LOW OSMOLAR CONTRAST MEDIA A Review

LOW OSMOLAR CONTRAST MEDIA A Review

RUTH DENNIS, MA, VET. MB, MICHAEL E. HERRTAGE, MA, BVSc

Conventional water-soluble iodine-containing contrast media such as salts of diatrizoic and iothalamic acids dissociate in solution resulting in preparations which are very high in osmolality. Intravascular or intrathecal injections of these compounds therefore represent a severe physicochemical insult to the body, with many associated side effects. Contrast media with lower osmolalities have been produced in two ways: first by producing compounds which do not dissociate in solution (metrizamide, and more recently iopamidol and iohexol), and second by creating dimers (ioxaglate). These media provide significant clinical advantages over the conventional, hyperosmolar media. A new class of nonionizing dimers with even lower osmolalities are currently being investigated. This paper reviews the development of the low osmolar media, their advantages, and their use in medical and veterinary radiology. Veterinary Radiology, Vol. 30, No. 1 , 1 9 8 9 ; ~ ~ 2-12.

Key words: contrast media, myelography, excretion urography, angiocardiography.

HE OSMOTIC PRESSURE of a solution depends solely T on the number of particles in the solution and not on particle size or weight. For an undissociated electrolyte in solution, the molar concentration (i.e. the molecular weight in grams dissolved in one litre of water) is the same as the osmolar concentration because each molecule of the original substance remains as a single entity. If a substance dissociates completely in solution (e.g. sodium chloride) then a molar solution has twice the osmolality because each original molecule has dissociated into two ions each of which exerts an osmotic pressure. If a substance dissociates partially in solution, then its osmolality is somewhere between one and two times molar. Conversely, if molecules associate in solution, then the osmotic effect is smaller than that of separate molecules.’

Accepted physiologic convention regards a fluid as isotonic if it exerts no osmotic pressure across ared blood cell membrane; hypertonic or hypotonic fluids have osmolalities respectively more or less than this. The same terminol- ogy regarding tonicity or osmolality may also be applied to contrast media.’

In 1923 it was discovered that the inorganic salt sodium iodide produced faint images of the urinary tract on radiographs taken for other purposes. This compound was too toxic to be used diagnostically, but the finding stimulated the production of the first organic iodine contrast media in 1930. These were used for many years until the 1950s, when triiodinated compounds were produced with each new one having fewer side effects than its predecessors.

From the Department of Clinical Veterinary Medicine, Madingley Road, Cambridge CB3 OES, England.

Address correspondence and reprint requests to Ruth Dennis, Depart- ment of ClinicalVeterinary Medicine, Madingley Road, Cambridge CB3 OES, England.

Received: May 22, 1987. Accepted for publication: July 9, 1987.

2

Three of these compounds, diatrizoate, metrizoate, and iothalamate are still widely used as contrast media. They are monomeric salts of triiodinated benzoic acid with various substituted side chains, and as strong acids they dissociate in solution (i.e. they are ‘‘ionic’?. The cations are usually sodium and methylglucamine (meglumine) (Fig.

Although only the iodinated anion is of radiologic significance, both anion and cation are equally osmotically active, giving the solution an osmolality double that of an equivalent nonionic (nondissociating) compound.’ The conventional contrast media therefore have a high osmolality and are hypertonic to plasma at the concentrations required for adequate radiographic contrast (isotonic concentrations of conventional contrast media contain only 6% iodine, which would be radiographically u~eless).~

The use of conventional ionic contrast media is not without side effects, and there are four reasons for this: their hypertonicity (hyperosmolality), their ionic charge, their chemical toxicity, and occasional allergic, anaphylactic, anaphylactoid, or idiosyncratic reactions.’

1).

Hypertonicity The main reason for the side effects of ionic contrast

media is hypertonicity. This hypertonicity, which for these contrast media is five to eight times that of normal body fluids, represents a severe physical insult to the body regardless of the nature of the chemical inje~ted.”~ The effects of this are numerous and result in a variety of side effects, most of which are directly proportional to the degree of hypertonicity.

Endothelial lesions in blood vessels.2~3~5-8 When capillary endothelial cells are directly exposed to a hypertonic chemical solution, dessication and weakening of the

VOL. 30, No. 1 Low OSMOLAR CONTRAST MEDIA 3

cement lines between them occurs, resulting in increased capillary permeability and a risk of thrombus formation.

Damage to the blood-brain barrier.’” An increase in the permeability of the endothelium of cerebral capillaries occurs by a similar mechanism and allows potentially toxic molecules to gain access to nerve cells, resulting in neurologic damage.

Effects on erythrocytes and b l o o d f l O ~ . ’ ~ ~ ’ ~ ’ ~ The hypertonicity causes water to leave red blood cells by osmosis and they become rigid, deformed “dessicocytes” which are unable to negotiate smaller capillaries. This causes block- age of capillaries with distal tissue anoxia which is most serious in the brain and myocardi~m.”~’~

Cardiovascular e f f e ~ f ~ . ” ’ ” ~ ’ ~ ~ ~ ~ ~ ’ ’ A variety of cardiovascular effects occur following any intravascular injection of hypertonic contrast medium. These include localized vasodilation, generalized vasodilation (which can lead to severe hypotension), osmotic hypervolaemia, and reflex cardiac changes. In man, vasodilation results in unpleasant sensations of heat, flushing, and discomfort, and is directly proportional to the degree of hypertonicity of the contrast medium. The cardiovascular side effects are a particular hazard in patients with a history of congestive heart failure and in infants undergoing angiocardiography.

Renal effects. Diuresis is induced in most patients after intravascular injections of hypertonic contrast media, due to the increase in blood o~rnolality.~ This may be danger- ous in patients with a history of congestive heart failure.

Acute renal failure is an unusual but well recognized complication of the intravascular use of conventional contrast media and is probably due to a combination of hypertonicity and direct chemical toxicity. Predisposing factors include preexisting renal insufficiency, dehydration, congestive heart failure, diabetes mellitus, and multiple mye- loma.8”’

Uncomfortable side effects. Subjective side effects are noted by human patients following intravenous or less commonly intraarterial injections, and include nausea and vomiting, chills, fever, faintness, headache, sneezing, peri- neal discomfort, and the presence of an unpleasant metallic taste in the m o ~ t h . ~ ’ ~ ’ ~ ~ ’ ’ ’ ~ ~ The discomfort worsens as osmolality and iodine concentrations of the contrast media increase.* These side effects are particularly distressing for patients undergoing repeat procedures who anticipate the discomfort, but are of less significance in veterinary radiography where patients are usually sedated or anaesthetized.

