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IODINATED CONTRAST MEDIA

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Diatrizoate salts and other iodinated contrast media are used in radiographic studies to delineate internal structures. The iodinated contrast media are classified as either ionic or nonionic and monomeric or dimeric.

Specific Substances

    A) Diatrizoate meglumine
    1) 3,5-Diacetamido-2,4,6-triiodobenzoic acid
    2) Amidotrizoate meglumine
    3) Diatrizoate methylglucamine
    4) Hypaque(R) meglumine
    5) Meglumine 3,5-diacetamindo-2,4,6-triiodobenzoate
    6) Methylglucamine 3,5, -diacetamido-2,4,6,-
    7) triiodobenzoate
    8) methylglucamine salt
    9) Urografic acid methlyglucamine salt
    10) NIOSH/RTECS LZ 4315000
    11) CAS 131-49-7
    Diatrizoate sodium
    1) 3,5 bis(acetylamino)-2,4,6-triiodobenzoic
    2) acid sodium salt
    3) 3,5, diacetamido-2,4,6-triiodobenzoic acid
    4) sodium salt
    5) Sodium 3,5-diacetamido-2,4,6trizoate
    6) Sodium diatrizoate
    7) NIOSH/RTECS LZ 4300000
    8) CAS 8064-12-8

    1.2.1) MOLECULAR FORMULA
    1) DIATRIZOATE MEGLUMINE: C11H9I3N2O4.C7H17NO5
    2) DIATRIZOATE SODIUM: C11H8I3N2NaO4

Available Forms Sources

    A) SOURCES
    1) Brand names of products containing diatrizoates include (JEF Reynolds , 1990):
    1) Angiografin (R)
    2) Cardiografin (R)
    3) Cystografin (R)
    4) Gastrografin (R)
    5) Hypaque (R)
    6) Peritrast (R)
    7) Radiolar-280 (R)
    8) Radioselectan (R)
    9) Reno-M (R)
    10) Triyosom (R)
    11) Urografin (R)
    12) Uropolinum (R)
    13) Urovison (R)
    14) Urovist (R)
    2) Diatrizoate meglumine (USP) contains approximately 47.1% iodine, sodium diatrizoate, 59.9%. There are 1.57 mEq (mmol) of sodium in each gram of sodium diatrizoate (JEF Reynolds , 1990).
    3) HYPAQUE (R) meglumine contains 60 grams of the meglumine salt of diatrizoic acid in each 100 mL of aqueous solution. Each milliliter contains about 282 milligrams of organically bound iodine (Prod Info, 1982).
    B) USES
    1) These compounds (diatrizoate salts and other iodinated contrast media) are used in radiographic studies to delineate internal structures.

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) Most toxic effects are seen after therapeutic administration or iatrogenic overdose.
    B) Minor side effects may include gastrointestinal upset, pain at the injection site, flushing, pallor, wheezing, urticaria, weakness, and itching.
    C) More serious effects may involve seizures, hypersensitivity reactions, dysrhythmias, hemolysis, hypotension, and renal failure.
    D) INTRATHECAL INJECTION - Intrathecal administration of ionic contrast media causes a characteristic "ascending tonic clonic seizure syndrome". Patients may develop paresthesias in the legs within a few hours of the event. This is soon followed by myoclonic jerking of the lower extremities which may occur spontaneously or be precipitated by minimal tactile stimulation. Myoclonic jerking progresses to the upper extremities and tonic clonic seizures may develop. If not aggressively controlled, the myoclonus/seizures cause hyperthermia, rhabdomyolysis, and metabolic acidosis, which may precipitate renal failure and death.
    0.2.5) CARDIOVASCULAR
    A) Hypotension, vagal reaction (hypotension and bradycardia), hypertension, and cardiac dysrhythmias have been reported as a reaction to therapeutic administration of iodinated contrast agents.
    0.2.6) RESPIRATORY
    A) Pulmonary edema, difficulty breathing, and cough may be seen. Hypersensitivity reactions may produce swelling of the glottis, dyspnea, wheezing, and bronchospasm.
    0.2.7) NEUROLOGIC
    A) Weakness and headache are often seen. Seizures, parkinsonism, paresthesias, and encephalopathy have been reported, but are uncommon.
    0.2.8) GASTROINTESTINAL
    A) Nausea, vomiting, metallic taste, and diarrhea are complications of therapy.
    0.2.9) HEPATIC
    A) Elevated serum aminotransferase has been noted.
    0.2.10) GENITOURINARY
    A) Renal failure may occur. Patients with pre-existing renal insufficiency, diabetes, dehydration and congestive heart failure are at increased risk.
    0.2.12) FLUID-ELECTROLYTE
    A) Dehydration may be a result of the greater osmolality of diatrizoates when administered to select geriatric patients and infants.
    0.2.13) HEMATOLOGIC
    A) Hemolysis, phlebitis, coagulation disorders, and a mild eosinophilia have all been seen after administration.
    0.2.14) DERMATOLOGIC
    A) Complications include flushing, sweating, pallor, urticaria, ioderma, epidermal necrolysis, and pain at the injection site.
    0.2.19) IMMUNOLOGIC
    A) Serious hypersensitivity reactions resulting in cardiac and respiratory failure may be seen.
    0.2.20) REPRODUCTIVE
    A) Diatrizoate meglumine, ethiodized oil, and ioflupane I 123 are classified as FDA pregnancy category C. Diatrizoate meglumine/diatrizoate sodium is classified as FDA pregnancy category B. These compounds cross the placental barrier and are evenly distributed in the fetus. Ioflupane I 123 and ethiodized oil have the potential to cause fetal harm since radioactive iodine products can permanently impair fetal thyroid function. Following administration, ethiodized oil and diatrizoate meglumine have also been shown to be excreted in breast milk. Although lactation studies have not been conducted with ioflupane I 123, iodine 123 is excreted in human milk.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturers do not report any carcinogenic potential of diatrizoate meglumine/diatrizoate sodium, ethiodized oil, or ioflupane I 123.

Laboratory Monitoring

    A) Monitor liver and kidney function.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Many of these substances are intended for parenteral use only. Those intended for enteral use are generally poorly absorbed. Gastrointestinal decontamination is rarely required.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and irrigate exposed areas with copious amounts of water. A physician may need to examine the area if irritation or pain persists.
    0.4.6) PARENTERAL EXPOSURE
    A) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue).
    1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
    2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.
    B) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
    C) HYPERTENSION: Monitor vital signs regularly. For mild/moderate asymptomatic hypertension (no end organ damage), pharmacologic treatment is generally not necessary. Sedation with benzodiazepines may be helpful in agitated patients with hypertension and tachycardia. For severe hypertension sodium nitroprusside is preferred. Labetalol, nitroglycerin, and phentolamine are alternatives. See main treatment section for doses.
    D) VENTRICULAR DYSRHYTHMIAS SUMMARY
    1) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.
    E) TORSADES DE POINTES: Hemodynamically unstable patients require electrical cardioversion. Treat stable patients with magnesium (first-line agent) and/or atrial overdrive pacing. Correct electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia) and hypoxia, if present.
    1) MAGNESIUM SULFATE/DOSE: ADULT: 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes. An optimal dose has not been established. Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram/hour, if dysrhythmias recur. CHILDREN: 25 to 50 mg/kg diluted to 10 mg/mL; infuse IV over 5 to 15 minutes.
    2) OVERDRIVE PACING: Begin at 130 to 150 beats per minute, decrease as tolerated.
    3) Avoid class Ia (eg, quinidine, disopyramide, procainamide), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol).
    F) ALLERGIC REACTION: MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.
    G) ATROPINE: ADULT DOSE: BRADYCARDIA: BOLUS: 0.5 mg IV may repeat every 3 to 5 min. Maximum: 3 mg. PEDIATRIC DOSE: 0.02 mg/kg IV/IO (0.04 to 0.06 mg/kg ET). Repeat once, if needed. Minimum dose: 0.1 mg. Maximum single dose: Child: 0.5 mg; Adolescent: 1 mg. Maximum total dose: Child: 1 mg; Adolescent: 2 mg.
    H) EXTRAVASATION INJURY: If extravasation occurs, stop the infusion. Disconnect the IV tubing, but leave the cannula or needle in place. Attempt to aspirate the extravasated drug from the needle or cannula. If possible, withdraw 3 to 5 mL of blood and/or fluids through the needle/cannula. Elevate the affected area. Most studies recommend the application of cold compress. Ice packs can be applied for 15 to 60 minutes 3 to 4 times daily for 1 to 3 days, or until symptom resolution. Administer analgesia for severe pain. If pain persists, there is concern for compartment syndrome, or injury is apparent, an early surgical consult should be considered. Close observation of the extravasated area is suggested. If tissue sloughing, necrosis or blistering occurs, treat as a chemical burn (antiseptic dressings, silver sulfadiazine, antibiotics when applicable). Surgical or enzymatic debridement may be required. Risk of infection is increased in chemotherapy patients with reduced neutrophil count following extravasation. Consider culturing any open wounds. Monitor the site for the development of cellulitis, which may require antibiotic therapy. Patients should be treated aggressively as soon as possible, using liposuction and saline washout (Gault method). Rhys-Davies exsanguinator may also be used to resolve soft tissue edema. HYALURONIDASE: Conflicting results exist regarding the use of hyaluronidase; however, some studies have reported a beneficial effect.
    I) INTRATHECAL INJECTION: Inadvertent intrathecal injection has been reported with iodinated contrast media. Aggressive seizure control (benzodiazepines, barbiturates, propofol) is mandatory to prevent secondary complications of hyperthermia, acidosis, rhabdomyolysis, renal failure and disseminated intravascular coagulation. Neuromuscular paralysis with continuous propofol or barbiturate infusion titrated to burst suppression by continuous EEG monitoring is likely to be necessary. Treat hyperthermia by controlling seizures and aggressive cooling. Fluids and pressors may be necessary to treat hypotension. Aggressive hydration in patients who develop rhabdomyolysis.
    1) Cerebrospinal fluid (CSF) drainage and CSF exchange should be initiated as soon as possible. This information was derived from experience with antineoplastic agents. Keep the patient upright if possible. Immediately drain AT LEAST 20 mL CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free normal saline or lactated ringers). Consult a neurosurgeon immediately for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative free normal saline (NS) or lactated ringers (LR) through ventricular catheter, drain fluid from lumbar catheter; typical volumes are 80 to 150 mL/hr for at least 24 hours). Fresh frozen plasma (FFP) (25 mL FFP/liter NS or LR) or albumin 5% should be added to the fluid used for perfusion to increase protein binding and replace CSF protein. Administer dexamethasone 4 mg intravenously every 6 hours to prevent arachnoiditis.

