Magnetic Resonance Printed in the USA.
Imaging, Vol. 8, pp. 589-598, All rights reserved.
1990 Copyright
0730-725x/w $3.00 + .oo 0 1990 Pergamon Press plc
l Original Contribution
PARAMAGNETIC OIL EMULSIONS AS ORAL MAGNETIC RESONANCE IMAGING CONTRAST AGENTS KING C.P. LI, PETERG.P. ANG, ROGER P. TART, BRETT L. STORM, RICHARD
ROLFES, AND PAUL C.K.
HO-TAI
Department of Radiology, University of Florida College of Medicine, Gainesville, Florida 82610, USA The combination of a paramagnetic agent with an oil emulsion can uniformly enhance the small bowel. Wediscovered that the entire small bowel becomes homogeneously brighter than its surroundings when imaged with all commonly utilized pulse sequences. We have tried various combinations of ferric ammonium citrate, ferrous sulfate, gadolinium-DPTA and corn oil, olive oil and peanut oil. All paramagnetic oil emulsions tested were uniformly distributed throughout the small bowel, but the enhancement effect is much stronger with the ferric ammonium citrate and gadolinium-DPTA oil emulsions. We have also developed a mixture of Geritol, corn oil, ice cream and milk, which uniformly coats the small bowel wall, has good enhancement effect, tastes good, and is nutritious. With this dietary con&as& retroperitoneal structures including the pancreas can be well delineated. We conclude that the combination of a paramagnetic agent with an oil emulsion can work as a safe and effective magnetic resonance imaging (MRI) oral contrast agent with high patient acceptance. Keywords: Contrast media; Magnetic resonance (MR); Contrast media, oral; Contrast media, fatty acids; Contrast media. effects.
oil emulsion so that the advantages of both groups of substances can be combined.
INTRODUCTION
In the past few years, a variety of agents have been advocated as potential oral magnetic resonance imaging (MRI) contrast agents. However, none of these agents satisfies all of the criteria of an “ideal” agent, which includes (i) uniform effect throughout the gastrointestinal tract, (ii) good patient acceptance, (iii) no side effects, and (iv) ability to mix freely with intestinal contents. In a previous experiment,’ we found that very concentrated oil emulsions distribute uniformly throughout the small bowel, but the enhancement effect is not adequate when Tl -weighted spin-echo pulse sequences are used. We also found that Geritol (Nabisco, Inc., East Hanover, NJ) can produce significant enhancement effects with all commonly used spin-echo (SE) and gradient-echo pulse sequences, but the distribution in the gastrointestinal (GI) tract is unpredictable.’ The purpose of this study is to develop a paramagnetic
MATERIALS
AND METHODS
In Vitro Experiments
Ten percent volume per volume (v/v) melted ice cream (Breyers vanilla ice cream, Kraft, Inc., Glenview, IL) with 8% fat content, was mixed, using a blender operated at high speed for approximately 2 min, with various concentrations of Mazola corn oil (CPC International, Englewood Cliffs, NJ) (5% to 50% v/v at 5% increments) and the corresponding concentrations of homogenized milk (85% to 20% v/v at 5% decrements). Similar emulsions were prepared by using 20% and 30% melted ice cream and the same variations of corn oil concentrations (5% to 50% v/v) and the corresponding concentrations of homogenized milk (75% to 10% and 65% to 0% v/v, respectively).
RECEWED 2/21&O; ACCEPTED 4/2/90. AcknowledgmentsWe thank Ms. Barbara Martineau for providing us with tremendous editorial assistance and Ms. Linda Pigott for typing the manuscript.
Address correspondence and reprint requests to King C.P. Li, M.D., Radiology & Imaging Associates, 550 West Thomas Rd., Suite 208A, Phoenix, AZ 85013, USA. 589
590
Magnetic Resonance Imaging 0 Volume 8, Number 5, 1990
For comparison, corn oil-milk emulsions were prepared by mixing lo%, 30% and 50% v/v corn oil with 90%, 70% and 50% v/v of milk, respectively. Similarly, ice cream-milk emulsions were prepared by mixing lo%, 30% and 50% v/v ice cream with 90%, 70%, and 50% milk. Two volunteers tasted all of the different emulsions and graded them on a scale of 0 to 10, with 0 being intolerable and 10 being good. Five ml of each emulsion was then placed into separate test tubes and imaged using a 1.5 T Siemens Magnetom 63 (Erlangen, West Germany) MR imager with IO-mm contiguous sections. SE pulse sequences with repetition time (TR) of 2000 msec, echo time (TE) of 45 and 90 msec, TR of 550 msec, and TE of 22 msec were used. Images were also obtained using gradient echo FLASH (Fast Low Angle Shot) pulse sequences with TR of 40 msec, TE of 18 msec and flip angles of lo”-90” at 10” increments. Signal