Na’ Iodine : part ic le rat lo

3 : 2 I

FIG. 1. Conventional ionic contrast media, e.g. iothalamate, diatrizoate, metrizoate. R groups vary between the compounds.

ions and calcium-chelating substances can also cause cardiac effect^.^'^'^'^'^^

The conventional ionic contrast media have been used for many years for myelography (e.g. methiodal sodium Skiodan* or Kontrast Ut ) but have severe side effects being acutely neurotoxic, commonly producing convul- sions, and causing occasional respiratory or cardiac arrests and They have a tendency to exacerbate neurologic deficits16 and to produce chronic adhesive arachnoiditis.” The effects are thought to be due to a combination of hypertonicity of the contrast medium and the presence of the ionized particle^.^'^^-'^'^^'^^ Iodinized oily contrast media had also been used for myelography (e.g. iophendy- late Pantopaquef, or Myodils; oleum iodisatum Lipio- do1 1 1 ) but were irritants, producing chronic adhesive ara~hnoiditis’~-’~’’’’’~ and tended to globulate resulting in poor detail and slow migration down the subarachnoid space. 15-19r22924

Chemical Toxicity The conventional contrast media are inherently toxic,

especially if the sodium salt is used’; patients with cardiac, hepatic, or renal failure are particularly at risk from sodium overdose.” In addition, peripheral vasodilation is greater and other uncomfortable side effects are worsened as the sodium ion content of the contrast medium in- creases. The meglumine salt is less toxic but more viscous than the sodium salt, and so contrast media are often produced as a combination of the two in order to reach a compromise between toxicity and viscosity. Adverse reactions may also occasionally result from the iodinated anion or from very minute quantities of iodine which may be released from the benzene ring.4 Toxicity has been found to correlate well both with protein binding and with the partition coefficient (1ipophilicity:hydrophilicity ratio) of contrast media.’5 Protein binding results in enzyme inhibition, and inhibition of acetylcholinesterase has proved to be a

298

Ionicity The main disadvantage of the ionicity of conventional

contrast media is that in order to contain diagnostic concentrations of iodine, the solutions must be hypertonic. However there may also be effects on local electrolyte balance and nerve cond~ction.’~ The presence of sodium

*Winthrop Laboratories, Division of Sterling Drug Inc., 1450 Broad-

?Leo, Aktiebologet Leo, Langvinkeisgatan 166, Halsingborg, Sweden. SLafayette Pharmacal, Inc., 522-526 North Earl Avenue, Lafayette,

gGlaxo Laboratories Ltd., Greenford, Middlesex, England. I( Fougera, Cantiague Road, P.O. Box 73, Hicksville, Long island, New

way, New York, NY 1OOO1.

Indiana.

York.

4 DENNIS AND HERRTACE 1989

lodlne : part ic le rat io

3 : 1

FIG. 2. Low osmolar, nonionic contrast media, e.g. metrizamide, iopamidol, iohexol. R groups vary between the compounds.

good indicator for clinical Toxicity is also in- versely proportional to the degree of hydrophilia of the contrast rnedia,l4 and in conventional agents the highly hydrophobic iodine atoms are exposed on short side chains which result in unfavorable partition coefficients?’

The organs most sensitive to chemical toxicity are the brain, heart, and kidneys.’6 Damage to the blood-brain barrier is due partly to the chemotoxicity of the cations (especially sodium) and the carboxyl group of the anion, as well as to hypert~nici ty . ’ ’~’~’~~ Cardiotoxicity may lead to death within a few hours of contrast medium administra- tion2”’ and renal toxicity may contribute to acute tubular necrosis.’

Allergic, Anaphylactic, Anaphylactoid, and Idiosyncratic Reactions

A range of hypersensitivity reactions occurs in up to 5% of human patients on whom intravascular contrast examinations are performed.’ These may occur within one minute of the administration of a test dose or several hours later.’ The precise mechanism of such reactions is, as yet, unknown,2’’ but the reaction rate is highest in patients with a known allergic or asthmatic problem and in those with cardiac disease.’ The reactions vary from mild (sneezing, urticaria’” to severe, with changes such as pharyngeal, pulmonary and cerebral oedema, bronchospasm, and fatal cardiovascular ~ ~ l l a p ~ e . ’ ~ ’ ~ ’ ~ ~ ~ A fatality rate of about one in 40,000 intravascular studies is well recognized in man.

Low Osmolar Media In the late 1960s, a Swedish radiologist, Torsten AlmCn,

realized that many of the adverse effects of contrast media were due to their hypertonicity. These side effects were often severe enough to require use of general anaesthesia for contrast studies.” AlmCn’s finding stimulated work on the production of contrast media with lower osmolalities, nearer to that of plasma, and in 1974 Nyegaard produced the first low osmolar contrast medium, metrizamide (Ami- paqueq). They achieved this by preparing a compound which did not dissociate in solution and so had no useless

lodlne : part lc le rat io

6 : 2 ( 3 : 1 )

I I

FIG. 3. Low osmolar, ionic, dimeric contrast media, e.g. ioxaglate. R groups vary between the compounds.

cations to raise the osmolality. The side chains of the triiodinated benzene ring were altered to become highly hydrophilic and this rendered the compound soluble without dissociation (Fig. 2).

This raised the ratio of iodine atoms per osmotic particle from 3:2 (for conventional ionic media) to 3: 1 (for metrizamide). At the same time osmolality was halved, due to nonionicity, and then actually reduced further due to the tendency of metrizamide particles to aggregate in solution. The resultant osmolality was about one third that of conventional media and side effects were far fewer.24

Metrizamide has now been in clinical use in both humans and animals for well over a decade. Although suitable for intravascular use, metrizamide is very expensive and so is normally reserved for myelography, which was revolutionized by its introduction.’ It has great advantages over previously used oily and ionic myelographic contrast media but its use is not without side effects and this prompted the development of two new low osmolar, nonionic contrast media, iopamidol (Niopam**) and iohexol (Omnipaquel), by modification of the metrizamide side chains. These media have been shown to have certain advantages: they produce far fewer side effects than metrizamide, they are stable in solution, they are autoclav- able (metrizamide is unstable in solution and must be made up from a lyophilized powder), and they are much cheaper. Iopamidol and iohexol have now largely superseded metrizamide where they are commercially available.

Another method of reducing osmolality has been to link two triiodinated benzene rings together producing a dimer. Only one of the dimer’s acid groups is ionized; the other one is substituted with a hydrophilic side chain (Fig. 3). Such a compound is ioxaglate (Hexabrixtt); a monoacid dimeric salt which produces two particles in solution but carries six iodine atoms; it therefore has an iodine to particle ratio of 3: 1 and is low in osmolality at diagnostic iodine concentrations. It is ionic, and cannot, therefore, be used safely in myelography,12 but for intravascular studies it shows the same reduction in side effects as the nonionic, low osmolar contrast media and is widely used in medical

glNyegard & Co., A/S Contrast Media Division, P.O. Box 4220, Torshov, Oslo 4, Norway.