Range Of Toxicity

    A) No specific toxic dose has been established. Adverse reactions have occurred at therapeutic doses. A fatality occurred when a child was given 15.5 mL/kg. Two patients developed encephalopathy after receiving iopromide (120 to 150 mL) for coronary angioplasty.

Clinical Effects

Summary Of Exposure

    A) Most toxic effects are seen after therapeutic administration or iatrogenic overdose.
    B) Minor side effects may include gastrointestinal upset, pain at the injection site, flushing, pallor, wheezing, urticaria, weakness, and itching.
    C) More serious effects may involve seizures, hypersensitivity reactions, dysrhythmias, hemolysis, hypotension, and renal failure.
    D) INTRATHECAL INJECTION - Intrathecal administration of ionic contrast media causes a characteristic "ascending tonic clonic seizure syndrome". Patients may develop paresthesias in the legs within a few hours of the event. This is soon followed by myoclonic jerking of the lower extremities which may occur spontaneously or be precipitated by minimal tactile stimulation. Myoclonic jerking progresses to the upper extremities and tonic clonic seizures may develop. If not aggressively controlled, the myoclonus/seizures cause hyperthermia, rhabdomyolysis, and metabolic acidosis, which may precipitate renal failure and death.

Heent

    3.4.2) HEAD
    A) SALIVARY GLAND ENLARGEMENT may be noted after injection (JEF Reynolds , 1990).
    3.4.3) EYES
    A) RETINAL DAMAGE - Emboli of the retinal arteries and infarcts of the retina have rarely been seen after therapeutic injection of diatrizoate meglumine into the carotid arteries (Grant, 1986; Levine & Henry, 1963) Catros et al, 1959).
    B) HEMIANOPSIA - Homonymous hemianopsia, associated with hemiplegia or hemiparesis, has been seen with diatrizoate injection, and was interpreted as most likely being an embolic obstruction of cerebral vessels rather than a direct toxic effect (Grant, 1986).
    C) CORNEAL INFILTRATES - Multiple, superficial, fluffy-appearing corneal infiltrates seen near the limbus, occurred as a rapid onset hypersensitivity reaction after intravenous injection of diatrizoate meglumine (Grant, 1986; Baum & Bierstock, 1978).
    D) LACRIMATION may be noted after injection (JEF Reynolds , 1990).
    E) BLEPHAROSPASM has occurred after carotid angiography (JEF Reynolds , 1990).
    F) PHOTOPHOBIA has been reported after carotid angiography (JEF Reynolds , 1990).
    G) PERIORBITAL HEMORRHAGE may be seen after carotid angiography (JEF Reynolds , 1990).
    3.4.4) EARS
    A) SENSORINEURAL HEARING LOSS - A 37-year-old man developed severe bilateral sensorineural hearing loss a few hours after undergoing drip intravenous pyelography with iohexol. Evaluation revealed complete deafness on the right and 60 dB sensorineural hearing loss on the left. Hearing loss did not improve (Karino & Fukaya, 2001).
    3.4.5) NOSE
    A) SNEEZING may be seen after therapeutic injection (Davies et al, 1975).
    3.4.6) THROAT
    A) LARYNGOSPASM and subsequent cardiac arrest resulting in death has been reported as an anaphylactoid reaction (Hartman et al, 1982).
    B) SUBMAXILLARY SWELLING occurred in a patient following the ingestion of six ipodate capsules needed for the preparation for an oral cholecystogram (Lasser, 1969).

Cardiovascular

    3.5.1) SUMMARY
    A) Hypotension, vagal reaction (hypotension and bradycardia), hypertension, and cardiac dysrhythmias have been reported as a reaction to therapeutic administration of iodinated contrast agents.
    3.5.2) CLINICAL EFFECTS
    A) CONDUCTION DISORDER OF THE HEART
    1) Tachycardia, bradycardia, ventricular fibrillation, circulatory failure, and cardiac arrest have rarely been reported after injection of diatrizoate and iopamidol (Benchimol & McNally, 1966; Hartman et al, 1982; Lalli, 1980; Edelstein, 1988; Davidson et al, 1989).
    2) Tachycardia occurred following an inadvertent intrathecal administration of diatrizoate (Lockman et al, 1999).
    B) HYPOTENSIVE EPISODE
    1) Hypotension may rarely occur after intravenous injection of diatrizoate and iopamidol (JEF Reynolds , 1990; Davidson et al, 1989). Care should be taken when administered to patients taking antihypertensives (USPDI, 1990).
    2) Some patients have a vagal reaction to contrast agents consisting of hypotension with prominent sinus bradycardia (Bush, 1990).
    C) TORSADES DE POINTES
    1) CASE REPORT - A 70-year-old male underwent sequential right and left coronary arteriogram, using diatrizoate solution as the contrast agent. Shortly following selective right coronary arteriography the patient experienced torsades de pointes (Goldfinger & Hoekenga, 1986).
    D) ANGINA
    1) Prolonged chest pain without ECG changes and angina have been reported following intravenous administration of iopamidol (Davidson et al, 1989).
    E) CONDUCTION DISORDER OF THE HEART
    1) Davidson et al (1989) has reported one case each of ventricular fibrillation and ventricular tachycardia following intravenous iopamidol administration.
    F) HYPERTENSIVE EPISODE
    1) Hypertension was reported in a 49-year-old male following intrathecal administration of diatrizoate (Lockman et al, 1999).

Respiratory

    3.6.1) SUMMARY
    A) Pulmonary edema, difficulty breathing, and cough may be seen. Hypersensitivity reactions may produce swelling of the glottis, dyspnea, wheezing, and bronchospasm.
    3.6.2) CLINICAL EFFECTS
    A) ACUTE LUNG INJURY
    1) Cough and pulmonary edema may rarely be seen after injection of diatrizoate or iopamidol(Davies et al, 1975; Edelstein, 1988; Davidson et al, 1989). Pulmonary edema has also been seen after inhalation of either salt form (Hartman et al, 1982; Edelstein, 1986).
    B) BRONCHOSPASM
    1) Hypersensitivity reactions may result in edema of the glottis and face, difficulty in breathing, and bronchospasm (JEF Reynolds , 1990; Edelstein, 1988).
    2) Sudden death has occurred following injection of radio contrast medium with the prominent symptoms being difficulty breathing suggesting laryngospasm or bronchospasm as a major role in the cause of death (Edelstein, 1988).
    a) CASE REPORT - A 59-year-old male experienced immediate nausea, increased heat, respiratory difficulty with wheezing, and respiratory arrest after being injected with diatrizoate in preparation for an aortography. Laryngeal edema was not evident on autopsy (Edelstein, 1988).
    b) CASE REPORT - A 61-year-old female had difficulty breathing followed by death following intravenous administration of diatrizoate. Autopsy revealed no laryngeal edema (Edelstein, 1988).
    C) SUFFOCATING
    1) Deaths have been reported after aspiration of diatrizoate containing contrast media (Ansell, 1968) McAlister & Siegel, 1984; (Chiu & Gambach, 1974).
    2) These solutions are hypertonic and draw fluid into the alveoli causing pulmonary edema, severe hypoxemia, acute inflammation with PMN cells, capillary congestion, alveolar damage and bleeding (McAllister & Askin, 1983; (Friedman et al, 1986).
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ACUTE LUNG INJURY
    a) When placed in the lungs of rats and dogs, rapid absorption of the fluid from the serum occurred, producing pulmonary edema. This condition cleared within 24 hours (McAlister & Askin, 1983; Reich, 1969; Frech et al, 1970).