intensities (SI) and standard deviations (SD) of the different emulsions at the different pulse sequences were also measured using the largest regions of interest possible. Geritol-oil emulsions were prepared by mixing 30% v/v of ice cream and 20% v/v of corn oil and 2% to 20% of Geritol at 2Vo increments and the corresponding amounts of milk (48% to 30% v/v at 2% decrements). Similar preparations were made by using 10% v/v and 0% corn oil, the same variation of Geritol concentrations and the corresponding amounts of milk. For comparison, pure water, pure homogenized milk, pure Geritol, pure corn oil, and Geritolmilk solutions with 4% to 20% v/v of Geritol at 4% increments were also prepared. These emulsions were subjected to taste tests and imaging tests as described above. In Vivo Experiments From the in vitro data, five different combinations were chosen on the basis of taste and enhancement effect and tested on human volunteers, one for each combination. The different combinations tested contained 20% v/v of corn oil and 30% v/v of ice cream and 4%, 6%, 8%, lo%, 12% v/v of Geritol and 46%, 44%, 42070,40% and 38% v/v of milk, respectively. For comparison, three different combinations of oil emulsions without Geritol were tested on three human volunteers. The combinations tested contained 30% v/v of ice cream, 15070,2O(rlo,25% v/v of corn oil and 55070,50% and 45% v/v of milk, respectively. The volunteers did not eat or drink anything at least four hours prior to ingestion of the emulsions. Five hundred ml of the oil emulsions were ingested uniformly over a two-hr period prior to scanning. All images were obtained using a 1.5 T Siemens Magnetom 63 MR imager using SE 2000/45/90, SE 550122 and
FLASH 50/15/40” pulse sequences. The volunteers were asked to grade the emulsions on a scale of 1 to 5 based on (i) the taste of the contrast (1 being great and 5 being intolerable), (ii) the amount of nausea experienced (1 being none and 5 being severe vomiting), and (iii) the amount of abdominal cramps (1 being none and 5 being severe). The volunteers also recorded the duration of discomfort, the timing and frequency of bowel movements and the overall impression of the contrast. The images were then reviewed jointly by two radiologists to evaluate the ability of the contrast agent to opacify the GI tract and to enhance delineation of the different abdominal organs. The delineation of the abdominal organs were scored on a scale of 1 to 5, 1 being very poor and 5 being excellent. From the initial in vivo data, the optimal combination was found to be 30% v/v of ice cream, 20% v/v of corn oil, 12% v/v of Geritol, and 38% v/v of milk. This combination was tested by five normal volunteers using the previously described ingestion protocol. Images were then obtained using a 1.5 T GE Signa MR imager using SE 2000/45/90, SE 550/30 and GRASS 50/15/40” pulse sequences. The volunteers and radiologists evaluated the contrast and images as described previously. In order to establish the fact that combinations of different types of paramagnetic agents with different types of oil can be effective, we tested five different combinations of generic components: 1. 1 mM water 2. 1 mM 3. 1 mM 4. 1 mM 5. 1 mM
ferric ammonium citrate, 20% v/v corn oil, Cd-DPTA, 20% v/v Cd-DPTA, 20% v/v Cd-DTPA, 20% v/v ferrous sulfate, 20%
corn oil, water peanut oil, water soybean oil, water v/v corn oil, water.
Each combination was tested on one normal volunteer. The ingestion, imaging and evaluation protocols were the same as the optimized Geritol-oil emulsions. RESULTS In Vitro Experiments The taste test and signal intensity measurement results are summarized in Figs. l-3. For brevity, the signa1 intensity measurement results of only one gradient echo pulse sequence (FLASH 40/18/30”), which was used in the in vivo study, are shown. From Fig. 1, it is apparent that corn oil emulsions with no ice cream tastes very bad. Increasing the amount of ice cream content leads to definite improvement in taste. Similar findings were obtained with the Geritol-oil emulsions, as shown in Fig. 2. Note that Geritol solutions with no ice cream or corn oil taste better than plain oil emulsions.
Paramagnetic oil emulsions as oral MRI contrast agents 0 K.C.P. LI or
0
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+
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-
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Fig. 1. Taste test results of various oil emulsions. Note the low taste score of corn oil emulsions without ice cream. Also note that increasing the ice cream content leads to definite improvement in taste.