**Bracco Industria Chimica Spa, Via E. Folli, 50 Milan, Italy. t tMay and Baker Ltd., Rainham Road South, Dagenham, Essex,

England. (RM 10 7XS, under license from Guerbet S.A.)


F I I I I I I I

(Urogrof in) -

h

0, iolhalamaie (Conroy)

I - 0 Y

E v // I

physiological osmolalily (plasma)

0 100 200 300 IODINE CONCENTRATION (mg/ml)

FIG. 4. A graph of osmolality vs. iodine concentration for conventional and low osmolar contrast media. (Adapted from The new low- osmolar, contrast media: a simple guide. Peter Dawson, RG Grainger, and Jean Pitfield. Clin Radio1 1983;34:221-226.)

radiology for excretion urography, angiography, arthrography, and other studies.

All of the new low osmolar compounds, metrizamide, iopamidol, iohexol, and ioxaglate, have approximately the same osmolality which is about one third that of conventional salts at the same iodine concentration, due to the significant degree of aggregration of molecules which occurs in This is shown graphically in Figure 4.

Image quality (radiopacity) of contrast studies depends mainly on the iodine concentration of the contrast medium and the total dose of iodine delivered. There is no reason why the new contrast media should have an inherently greater radiodiagnostic efficiency, but the reduction in side effects permits the injection of more concentrated and greater volumes of solution when required.12 Image quality also depends on clarity and definition of the contrast medium accumulation and osmotic dilution of the low osmolar contrast media by body fluids is much less and occurs more slowly than with hyperosmolar contrast media resulting in sharper pictures for a greater length of time.

A large number of studies comparing low osmolar contrast media with conventional contrast media for vascular and intrathecal studies have shown radiographic contrast to be as good, and in some cases better, with the new

TABLE 1. Viscosity of Contrast Media

Contrast median

Viscosity (c P)

(mgirnl) 20°C 37°C

Iodine concentration

sodium salt of hyperosmolar

meglumine/sodium salt of medium 350 6.0 3.4

hyperosomolar medium 370 17.3 8.4 ioxaglate (HEXABRIX 320) 320 15.7 7.5 rnetrizamide* (AMIPAQUE) 300 12.7 6.2 iopamidol (NIOPAM 300) 300 8.8 4.7 iohexol (OMNIPAQUE 300) 300 11.6 6.1

*Made up to 300 mg I/ml concentration from freeze-dried powder and

Data was obtained from references 12, 14, 27, 29, and 46. diluent.

contrast media.’0’23’30-43 Comparisons between two or more of the new contrast media have shown no advantage for one over the others, and metrizamide, iohexol, and iopamidol appear to produce similarly good or excellent myelographic studies at equal iodine concentration^.^^'^^-^^

The viscosity of a contrast medium is important since it influences the ease of handling and administration of the agent. Conventional ionic contrast media usually contain meglumine salts which reduce the toxicity due to sodium ions but which increase the viscosity of the solutions. When comparing the viscosity of different contrast media, similar iodine concentrations must be compared.I2 The viscosity of the new contrast media is of a similar magnitude to conventional contrast media, but ioxaglate has the greatest viscosity at equal iodine concentrations because it is a dimer.I2 However, for all contrast media the viscosity can be greatly reduced by warming the ampoule to a physiologic temper- ature.” Some examples are given in Table 1.

The development of a third generation of low osmolar media is under way in the form of a dimer (like ioxaglate) which is completely nonionic. Two such compounds are iodixanol’fl and iotrolanfS (Fig. 5). These compounds have an iodine to particle ratio of 6 : 1 (compared with that of 3 : 1 for the nonionic monomers). This theoretically produces a further halving of the osmolality at any given iodine concentration and so ,solutions in the 300 mg to 400 mg iodine per ml range would be expected to have an osmolality very close to that of plasma. In fact, at concentrations of less than about 400 mg iodine per ml such compounds are actually hypo-osmolar due- to molecule aggregation and since hypo-osmolality might be considered undesirable, the manufacturers add small amounts of saline so that the final solution is iso-osmolar with plasma.25

SSSchering AG, Berlin/ Bergkamen, Germany.

6 DENNIS AND HERRTAGE 1989

lw;3 lodlne : partlcle ratlo

6 : l R5 I I

FIG. 5 . Low osmolar, nonionic, dimericcontrast mediae.g. iodixanol, iotrolan. R groups vary between the compounds.

Their chemotoxicity appears to be similar to that of the nonionic monomers as they are highly hydrophilic and the toxic iodine atoms are well shielded by the long side chains of the molecule. Their viscosity is higher than that of the monomers, due to the large size of the molecules, but it can be reduced to an acceptable level by warming the solution to 37” C . Indeed, for myelography a higher viscosity may be regarded as advantageous as diffusion of contrast is much

The low osmolar contrast media have four main advantages over conventional, hypertonic contrast media: reduced tonicity, nonionicity, reduced chemical toxicity, and fewer hypersensitivity reactions.

sense of warmth or mild discomfort on injection in many instances, but this is always much less than that due to conventional, hyperosmolar contrast media, and overt pain is rare.

Most studies have compared new, low osmolar contrast media with conventional, hyperosmolar contrast media, but a number of trials have been performed comparing two or more of the new contrast media and no significant differences have been noted for intravascular stud-

although there are some advantages of ies, iohexol over iopamidol for myelography. Comparisons between the ionic ioxaglate and the three nonionic contrast media have shown that the benefits are due mainly to the reduction in osmolality and not to the effects of nonionicity . 32

The main advantage of the reduction in uncomfortable side effects in humans is that the patients are less likely to move during the study, thus obviating the need for general anaesthesia in most if not all studies, and thereby reducing risk, time, and In veterinary radiology, most patients are anaesthetized for contrast studies but occasionally general anaesthesia may be contraindicated, in which case a reduction in uncomfortable side effects is advantageous.

