The studies on the possibility of preparing IV fat emulsions began in the 1920's; since then, a very large number of emulsions with various fats and emulsifiers have been investigated. However, none of the early fat emulsions could be used safely in man. By the trial and error technique, a method was finally found to prepare soybean oil and egg yolk phospholipids to make a fat emulsion that had a low incidence of adverse reactions. A newly devised biological test system based on nutritional concepts was of crucial importance. It meant that any energy supplying nutrient should be tested in animals in relation to the energy requirement of the species used and not identical to the human dose/kg body weight as in the "classical" toxicity and tolerance tests. With the development of well-tolerated IV fat emulsions it has been possible to devise a TPN regimen that is adequate from a nutritional point of view as well as an adequate alternative to the ordinary oral food. This regimen, which can be administered by the peripheral route, means that the original aims for developing IV fat emulsions were finally achieved.

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Effect of intravenously injected iodinated lipid emulsion on the liver. An experimental study correlating computed tomography findings with in vivo microscopy and electron microscopy findings.

Iodinated lipid emulsions have been shown to have great potential as site specific contrast media for the liver and spleen. Because of unacceptable adverse reactions none of these emulsions has been adopted for clinical use. In an attempt to find an explanation for these adverse reactions we tested three iodinated lipid emulsions, EOE-13, AG 60.99 and AG 66.18. The following models were used: Computed tomography (CT) of the rabbit liver, in vivo microscopy and electron microscopy of the rat liver. The emulsions contained particles of different sizes and were used in varying doses. We found that the larger the emulsion particles, the more likely they were to be taken up by the Kupffer cells and thereby the higher the opacification of the liver achieved at CT. We also observed changes in the microcirculation of the liver when the emulsions were given in doses required to secure satisfactory opacification of the liver at CT. The main changes were 1) a marked increase in the size of the Kupffer cells, and 2) damage to the sinusoidal endothelium, both contributing to sinusoidal congestion. These changes strongly suggest activation of the macrophages and this in turn probably results in the release of toxic mediators. We suspect that the adverse reactions observed in patients when using iodinated lipid emulsions are due to these toxic mediators.

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Experimental investigation of a new iodinated lipid emulsion for computed tomography of the liver.

Iodinated lipid emulsions are highly efficient macrophage imaging agents. Nevertheless, none of them has been accepted for clinical use because of adverse reactions. We have tested a new iodinated lipid emulsion, Intraiodol. The size and surface properties of the particles of this emulsion are similar to those of Intralipid which in turn closely resemble the naturally occurring chylomicrons. Using computed tomography (CT) of the rabbit liver as well as vital microscopy and electron microscopy of the rat liver we found that Intraiodol has low efficiency as a liver-specific contrast medium because its particles are predominantly taken up by the hepatocytes and to a less extent by the Kupffer cells, as is Intralipid. The low efficiency of Intraiodol could be fully compensated by an increase in dosage without any significant effect on sinusoidal blood flow. This in turn suggests that the likelihood of release of toxic mediators (and thereby related adverse reactions from activated macrophages) is reduced. We believe that this new way of delivering iodinated lipid particles to the liver represents an important advance in the search for a non-toxic lipid emulsion for CT of the liver.

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Clinical trials with a new iodinated lipid emulsion for computed tomography of the liver.

A new iodinated lipid emulsion, Intraiodol, for which animal studies have indicated better tolerance than for other iodinated lipid emulsions, was tested in 15 patients with malignant lesions, and in one patient with focal nodular hyperplasia. Repeated CT scans of the liver and spleen and blood tests were performed for 24 hours after intravenous injection of Intraiodol. The uptake of Intraiodol in the liver (peak mean 28.6 HU) was higher than in the spleen (peak mean 21.8 HU). The uptake of Intraiodol in malignant lesions was minimal (peak mean 2.8 HU). The detection rate of hepatic lesions was equal to or better than that achieved by US, CT, and/or CT angiography. However, liver uptake of Intraiodol was low in 2 patients with severe fatty infiltration. Intraiodol produced vascular enhancement up to one hour after injection since it was eliminated slowly from the circulation. The observed adverse reactions consisted of temporary metallic taste in 5 of the patients, fever and exacerbation of back pain in one patient, and transient thrombocytopenia in one patient. Alkaline phosphatase increased (17%, p less than 0.01) only at two hours, and erythrocyte count (6%, p less than 0.05) at 24 hours after injection. Our initial results indicate diagnostic advantages of Intraiodol without serious adverse reactions. Further clinical studies are required to confirm these findings.

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