From Figs. 3(A)-(D), it is apparent that the addition of ice cream to the corn oil emulsion leads to a decrease in the signal intensity. However, the effect is relatively insignificant, except when T2-weighted SE pulse sequence is used (Fig. 3(B)). The difference between lo%, 20% and 30% v/v of ice cream is not very large, except in TZ-weighted SE and gradient echo with a large flip angle. Because of the better taste with the higher concentration of ice cream, 30% v/v ice cream was later used for the preparation of Geritol-oil emulsions. The intensity of the corn oil emulsions peaks at approximately 40% v/v corn oil at SE 550122, but peaks at 15%-25% for the other pulse sequences. Therefore, a concentration of 20% v/v of corn oil was used for the preparation of Geritol-oil emulsions for the in vivo study. From Fig. 3(D), it is apparent that pure corn oil has the highest signal at SE
550/22 and pure water has the highest signal with the other sequences. It is also apparent that none of the unmixed components has a high signal intensity with all of the pulse sequences. From Figs. 4(A)-(C), it is apparent that the addition of ice cream and corn oil to Geritol solutions leads to a decrease in the signal intensity in all pulse sequences. The higher concentration of corn oil leads to a greater loss of signal in all pulse sequences. However, the signal intensity increases with the concentration of Geritol from 2.5% v/v to a peak of 7.5%12.5% v/v and then decreases again. Therefore, it is apparent that for maximum enhancement effect, a concentration of 7.5% to 12.5% v/v of Geritol should be used. No significant difference between the signal intensity of 10% and 20% v/v of corn oil is seen with the SE pulse sequences and only a small difference is
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Fig. 4. (A) Signal intensities of Geritol-oil emulsions at SE 550/22. The signal intensity of Geritol emulsions without corn oil or ice cream decreases with increasing concentration of Geritol. The addition of 30% ice cream alone decreases the signal intensity significantly especially with 2.5% to 10% and 16% to 20% v/v Geritol. The addition of corn oil further decreases the signal intensity, but there is no difference between 10% and 20% v/v of corn oil. (B) Signal intensities of Geritol-oil emulsions at SE 2000/W The trends-of signal intensities are similar to that obtained using SE 550/22. However, the differences between Geritol alone, Geritol plus ice cream and Geritol-oil emulsions are greater. There is again no significant difference between 10% and 20% v/v of corn oil. (C) Signal intensities of Geritol-oil emulsions at FLASH 40/18/30”. The trends of signal intensities are similar to that obtained using SE 2000/W, except that there is a decrease in signal intensity associated with increasing content of corn oil. (D) Signal intensities of unmixed components of Geritol-oil emulsions. Corn oil has by far the highest signal intensity at SE 550/22, but low signal intensity at SE 2090/!90. Geritol has intermediate signal intensity at SE 550/22 and very low signal intensity at 2000/90, due to the T2 shortening effect of high concentrations of ferric ammonium citrate. Note also that none of the unmixed components have high signal intensity with all pulse sequences tested.
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594
Magnetic Resonance Imaging 0 Volume 8, Number 5, 1990 Table 1. Initial in vivo optimization
Contrast agent (olo v/v)
Taste=
Nauseab
Abdominal crampsc
study using different concentrations
Organ delineationd with best sequence
070 Small bowel opacified
of contrast agents
Degree of bowel enhancemenP SE 550/22
SE 2000/90
FLASH 50/15/40
a. Geritol (with 20% v/v corn oil, 30% v/v ice cream) 4 6 8 10 12
1 1 1 2 2
1 1 1 1 1
1 1 1 1 1
2 3 4 4 5
20 50 70 80 >90
1 2 3 4 5
4 4 4 5 5
1 1 1
1 1 1
3 3 4
60 70 70
1 2 2
4 4 4
b. Corn oil (with milk) 15 20 25
3 3 4
3 3 3
a I = Great; 5 = Intolerable b 1 = None; 5 = Severe, vomiting ’ 1 = None; 5 = Severe d 1 = Very poor; 5 = Excellent ’ 1 = Very poor;
5 = Excellent
noted with the gradient echo pulse sequences. From Fig. 4(D), it is obvious that none of the unmixed components has high signal intensity with all the pulse sequences. In Vivo Experiments Table la summarizes the results of the in vivo optimization study using different concentrations of Geritol mixed with 20% v/v corn oil, 30% v/v ice cream and milk. From this study, it is apparent that increasing the concentration of Geritol leads to better enhancement of the bowel with Ti-weighted SE and gradient echo pulse sequences. The percentage of small bowel opacified and the degree of organ delin-
eation is also increased with increasing concentrations of Geritol, but the taste is worse. From this study, we conclude that the optimal Geritol-oil emulsion should contain 12% v/v of Geritol, 20% v/v of corn oil, 30% v/v of ice cream, and 38% v/v of milk. Table lb summarizes the results of the in vivo optimization study using different concentrations of corn oil with corresponding amounts of milk. It is obvious from this study that the enhancement effect of oil emulsion alone is inadequate, especially with the T, weighted SE sequence. The taste is also fairly bad, especially with the higher concentrations of oil. However, the distribution throughout the bowel is fairly uniform with the higher concentrations of oil.
Table 2. In vivo study using the optimized Geritol-oil emulsion (30% v/v ice cream, 20% v/v corn oil, 12% v/v Geritol, 38% v/v milk)
Volunteer
Taste=
Nauseab
2 2 1 1 2
1 1 1 1 1
1 2 3 4 5 a 1 = Great; b c d ’
1= 1= 1= 1=
None; None; Very poor; Very poor;
5= 5= 5= 5= 5=
Abdominal crampsC
Intolerable Severe, vomiting Severe Excellent Excellent
1 1 1 1 1
Organ delineationd with best sequence 5 5 5 4 4
% Small bowel opacified >90 >90 >90 80 80
Degree of bowel enhancemenP SE 550/22
SE 2000/90
GRASS 50/15/40
5 5 5 5 5
5 5 5 5 5
5 5 5 5 5
Paramagnetic oil emulsions as oral MRI contrast agents 0 K.C.P. LI ET AL.
A
595
B
Fig. 5. (A)-(B) GRASS 50/15/40” coronal images obtained using Geritol-oil
emulsion (ice cream 30070,corn oil 20070,Geritol 12070,and milk 38% v/v). (A) Notice the excellent enhancement and uniform distribution throughout the small bowel. (B) Cornonal image at a more anterior location. Notice that even valvulae conniventes are well delineated. Also note that there is good differentiation between the colon filled with low intensity gas and the small bowel filled with high intensity contrast.