4,12,26,27,32,44,49

Reduction in Hypertonicity Nonionicity Most of the side effects associated with conventional

contrast media are due to their hypertonicity. Metriz- amide, iopamidol, iohexol, and ioxaglate have a much lower tonicity at similar iodine concentrations, and this has meant a great reduction in all associated side ef-

There are now a number of reports of the use of low osmolar contrast media for a wide range of studies on human patients. These include cervical and lumbar myelography; angi~cardiography~”~~; a ~ r t ~ g r a p h y ~ ~ ’ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ * , car- ~ t i d ” ’ ~ ~ ; and peripheral arteri~graphy~~-~~’~~~~’; hepatic ang i~graphy~~; coronary arteri~graphy~’; limb ~ e n o g r a p h y ~ ~ ” ~ ; excretion ~ r o g r a p h y , ’ ~ ’ ~ ~ and alimentary studies.52 The reduction in the incidence and severity of uncomfortable side effects is striking and consistent in all studies, such that many previously painful procedures are rendered pain free. This occurs with ionic (ioxaglate) and nonionic (metrizamide, iopamidol and iohexol) low osmolar contrast media and is due largely to a reduction in vasodilation and the resultant sensations of heat and flushing.7”0 Experimental studies on the effects of injection of iothalamate, metrizamide, iopamidol, and ioxaglate at equal iodine concentrations into the femoral artery of dogs have shown a vasodilation of only 32% for the three low osmolar media compared with 93% for i~ tha lamate .~”~ This reduction in vasodilation has been borne out in clinical trials on human There is still a fleeting

feCtS.2-4,7-10~12~14,29,45r46

For metrizamide, iopamidol, and iohexol, there is the additional advantage that, since nonionic, they are suitable for myelography.” Ioxaglate, an ionic medium, is neurotoxic and must not be used in the subarachnoid

Reduction in Chemical Toxicity Third, there is a reduction in both general systemic and

neurologic toxicity with all of the low osmolar contrast The larger side chains of the new con-

trast media shield the highly hydrophobic iodine atoms (“steric hindrance”) rendering the molecules much more hydrophilic and less inherently In addition the nonionic low osmolar contrast media, metrizamide, iopamidol, and iohexol, contain no toxic sodium ions thus removing the risk of sodium overdose in patients with cardiac, renal, or hepatic disease.” Ioxaglate is ionic, with cations of sodium and meglumine, but as a dimer it has a lower proportion of sodium ions for its iodine content than do conventional media.”

Reduction in neurotoxicity is largely a function of the reduced osmolality which results in less damage to the blood-brain barrier, although the absence of the toxic anions and cations is also imp~rtant.”~’

Reduction in Hypersensitivity Reactions

media.3’9, 14~20r29,46

Finally, there have been far fewer severe allergic, ana-


phylactic, anaphylactoid, and idiosyncratic reactions with all of the new low osmolar contrast media, and the death rate in humans of about one in 40,000 appears to have been

The reason for this is unclear, but it is thought to be related to the lower osmolality of the new contrast media’’ and the main factor is probably their reduced cardiot~xici ty .~~

Clinical Uses of Low Osmolar Media Myelography

Metrizamide is relatively nontoxic in the subarachnoid space so it can be injected there in comparatively large amounts at high iodine concentrations.” It is completely absorbed’ and lacking in long-term toxic effects including those of chronic adhesive arachnoiditi~.~’~”~’~~~~~’~~ It is easily miscible with CSF and gives accurate outlining of the subarachnoid space, and as its specific gravity is greater than that of CSF, its position in the subarachnoid space may be manipulated by gravity.”

However, the high incidence of side effects in humans, some of which are alarmingly severe, has been a cause for concern.23y38157 In most studies, at least one half of the patients suffered from side effects, the most common being a severe headache, although nausea and vomiting also occurred f r eq~en t ly .~~ Severe disturbances of the electro- encephalo-gram (EEG) are seen in about 4% of patients,57 and occasionally severe mental disturbances are Metrizamide is known to have some epileptogenic poten- tial, especially when it enters the cranial cavity, and this is potentiated by neuroleptics. Therefore the use of phenothi- azines as premedicants should be a v ~ i d e d . ~ ~ ’ ~ ~ ’ ~ ~ The incidence of seizures has made the use of anticonvulsants as premedicants routine in many places, thus adding to the cost and time of the In addition, patients normally have to remain upright for 24 hours after myelography to prevent contrast medium from entering the brain.

In veterinary radiology metrizamide has been shown to have very marked advantages over previously used contrast media, but its use is not without side effects and it has been suggested that metrizamide is less tolerated in dogs than in horses, other experimental species, or human^.^^'^' The largest study consisted of 107 examinations in which almost one half of the dogs suffered some side effect, although these figures were acknowledged to be higher than in other studies.61 The most common complications were either focal or generalized seizures that occurred in 32% of dogs; these were usually associated with cisternal rather than lumbar injections and with high volumes of contrast medium. These seizures were most likely to occur in large dogs (weighing more than 29 kg) receiving more than 7 ml of contrast medium by the cisternal route. The

authors pointed out that veterinary reports of metrizamide myelography had indicated a greater incidence of neurologic side effects (including generalized seizures) in animals than in humans, and they have postulated that this might be due to the presence of intracranial contrast medium, albeit very diluted, following recovery from anaesthesia. Other studies also reported the occurrence of partial and generalized seizures, some of which occurred despite the use of diazepam, in six to 100% of patient^.'^'^^^^^'^''^'^^^ A higher concentration of metrizamide (300 mg iodine per ml) was found to be more epileptogenic than an isotonic concentration (170 mg iodine per ml) and also to result in varying degrees of arachnoid fibrosis after repeated injections in

Other factors associated with the incidence of seizures in dogs following metrizamide myelography are the nature of the premedicant and anaesthetic agents used, and the dura- tion of anaesthesia following the myelogram. Soon after the introduction of metrizamide to veterinary radiology it was recommended that acepromazine be avoided as a premedicant and that diazepam be used prophylactically, as in humans, to raise the epileptogenic threshold.I8 Neuro- leptanalgesics and morphine and its derivatives have also been shown to increase seizure frequency either by lower- ing the seizure threshold or by synergism with metrizamide,60 and two papers have reported seizures in dogs anaesthetized with thiopentone but not in dogs in which pentobarbitone was It was also found that there was a much lower incidence of seizures in dogs whose anaesthesia was prolonged for surgery (8%) than in those allowed to recover immediately after the myelogram (5 I%), which suggests that absorption and removal of the metrizamide is important in preventing seizures.60

Other reported side effects have included transient apnoea during the injection,18’61 grand ma1 seizure patterns on the EEG,60 transient muscle spasms and opisthoto- nu3,17’18’60 jaw champing,60 h y p e r p y r e ~ i a , ~ ~ ’ ~ ~ vomiting during or after recovery,61 and exacerbation of neurologic

In one study one dog died an hour postmye- lography following seizures, but contrast medium was seen to have entered the central canal of the spinal cord.17

There are a number of reports on the use of metrizamide for equine myelography in a total of 35 horse^.^^-^^ All reports described side effects in some of the horses, and these were usually muscle fasciculations or strenuous neck or limb movements during recovery, but subsequent neck stiffness? mild and postmyelographic pyrexia also One horse died of anaphylactic shock during myelography, which was attributed to a previous metrizamide myelogram five weeks earlier.68 In most cases where CSF was examined or an histopathological exami- nation of the spinal cord carried out, there were signs of a mild, acute suppurative meningitis p~s tmyelography.~~-~~

Iopamidol and iohexol were developed in an attempt to

dogs?