Neurologic

    3.7.1) SUMMARY
    A) Weakness and headache are often seen. Seizures, parkinsonism, paresthesias, and encephalopathy have been reported, but are uncommon.
    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) Headache has been seen after therapeutic injection of iodinated contrast agents (JEF Reynolds , 1990; Haslam et al, 1987).
    B) FATIGUE
    1) Weakness may be seen after injection (JEF Reynolds , 1990).
    C) DROWSY
    1) Increasing lethargy and disorientation occurred among three pediatric patients following the intravenous administration of diatrizoate meglumine (Haslam et al, 1987).
    D) SEIZURE
    1) Seizures are a rare complication after therapeutic intravenous administration of diatrizoate and iopamidol(JEF Reynolds , 1990; Haslam et al, 1987; Levey et al, 1988; Sharp et al, 1999). They are more likely to occur after administration to a pediatric patient than an adult (USPDI, 1990). In a large series, seizures have been reported in 0.2% of cerebral arteriograms and 0.4% of arch aortograms (Junck & Marshall, 1983).
    2) CASE REPORT - A 67-year-old patient received an iatrogenic overdose of diatrizoate (400 mL) during coronary angiography; the patient experienced protracted seizures thereafter requiring sodium pentothal for control. Non-contrasted CT examination revealed retention of contrast media in the cerebral cortex, basal ganglia, and thalamus. The patient later developed a parkinson-like syndrome and mild acute-on-chronic renal failure. Renal function returned to baseline and the neurologic examination revealed only mild cognitive dysfunction at the time of discharge on hospital day 46; CT and MRI examination at this time were significant for resolution of contrast enhancing areas and mild cortical atrophy (May, 1993).
    3) Accidental intrathecal administration of amidetrizoate and diatrizoate meglumine have been associated with the occurrence of generalized seizures (Nakazawa et al, 1988; Lockman et al, 1999).
    4) Absence status epilepticus, confirmed by EEG, occurred in two patients following the intravenous administration of metrizamide. Both patients recovered following the administration of divalproex sodium (Ahmed et al, 1988).
    E) APHASIA
    1) Aphasia has occurred after cerebral arteriography (JEF Reynolds , 1990).
    F) PARESTHESIA
    1) Paresthesias and hemiplegia may occur after cerebral arteriography (JEF Reynolds , 1990).
    G) TOXIC ENCEPHALOPATHY
    1) WITH THERAPEUTIC USE
    a) IOPROMIDE: Two patients developed encephalopathy after receiving iopromide for coronary angioplasty. The first patient, a 47-year-old man with a diagnosis of acute anterior myocardial infarction, developed confusion, agitation, nausea and headache about 1 hour after coronary angioplasty using 150 mL of iopromide. A CT of the brain showed extravascular localized contrast media in the sagittal sinus (inferior and superior) and occipital lobe. Following supportive care, his symptoms normalized within 8 hours. Another patient, a 70-year-old man with a history of diabetes mellitus and a diagnosis of subacute inferior myocardial infarction, developed nausea and confusion within 1 hour of receiving 120 mL of iopromide during coronary angioplasty. A CT scan of the brain showed extravascular localized contrast media in sagittal sinus and occipital lobe. He recovered after 12 hours of supportive care (Kocabay & Karabay, 2011).
    H) CEREBROVASCULAR DISEASE
    1) Homonymous hemianopsia, associated with hemiplegia or hemiparesis, has been seen with diatrizoate injection, and was interpreted as most likely being an embolic obstruction of cerebral vessels rather than a direct toxic effect (Grant, 1986).
    I) AMNESIA
    1) CASE REPORT - A 69-year-old female experienced transient global amnesia following a coronary angiographic procedure using metrizoate as the iodinated contrast agent. The patient's memory returned seven hours later (Koehler et al, 1986).
    J) MENINGITIS
    1) CASE REPORT - Meningism has been reported in a 28-year-old male thirty hours after lumbar radiculography using iopamidol. The patient slowly recovered after five days (Wallers & Chaudhuri, 1985).
    2) CASE REPORT - A 74-year-old woman developed aseptic meningitis with fever, confusion, headache, neck stiffness, nausea and sterile CSF pleocytosis 18 hours after lumbar myelography with iohexol. She recovered uneventfully (Cissoko et al, 2000).
    K) CEREBRAL EDEMA
    1) WITH THERAPEUTIC USE
    a) Cerebral edema has been reported during postmarketing surveillance of iopromide administration in pediatric patients; however, it is not always possible to reliably estimate the frequency of postmarketing reaction or establish a causal relationship to product exposure (Prod Info ULTRAVIST(R) intravenous injection, intra-arterial injection, 2012).
    b) Four children with large vascular brain tumors developed abrupt deterioration of mental status, hypertension and bradycardia shortly after ionic contrast enhanced cranial CT. Two patients developed seizures, two died and two required emergency craniotomy. All patients had evidence of intracranial hypertension prior to CT. The authors speculated that the patients developed acute elevation in intracranial pressure from cerebral edema due to the contrast media (Haslam et al, 1987).
    2) WITH POISONING/EXPOSURE
    a) Brain edema resulting in death has resulted from an overdose of 15.5 mL/kg (Junck & Marshall, 1986).
    b) Other cases of lethal brain edema have also been reported, one with extensive petechiae (Batsakis, 1957).
    L) CORTICAL BLINDNESS
    1) Transient cortical blindness has been reported to complicate 0.3% to 1% of vertebral arteriograms and is thought to result from a direct effect of the contrast agent on the occipital cortex (Junck & Marshall, 1983). Complete recovery typically occurs over hours to days.
    M) NEUROPATHY
    1) Spinal cord injury is a well-known risk of aortography but may also occur with vertebral, thyrocostocervical, bronchial, or intercostal artery injection, especially with inadvertently excessive doses of the contrast agent (Junck & Marshall, 1983).
    N) COMA
    1) CASE REPORT - A 73-year-old woman developed seizures, coma, disconjugate gaze, hyperreflexia, bilateral extensor plantar responses, and respiratory arrest during coronary stent placement using diatrizoate meglumine and diatrizoate sodium (Sharp et al, 1999). The following day she became responsive with slurred speech, , gait and balance instability, and a bilateral postural tremor. Over the next three days, the patient's speech, language, balance and coordination gradually resolved.

Gastrointestinal

    3.8.1) SUMMARY
    A) Nausea, vomiting, metallic taste, and diarrhea are complications of therapy.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) Nausea, retching, and metallic taste are all possible symptoms seen after injection by diatrizoate (Davies et al, 1975; Haslam et al, 1987).
    2) Vomiting has been reported following intravenous administration of iopamidol (Davidson et al, 1989).
    B) INTESTINAL OBSTRUCTION
    1) Injection of diatrizoate into the superior mesenteric artery has resulted in small bowel injury (JEF Reynolds , 1990).
    2) CASE REPORT - Severe mucosal damage was seen proximal to an obstruction in a 54-year-old who had received a sodium diatrizoate enema (Creteur et al, 1983).
    C) DIARRHEA
    1) Mild diarrhea may occur after rectal or oral therapeutic use of either salt (JEF Reynolds , 1990).

Hepatic

    3.9.1) SUMMARY
    A) Elevated serum aminotransferase has been noted.
    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) Treatment with sodium diatrizoate may result in a rise in serum aminotransferase (Clark, 1977).

Genitourinary

    3.10.1) SUMMARY
    A) Renal failure may occur. Patients with pre-existing renal insufficiency, diabetes, dehydration and congestive heart failure are at increased risk.
    3.10.2) CLINICAL EFFECTS
    A) RENAL FAILURE SYNDROME
    1) Renal failure may occur as a complication of intravenous therapy, possibly due to hypotension, vasoconstriction, or predisposing factors (Kone et al, 1986; Catterall et al, 1981; Weinrauch et al, 1977).
    a) Risk factors include preexisting renal insufficiency, diabetic nephropathy, volume depletion, vascular disease and cardiac failure. The incidence of acute renal failure after administration of contrast agents in patients with these high-risk factors is 9% to 16% compared to 2% to 5% in patients without these risk factors (Brezis & Epstein, 1989).
    1) To prevent contrast-induced renal failure in patients with pre-existing renal insufficiency, vigorous volume expansion is recommended (Misson & Cutler, 1985).
    b) Acute renal failure following contrast administration is a recognized hazard in patients with multiple myeloma (Harkonen & Kjellstrand, 1981).
    c) The sodium salt appears to produce more severe reaction than the meglumine salts (JEF Reynolds , 1990).
    d) Concomitant use of certain drugs may increase the risk for renal failure including: ACE inhibitors, aminoglycosides, certain cancer chemotherapy agents, and non-steroidal anti-inflammatory drugs (Thomsen & Bush, 1998).
    2) Acute renal failure has been reported following the intravenous administration of ioxaglate, iohexol, and iopamidol, used as contrast agents for diagnostic purposes (Cedgard et al, 1986; Aron et al, 1989; Elliott & Reger, 1988).
    B) ABNORMAL RENAL FUNCTION
    1) Transient proteinuria and enzymuria were reported following administration of diatrizoate in preparation for renal arteriographies (Nicot et al, 1984).
    2) Approximately 73% (n=1077) of patients experienced some degree of elevated serum creatinine following intravenous administration of iopamidol, used in cardiac catherization (Davidson et al, 1989).
    3) The most common presentation of contrast-induced renal dysfunction is a modest rise in the serum creatinine concentration that peaks the third day after the procedure. Preprocedural renal function is regained within ten days in most patients (Misson & Cutler, 1985).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) Severe metabolic acidosis occurred following the accidental intrathecal administration of amidetrizoate and diatrizoate (Nakazawa et al, 1988; Lockman et al, 1999).

Hematologic

    3.13.1) SUMMARY
    A) Hemolysis, phlebitis, coagulation disorders, and a mild eosinophilia have all been seen after administration.
    3.13.2) CLINICAL EFFECTS
    A) HEMOLYSIS
    1) Hemolysis and hemoglobinuria were seen in 3 children who received diatrizoate for coronary angiography (Cohen, 1969).
    2) CASE REPORT - Intravascular hemolysis was also reported in a 51-year-old female with sickle cell disease following administration of diatrizoate for coronary angiography and ventriculography (Rao et al, 1985).
    B) DISSEMINATED INTRAVASCULAR COAGULATION
    1) Coagulation may be depressed (Stein & Hilgartner, 1968), and fibrinolysis may occur after injection (Chandra & Abraham, 1973; Schulze & Kaps, 1977) Schulze, 1978). Asymptomatic DIC was reported in 41% of patients undergoing excretory urography (Simon et al, 1979), and others have reported DIC as a complication (Junck & Marshall, 1986).
    2) Disseminated intravascular coagulation occurred in a patient following the accidental intrathecal administration of amidetrizoate (Nakazawa et al, 1988).
    C) PHLEBITIS
    1) Phlebitis, thrombosis, and possible embolism have been complications seen with therapeutic intravenous administration (JEF Reynolds , 1990).
    D) EOSINOPHIL COUNT RAISED
    1) A transient, non-harmful eosinophilia was reported by Vincent et al (1977).
    E) THROMBOCYTOPENIC DISORDER
    1) CASE REPORT - A 66-year-old female underwent a coronary angiography using diatrizoate as the contrast agent and, four hours later, developed thrombocytopenia. The platelet count gradually returned to normal after six units of platelets were given. Three weeks later, the patient underwent an angioplasty procedure using diatrizoate and again developed thrombocytopenia. Over the next several days, the platelet count spontaneously increased without administration of a platelet transfusion (Chang et al, 1989).