Table 3. In vivo study using various combinations
Tastea
Components
Nauseab
Abdominal crampsC
Organ delineationd with best sequence
of generic components % Small bowel opacified
Degree of bowel enhancemenF SE 550/22
SE 2000/90
GRASS SO/ 1S/40
1 mM ferric ammonium citrate + 20% v/v corn oil + water
3
1
1
5
80
4
5
5
1 mM Gd-DPTA + 20% v/v corn oil + water
3
1
1
5
>90
5
5
5
1 mM Gd-DPTA + 20% v/v peanut oil + water
3
1
1
5
>90
5
5
5
1 mM Gd-DPTA + 20% v/v soybean oil + water
3
1
1
5
80
5
5
5
1 mM ferrous sulfate + 20% v/v corn oil + water
4
1
1
4
80
3
5
3
a 1 = Great; b ’ d e
1= 1= 1= 1=
None; None; Very poor; Very poor;
5= 5= 5= 5= 5=
Intolerable Severe, vomiting Severe Excellent Excellent
596
Magnetic Resonance Imaging 0 Volume 8, Number 5, 1990
Table 2 summarizes the results of the in vivo study using the optimized Geritol-oil emulsion in live volunteers. The distribution in the small bowel is slightly variable, but in general is very good and much better than Geritol alone. The degree of bowel enhancement and organ delineation was also very good to excellent in all of the volunteers (Figs. 5-7) and the taste was also rated very good to excellent in all cases. From this study, it is obvious that the optimized Geritol-oil emulsion satisfies all the criteria of an ideal oral MRI contrast agent and promises to be extremely useful clinically. Table 3 summarizes the results of the in vivo study using various combinations of generic components. Without the ice cream, the generic combinations tasted fairly bad. However, the distribution throughout the small bowel and degree of opacification are very good to excellent with the various combination of ferric ammonium citrate, Gd-DTPA and the various
vegetable oils (Fig. 8). Compared with the other two paramagnetic substances tested, ferrous sulfate produced less enhancement effect. Soybean oil emulsion appeared to have a less uniform distribution throughout the bowel. From this study, it is obvious that many different combinations of paramagnetic agents and an oil can work very well as an oral MRI contrast agent. DISCUSSION
In the past few years, a variety of agents have been advocated as potential oral MRI contrast agents. However, none of these agents satisfies all of the criteria of an “ideal” agent. The potential oral MRI contrast agents that have been proposed can be divided into four different categories. The first group consists of miscible-positive agents, such as MnC12,2,3 ferric citrate,4 metal chelates,5 and Gd-DPTA.6 The disadvantages of these agents include significant dilutional
Fig. 6. (A)-(D) Sequential axial images obtained using GRASS 50/15/40” and Geritol-oil emulsion. Notice the uniform enhancement of the entire small bowel and excellent delineation of retroperitoneal structures.
Paramagnetic oil emulsions as oral MRl contrast agents 0 K.C.P. LI ET AL.
Fig. 7. (A)-(C) Coronal images of a female volunteer obtained using Geritol-oil emulsion with GRASS 50/15/40” (A), SE 550/30 (B), and SE 2OOO/!Xl (C). Notice the uniform enhancement of the entire small bowel with all three pulse sequences.
effects from gastric, biliary and pancreatic secretions in the proximal small bowel and complex absorptive process in the distal small bowel, resulting in unpredictable and varying concentrations in the GI tract. The second group consists of miscible-negative agents such as ferrite. ‘,’ The disadvantages of this group include the fact that with high concentrations, the homogeneity of the magnetic field may be distorted. This is especially detrimental in gradient-echo imaging. The third group consists of immiscible-positive
agents. The major disadvantage of this group is that even with very concentrated oil emulsions, the enhancement effect is not adequate when ri-weighted pulse sequences are used. The fourth group consists of immiscible-negative agents such as CO2 gas tablets, perfluorocarbonsgJO and kaolin-pectin. This group has high potential; however, CO* is limited to applications to the proximal GI tract. Perfluorocarbons are not currently FDA-approved for clinical use and kaolin-pectin may cause severe constipation in the dosages suggested.
Magnetic Resonance Imaging 0 Volume 8, Number 5, 1990
unteer obtained using GRASS 50/15/40”, 1 mM Gd-DTPA, Fig. 8. (A)-(B) Axial images of the lower abdomen of a male VOll and 20% soybean oil emulsified in water. Notice the uniform enh rancement of the distal small bowel without significant dilutional effect.
Our new concept of a MRI oral contrast agent is to combine a paramagnetic agent with an oil emulsion. Our prototype agent is a mixture of corn oil, ice cream, milk, and Geritol. (Geritol is a commercially available dietary supplement which contains in each l/2 fluid ounce: 50 mg ferric ammonium citrate, 2.5 mg thiamine, 2.5 mg riboflavin, 50 mg niacinamide, 2 mg panthenol, 0.5 mg pyridoxine, 0.75 mg cyanocobalamin, 25 mg methionine, 50 mg choline bitartrate, and 12% v/v of alcohol.) With this prototype, all of the criteria for an ideal oral MRI contrast agents were satisfied. We have also shown that a variety of different combinations of paramagnetic agents and oils can work very well as oral MRI contrast agents. In conclusion, we believe that our new concept forms the basis for making many different products by varying the paramagnetic agent involved and the ingredients of the oil emulsions. This family of compounds can then be used as MRI GI contrast agents.