reduce the problems associated with metrizamide and at the same time to share its advantages. The lack of long- term side effects (mainly arachnoiditis) with metrizamide is believed to be due at least partly to its low o~mola l i t y~~’~’ and does appear to be shared by the two newer contrast media.23

The results of a number of human clinical trials of for both cervical

and lumbar myelography in the conscious patient have been published, the largest performed on over one thou- sand patients.20 Several have compared the side effects with those due to m e t r i ~ a m i d e . ~ ~ ’ ~ ~ ’ ~ ~ ’ ~ ~ The most dramatic and consistent finding in all trials was the reduction in the severity of the side effects such that most were mild, transient, and did not require treatment. The most frequent side effect remained headaches, but these were rarely severe or prolonged as is often the case with metrizamide. Mental changes were either completely absent or much reduced, there was no deterioration in neurologic status, and there were far fewer EEG changes. Those mental changes which did occur did not correlate with intracranial spillage of contrast medium.43 No seizures were reported with iohexol despite the fact that in some studies prophylactic diazepam was not used or that contrast medium entered the brain.23 There has been one report of generalized seizures following iopamidol myelographys8 but the dose of iodine adminis- tered was 6 g (20 ml of a 300 mg iodine per ml solution) which was considered to be excessive.42 With iopamidol and iohexol, anticonvulsants are not required69 and it has been suggested that there is no need for human patients to remain upright for long periods following the procedure as the presence or absence of contrast medium around the brain does not seem to influehce the incidence of side

Of the other side effects, nausea and vomiting were still the most frequent, although they were strikingly reduced in both incidence and severity. Other side effects recorded include neck- or b a ~ k a ~ h e , 2 ~ ’ ~ ~ - ~ ~ ’ ~ ~ ~ ~ ~ ’ ~ ~ pyrexia,23737338

ny~ tagmus ,~~ sweating,43 hyp~tens ion ,~~ and skin but these also were mild.

Iopamidol and iohexol have also been compared for myel~graphy.~~ 943 770 Iopamidol was found to produce myelograms of a similar quality to iohexol, but also to result in a significantly higher incidence of mild and severe side effects, the latter usually a prolonged Iopamidol does seem to produce more EEG abnormali- ties23 and to be more epileptogenic than iohe~ol ;~ and so based on current evidence iohexol may be preferred for myelography in man.

A small number of reports of the use of iopamidol and iohexol for myelography in domestic animals have been

These include two papers on iopamidol myelography in the dog19 and in the horse:1 aseries of 100 iohexol myelograms in dogs and cats (and a comparison

iopamido~20~38~40-42’58 and ioheXo136939,57969

effeCtS.23,40r43r69

published. 19,24971 972

with metrizamide and i~pamidol),’~ and one report of myelography in the cat in which two studies were performed with iohexol and three with iopamid01.~~ There are no publications as yet on the use of ioxaglate, iohexol, or iopamidol for other clinical procedures.

For iohexol, concentrations of 300 mg iodine per ml were used in cats and small dogs and of 350 mg iodine per ml in medium and large dogs, although the lower concentration would have been adequate in all patients.24 All animals received premedication with acepromazine, but no seizures occurred. Of the 68 patients allowed to recover from anaesthesia none showed any side effects or worsen- ing of neurologic status. It was found that iohexol could be used with confidence even with acepromazine premedication.

For iopamidol, a concentration of 200 mg iodine per ml was used in three feline studies. There were no side effects but the cats were not allowed to recover from anaesthesia. In another study on 27 dogs, all received premedication with diazepam and iopamidol was used at a concentration of 300 mg iodine per ml. In five dogs transient cardiorespi- ratory alterations were noted during the injection. Two dogs exhibited seizures, one of which was controlled with further diazepam; both had evidence of intracranial contrast medium, but this was present in 20 of 22 dogs in which this was evaluated. One dog died seven hours after the study but the death was attributed to extensive traumatic subdural haemorrhage due to needle placement. Two dogs showed contrast medium within the central canal but neither showed side effects, while one dog died when this occurred with metri~arnide.’~ These results do correlate with studies in humans in which a significantly higher incidence of side effects was found with iopamidol than with iohex01 .~~’~~

In the seven horses myelography was performed with iopamidol at concentrations of 300 or 370 mg iodine per ml. No dramatic vital changes occurred on injection and no muscle spasms, head and neckjerks, or seizures were noted in the five horses allowed to recover. Two horses received acepromazine as a premedicant and one also received diazepam. In two horses where CSF was examined before and four days after myelography there was a small rise in white-cell count, but this was much less than that noted at two days with metri~amide;~ and there were no gross signs of meningeal inflammation.

The side effects of nausea and vomiting during myelography are unimportant in veterinary radiology since patients are anaesthetized, but the incidence of seizures, severe headache, and mental disturbances following the use of metrizamide must be considered. Many veterinary radiologists routinely prernedicate patients with diazepam before metrizamide myelography and the head is normally elevated during the procedure and the recovery period as it is well recognized that the presence of intracranial contrast


medium may precipitate seizures. It seems likely that in animals, as in humans, premedication with anticonvulsants and elevation of the head following the procedure will be unnecessary .

Diagnostic radiographs of good or excellent quality were obtained in all instances regardless of species. Con- centrations of 300 mg iodine per ml appear to be satisfactory in small animals, though in horses the greater radiopacity achieved with 370 mg iodine per ml may be preferred. One study reported occasional difficulty in producing good myelograms in the caudal cervical region in very large dogs, although this was overcome by using relatively large volumes of contrast medium (up to 8 ml) with a smaller degree of table tilt (10’ to 15O) initiall~.’~ Iohexol was found to give excellent delineation of the cauda e q ~ i n a . ’ ~ In one report a blind, randomized exami- nation of five myelograms for each of metrizamide, iohexol, and iopamidol was performed, producing significantly better myelograms by iohexol and iopamidol, although they were not significantly different from each other.24

In conclusion, it appears that both iohexol and iopamidol may have significant clinical advantages over metrizamide for myelography, with some possible radiographic gain as well.

Excretion Urography The required properties of a suitable contrast medium

for excretion urography include a high clinical tolerance, rapid renal excretion, the production of high quality radiographs, low viscosity for ease of injection, and a lack of adverse effects on kidney

The conventional ionic, hyperosmolar contrast media produce satisfactory results in most instances and are still widely used, but they do have some disadvantages. The unpleasant subjective side effects experienced by most patients during and after the injection have been discussed, and there is also the occasional death due to an unexpected severe reaction. In addition, poor quality radiographs are often produced in patients with poor kidney function due to a combination of reduced renal blood flow and osmostic dilution within the kidneys.46 The conventional contrast media produce an osmotic diuresis because of their hypertonicity and there is some disagreement in the literature as to whether this is advantageous. On the one hand it dis- tends the collecting system and ureters, but on the other hand radiographic contrast is reduced.