Dermatologic

    3.14.1) SUMMARY
    A) Complications include flushing, sweating, pallor, urticaria, ioderma, epidermal necrolysis, and pain at the injection site.
    3.14.2) CLINICAL EFFECTS
    A) FLUSHING
    1) Injection may cause a sensation of heat (Davies et al, 1975).
    B) EXCESSIVE SWEATING
    1) Sweating has been noted after injection (JEF Reynolds , 1990).
    C) ITCHING OF SKIN
    1) Pruritus may occur after injection (JEF Reynolds , 1990).
    D) PALE COMPLEXION
    1) Pallor after injection may be seen (JEF Reynolds , 1990).
    E) URTICARIA
    1) Urticaria has resulted from hypersensitivity reactions (Davies et al, 1975).
    F) DISORDER OF SKIN
    1) IODERMA - A few rare cases of ioderma have involved the administration of diatrizoates salts and other iodine salts (Sparrow, 1979; Heydenreich & Larsen, 1977).
    G) SKIN NECROSIS
    1) Skin necrosis may occur after extravasation of diatrizoate injection (USPDI, 1990).
    2) CASE REPORT - Extensive tissue necrosis occurred in a 6-year-old female after the administration of a sodium iothalamate solution as part of a renal biopsy procedure. Symptoms began to develop within hours of the injection. There was no evidence that extravasation had occurred (Leung & Cheng, 1980).
    H) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE
    1) CASE REPORT - A CT scan, using a diatrizoate solution, was performed on a 55-year-old female. Within 12 hours, the patient developed erythema and urticarial plaques over her body and buccal mucosa. A skin biopsy was consistent with the diagnosis of toxic epidermal necrolysis. The patient subsequently died (Kaftori et al, 1988).
    2) CASE REPORT - A 33-year-old man developed toxic epidermal necrolysis after a body CT with iohexol (Rosado et al, 2001).
    I) INJECTION SITE PAIN
    1) There may be pain at the site of the injection (Dotter, 1953).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) THYROTOXIC CRISIS
    1) WITH THERAPEUTIC USE
    a) Thyrotoxic crisis has been reported during postmarketing surveillance of iopromide; however, it is not always possible to reliably estimate the frequency of postmarketing reaction or establish a causal relationship to product exposure. Patients with hyperthyroidism or with an autonomously functioning thyroid nodule may develop thyroid storm after the intravascular administration of an iodinated contrast agent (Prod Info ULTRAVIST(R) intravenous injection, intra-arterial injection, 2012).
    B) HYPERTHYROIDISM
    1) WITH THERAPEUTIC USE
    a) In a nested case-control study, the association between iodinated contrast media exposure and incident thyroid dysfunction was evaluated in patients without preexisting hyperthyroidism or hypothyroidism. Incident hyperthyroid or hypothyroid cases were characterized in 2 parallel analyses by a change in thyrotropin level from normal (at baseline) to low or high (follow-up measurement); 178 of incident hyperthyroid cases were matched with 655 euthyroid controls and 213 of incident hypothyroid cases were matched to 779 euthyroid controls. Overall, there was a significant association between iodinated contrast media exposure and incident hyperthyroidism (odds ratio (OR), 1.98; 95% CI, 1.08 to 3.60), incident overt hyperthyroidism (followup thyrotropin concentration up to 0.1 mIU/L; OR, 2.5; 95% CI, 1.06 to 5.93), and incident overt hypothyroidism (followup thyrotropin concentration greater than 10 mIU/L; OR, 3.05; 95% CI, 1.07 to 8.72), but not incident hypothyroidism (OR, 1.58; 95% CI, 0.95 to 2.62) (Rhee et al, 2012).
    C) HYPOTHYROIDISM
    1) WITH THERAPEUTIC USE
    a) In a nested case-control study, the association between iodinated contrast media exposure and incident thyroid dysfunction was evaluated in patients without preexisting hyperthyroidism or hypothyroidism. Incident hyperthyroid or hypothyroid cases were characterized in 2 parallel analyses by a change in thyrotropin level from normal (at baseline) to low or high (follow-up measurement); 178 of incident hyperthyroid cases were matched with 655 euthyroid controls and 213 of incident hypothyroid cases were matched to 779 euthyroid controls. Overall, there was a significant association between iodinated contrast media exposure and incident hyperthyroidism (odds ratio (OR), 1.98; 95% CI, 1.08 to 3.60), incident overt hyperthyroidism (followup thyrotropin concentration up to 0.1 mIU/L; OR, 2.5; 95% CI, 1.06 to 5.93), and incident overt hypothyroidism (followup thyrotropin concentration greater than 10 mIU/L; OR, 3.05; 95% CI, 1.07 to 8.72), but not incident hypothyroidism (OR, 1.58; 95% CI, 0.95 to 2.62) (Rhee et al, 2012).

Immunologic

    3.19.1) SUMMARY
    A) Serious hypersensitivity reactions resulting in cardiac and respiratory failure may be seen.
    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLACTOID REACTION
    1) Anaphylactic shock and other hypersensitivity reactions have been seen after intravenous injection. Symptoms have included bronchospasm, facial and glottic edema, urticaria, difficulty with breathing, and vascular collapse (Erffmeyer et al, 1985; JEF Reynolds , 1990).
    B) CASE REPORT
    1) ADVERSE EFFECTS
    a) Yamaguchi et al (1990) studied various contrast media (CM) for incidence of adverse effects. For non-ionic CM, 0.04% of the 168,383 cases had a serious reaction, for the 169,284 ionic CM cases, the incidence was 0.22%.
    b) A serious reaction was defined as either a sudden blood pressure drop, dyspnea, cardiac arrest, or loss of consciousness.
    c) The incidence of diatrizoate plus methylprednisolone adverse effects was 4%, with 2.9% being mild, 0.9% moderate, and 0.2% severe (Wolf-Silvay-Mandeau, 1990).
    d) Mortality ratios in various studies for use of ionic contrast media have ranged from 1 in 15,000 to 1 in 75,000, and have not been of practical use (Palmer, 1990).

Reproductive

    3.20.1) SUMMARY
    A) Diatrizoate meglumine, ethiodized oil, and ioflupane I 123 are classified as FDA pregnancy category C. Diatrizoate meglumine/diatrizoate sodium is classified as FDA pregnancy category B. These compounds cross the placental barrier and are evenly distributed in the fetus. Ioflupane I 123 and ethiodized oil have the potential to cause fetal harm since radioactive iodine products can permanently impair fetal thyroid function. Following administration, ethiodized oil and diatrizoate meglumine have also been shown to be excreted in breast milk. Although lactation studies have not been conducted with ioflupane I 123, iodine 123 is excreted in human milk.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the teratogenic potential of ethiodized oil, diatrizoate meglumine, diatrizoate sodium, or ioflupane I 123 (Prod Info LIPIODOL(R) intralymphatic injection, intrauterine injection, 2014; Prod Info DA TSCAN(R) IV injection, 2011; Prod Info MD-Gastroview(R) oral, rectal solution, 2009; Prod Info GASTROGRAFIN(R) oral, rectal solution, 2007; Prod Info CYSTOGRAFIN(R) injection, 2006).
    B) ANIMAL STUDIES
    1) In animal teratology studies, there was no evidence of teratogenicity in animals exposed to diatrizoate meglumine, or ioflupane I 123 (Prod Info MD-Gastroview(R) oral, rectal solution, 2009; Prod Info GASTROGRAFIN(R) oral, rectal solution, 2007).
    2) Animal studies showed that ethiodized oil was not embryotoxic or teratogenic with oral administration of doses up to 110 mg iodine/kg/day in rats between gestation days 6 to 17 or doses of 12.5 mg Iodine/kg given once every 3 days in rabbits between gestation days 6 to 18. However, no animal studies have been conducted using injection route of ethiodized oil (Prod Info LIPIODOL(R) intralymphatic injection, intrauterine injection, 2014).
    3) Diagnostic iodinated contrast media have shown an ability to cross the placenta and enter the fetus when given at recommended clinical doses. However, in vivo tests in animals have not shown any mutagenic or teratogenic effects from low-osmolality contrast media (American College of Radiology (ACR), 2010).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to diatrizoate meglumine and diatrizoate sodium during pregnancy in humans (Prod Info DA TSCAN(R) IV injection, 2011; Prod Info MD-Gastroview(R) oral, rectal solution, 2009; Prod Info GASTROGRAFIN(R) oral, rectal solution, 2007; Prod Info CYSTOGRAFIN(R) injection, 2006).
    B) PREGNANCY CATEGORY
    1) Ethiodized oil, diatrizoate meglumine and ioflupane I 123 are classified as FDA pregnancy category C (Prod Info LIPIODOL(R) intralymphatic injection, intrauterine injection, 2014; Prod Info CYSTOGRAFIN(R) injection, 2006; Prod Info DA TSCAN(R) IV injection, 2011).
    2) Diatrizoate meglumine/diatrizoate sodium is classified as FDA pregnancy category B (Prod Info MD-Gastroview(R) oral, rectal solution, 2009; Prod Info GASTROGRAFIN(R) oral, rectal solution, 2007).
    3) Due to the lack of human safety information, it is recommended that ethiodized oil be used in pregnant women only if clearly necessary. Iodine transfer resulting from the use of ethiodized oil during pregnancy may cause brain damage and permanent hypothyroidism. When used during pregnancy, closely monitor the neonate and test thyroid function (Prod Info LIPIODOL(R) intralymphatic injection, intrauterine injection, 2014).
    C) PLACENTAL BARRIER
    1) Diagnostic iodinated contrast media have shown an ability to cross the placenta and enter the fetus when given at recommended clinical doses. However, in vivo tests in animals have not shown any mutagenic or teratogenic effects from low-osmolality contrast media (American College of Radiology (ACR), 2010).
    2) DIATRIZOATE SALTS
    a) IV: Diatrizoate salts administered intravenously have been shown to cross the placenta and distribute evenly in fetal tissues (Prod Info MD-Gastroview(R) oral, rectal solution, 2009; Prod Info GASTROGRAFIN(R) oral, rectal solution, 2007).
    3) IOFLUPANE I 123
    a) Ioflupane I 123 has the potential to cause fetal harm since radioactive iodine products cross the placenta and can permanently impair fetal thyroid function. Ioflupane I 123 doses of 185 megabecquerels (5 millicuries) result in an absorbed radiation dose to the uterus of 0.3 rad (3 micrograys). Congenital anomalies have not been associated with radiation doses under 5 rad (50 micrograys) (Prod Info DA TSCAN(R) IV injection, 2011).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) DIATRIZOATE MEGLUMINE
    a) Following intravascular administration, diatrizoate meglumine has been shown to be excreted in human breast milk (Prod Info MD-Gastroview(R) oral, rectal solution, 2009; Prod Info GASTROGRAFIN(R) oral, rectal solution, 2007).
    b) Oral or rectal administration of diatrizoate meglumine may result in absorption of small amounts of enteral gastrointestinal radiopaque agents (Prod Info MD-Gastroview(R) oral, rectal solution, 2009; Prod Info GASTROGRAFIN(R) oral, rectal solution, 2007).
    2) IOFLUPANE I 123
    a) Although lactation studies have not been conducted with ioflupane I 123, iodine 123 is excreted in human milk. Because iodine 123 has a physical half-life of 13.2 hours, a nursing mother may consider interrupting nursing and pumping and discarding breast milk for 6 days after ioflupane I 123 administration (Prod Info DA TSCAN(R) IV injection, 2011).
    3) ETHIODIZED OIL
    a) Ethiodized oil is excreted in human breast milk. Because of a risk of hypothyroidism in nursing infants, avoid using ethiodized oil in nursing mothers. If the drug is continued while breastfeeding, monitor the infant's thyroid function (Prod Info LIPIODOL(R) intralymphatic injection, intrauterine injection, 2014).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects on fertility from exposure to ethiodized oil, diatrizoate meglumine, diatrizoate sodium, or ioflupane I 123 (Prod Info LIPIODOL(R) intralymphatic injection, intrauterine injection, 2014; Prod Info DA TSCAN(R) IV injection, 2011; Prod Info MD-Gastroview(R) oral, rectal solution, 2009; Prod Info GASTROGRAFIN(R) oral, rectal solution, 2007).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturers do not report any carcinogenic potential of diatrizoate meglumine/diatrizoate sodium, ethiodized oil, or ioflupane I 123.
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, the manufacturers do not report any carcinogenic potential of diatrizoate meglumine/diatrizoate sodium, ethiodized oil, or ioflupane I 123 (Prod Info LIPIODOL(R) intralymphatic injection, intrauterine injection, 2014; Prod Info DA TSCAN(R) IV injection, 2011).
    3.21.4) ANIMAL STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, the manufacturers do not report any carcinogenic potential of diatrizoate meglumine/diatrizoate sodium, ethiodized oil, or ioflupane I 123 in animals (Prod Info LIPIODOL(R) intralymphatic injection, intrauterine injection, 2014; Prod Info DA TSCAN(R) IV injection, 2011; Prod Info MD-Gastroview(R) oral, rectal solution, 2009; Prod Info GASTROGRAFIN(R) oral, rectal solution, 2007).