Chem. Phys. Med. NMR 16:123-128;
1. Li, K.C.P.; Tart, R.P.; Storm, B.; RoIfes, R.; Ang, P.; Ros, P.R. MRI oral contrast agents: Comparative study of five potential agents in humans. Proceedings of the Eighth Annual Meeting of the Society of Magnetic Resonance in Medicine, Amsterdam, August 1989; p. 791.
2. Burnett, K.R.; Goldstein, E.J.; Wolf, G.L.; Sen, S.; Mamourian, A.C. The oral administration of MnCI,: A potential alternative to i.v. injection for tissue contrast enhancement in magnetic resonance imaging. 1984.
1984.
Wesbey, G.E.; Brasch, R.C.; Goldberg, H.I.; Engelstad, B.L.; Moss, A.A. Dilute oral iron solutions as gastrointestinal contrast agents for magnetic resonance imaging: initial clinical experience. Magn. Reson. Imaging 3:57-64; 1985. Runge, V.M.; Stewart, R.G.; Clanton, J.A.; Jones, M.M.; Lukehart, C.M.; Partain, C.L.; James, A.E., Jr. Work in Progress. Potential oral and intravenous paramagnetic NMR contrast agents. Radiology 147:789-791; 1983.
6.
7.
8.
REFERENCES
Magn. Reson. Imaging 12:307-314;
Mamourian, A.C.; Burnett, K.R.; Goldstein, E.J.; Wolf, G.L.; Kressel, H.Y.; Baum, S. Proton relaxation enhancement in tissue due to ingested manganese chloride: Time course and dose response in the rat. Physiol.
9.
Laniado, M.; Kornmesser, W.; Hamm, B.; Clauss, W.; Weinmann, H.; Felix, R. MR imaging of the gastrointestinal tract: Value of Gd-DPTA. AJR 150:817-821; 1988. Widder, D. J.; Edelman, R.R.; Grief, W.L.; Monda, L. Magnetite albumin suspension: a superparamagnetic oral MR contrast agent. AJR 149:839-843; 1987. Hahn, P.F.; Stark, D.D.; Sanjay, S.; Lewis, J.M.; Wittenberg, J.; Ferrucci, J.T. Ferrite particles for bowel contrast in MR imaging: Design issues and feasibility studies. Radiology 164:37-41; 1987. Mattrey, R.F. Perfluorocytlbromide: A new contrast agent for CT, sonography, and MR imaging. AJR 152: 247-252;
1989.
10. Mattrey, R.F.; Hajek, P.C.; Gylys-Morin, V.M.; Baker, L.L.; Martin, J.; Long, D.C.; Long, D.M. Perfluorochemicals as gastrointestinal contrast agents for MR imaging: Preliminary studies in rats and humans. AJR 148:1259-1263;
1987.
Imaging, Vol. 8, pp. 589-598, All rights reserved.
1990 Copyright
0730-725x/w $3.00 + .oo 0 1990 Pergamon Press plc
l Original Contribution
PARAMAGNETIC OIL EMULSIONS AS ORAL MAGNETIC RESONANCE IMAGING CONTRAST AGENTS KING C.P. LI, PETERG.P. ANG, ROGER P. TART, BRETT L. STORM, RICHARD
ROLFES, AND PAUL C.K.
HO-TAI
Department of Radiology, University of Florida College of Medicine, Gainesville, Florida 82610, USA The combination of a paramagnetic agent with an oil emulsion can uniformly enhance the small bowel. Wediscovered that the entire small bowel becomes homogeneously brighter than its surroundings when imaged with all commonly utilized pulse sequences. We have tried various combinations of ferric ammonium citrate, ferrous sulfate, gadolinium-DPTA and corn oil, olive oil and peanut oil. All paramagnetic oil emulsions tested were uniformly distributed throughout the small bowel, but the enhancement effect is much stronger with the ferric ammonium citrate and gadolinium-DPTA oil emulsions. We have also developed a mixture of Geritol, corn oil, ice cream and milk, which uniformly coats the small bowel wall, has good enhancement effect, tastes good, and is nutritious. With this dietary con&as& retroperitoneal structures including the pancreas can be well delineated. We conclude that the combination of a paramagnetic agent with an oil emulsion can work as a safe and effective magnetic resonance imaging (MRI) oral contrast agent with high patient acceptance. Keywords: Contrast media; Magnetic resonance (MR); Contrast media, oral; Contrast media, fatty acids; Contrast media. effects.
oil emulsion so that the advantages of both groups of substances can be combined.