The low osmolar contrast media (including ioxaglate) fulfill all requirements for excretion urography. They are rapidly and almost exclusively excreted by the kid- n e y ~ ~ ’ ~ ~ ’ ~ ~ and as there is less osmotic d i ~ r e s i s , ~ ’ ~ ’ ~ ’ ~ ~ the radiographs should have better contrast, especially in patients with poor renal f~nction.~’~’’ However, there is less distention of the collecting system and ureters and the

study may be s10wer .~’~’~~ In practice, the advantages of the new contrast media for

excretion urography are much less marked than for arteri- ~graphy’’~ and in view of their greater cost it is generally recommended that their use for excretion urography be restricted to certain patients. These include patients who have suffered a previous significant reaction to contrast media or who are very anxious, and any other patient from

For renal studies in the dog it has been shown that, as in humans, all three contrast media are rapidly and massively excreted by the kidneys with negligible protein binding and no metabolites, and they are therefore likely to be excellent urographic

Angiocardiography In humans, cardiovascular complications and even deaths

have been reported following the injection of conventional, hypertonic contrast media into the heart chambers and major vessels, especially in patients with pulmonary hypertension.3973y74

The low osmolar contrast media (including ioxaglate) have been shown to have lesser adverse effects on myocar- dial contractility, cardiac workload, and pulmonary pres-

less arrhythmogenicity, and reduced precipitation of ventricular fibrillati~n.~’~’” In addition, the reduction in incidence and severity of subjective side effects permits more studies to be performed on conscious patients.

The new contrast media are safer for angiocardiography, especially in in patients with pulmonary hypertension or cardiac failure: and in other at-risk g r o ~ p s . ’ ~ ~ ’ ~ ’ ~ ~

Experimentally, ionic contrast media are said to have a profound negative inotropic effect on the canine heart, whereas the nonionic contrast media have a positive effect,75 which is probably due more to the absence of sodium ions and calcium chelating substances than to low osmolality and so is presumably not shared by i0xag1ate.l~ Cardiovascular parameters are also less influenced in cats,I4 and so it is reasonable to assume that the nonionic low osmolar contrast media would be safer for angiocardiography in cats, small dogs, and vulnerable patients than are conventional ionic contrast media.

an at-risk grOUp.~~4’12,13r28,44r45

Gastro-intestinal Studies The low osmolar contrast media are suitable, though

expensive, for use in esophageal and gastrointestinal studies in instances where barium or hypertonic iodinated contrast media are unsuitable. In patients with intestines of small diameter (such as young children) barium may inspissate in the gut proximal to stricture^.^' Conventional iodinated contrast media have been used for enteric studies in humans and animals where there is suspected perforation of part of the gut, but their high osmolality may cause severe pulmonary edema if accidentally inhaled or if a broncho-


TABLE 2. Price of Contrast Media for Myelography and Other Studies (United Kingdom)*

Product Price Container

Myelography -for 10 ml of a 300 mg iodine per ml preparation (total 3 g) Metrizamide f20.30 (El 1.50 is used at the usual isotonic (Amipaque) concentration of 170 mg iodine per

mu

Iopamidol f8.85 (10 ml vial) (Niopam) f3.37 (50 ml bottle)

Iohexol f8.31 ( 10 ml vial) (Omnipaque) f3.37 (50 ml bottle)

Other studies - 50 ml of a 30 mg iodine per ml preparation (total 15 g iodine) conventional f3.00 media approximately

Ioxaglate f9.50 (Hexabrix)

Metrizamide f101.40 (Amipaque)

Iopamidol 216.85 (50 ml bottle) (Niopam) f44.23 (10 ml vials)

Iohexol f16.85 (50 ml bottle) (Omnipaque) f41.57 (10 ml vials)

the price of those in the United Kingdom.

esophageal fistula is present.52 In addition, osmotic dilution of the contrast medium results in loss of contrast and definition as the study progresses. Low osmolar media are therefore more suitable for such studies as they produce better radiographs with less risk to the patient.52

Arthrography

The injection of a hypertonic contrast medium into a joint space induces flow of fluid into the joint by osmosis, causing reduced radiographic contrast and def ini t i~n.~ In practice this may mean repeating the study or adding adrenalin to the contrast medium. The lower osmolality of the new contrast media (including ioxaglate) makes them more suitable for injection into joints than conventional media as there is less joint effusion and dilution of the contrast m e d i ~ r n . ~

Other Uses The use of low osmolar contrast media for dacryocys-

torhinography in humans is said to produce less irritation and glandular damage than do conventional contrast media,

*The United States prices of iopamidol and iohexol are roughly twice

and there should be less osmotic dilution of the contrast m e d i ~ m . ~ Following hysterosalpingography there is less peritoneal i r r i ta t i~n.~

Price and Presentation of Low Osmolar Media The first low osmolar medium, metrizamide, is very

expensive (although in the United States analytical grade metrizamide is available at a much lower cost) and also slightly inconvenient since it must be freshly made from lyophilized powder and a diluent. The three new contrast media are considerably cheaper but are still more expensive than the conventional ionic contrast media; comparisons must be made on the basis of the iodine content of the media.4 All are available in a number of different volumes : iopamidol and iohexol are available in iodine concentrations varying from 200 to 370 mg iodine per ml (iopamidol) and from 180 to 350 mg iodine per ml (iohexol). They have the additional advantage over metrizamide of being auto- clavable and so multiple doses may be taken from the same bottle. Ioxaglate is only available at a concentration of 320 mg iodine per ml but may be easily diluted to produce weaker solutions.

Dual usage of iopamidol and iohexol for myelography and vascular studies has created problems in pricing because the alternatives are the very expensive metrizamide for myelography and the much cheaper conventional contrast media for vascular studies.12 The price for a single 50 ml bottle is much cheaper than the price for five 10 ml vials. Thus it is very expensive to use the contrast media marketed in vials for vascular studies and very cheap to perform several myelograms from a 50 ml bottle. Table 2 shows some sample 1988 United Kingdom prices (all exclusive of the value added tax and bought in small quantities with no hospital discounts).

For myelography, both iopamidol and iohexol offer clinical and financial advantages over metrizamide, and so it would be reasonable to discontinue the use of metrizamide. Evidence so far would tend to favor the use of iohexol, although there is limited data available for comparisons between the two.

For most other procedures on healthy patients, the use of the cheaper conventional contrast media is still justified, although there is a case for using the new contrast media for vascular studies in very small or other at-risk patients. It is hoped that the price of the new contrast media will eventually be reduced.

REFERENCES 1. Keele CA, Neil E. Ch. I . Thecelland body fluids. In: Samson Wright’s

Applied Physiology. 12th ed. London: Oxford University Press, 1971. 2. Grainger RG. Osmolality of intravascular contrast media. Br J

Radiol. 1980;53:739-746. 3. May and Baker. Manufacturer’s data for Hexabrix 320. 2nd ed.

