciency (possibly related to dehydration / hyperuricemia)

    • Ratio 3 nonionic LOCM appear to be 50% less nephrotoxic than ratio 1.5 ionic HOCM

    • Diabetics with normal renal function are not at increased risk!

  • Dehydration

  • Cardiovascular disease

  • Use of diuretics

  • Advanced age <70 years

  • Multiple myeloma (in dehydrated patients)

  • Hypertension

  • Hyperuricemia / uricosuria

  • High dose of contrast material

• CAVE:

  • Small decreases in renal function may greatly exacerbate the mortality caused by the underlying condition!

  • Metformin (Glucophage ) should be discontinued for 48 hours after contrast medium administration (accumulation of metformin may result in lactic acidosis, which is fatal in 50%)!

    • It is not necessary to stop metformin after gadolinium administration because gadolinium is not nephrotoxic!

  • Avoid concomitant use of nephrotoxic drugs (eg, gentamycin, NSAIDs)

• Proposed mechanisms:

  • contrast agents are concentrated in nephrons + collecting tubules

    • Vasoconstriction

      • increase in intrarenal pressure induced by hypertonicity

      • intrarenal smooth muscle contraction in response to hypertonic substances

    • RBC aggregation in medullary circulation

    • Direct tubular cell injury

• Potential antidotes:

  • Hydration (0.9% saline at 100 mL/h) 12 hours before + 12 hours after angiography

  • Extracellular volume expansion is the most effective + widely recommended measure!

  • immediate dense nephrogram persisting for up to 24 hours (in 75%) gradually increasing dense nephrogram resembling bilateral acute ureteral obstruction (in 25%):

  • bilaterally enlarged smooth kidneys

  • poor opaci.cation of urine-conducting structures

  • effacement of collecting system (interstitial edema)

Cx: 34% mortality (0.4% of all patients)

Rx: 0.1% require renal replacement therapy

Assessment of Patients before Contrast Injection

• General status

  • Assess hemodynamic, neurologic, general nutritional, anxiety status

• History of signi. cant allergies

  • Prior anaphylactic response to any allergen

  • Asthma

• Renal disease

  • Renal dysfunction: obtain baseline BUN + creatinine

  • Diabetes mellitus

  • Multiple myeloma

    • Hydrate patients and limit contrast dose!

• Cardiac disease

  • Angina

  • CHF with minimal exertion

  • Severe aortic stenosis

  • Primary pulmonary hypertension

  • Severe cardiomyopathy

    • Limit contrast dose!

Treatment of Contrast Reactions

• 94-100% of severe + fatal anaphylactoid reactions occur within 20 minutes of contrast medium injection

  • use a plastic cannula for IV access

  • maintain IV access for 30 minutes

  • have emergency drugs close to the room where contrast injections are done

  • post a listing of available medications + their common doses in the room

Oral Steroid Premedication Protocol

• 32 mg methylprednisolone (Medrol ) PO 12 and 2 hours prior to contrast injection

• 50 mg prednisone PO 13 + 7 + 1 hour prior to contrast injection, plus

  • 50 mg diphenhydramine (Benadryl ) IV / IM / PO 1 hour prior to contrast injection

• nonionic low-osmolality contrast agent

  • Indication: previous respiratory adverse contrast reaction, history of signi.cant allergies / severe asthma

  • Caution in patients with: active tuberculosis, diabetes mellitus, peptic ulcer disease

• Antihistamines alone have not proved to be effective!

Treatment of Premedicated Patients

• Patient on -blocker

  • if response to epinephrine inadequate

  • 1-5 mg glucagon IV + subsequent slow drip of 5 mg glucagon over 60 min

• Patient on calcium channel blocker (eg, nifedipine, nicardipine)

  • calcium IV

• Excessive vasoconstriction on epinephrine IV

  • infusion of 0.5-10 g/kg/min of reconstituted sodium nitroprusside (Nipride ) (50 mg in 500-1000 mL of 5% dextrose wrapped in metal foil during use to protect solution from light)

• Metformin (Glucophage )

  • Stop metformin medication at time of contrast injection + for subsequent 48 hours

  • Reinstate medication if renal function remains normal

  • Contrast material is contraindicated if patient is in renal failure because of risk of lactic acidosis!