INTRODUCTION
In the past few years, a variety of agents have been advocated as potential oral magnetic resonance imaging (MRI) contrast agents. However, none of these agents satisfies all of the criteria of an “ideal” agent, which includes (i) uniform effect throughout the gastrointestinal tract, (ii) good patient acceptance, (iii) no side effects, and (iv) ability to mix freely with intestinal contents. In a previous experiment,’ we found that very concentrated oil emulsions distribute uniformly throughout the small bowel, but the enhancement effect is not adequate when Tl -weighted spin-echo pulse sequences are used. We also found that Geritol (Nabisco, Inc., East Hanover, NJ) can produce significant enhancement effects with all commonly used spin-echo (SE) and gradient-echo pulse sequences, but the distribution in the gastrointestinal (GI) tract is unpredictable.’ The purpose of this study is to develop a paramagnetic
MATERIALS
AND METHODS
In Vitro Experiments
Ten percent volume per volume (v/v) melted ice cream (Breyers vanilla ice cream, Kraft, Inc., Glenview, IL) with 8% fat content, was mixed, using a blender operated at high speed for approximately 2 min, with various concentrations of Mazola corn oil (CPC International, Englewood Cliffs, NJ) (5% to 50% v/v at 5% increments) and the corresponding concentrations of homogenized milk (85% to 20% v/v at 5% decrements). Similar emulsions were prepared by using 20% and 30% melted ice cream and the same variations of corn oil concentrations (5% to 50% v/v) and the corresponding concentrations of homogenized milk (75% to 10% and 65% to 0% v/v, respectively).
RECEWED 2/21&O; ACCEPTED 4/2/90. AcknowledgmentsWe thank Ms. Barbara Martineau for providing us with tremendous editorial assistance and Ms. Linda Pigott for typing the manuscript.
Address correspondence and reprint requests to King C.P. Li, M.D., Radiology & Imaging Associates, 550 West Thomas Rd., Suite 208A, Phoenix, AZ 85013, USA. 589
590
Magnetic Resonance Imaging 0 Volume 8, Number 5, 1990
For comparison, corn oil-milk emulsions were prepared by mixing lo%, 30% and 50% v/v corn oil with 90%, 70% and 50% v/v of milk, respectively. Similarly, ice cream-milk emulsions were prepared by mixing lo%, 30% and 50% v/v ice cream with 90%, 70%, and 50% milk. Two volunteers tasted all of the different emulsions and graded them on a scale of 0 to 10, with 0 being intolerable and 10 being good. Five ml of each emulsion was then placed into separate test tubes and imaged using a 1.5 T Siemens Magnetom 63 (Erlangen, West Germany) MR imager with IO-mm contiguous sections. SE pulse sequences with repetition time (TR) of 2000 msec, echo time (TE) of 45 and 90 msec, TR of 550 msec, and TE of 22 msec were used. Images were also obtained using gradient echo FLASH (Fast Low Angle Shot) pulse sequences with TR of 40 msec, TE of 18 msec and flip angles of lo”-90” at 10” increments. Signal intensities (SI) and standard deviations (SD) of the different emulsions at the different pulse sequences were also measured using the largest regions of interest possible. Geritol-oil emulsions were prepared by mixing 30% v/v of ice cream and 20% v/v of corn oil and 2% to 20% of Geritol at 2Vo increments and the corresponding amounts of milk (48% to 30% v/v at 2% decrements). Similar preparations were made by using 10% v/v and 0% corn oil, the same variation of Geritol concentrations and the corresponding amounts of milk. For comparison, pure water, pure homogenized milk, pure Geritol, pure corn oil, and Geritolmilk solutions with 4% to 20% v/v of Geritol at 4% increments were also prepared. These emulsions were subjected to taste tests and imaging tests as described above. In Vivo Experiments From the in vitro data, five different combinations were chosen on the basis of taste and enhancement effect and tested on human volunteers, one for each combination. The different combinations tested contained 20% v/v of corn oil and 30% v/v of ice cream and 4%, 6%, 8%, lo%, 12% v/v of Geritol and 46%, 44%, 42070,40% and 38% v/v of milk, respectively. For comparison, three different combinations of oil emulsions without Geritol were tested on three human volunteers. The combinations tested contained 30% v/v of ice cream, 15070,2O(rlo,25% v/v of corn oil and 55070,50% and 45% v/v of milk, respectively. The volunteers did not eat or drink anything at least four hours prior to ingestion of the emulsions. Five hundred ml of the oil emulsions were ingested uniformly over a two-hr period prior to scanning. All images were obtained using a 1.5 T Siemens Magnetom 63 MR imager using SE 2000/45/90, SE 550122 and
FLASH 50/15/40” pulse sequences. The volunteers were asked to grade the emulsions on a scale of 1 to 5 based on (i) the taste of the contrast (1 being great and 5 being intolerable), (ii) the amount of nausea experienced (1 being none and 5 being severe vomiting), and (iii) the amount of abdominal cramps (1 being none and 5 being severe). The volunteers also recorded the duration of discomfort, the timing and frequency of bowel movements and the overall impression of the contrast. The images were then reviewed jointly by two radiologists to evaluate the ability of the contrast agent to opacify the GI tract and to enhance delineation of the different abdominal organs. The delineation of the abdominal organs were scored on a scale of 1 to 5, 1 being very poor and 5 being excellent. From the initial in vivo data, the optimal combination was found to be 30% v/v of ice cream, 20% v/v of corn oil, 12% v/v of Geritol, and 38% v/v of milk. This combination was tested by five normal volunteers using the previously described ingestion protocol. Images were then obtained using a 1.5 T GE Signa MR imager using SE 2000/45/90, SE 550/30 and GRASS 50/15/40” pulse sequences. The volunteers and radiologists evaluated the contrast and images as described previously. In order to establish the fact that combinations of different types of paramagnetic agents with different types of oil can be effective, we tested five different combinations of generic components: 1. 1 mM water 2. 1 mM 3. 1 mM 4. 1 mM 5. 1 mM
ferric ammonium citrate, 20% v/v corn oil, Cd-DPTA, 20% v/v Cd-DPTA, 20% v/v Cd-DTPA, 20% v/v ferrous sulfate, 20%
corn oil, water peanut oil, water soybean oil, water v/v corn oil, water.