Franklin Scientific Projects Ltd., 1983. 4. Grainger RG. Formulation and clinical introduction of low osmolal-

ity contrast media. Proc Symp Niopam 1982. Franklin Scientific Projects

Ltd., 1983. 5. Goldberg M. Systemic reactions to intravascular contrast media.

Anesthesiology 1984;60:46-56. 6. Walters HL, Clemenson J, Browse NL, Lea TM. 125-1 fibrinogen

uptake following leg phlebography: a comparison of an ionic and nonionic contrast medium. Radiology 1980;135:619-621.

7. Grainger RG. Intravascular contrast media-the past, the present and the future. Br J Radiol 1982;55:1-18.


8. Bettmann MA. Angiographic contrast agents: conventional and new media compared. American Journal of Radiology 1982;139:787-794.

9. Sage MR, Wilcox J, Evil1 CA, Benness GT. Comparison of blood- brain barrier disruption by intracarotid iopamidol and methylglucamine iothalamate. AJNR 1983;4:893-895.

10. Grainger RG. A clinical trial of a new low osmolality contrast medium. Br J Radiol 1979;52:781-786.

1 I . Dawson P. Adverse reactions to contrast media. In: The importance of low osmolar media to clinical radiology. Franklin Scientific Publications, 1984.

12. Dawson P, Grainger RG, Pitfield J. The new low-osmolar contrast media: a simple guide. Clin Radiol 1983;34:221-226.

13. Davies P, Panto PN, Buckley J , Richardson RE. The old and the new: a study of five contrast media for urography. Br J Radiol

14. Niopam: the medium of the future. Merck: Manufacturers’ data for iopamidol. Franklin Scientific Projects Ltd.

15. Bullock LP, Zook BC. Myelography in dogs, using water-soluble contrast medium. J Am Vet Med Assoc. 1967;151:321-327.

16. Stowater JL, Kneller SK. Clinical evaluation of metrizamide as a myelographic agent in the dog. J Am Vet Med Assoc. 1979;175:191-195.

17. Wright JA, Clayton Jones DG. Metrizamide myelography in sixty-eight dogs. J Small Anim Pract 1981;22415435.

18. Lord PF, Olsson S-E. Myelography with metrizamide in the dog: a clinical study on its use for the demonstrationof spinalcord lesions other than those caused by intervertebral disc protrusions. Vet Radiol 1976;17: 4249.

19. Cox FH, Jakovljevic S. The use of iopamidol for myelography in dogs: a study of twenty-seven cases. J Small Anim Pract 1986;27:159- 165.

20. Bassi P, Cecchini A, Dettori P, Signorini E. Myelography with iopamidol, a nonionic water-soluble contrast medium: incidence of complications. Neuroradiology I982;2485-90.

21. Funkquist B. Thoraco-lumbar myelography with water-soluble contrast medium in dogs I. Technique of myelography; side-effects and complications. J Small Anim Pract 1962;3:53-66.

22. Hoerlein BF. Various contrast mediums in canine myelography. J Am Vet Med Assoc 1953;123:311-314.

23. Lamb JT. Iohexol vs. iopamidol for myelography. Invest Radiol

24. Wheeler SJ, Davies JV. Iohexol myelography in the dog and cat: a series of one hundred cases, and a comparison with metrizamide and iopamidol. J Small Anim Pract 1985;26:247-256.

25. Dawson P, Howell M. The non-ionic dimers: a new class of contrast agents. Br J Radiol 1986;59:987-991.

26. Whitehouse GH. Some recent advances in contrast media for aortography. In: The importance of low osmolar media to clinical radiology. Franklin Scientific Publications, 1984.

27. Molyneux AJ. Comparative trials of iopamidol in general angiography. Proc Symp Niopam 1982. Franklin Scientific Projects Ltd., 1983.

28. Carmichael JHE, Lamb GHR, Pilling DW. The use of iopamidol in intravenous urography. Proc Symp Niopam 1982. Franklin Scientific Projects Ltd., 1983.

29. Felder E, Pitre D, Tirone P. Radiopaque contrast media XLIV- Preclinical studies with a new nonionic contrast agent. I1 Farmaco

30. Fletcher EWL. Iopamidol in peripheral angiography: a comparison with diatrizoate. Proc Symp Niopam 1982. Franklin Scientific Proj- ects Ltd., 1983.

31. Partridge JB, Turnbull CM, Morrison GW, Stoker JB, Boyle RM, Robinson PJ. Clinical cardiovascular experiences with iopamidol, a new, non-ionic contrast medium, Proc Symp Niopam 1982. Franklin Scientific Projects Ltd., 1983.

32. Grainger RG. A clinical trial of iopamidol370 and 300 for arteri- ography. Proc Symp Niopam 1982. Franklin Scientific Projects Ltd., 1983.

33. Owens AP, MacErlean DP, Assaf RAE. Comparison of iopamidol with conventional contrast media in translumbar aortography. Proc Symp Niopam 1982. Franklin Scientific Projects Ltd., 1983.

34. Allan PL, Best JJK. A comparison of iopamidol with iothalamate in transfemoral angiography and peripheral angiography. Proc Symp

1985;58:593-597.

1985;20(suppl):S37-S43.

1977;N.l1:834-844.

Niopam 1982. Franklin Scientific Projects Ltd., 1983. 35. Nunnerley H, Ruffel E. The use of iopamidol in hepatic angi-

ography. Proc Symp Niopam 1982. Franklin Scientific Projects Ltd., 1983.

36. Nakstad P, Helgetveit A, Aaserud 0, Ganes T, Nyberg-Hansen R. Iohexol compared with metrizamide in cervical and thoracic myelography. Neuroradiology 1984;26:479484.

37. Moschini L, Manara 0, Bonaldi G, Cassinari V, Quilici N, Belloni G. Iopamidol and metrizamide in cervical myelography: side effects, EEG, and CSF changes. AJNR 1983;4:848-850.

38. Lamb JT, Holland IM. Myelography with iopamidol. AJNR

39. Batty VB. Cervical myelography using iohexol (Omnipaque), a new contrast medium. Clin Radiol 1984;35:75-77.

40. Belloni G, Bonaldi G, Moschini L, Quilici N. Cervical myelography with iopamidolo. Neuroradiology 1981;21:97-99.

41. McAllister VL, Hall K. A randomized blind trial of iopamidol (Niopam) and metrizamide (Amipaque) in lumbar radiculography. Proc Symp Niopam 1982. Franklin Scientific Projects Ltd., 1983.

42. Molyneux AJ. Preliminary experiences with iopamidol (Niopam) in lumbar and cervical myelography. Proc Symp Niopam 1982. Franklin Scientific Projects Ltd., 1983.