Genotoxicity

    A) DIATRIZOATE MEGLUMINE/DIATRIZOATE SODIUM
    1) At the time of this review, the manufacturer does not report any mutagenic potential of diatrizoate meglumine/diatrizoate sodium (Prod Info MD-Gastroview(R) oral, rectal solution, 2009; Prod Info GASTROGRAFIN(R) oral, rectal solution, 2007).
    B) ETHIODIZED OIL
    1) There was no evidence of mutagenicity in the following tests: in vitro bacterial reverse mutation assays, chromosomal aberration test in the in vitro mouse lymphoma assay, and in vivo micronucleus tests (Prod Info LIPIODOL(R) intralymphatic injection, intrauterine injection, 2014).
    C) IOFLUPANE I 123
    1) In vitro and in vivo mutagenicity studies of ioflupane I 123 revealed no evidence of genotoxicity or mutagenicity (Prod Info DA TSCAN(R) IV injection, 2011).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor liver and kidney function.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor kidney and renal function.
    B) LABORATORY INTERFERENCE
    1) Administration of this drug may interfere with thyroid-function tests. PBI (protein bound iodine) may be increased (USPDI, 1990).
    2) Trypsin activity, as measured by spectrophotometry, may be altered by the use of diatrizoate salts (Cowen et al, 1972).
    3) Copper-reduction tablet tests in urine may develop a black coloration when the test is used on patients treated with diatrizoates (Lee & Schoen, 1966).
    4) Phenolsulfonphthalein Excretion Test (PSP): Excretion of PSP may be reduced (USPDI, 1990).
    5) Coagulation Measures - Prothrombin time or INR and thromoplastin time may be increased because diatrizoates interfere with clotting at several stages (USPDI, 1990).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Monitor liver and kidney function.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Many of these substances are intended for parenteral use only. Those intended for enteral use are generally poorly absorbed. Gastrointestinal decontamination is rarely required.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Many of these substances are intended for parenteral use only. Those intended for enteral use are generally poorly absorbed. Gastrointestinal decontamination is rarely required.
    6.5.3) TREATMENT
    A) GENERAL TREATMENT
    1) There is no specific antidote or treatment. Renal failure and hemolysis are treated symptomatically.
    B) FLUID/ELECTROLYTE BALANCE REGULATION
    1) Ensure adequate hydration after ingestion of high osmolarity contrast agents.
    C) GENERAL TREATMENT
    1) Treatment should include recommendations listed in the PARENTERAL EXPOSURE section when appropriate.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

    A) SUMMARY
    1) Diatrizoates are removed by either peritoneal or hemodialysis (USPDI, 1990).
    B) HEMODIALYSIS
    1) Since radiocontrast media have small distribution volumes and little protein binding, it may be useful to consider hemodialysis as a method for the removal of contrast media (Bahlman et al, 1973) (Berg et al, 1998).

Range Of Toxicity

Summary

    A) No specific toxic dose has been established. Adverse reactions have occurred at therapeutic doses. A fatality occurred when a child was given 15.5 mL/kg. Two patients developed encephalopathy after receiving iopromide (120 to 150 mL) for coronary angioplasty.

Therapeutic Dose

    7.2.1) ADULT
    A) DIATRIZOATE MEGLUMINE
    1) Varies by indication and product: 0.5 to 300 mL (rarely, 600 mL) (Prod Info HYPAQUE-CYSTO(TM) injection, 2003; Prod Info HYPAQUE(TM) MEGLUMINE IV injection, 2002; Prod Info RENO-60(R) injection, 2003; Prod Info CYSTOGRAFIN(R) injection, 2003)
    B) ETHIODIZED OIL
    1) CERVICAL LYMPHOGRAPHY: 1 to 2 mL (Prod Info LIPIODOL(R) intralymphatic injection, intrauterine injection, 2014).
    2) ENDOMETRIAL CAVITY: Administer in increments of 2 mL until tubal patency is determined (Prod Info LIPIODOL(R) intralymphatic injection, intrauterine injection, 2014).
    3) PENILE LYMPHOGRAPHY: 2 to 3 mL (Prod Info LIPIODOL(R) intralymphatic injection, intrauterine injection, 2014).
    4) SELECTIVE HEPATIC INTRAARTERIAL INJECTION: Administer 1.5 to 15 mL slowly under continuous radiologic monitoring. Stop injection when stagnation or reflux are evident. MAX dose: 20 mL (Prod Info LIPIODOL(R) intralymphatic injection, intrauterine injection, 2014).
    5) UNILATERAL LYMPHOGRAPHY OF LOWER EXTREMITIES: 6 to 8 mL. Rate should not exceed 0.2 mL/min over a period of no less than 1.25 hours (Prod Info LIPIODOL(R) intralymphatic injection, intrauterine injection, 2014).
    6) UNILATERAL LYMPHOGRAPHY OF UPPER EXTREMITIES: 2 to 4 mL. Rate should not exceed 0.2 mL/min over a period of no less than 1.25 hours (Prod Info LIPIODOL(R) intralymphatic injection, intrauterine injection, 2014).
    7.2.2) PEDIATRIC
    A) DIATRIZOATE MEGLUMINE
    1) DIATRIZOATE MEGLUMINE: Varies by indication, product, and patient's weight: 0.5 to 180 mL (Prod Info HYPAQUE(TM) MEGLUMINE IV injection, 2002; Prod Info HYPAQUE-CYSTO(TM) injection, 2003; Prod Info RENO-60(R) injection, 2003).
    B) ETHIODIZED OIL
    1) LYMPHOGRAPHY: The recommended dose is at least 1 mL to a maximum of 6 mL based on the anatomic area to be visualized. MAX dose: 0.25 mL/kg (Prod Info LIPIODOL(R) intralymphatic injection, intrauterine injection, 2014).

Minimum Lethal Exposure

    A) CASE REPORTS
    1) A dose of 15.5 milliliters per kilogram given during aortography to a 7-year-old, 22 kilogram child led to retinal hemorrhages, brain edema, and death (Junck & Marshall, 1986).
    2) Ten milliliters was injected into the uterus of a 119 kilogram woman. She developed bradycardia, then cardiac arrest. Resuscitation was not successful (Edelstein, 1986).

Maximum Tolerated Exposure

    A) IOPROMIDE: Two patients developed encephalopathy after receiving iopromide for coronary angioplasty. The first patient, a 47-year-old man with a diagnosis of acute anterior myocardial infarction, developed confusion, agitation, nausea and headache about 1 hour after coronary angioplasty using 150 mL of iopromide. A CT of the brain showed extravascular localized contrast media in the sagittal sinus (inferior and superior) and occipital lobe. Following supportive care, his symptoms normalized within 8 hours. Another patient, a 70-year-old man with a history of diabetes mellitus and a diagnosis of subacute inferior myocardial infarction, developed nausea and confusion within 1 hour of receiving 120 mL of iopromide during coronary angioplasty. A CT scan of the brain showed extravascular localized contrast media in sagittal sinus and occipital lobe. He recovered after 12 hours of supportive care (Kocabay & Karabay, 2011).

Toxicity Information

    7.7.1) TOXICITY VALUES

Pharmacology Toxicology

Pharmacologic Mechanism

    A) RADIOLOGY - The iodine in the compounds is radiopaque, and allows the visualization of body structures using X-rays (USPDI, 1990).
    B) MECONIUM ILEUS - Works as an osmotic agent, drawing fluids into the intestine and dislodging the meconium impaction (USPDI, 1990).
    C) OSMOLALITY - Reducing the osmolality of various contrast media has produced a reduction in toxicity (Dawson, 1990).

Toxicologic Mechanism

    A) NEPHROTOXICITY - The mechanism of contrast media-induced nephrotoxicity is not completely understood. Contrast media are believed to initially cause natriuresis and increase the metabolic rate and oxygen demand in the loop of Henle (Gerlach & Pickworth, 2000). Contrast media can also increase the generation of adenosine and endothelin, causing vasoconstriction the afferent arteriole, reducing renal blood flow and glomerular filtration rate and inducing renal ischemia (reviewed in Pflueger et al, 2000). The increase in blood viscosity caused by radiographic contrast media may exacerbate renal ischemia.

Physicochemical

Physical Characteristics

    A) DIATRIZOATE MEGLUMINE is a clear to pale yellow, slightly viscous liquid (Prod Info HYPAQUE-CYSTO(TM) injection, 2003) with a slightly sweet taste, is soluble in water (89 g/100 mL), and has a melting point of 189 to 193 degrees C (Budavari, 1989).
    B) DIATRIZOATE MEGLUMINE/DIATRIZOATE SODIUM:
    1) HYPAQUE(TM)-76 IV solution has an osmolality of 2016 mOsm/kg (determined by VPO), and a viscosity of 9 cp at 37 degrees C (Prod Info HYPAQUE(TM) -76 IV injection, 2002).
    2) RENOCAL-76(R) IV solution has an osmolality of 1870 mOsm/kg, and a viscosity of 15 cps at 25 degrees C and 9.1 cps at 37 degrees C (Prod Info RENOCAL-76(R) injection, 2000).
    C) DIATRIZOATE SODIUM is a white powder without odor and a clear to pale yellow, slightly viscous liquid with a slightly salty taste; is soluble in water (60 g/100 mL), slightly soluble in alcohol, and almost insoluble in acetone and ether (Prod Info HYPAQUE(TM) SODIUM IV injection, 2002; USPDI, 1990; JEF Reynolds , 1990; Budavari, 1989); 50% parenteral solution: osmolality of 1515 mOsm/kg (determined by VPO), and a viscosity of about 3.25 cp at 25 degrees C and 2.34 cp at 37 degrees C (Prod Info HYPAQUE(TM) SODIUM IV injection, 2002).
    D) ETHIODIZED OIL is a clear, pale yellow to amber colored oil with a viscosity of 34 to 70 mPa s at 20 degrees C and a density of 1.28 g/cm(3) at 20 degrees C (Prod Info LIPIODOL(R) intralymphatic injection, intrauterine injection, 2014).
    E) IOFLUPANE I 123 is a clear, colorless solution (Prod Info DA TSCAN(R) IV injection, 2011).
    F) OSMOLALITY AND VISCOSITY:
    1) The osmolality of the injection with iodine concentration of 370 mg/mL ranges from 1940 to 2140 mOsm/kg of water, depending on the product (Hirshfeld, 1990; Swanson, 1990).