Each combination was tested on one normal volunteer. The ingestion, imaging and evaluation protocols were the same as the optimized Geritol-oil emulsions. RESULTS In Vitro Experiments The taste test and signal intensity measurement results are summarized in Figs. l-3. For brevity, the signa1 intensity measurement results of only one gradient echo pulse sequence (FLASH 40/18/30”), which was used in the in vivo study, are shown. From Fig. 1, it is apparent that corn oil emulsions with no ice cream tastes very bad. Increasing the amount of ice cream content leads to definite improvement in taste. Similar findings were obtained with the Geritol-oil emulsions, as shown in Fig. 2. Note that Geritol solutions with no ice cream or corn oil taste better than plain oil emulsions.
Paramagnetic oil emulsions as oral MRI contrast agents 0 K.C.P. LI or
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Fig. 1. Taste test results of various oil emulsions. Note the low taste score of corn oil emulsions without ice cream. Also note that increasing the ice cream content leads to definite improvement in taste.
From Figs. 3(A)-(D), it is apparent that the addition of ice cream to the corn oil emulsion leads to a decrease in the signal intensity. However, the effect is relatively insignificant, except when T2-weighted SE pulse sequence is used (Fig. 3(B)). The difference between lo%, 20% and 30% v/v of ice cream is not very large, except in TZ-weighted SE and gradient echo with a large flip angle. Because of the better taste with the higher concentration of ice cream, 30% v/v ice cream was later used for the preparation of Geritol-oil emulsions. The intensity of the corn oil emulsions peaks at approximately 40% v/v corn oil at SE 550122, but peaks at 15%-25% for the other pulse sequences. Therefore, a concentration of 20% v/v of corn oil was used for the preparation of Geritol-oil emulsions for the in vivo study. From Fig. 3(D), it is apparent that pure corn oil has the highest signal at SE
550/22 and pure water has the highest signal with the other sequences. It is also apparent that none of the unmixed components has a high signal intensity with all of the pulse sequences. From Figs. 4(A)-(C), it is apparent that the addition of ice cream and corn oil to Geritol solutions leads to a decrease in the signal intensity in all pulse sequences. The higher concentration of corn oil leads to a greater loss of signal in all pulse sequences. However, the signal intensity increases with the concentration of Geritol from 2.5% v/v to a peak of 7.5%12.5% v/v and then decreases again. Therefore, it is apparent that for maximum enhancement effect, a concentration of 7.5% to 12.5% v/v of Geritol should be used. No significant difference between the signal intensity of 10% and 20% v/v of corn oil is seen with the SE pulse sequences and only a small difference is
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594
Magnetic Resonance Imaging 0 Volume 8, Number 5, 1990 Table 1. Initial in vivo optimization
Contrast agent (olo v/v)
Taste=
Nauseab
Abdominal crampsc
study using different concentrations
Organ delineationd with best sequence
070 Small bowel opacified
of contrast agents
Degree of bowel enhancemenP SE 550/22
SE 2000/90
FLASH 50/15/40
a. Geritol (with 20% v/v corn oil, 30% v/v ice cream) 4 6 8 10 12
1 1 1 2 2
1 1 1 1 1
1 1 1 1 1
2 3 4 4 5
20 50 70 80 >90
1 2 3 4 5
4 4 4 5 5
1 1 1
1 1 1
3 3 4
60 70 70
1 2 2
4 4 4
b. Corn oil (with milk) 15 20 25
3 3 4
3 3 3
a I = Great; 5 = Intolerable b 1 = None; 5 = Severe, vomiting ’ 1 = None; 5 = Severe d 1 = Very poor; 5 = Excellent ’ 1 = Very poor;
5 = Excellent
noted with the gradient echo pulse sequences. From Fig. 4(D), it is obvious that none of the unmixed components has high signal intensity with all the pulse sequences. In Vivo Experiments Table la summarizes the results of the in vivo optimization study using different concentrations of Geritol mixed with 20% v/v corn oil, 30% v/v ice cream and milk. From this study, it is apparent that increasing the concentration of Geritol leads to better enhancement of the bowel with Ti-weighted SE and gradient echo pulse sequences. The percentage of small bowel opacified and the degree of organ delin-
eation is also increased with increasing concentrations of Geritol, but the taste is worse. From this study, we conclude that the optimal Geritol-oil emulsion should contain 12% v/v of Geritol, 20% v/v of corn oil, 30% v/v of ice cream, and 38% v/v of milk. Table lb summarizes the results of the in vivo optimization study using different concentrations of corn oil with corresponding amounts of milk. It is obvious from this study that the enhancement effect of oil emulsion alone is inadequate, especially with the T, weighted SE sequence. The taste is also fairly bad, especially with the higher concentrations of oil. However, the distribution throughout the bowel is fairly uniform with the higher concentrations of oil.