P.1134

Useful Medications

• Alpha- and -adrenergic agents:

  • Action: vasoconstriction, increased cardiac output

  • Epinephrine

    • 1 mL glass vials of epinephrine 1:1,000

      • Adult dose: 0.1-0.2 mL epinephrine (1:1,000) (= 0.1-0.2 mg) SQ

      • Pediatric dose: 0.01 mL/kg up to 0.3 mL/dose

      • Repeat in 15-30 minutes if needed

      • Indications: bronchospasm, facial edema, severe urticaria, laryngospasm

    • prepackaged 10-mL syringes of epinephrine 1:10,000

      • Adult dose: 1-3 mL epinephrine (1:10,000) (= 0.1 mg) slowly IV

      • Pediatric dose: 0.1 mL/kg slowly IV

      • Repeat every 5-15 minutes if needed

      • Indications: bronchospasm / laryngospasm with peripheral vascular collapse

      • Maximum dose: 1.0 mg

  • Dopamine (Inotropin )

    • Adult dose: 2-5 pg/kg/min IV; rarely need to exceed 20 pg/kg/min

    • Indications: hypotension

    • Cx: arrhythmia, myocardial ischemia, nausea, vomiting, tremulousness, headache

• Atropine sulfate

  • Adult dose: 0.6-1.0 mg slowly IV

  • Pediatric dose: 0.02 mg/kg slowly IV (0.2 mg/kg of the 0.1 mg/mL solution); min dose of 0.1 mg (children) + 1.0 mg (adolescents)

  • Repeat after 5 min

  • Maximum dose: 0.04 mg/kg (2-3 mg) in adults

  • Indications: bradycardia, hypotension

  • Cx: angina, myocardial infarction

• Metered-dose inhalers of -adrenergic bronchodilators

  • Metaproteranol (Alupent )

  • Terbutaline (Brethaire )

  • Albuterol (Proventil , Ventolin )

  • Dose: 2 puffs every 20-30 minutes, as needed

• H1 antagonists = antihistamines

  • Diphenhydramine (Benadryl )

    • Adult dose: 25-50 mg PO/IM/IV

    • Pediatric dose: 1-2 mg/kg IV, up to 50 mg

  • Hydroxyzine (Vistaril )

    • Dose: 25-50 mg PO/IM/IV

    • Indications: hives, rash, itching

    • Cx: hypotension, sedation

• H2 receptor blockers

  • Cimetidine (Tagamet )

    • Dose: 300 mg PO / slowly IV (diluted in 10 mL D5W solution)

  • Ranitidine (Zantac )

    • Dose: 50 mg PO / slowly IV (diluted in 10 mL D5W solution)

    • Indications: hypotension; bronchospasm

• Aminophylline

  • 250 mg in 250 mL of 5% dextrose

    • Dose: 6 mg/kg IV in D5W over 15-20 minutes (loading dose); then 0.4-1.0 mg/kg/hour

    • Indications: bronchospasm, pulmonary edema

    • Cx: hypotension, cardiac arrhythmia

• Terbutaline

  • 0.25-0.50 mg IM/SQ

• Sedatives

  • Midazolam (Versed )

    • Dose: 0.5-1.0 mg IV; short acting

    • Indications: sedation

  • Diazepam (Valium )

    • Dose: 2-10 mg IV

    • Indications: seizures

  • Pentobarbital (Nembutal )

    • Dose: <50 mg/min IV; 150-200 mg IM

    • Indications: toxic convulsions

    • Cx: respiratory depression, apnea, laryngospasm, hypotension

• Pain

  • Fentanyl

    • Dose: 25-50 mg IV; short acting

  • Morphine

    • Dose: 1-3 mg IV Indications: pain; pulmonary edema

  • Demerol

    • Cx: respiratory depression

• Volume expander

  • Crystalloid solution as 0.9% saline

  • Hydroxylethyl starch (high-molecular-weight colloid)

• Furosemide (Lasix )

  • Adult dose: 20-40 mg IV slow push / PO

  • Pediatric dose: 1 mg/kg/dose IV up to 40 mg

  • Effect: 5-15 minutes after IV; 60 minutes after PO

  • Indications: acute pulmonary edema, CHF, hypertensive emergency

• Corticosteroids

  • Methylprednisolone (Solu-Medrol )

    • Dose: (a) 32 mg PO; 12 & 2 hours prior

    • (b) 100-1,000 mg (anaphylaxis with shock)