Ph

    A) DIATRIZOATE MEGLUMINE/DIATRIZOATE SODIUM:
    1) INJECTION: 6 to 7.7 (Prod Info HYPAQUE(TM) -76 IV injection, 2002; Prod Info RENOCAL-76(R) injection, 2000; Prod Info RENOGRAFIN(R) -60 injection, 2003)
    2) ORAL AND RECTAL SOLUTION: 6 to 7.6 (Prod Info MD-Gastroview(R) oral, rectal solution, 2009; Prod Info GASTROGRAFIN(R) oral, rectal solution, 2007)
    B) DIATRIZOATE SODIUM: 6.5 to 7.7 (50% parenteral solution) (Prod Info HYPAQUE(TM) SODIUM IV injection, 2002)
    C) IOFLUPANE I 123: 4.2 to 5.2 (Prod Info DA TSCAN(R) IV injection, 2011)

Molecular Weight

    A) DIATRIZOATE MEGLUMINE: 809.13 (Prod Info GASTROGRAFIN(R) oral, rectal solution, 2007)
    B) DIATRIZOATE SODIUM: 635.9 (Prod Info GASTROGRAFIN(R) oral, rectal solution, 2007)

References

General Bibliography

    1) AMA Department of DrugsAMA Department of Drugs: AMA Evaluations Subscription, American Medical Association, Chicago, IL, 1992.
    2) Addiego JE, Ridgway D, & Bleyer WA: The acute management of intrathecal methotrexate overdose: pharmacologic rationale and guidelines. J Pediatr 1981; 98(5):825-828.
    3) Ahmed I, Pepple R, & Jones RP: Absence status epilepticus resulting from metrizamide and omnipaque myelography. Clin Electroenceph 1988; 19:37-42.
    4) American College of Radiology (ACR): Manual on contrast media, v.7. American College of Radiology (ACR). Reston, VA. 2010. Available from URL: http://www.acr.org/SecondaryMainMenuCategories/quality_safety/contrast_manual/FullManual.aspx. As accessed 2010-06-21.
    5) American Heart Association: 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2005; 112(24 Suppl):IV 1-203. Available from URL: http://circ.ahajournals.org/content/vol112/24_suppl/. As accessed 12/14/2005.
    6) Ansell G: (Letter). Br Med J 1970; 3:707.
    7) Ansell G: A national survey of radiological complications. Interim report. Clin Radiol 1968; 19:175.
    8) Aron NB, Feinfeld DA, & Peters AT: Acute renal failure associated with ioxaglate, a low-osmolality radiocontrast agent. Am J Kidn Dis 1989; 13:189-193.
    9) Artigas A, Bernard GR, Carlet J, et al: The American-European consensus conference on ARDS, part 2: ventilatory, pharmacologic, supportive therapy, study design strategies, and issues related to recovery and remodeling.. Am J Respir Crit Care Med 1998; 157:1332-1347.
    10) Banerjee A, Brotherston TM, Lamberty BG, et al: Cancer chemotherapy agent-induced perivenous extravasation injuries. Postgrad Med J 1987; 63(735):5-9.
    11) Batsakis JG: Brain damage following Urokon injection in the brachial artery: report of a case. Univ Mich Med Bull 1957; 23:45-52.
    12) Baum JL & Bierstock SR: Peripheral corneal infiltrates following intravenous injection of diatrizoate meglumine. Am J Ophthalmol 1978; 85:613-614.
    13) Bellin MF, Jakobsen JA, Tomassin I, et al: Contrast medium extravasation injury: guidelines for prevention and management. Eur Radiol 2002; 12(11):2807-2812.
    14) Benchimol A & McNally EM: Hemodynamic and electrocardiographic effects of selective coronary angiography in men. New Engl J Med 1966; 274:1217-1224.
    15) Berg KJ, Rolfsen B, & Stake G: Iodixanol is readily eliminated by hemodialysis. Acta Radiologica 1998; 39:372-374.
    16) Blaney SM, Poplack DG, Godwin K, et al: Effect of body position on ventricular CSF methotrexate concentration following intralumbar administration. J Clin Oncol 1995; 13(1):177-179.
    17) Bohn HP, Reich L, & Suljaga-Petchel K: Inadvertent intrathecal use of ionic contrast media for myelography. AJNR Am J Neuroradiol 1992; 13(6):1515-1519.
    18) Brezis M & Epstein FH: A closer look at radiocontrast-induced nephropathy. N Eng J Med 1989; 320:179-181.
    19) Brophy GM, Bell R, Claassen J, et al: Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17(1):3-23.
    20) Brower RG, Matthay AM, & Morris A: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Eng J Med 2000; 342:1301-1308.
    21) Brown AS, Hoelzer DJ, & Piercy SA: Skin necrosis from extravasation of intravenous fluids in children. Plast Reconstr Surg 1979; 64(2):145-150.
    22) Budavari S: The Merck Index, 11th ed, Merck & Company, Rahway, NJ, 1989.
    23) Burgess JL, Kirk M, Borron SW, et al: Emergency department hazardous materials protocol for contaminated patients. Ann Emerg Med 1999; 34(2):205-212.
    24) Bush WH: Treatment of systemic reactions to contrast media. Urology 1990; 35:145-150.
    25) Cataletto M: Respiratory Distress Syndrome, Acute(ARDS). In: Domino FJ, ed. The 5-Minute Clinical Consult 2012, 20th ed. Lippincott Williams & Wilkins, Philadelphia, PA, 2012.
    26) Cattell WR, Fry IK, & Spencer AG: Excretion urography I. Factors determining the excretion of hypaque. Br J Radiol 1967; 40:561-571.
    27) Catterall JR, Ferguson RJ, & Miller HC: Intravascular haemolysis with acute renal failure after angiocardiography. Br Med J 1981; 282:779-780.
    28) Cedgard S, Herlitz H, & Geterud K: Acute renal insufficiency after administration of low-osmolar contrast media (letter). Lancet 1986; 2:1281.
    29) Chait LA & Dinner MI: Ulceration caused by cytotoxic drugs. SA Med J 1975; 49:1935-1936.
    30) Chamberlain JM, Altieri MA, & Futterman C: A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Ped Emerg Care 1997; 13:92-94.
    31) Chandra R & Abraham J: Preliminary studies on in vitro and in vivo effects of 50 per cent hypaque on coagulation in man. Angiology 1973; 24:199-204.
    32) Chang JC, Lee D, & Gross HM: Acute thrombocytopenia after IV administration of a radiographic contrast medium. AJR 1989; 152:947-949.
    33) Charlton NP , Lawrence DT , Brady WJ , et al: Termination of drug-induced torsades de pointes with overdrive pacing. Am J Emerg Med 2010; 28(1):95-102.
    34) Chin RF , Neville BG , Peckham C , et al: Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study. Lancet Neurol 2008; 7(8):696-703.
    35) Chiu CL & Gambach RR: Hypaque pulmonary edema. Radiology 1974; 111:91.
    36) Choonara IA & Rane A: Therapeutic drug monitoring of anticonvulsants state of the art. Clin Pharmacokinet 1990; 18:318-328.
    37) Cissoko H, Lemesle F, & Jonville-Bera AP: Aseptic meningitis after iohexol myelography (letter). Ann Pharmacotherapy 2000; 34:812-813.
    38) Clark F: Adverse Drug React Bull 1977; 232.
    39) Cohan RH, Ellis JH, & Garner WL: Extravasation of radiographic contrast material: recognition, prevention, and treatment. Radiology 1996; 200(3):593-604.
    40) Cohen LS: Hemolysis and hemoglobinuria following angiography. Radiol 1969; 92:329-332.
    41) Cowen AE, McGeary HM, & Campbell CP: Interference by gastrografin with a spectrophotometric trypsin assay. Gut 1972; 13:395-397.
    42) Creteur V, Douglas D, & Galante M: Inflammatory colonic changes produced by contrast material. Radiology 1983; 147:77-78.
    43) Davidson CJ, Hlatky M, & Morris KG: Cardiovascular and renal toxicity of a nonionic radiographic contrast agent after cardiac catheterization. Ann Int Med 1989; 110:119-124.
    44) Davies P, Roberts MB, & Roylance J: Acute reactions to urographic contrast media. Br Med J 1975; 2:434-437.
    45) Dawson P: Iodinated intravascular contrast agents past and present: toxicity considerations. Invest Radiol 1990; 25:S11.
    46) Dorr RT & Fritz WL: Cancer Chemotherapy Handbook, Elsevier, New York, NY, 1980.
    47) Dotter CT: Contrast substances for angiocardiography: study of side effects. Radiol 1953; 60:691-698.
    48) Drew BJ, Ackerman MJ, Funk M, et al: Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of Cardiology Foundation. J Am Coll Cardiol 2010; 55(9):934-947.
    49) Edelstein JM: Sudden death associated with contrast medium, Sinografin(R). J For Sci 1986; 31:1142-1144.
    50) Edelstein JM: Sudden death following administration of radio contrast media. J Foren Sci 1988; 33:734-737.
    51) Elliott C & Reger M: Acute renal failure following low osmolality radiocontrast dye. Clin Cardiol 1988; 11(6):420-422.
    52) Erffmeyer JE, Siegle RL, & Lieberman P: Anaphylactoid reactions to radiocontrast material. J All Clin Immunol 1985; 75:401-410.
    53) Frech RS, Davie JM, & Adatepe M: Comparison of barium sulfate and oral 40% diatrizoate injected into the trachea of dogs. Radiology 1970; 95:299.
    54) Friedman BI, Hartenber MA, & Mulroy JJ: Gastrografin aspiration in a 3 3/4-year-old girl. Pediatr Radiol 1986; 16:506-507.
    55) Gerlach AT & Pickworth KK: Contrast medium-induced nephrotoxicity: pathophysiology and prevention. Pharmacotherapy 2000; 20:540-548.
    56) Goldfinger TM & Hoekenga DE: Torsades de pointes immediately following right coronary arteriography. Catheter Cardiovasc Diagn 1986; 12:107-109.
    57) Gosselin S & Isbister GK: Re: Treatment of accidental intrathecal methotrexate overdose. J Natl Cancer Inst 2005; 97(8):609-610.
    58) Grant WM: Toxicology of the Eye, 3rd ed, Charles C Thomas, Springfield, IL, 1986.
    59) Haas CF: Mechanical ventilation with lung protective strategies: what works?. Crit Care Clin 2011; 27(3):469-486.
    60) Harkonen S & Kjellstrand C: Contrast nephropathy. Am J Nephrol 1981; 1:69-77.
    61) Hartman GW, Hattery RR, & Witten DM: Mortality during excretory urography. Mayo Clinic experience. Am J Roetgenology 1982; 139:919-922.