43. Macpherson P, Teasdale E, Coutinho C, McGeorge A. Iohexol versus iopamidol for cervical myelography: a randomized double blind study. Br J Radiol 1985;58:849-851.

44. Grainger RG. A review of the meeting on contrast media held in San Francisco on 19th-22nd October 1983. In: The importance of low osmolar media to clinical radiology. Franklin Scientific Publications, 1984.

45. Grainger RG. Low osmolar contrast media. Br Med J 1984;289:

46. Omnipaque (iohexol). Nyegaard: manufacturers’data for iohexol. Oslo: Nyegaard and Co.

47. Ruttley M. Hexabrix 320 and Urografin 370 compared with left ventriculography for ischaemic heart disease and mitral valve disease. In: The importance of low osmolar media to clinical radiology. Franklin Scientific Publications, 1984.

48. Reidy JF, Padayachee TS, Gosling RS. Comparison of iopamidol and Urografin 370 in lumbar aortography: the effect on femoral artery flow. Proc Symp Niopam 1982. Franklin Scientific Projects Ltd., 1983.

49. Grainger RG. A comparison of conventional ionic, non-ionic, and monoacid dimer contrast media. In: The importance of low osmolar media to clinical radiology. Franklin Scientific Publications, 1984.

50. Reston P. Experiences in a busy district general hospital. In: The importance of low osmolar media to clinical radiology. Franklin Scien- tific Publications, 1984.

51. Thomas ML. Ascending phlebography of the legs using Niopam 300: acomparision with Conray280. Proc. Symp. Niopam 1982. Franklin Scientific Projects Ltd., 1983.

52. Carty H. The influence of low osmolar media in paediatric practice. In: The importance of low osmolar media to clinical radiology. Franklin Scientific Publications, 1984.

53. Steiner RM, Grainger RG, Menon N, Weiss D, Kanofsky PB, Menduke H. The effect of contrast media of low osmolality on the peripheral arterial blood flow of the dog. Clin Radiol 1980;31:621-627.

54. Golman K, Olivercrona H, Gustafson C, Salvesen S, Almen T, Maly P. Excitation and depression of non-anaesthetised rabbits following injection of contrast media into the subarachnoid space. Acta Radiol

55. Ansell G, Tweedie Mc K, West CR, Price Evans DA, Couch L. The current status of reactions to intravenous contrast media. Invest Radiol

56. Metrizamide-a non-ionic water-soluble contrast medium. Acta Radiol (suppl335) 1973.

57. Kendall B, Schneidau A, Stevens J , Harrison M. Clinical trial of iohexol for lumbar myelography. Br J Radiol 1983;56:539-542.

58. Carella A, Frederico F, Di Cuonzo F, Vinjau E, Lamberti P. Adverse side effects of metrizamide and iopamidolo in myelography. Neuroradiology 198222247-249,

59. Bartels JE, Braund KG, Redding RW. An experimental evaluation of a non-ionic agent Amipaque (metrizamide) as a neuroradiologic medium in the dog. Vet Radiol 1977;18:117-123.

1983;4:851-853.

144-1 45.

(SUPPI 362) 198083-86.

1980; 15(~~ppl):S32-S39.


60. Davis EM, Glickman L, Rendano VT, Short CE. Seizures in dogs following metrizamide myelography. J Am Anim Hosp Assoc 1981;17: 642-648.

61. Adams HM, Stowater JL. Complications of metrizamide myelography in the dog: a summary of 107 case histories. Vet Radiol 1981;22:27-33.

62. Bartels JE, Braund KG. Experimental arachnoid fibrosis produced by metrizamide in the dog. Vet Radiol 1980;21:78-81.

63. Northington JW. Metrizamide myelography in five dogs and two cats with suspected spinal cord neoplasms. Vet Radiol 1980;21:149-155.

64. Stowater JL, Kneller SK, Froehlich PS. Metrizamide myelography in two horses. Vet Med & Small Anim Clin 1978;73:177-183.

65. Beech J . Metrizamide myelography in the horse. J Am Vet Rad SOC 1979;20:22-32.

66. Nyland TG, Blythe L, Pool R, Helphrey M, O'Brien TR. Metriz- amide myelography in the normal horse: clinical, radiographic and patho- logic findings. J Am Vet Rad SOC 1979;2066.

67. Nyland TG, Blythe LL, Pool RR, Helphrey MG, O'Brien TR.

Metrizamide myelography in the horse: clinical, radiographic, and patho- logic changes. Am J Vet Res 1980;41:204-211.

68. Conrad RL. Metrizamide myelography of the equine cervical spine. Vet Radiol 1984;25:73-77.

69. Kendall B, Stevens J. Cervical myelography with iohexol. Br J Radiol 1984;57:785-787.

70. Lamb JT. A comparison of iopamidol and iohexol for myelography. Neuroradiology 1984;26: 157.

71. May SA, Wyn-Jones G, Church S, Brouwer GJ, Jones RS. Iopa- midol myelography in the horse. Equine Vet J 1986;18:199-202.

72. Wheeler SJ, Clayton Jones DG, Wright JA. Myelography in the cat. J Small Anim Pract 1985;26143-152.

73. Dotter C, Jackson F. Death following angiocardiography. Radi- ology 1950;54:527.

74. Snider G. Primary pulmonary hypertension: a fatality during pulmonary angiography. Chest 1973;64:628.

75. Higgins CB. Effects of contrast materials on left ventricular function. Invest Radiol 1980;15(suppl):S220-S231.

EDITORIAL POLICY

Veterinary Radiology is published bimonthly under the direction of the Editor and Associate Editors, as the Official Journal of the American College of Veterinary Radiology and the International Veterinary Radiology Association. Its purposes are to establish and maintain the highest feasible standards for the publication of matters pertaining to veterinary radiology and allied disciplines, to sustain its recognition as an established refereed journal which is the one of choice for the best presentation and largest select readership for publications related to veterinary radiology, and to serve as a source of continuing education in veterinary radiology and allied disciplines. This journal invites original reports of basic and applied investigation in all aspects of veterinary radiology and alternative imaging and therapeutic technics as well as reports concerning the clinical application of these diagnostic and therapeutic modes. This journal will serve as a forum for the interests of radiologists and allied specialists, as well as practicing clinicians. Readers may comment on anything pertaining to the scope of the journal by writing to the Editor. Although all journal content will be scrutinized carefully, neither the journal staff nor the American College of Veterinary Radiology is responsible for the validity of the observations reported by authors whose manuscripts are published. No manuscript can be published until a transfer of copyright agreement has been completed in accordance with Public Law 94-553 (see Instructions to Authors).

LOW OSMOLAR CONTRAST MEDIA A Review

Documents

Transcript of LOW OSMOLAR CONTRAST MEDIA A Review