    62) Haslam RHA, Cochrane DD, & Amundson GM: Neurotoxic complications of contrast computed tomography in children. J Pediatr 1987; 111:837-840.
    63) Hegenbarth MA & American Academy of Pediatrics Committee on Drugs: Preparing for pediatric emergencies: drugs to consider. Pediatrics 2008; 121(2):433-443.
    64) Heydenreich G & Larsen PO: Iododerma after high dose urography in an oliguric patient. Br J Derm 1977; 97:567-569.
    65) Hirsh JD & Conlon PF: Implementing guidelines for managing extravasation of antineoplastics. Am J Hosp Pharm 1983; 40:1516-1519.
    66) Hirshfeld JW: Cardiovascular effects of iodinated contrast agents.. Am J Cardiol 1990; 66:9F-17F.
    67) Hoff JV, Beatty PA, & Wade JL: Dermal necrosis from dobutamine. N Engl J Med 1979; 300:1280.
    68) Hvidberg EF & Dam M: Clinical pharmacokinetics of anticonvulsants. Clin Pharmacokinet 1976; 1:161.
    69) Ignoffo RJ & Friedman MA: Therapy of local toxicities caused by extravasation of cancer chemotherapeutic drugs. Cancer Treat Rev 1980; 7(1):17-27.
    70) JEF Reynolds : Martindale: The Extra Pharmacopoeia (electronic version). The Pharmaceutical Press. London, UK (Internet Version). Edition expires 1990; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    71) Junck L & Marshall WH: Fatal brain edema after contrast agent overdose. AJNR 1986; 7:522-525.
    72) Junck L & Marshall WH: Neurotoxicity of radiological contrast agents. Ann Neurol 1983; 13:469-484.
    73) Kaftori JK, Abraham Z, & Gilhar A: Toxic epidermal necrolysis after excretory pyelography: immunologic-mediated contrast medium reaction?. Intl J Dermatol 1988; 27:346-347.
    74) Karino S & Fukaya T: Sudden hearing loss following drip intravenous pyelography with iohexol: a case report. Auris Nasus Larynx 2001; 28:95-97.
    75) Katayama H: Adverse reactions to contrast media: what are the risk factors?. Invest Radiol 1990; 25:S16-S17.
    76) Keren A, Tzivoni D, & Gavish D: Etiology, warning signs and therapy of torsade de pointes: a study of 10 patients. Circulation 1981; 64:1167-1174.
    77) Khan IA & Gowda RM: Novel therapeutics for treatment of long-QT syndrome and torsade de pointes. Int J Cardiol 2004; 95(1):1-6.
    78) Killeffer JA & Kaufman HH: Inadvertent intraoperative myelography with Hypaque: case report and discussion. Surg Neurol 1997; 48(1):70-73.
    79) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    80) Kocabay G & Karabay CY : Iopromide-induced encephalopathy following coronary angioplasty. Perfusion 2011; 26(1):67-70.
    81) Koehler PJ, Endtz LJ, & Bakker PBD: Transient global amnesia after coronary angiography. Clin Cardiol 1986; 9:170-171.
    82) Kollef MH & Schuster DP: The acute respiratory distress syndrome. N Engl J Med 1995; 332:27-37.
    83) Kone BC, Watson AJ, & Gimenez LF: Acute renal failure following percutaneous transhepatic cholangiography. Arch Intern Med 1986; 146:1405-1407.
    84) Lalli AF: Contrast media reactions. Data analysis & hypothesis. Radiology 1980; 34(1):1-12.
    85) Larson DL: Treatment of tissue extravasation by antitumor agents. Cancer 1982; 49:1796-1799.
    86) Lasser EC: Sialadenopathy due to cholecystographic contrast media (letter). JAMA 1969; 207:2291-2292.
    87) Lee S & Schoen I: Black-copper reduction reaction simulating alkaptonuria. Occurrence after intravenous urography. N Engl J Med 1966; 275:266-267.
    88) Leung PC & Cheng CY: Extensive local necrosis following the intravenous use of X-ray contrast medium in the upper extremity. Br J Radiol 1980; 53:361-364.
    89) Levey AI, Weiss H, & Yu R: Seizures following myelography with iopamidol. Ann Neurol 1988; 23:397-398.
    90) Levine RA & Henry MD: Ischemic infarction of the retina. Am J Ophthalmol 1963; 55:365-367.
    91) Lieberman P, Nicklas R, Randolph C, et al: Anaphylaxis-a practice parameter update 2015. Ann Allergy Asthma Immunol 2015; 115(5):341-384.
    92) Lieberman P, Nicklas RA, Oppenheimer J, et al: The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol 2010; 126(3):477-480.
    93) Link MS, Berkow LC, Kudenchuk PJ, et al: Part 7: Adult Advanced Cardiovascular Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2015; 132(18 Suppl 2):S444-S464.
    94) Lockman P, Marchbanks B, & Shum S: Inadvertent intrathecal administration of Hypaque(R) (abstract). J Tox Clin Tox 1999; 37:602.
    95) Loddenkemper T & Goodkin HP: Treatment of Pediatric Status Epilepticus. Curr Treat Options Neurol 2011; Epub:Epub.
    96) Loth TS & Eversmann WW Jr: Treatment methods for extravasation of chemotherapeutic agents. J Hand Surg 1986; 388-396.
    97) Lynch DJ, Key JC, & White RR: Management and prevention of infiltration and extravasation injury. Surg Clin North Am 1979; 59:939-949.
    98) Manno EM: New management strategies in the treatment of status epilepticus. Mayo Clin Proc 2003; 78(4):508-518.
    99) Maruyama K, Setoguchi Y, Maruyama J, et al: Intrathecal injection of high-dose meglumine amidotrizoate with complete recovery. Intensive Care Med 1993; 19(4):232-234.
    100) McAlister WH & Askin FB: The effect of some contrast agents in the lung: an experimental study in the rat and dog. AJR 1983; 140:245.
    101) Meggs WJ & Hoffman RS: Fatality resulting from intraventricular vincristine administration. J Toxicol Clin Toxicol 1998; 36(3):243-246.
    102) Misson RT & Cutler RE: Radiocontrast-induced renal failure. West J Med 1985; 142:657-664.
    103) Myers GE & Bloom FL: Cimetidine (Tagamet) combined with steroids and H1 antihistamines for the prevention of serious radiographic contrast material reactions. Catheter Cardiovasc Diag 1981; 7:65-69.
    104) NHLBI ARDS Network: Mechanical ventilation protocol summary. Massachusetts General Hospital. Boston, MA. 2008. Available from URL: http://www.ardsnet.org/system/files/6mlcardsmall_2008update_final_JULY2008.pdf. As accessed 2013-08-07.
    105) Nakazawa K, Yoshinari M, & Kinefuchi S: Inadvertent intrathecal administration of amidetrizoate. Inten Care Med 1988; 15:55-57.
    106) Naradzay J & Barish RA: Approach to ophthalmologic emergencies. Med Clin North Am 2006; 90(2):305-328.
    107) National Heart,Lung,and Blood Institute: Expert panel report 3: guidelines for the diagnosis and management of asthma. National Heart,Lung,and Blood Institute. Bethesda, MD. 2007. Available from URL: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.
    108) National Institutes of Health Clinical Center Nursing Department: SOP: care of the patient receiving intravenous cytotoxics or biological agents. NIH. Bethesda, MDAvailable from URL: http://www.cc.nih.gov/nursing/ivctxsop.html.
    109) Neumar RW , Otto CW , Link MS , et al: Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122(18 Suppl 3):S729-S767.
    110) Nicot GS, Merle LJ, & Charmes JP: Transient glomerular proteinuria, enzymuria, and nephrotoxic reaction induced by radiocontrast media. JAMA 1984; 252:2432-2434.
    111) Nowak RM & Macias CG : Anaphylaxis on the other front line: perspectives from the emergency department. Am J Med 2014; 127(1 Suppl):S34-S44.
    112) O'Marcaigh AS, Johnson CM, & Smithson WA: Successful treatment of intrathecal methotrexate overdose by using ventriculolumbar perfusion and trathecal instillation of carboxypeptidase G2. Mayo Clin Proc 1996; 71:161-165.
    113) Palmer J: Morbidity and mortality with intravenous contrast media: ionic and nonionic. Invest Radiol 1990; 25:S18-S19.
    114) Peate WF: Work-related eye injuries and illnesses. Am Fam Physician 2007; 75(7):1017-1022.
    115) Peberdy MA , Callaway CW , Neumar RW , et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Part 9: post–cardiac arrest care. Circulation 2010; 122(18 Suppl 3):S768-S786.
    116) Perticone F, Ceravolo R, & Cuccurullo O: Prolonged magnesium sulfate infusion in the treatment of ventricular tachycardia in acquired long QT syndrome. Clin Drug Inverst 1997; 13:229-236.
    117) Pflueger A, Larson TS, & Nath KA: Role of adenosine in contrast media-induced acute renal failure. Mayo Clin Proc 2000; 75:1275-1283.
    118) Product Information: CYSTOGRAFIN(R) injection, diatrizoate meglumine, 30% injection. Bracco Diagnostics,Inc, Princeton, NJ, 2003.
    119) Product Information: CYSTOGRAFIN(R) injection, diatrizoate meglumine 30% injection. Bracco Diagnostics Inc, Princeton, NJ, 2006.
    120) Product Information: Cordarone(R) oral tablets, amiodarone HCl oral tablets. Wyeth Pharmaceuticals Inc (per FDA), Philadelphia, PA, 2015.
    121) Product Information: DA TSCAN(R) IV injection, ioflupane I 123 IV injection. GE Healthcare, Arlington Heights, IL, 2011.
    122) Product Information: GASTROGRAFIN(R) oral, rectal solution, diatrizoate meglumine and diatrizoate sodium oral, rectal solution. Bracco Diagnostics Inc, Princeton, NJ, 2007.
    123) Product Information: HYPAQUE(TM) -76 IV injection, diatrizoate meglumine, diatrizoate sodium 76% IV injection. Amersham Health,Inc, Princeton, NJ, 2002.
    124) Product Information: HYPAQUE(TM) MEGLUMINE IV injection, diatrizoate meglumine, 60% IV injection. Amersham Health,Inc, Princeton, NJ, 2002.
    125) Product Information: HYPAQUE(TM) SODIUM IV injection, diatrizoate sodium, 50% IV injection. Amersham Health,Inc, Princeton, NJ, 2002.
    126) Product Information: HYPAQUE-CYSTO(TM) injection, diatrizoate meglumine, 30% injection. Amersham Health,Inc, Princeton, NJ, 2003.
    127) Product Information: Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, isoproterenol HCl intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection. Hospira, Inc. (per FDA), Lake Forest, IL, 2013.
    128) Product Information: LIPIODOL(R) intralymphatic injection, intrauterine injection, ethiodized oil intralymphatic injection, intrauterine injection. Guerbet LLC (per FDA), Bloomington, IN, 2014.
    129) Product Information: Lidocaine HCl intravenous injection solution, lidocaine HCl intravenous injection solution. Hospira (per manufacturer), Lake Forest, IL, 2006.
    130) Product Information: MD-Gastroview(R) oral, rectal solution, diatrizoate meglumine and diatrizoate sodium oral, rectal solution. Mallinckrodt Inc, St. Louis, MO, 2009.
    131) Product Information: NITROPRESS(R) injection for IV infusion, Sodium Nitroprusside injection for IV infusion. Hospira, Inc., Lake Forest, IL, 2007.
    132) Product Information: NITROPRESS(R) injection, sodium nitroprusside injection. Hospira,Inc, Lake Forest, IL, 2004.
    133) Product Information: RENO-60(R) injection, diatrizoate meglumine, 60% injection. Bracco Diagnostics,Inc, Princeton, NJ, 2003.
    134) Product Information: RENOCAL-76(R) injection, diatrizoate meglumine, diatrizoate sodium injection. Bracco Diagnostics,Inc, Princeton, NJ, 2000.
    135) Product Information: RENOGRAFIN(R) -60 injection, diatrizoate meglumine, diatrizoate sodium injection. Bracco Diagnostics,Inc, Princeton, NJ, 2003.
    136) Product Information: ULTRAVIST(R) intravenous injection, intra-arterial injection, iopromide intravenous injection, intra-arterial injection. Bayer HealthCare Pharmaceuticals Inc. (per FDA), Wayne, NJ, 2012.
    137) Product Information: diazepam IM, IV injection, diazepam IM, IV injection. Hospira, Inc (per Manufacturer), Lake Forest, IL, 2008.
    138) Product Information: diphenhydramine HCl intravenous injection solution, intramuscular injection solution, diphenhydramine HCl intravenous injection solution, intramuscular injection solution. Hospira, Inc. (per DailyMed), Lake Forest, IL, 2013.
    139) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    140) Product Information: lorazepam IM, IV injection, lorazepam IM, IV injection. Akorn, Inc, Lake Forest, IL, 2008.
    141) Product Information: magnesium sulfate heptahydrate IV, IM injection, solution, magnesium sulfate heptahydrate IV, IM injection, solution. Hospira, Inc. (per DailyMed), Lake Forest, IL, 2009.
    142) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    143) Rao AK, Thompson R, & Durlacher L: Angiographic contrast agent-induced acute hemolysis in a patient with hemoglobin SC disease. Arch Intern Med 1985; 145:759-760.
    144) Reich SB: Production of pulmonary edema by aspiration of water soluble nonabsorbable contrast media. Radiology 1969; 92:367.
    145) Rhee CM, Bhan I, Alexander EK, et al: Association between iodinated contrast media exposure and incident hyperthyroidism and hypothyroidism. Arch Intern Med 2012; 172(2):153-159.
    146) Rosado A, Canto G, & Veleiro B: Toxic epidermal necrolysis aftr repeated injections of iohexol. AJR 2001; 176:262-263.
    147) Rosati G, LetodiPriolo S, & Tirone P: Serious or fatal complications after inadvertent administration of ionic water-soluble contrast media in myelography. Eur J Radiol 1992; 15(2):95-100.
    148) Salvolini U, Bonetti MG, & Ciritella P: Accidental intrathecal injection of ionic water-soluble contrast medium: report of a case, including treatment. Neuroradiology 1996; 38(4):349-351.
    149) Schaverien MV, Evison D, & McCulley SJ: Management of large volume CT contrast medium extravasation injury: technical refinement and literature review. J Plast Reconstr Aesthet Surg 2008; 61(5):562-565.
    150) Schulze B & Kaps HP: Arzneimittelforschung 1977; 27:972.
    151) Scott R, Besag FMC, & Neville BGR: Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomized trial. Lancet 1999; 353:623-626.
    152) Sharp S, Stone J, & Beach R: Contrast agent neurotoxicity presenting as subarachnoid hemorrhage. Neurology 1999; 52:1503-1505.
    153) Simon RA, Schatz M, & Stevenson DD: Radiographic contrast media infusions. Measurement of histamine, complement, and fibrin split products and correlation with clinical parameters. J Allergy Clin Immunol 1979; 63:281-288.
    154) Smith WM & Gallagher JJ: "Les torsades de pointes": an unusual ventricular arrhythmia. Ann Intern Med 1980; 93:578-584.
    155) Sparrow GP: Iododerma due to radiographic contrast medium. J Roy Soc Med 1979; 72:60-61.
    156) Sreenath TG, Gupta P, Sharma KK, et al: Lorazepam versus diazepam-phenytoin combination in the treatment of convulsive status epilepticus in children: A randomized controlled trial. Eur J Paediatr Neurol 2009; Epub:Epub.
    157) Stein HL & Hilgartner MW: Alteration of coagulation mechanism of blood by contrast media. Am J Roentgenol, Rad Ther & Nucl Med 1968; 104:458-463.
    158) Stolbach A & Hoffman RS: Respiratory Principles. In: Nelson LS, Hoffman RS, Lewin NA, et al, eds. Goldfrank's Toxicologic Emergencies, 9th ed. McGraw Hill Medical, New York, NY, 2011.
    159) Swanson: Pharmaceuticals in medical imaging., Macmillan Publishing Company, New York, 1990, pp 1-35, 42, 95-97.
    160) Taenzer V, Koeppe P, & Samwer KF: Comparative pharmacokinetics of sodium -and methylglucamine diatrizoate in urography. Eur J Clin Pharmacol 1973; 6:137-140.
    161) Tartiere J, Gerard JL, Peny J, et al: Acute treatment after accidental intrathecal injection of hypertonic contrast media. Anesthesiology 1989; 71(1):169-169.
    162) Tepel M, van der Giet M, & Schwarzfeld C: Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Eng J Med 2000; 343:180-184.
    163) The University of Kansas Hospital: Guide to extravasation management in adult & pediatric patients. The University of Kansas Hospital. Kansas City, KS. 2009. Available from URL: http://www2.kumc.edu/pharmacy/guidelines/Extravasations%20diagram.pdf. As accessed 2012-09-11.
    164) Thomsen HS & Bush WH: Adverse effects of contrast media: incidence, prevention, and management. Drug Safety 1998; 19:313-324.
    165) Thomsen HS & Bush WH: Treatment of the adverse effects of contrast media. Acta Radiologica 1998a; 39:212-218.
    166) Tonolini M, Campari A, & Bianco R: Extravasation of radiographic contrast media: prevention, diagnosis, and treatment. Curr Probl Diagn Radiol 2012; 41(2):52-55.
    167) Tsai YS, Cheng SM, Ng SP, et al: Squeeze maneuver: an easy way to manage radiological contrast-medium extravasation. Acta Radiol 2007; 48(6):605-607.
    168) USPDI: Drug Information for the Health Care Professional, 10th ed, US Pharmaceutical Convention, Inc, Rockville, MD, 1990.
    169) Upton J, Mulliken JB, & Murray JE: Major intravenous extravasation injuries. Am J Surg 1979; 137(4):497-506.
    170) Upton J, Mulliken JB, & Murray JE: Major intravenous extravasation injuries. Am J Surg 1979a; 137:497-506.
    171) Vanden Hoek TL, Morrison LJ, Shuster M, et al: Part 12: cardiac arrest in special situations: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122(18 Suppl 3):S829-S861.
    172) Vanden Hoek,TL; Morrison LJ; Shuster M; et al: Part 12: Cardiac Arrest in Special Situations 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. American Heart Association. Dallas, TX. 2010. Available from URL: http://circ.ahajournals.org/cgi/reprint/122/18_suppl_3/S829. As accessed 2010-10-21.
    173) Wallers K & Chaudhuri AKR: Severe meningeal irritation after intrathecal injection of iopamidol. Br Med J 1985; 291:1688.
    174) Weinrauch LA, Healy RW, & Leland OS Jr: Coronary angiography and acute renal failure in diabetic azotemic nephropathy. Ann Intern Med 1977; 86:56-59.
    175) Wengstrom Y, Margulies A, & European Oncology Nursing Society Task Force: European Oncology Nursing Society extravasation guidelines. Eur J Oncol Nurs 2008; 12(4):357-361.
    176) Widemann BC, Balis FM, Shalabi A, et al: Treatment of accidental intrathecal methotrexate overdose with intrathecal carboxypeptidase G2. J Nat Cancer Inst 2004; 96(20):1557-1559.
    177) Willson DF, Truwit JD, Conaway MR, et al: The adult calfactant in acute respiratory distress syndrome (CARDS) trial. Chest 2015; 148(2):356-364.
    178) Wilson DF, Thomas NJ, Markovitz BP, et al: Effect of exogenous surfactant (calfactant) in pediatric acute lung injury. A randomized controlled trial. JAMA 2005; 293:470-476.
    179) Wise GR: Vasopressor-drug therapy for complications of cerebral arteriography. New Engl J Med 1970; 282:610-612.
    180) Witten DM: Reactions to urographic contrast media. JAMA 1975; 231:974-977.
    181) Yamaguchi K, Katayama H, & Kozuka T: Pretesting as a predictor of severe adverse reactions to contrast media. Invest Radiol 1990; 25:S22-S23.
    182) Yosowitz P, Ekland DA, & Shaw RC: Peripheral intravenous infiltration necrosis. Ann Surg 1975; 182:553-556.
    183) de Caen AR, Berg MD, Chameides L, et al: Part 12: Pediatric Advanced Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2015; 132(18 Suppl 2):S526-S542.
    184) vanderLeede H, Jorens PG, Parizel P, et al: Inadvertent intrathecal use of ionic contrast agent. Eur Radiol 2002; 12(Suppl 3):S86-S93.