Table 2. In vivo study using the optimized Geritol-oil emulsion (30% v/v ice cream, 20% v/v corn oil, 12% v/v Geritol, 38% v/v milk)
Volunteer
Taste=
Nauseab
2 2 1 1 2
1 1 1 1 1
1 2 3 4 5 a 1 = Great; b c d ’
1= 1= 1= 1=
None; None; Very poor; Very poor;
5= 5= 5= 5= 5=
Abdominal crampsC
Intolerable Severe, vomiting Severe Excellent Excellent
1 1 1 1 1
Organ delineationd with best sequence 5 5 5 4 4
% Small bowel opacified >90 >90 >90 80 80
Degree of bowel enhancemenP SE 550/22
SE 2000/90
GRASS 50/15/40
5 5 5 5 5
5 5 5 5 5
5 5 5 5 5
Paramagnetic oil emulsions as oral MRI contrast agents 0 K.C.P. LI ET AL.
A
595
B
Fig. 5. (A)-(B) GRASS 50/15/40” coronal images obtained using Geritol-oil
emulsion (ice cream 30070,corn oil 20070,Geritol 12070,and milk 38% v/v). (A) Notice the excellent enhancement and uniform distribution throughout the small bowel. (B) Cornonal image at a more anterior location. Notice that even valvulae conniventes are well delineated. Also note that there is good differentiation between the colon filled with low intensity gas and the small bowel filled with high intensity contrast.
Table 3. In vivo study using various combinations
Tastea
Components
Nauseab
Abdominal crampsC
Organ delineationd with best sequence
of generic components % Small bowel opacified
Degree of bowel enhancemenF SE 550/22
SE 2000/90
GRASS SO/ 1S/40
1 mM ferric ammonium citrate + 20% v/v corn oil + water
3
1
1
5
80
4
5
5
1 mM Gd-DPTA + 20% v/v corn oil + water
3
1
1
5
>90
5
5
5
1 mM Gd-DPTA + 20% v/v peanut oil + water
3
1
1
5
>90
5
5
5
1 mM Gd-DPTA + 20% v/v soybean oil + water
3
1
1
5
80
5
5
5
1 mM ferrous sulfate + 20% v/v corn oil + water
4
1
1
4
80
3
5
3
a 1 = Great; b ’ d e
1= 1= 1= 1=
None; None; Very poor; Very poor;
5= 5= 5= 5= 5=
Intolerable Severe, vomiting Severe Excellent Excellent
596
Magnetic Resonance Imaging 0 Volume 8, Number 5, 1990
Table 2 summarizes the results of the in vivo study using the optimized Geritol-oil emulsion in live volunteers. The distribution in the small bowel is slightly variable, but in general is very good and much better than Geritol alone. The degree of bowel enhancement and organ delineation was also very good to excellent in all of the volunteers (Figs. 5-7) and the taste was also rated very good to excellent in all cases. From this study, it is obvious that the optimized Geritol-oil emulsion satisfies all the criteria of an ideal oral MRI contrast agent and promises to be extremely useful clinically. Table 3 summarizes the results of the in vivo study using various combinations of generic components. Without the ice cream, the generic combinations tasted fairly bad. However, the distribution throughout the small bowel and degree of opacification are very good to excellent with the various combination of ferric ammonium citrate, Gd-DTPA and the various
vegetable oils (Fig. 8). Compared with the other two paramagnetic substances tested, ferrous sulfate produced less enhancement effect. Soybean oil emulsion appeared to have a less uniform distribution throughout the bowel. From this study, it is obvious that many different combinations of paramagnetic agents and an oil can work very well as an oral MRI contrast agent. DISCUSSION
In the past few years, a variety of agents have been advocated as potential oral MRI contrast agents. However, none of these agents satisfies all of the criteria of an “ideal” agent. The potential oral MRI contrast agents that have been proposed can be divided into four different categories. The first group consists of miscible-positive agents, such as MnC12,2,3 ferric citrate,4 metal chelates,5 and Gd-DPTA.6 The disadvantages of these agents include significant dilutional
Fig. 6. (A)-(D) Sequential axial images obtained using GRASS 50/15/40” and Geritol-oil emulsion. Notice the uniform enhancement of the entire small bowel and excellent delineation of retroperitoneal structures.
Paramagnetic oil emulsions as oral MRl contrast agents 0 K.C.P. LI ET AL.
Fig. 7. (A)-(C) Coronal images of a female volunteer obtained using Geritol-oil emulsion with GRASS 50/15/40” (A), SE 550/30 (B), and SE 2OOO/!Xl (C). Notice the uniform enhancement of the entire small bowel with all three pulse sequences.
effects from gastric, biliary and pancreatic secretions in the proximal small bowel and complex absorptive process in the distal small bowel, resulting in unpredictable and varying concentrations in the GI tract. The second group consists of miscible-negative agents such as ferrite. ‘,’ The disadvantages of this group include the fact that with high concentrations, the homogeneity of the magnetic field may be distorted. This is especially detrimental in gradient-echo imaging. The third group consists of immiscible-positive
agents. The major disadvantage of this group is that even with very concentrated oil emulsions, the enhancement effect is not adequate when ri-weighted pulse sequences are used. The fourth group consists of immiscible-negative agents such as CO2 gas tablets, perfluorocarbonsgJO and kaolin-pectin. This group has high potential; however, CO* is limited to applications to the proximal GI tract. Perfluorocarbons are not currently FDA-approved for clinical use and kaolin-pectin may cause severe constipation in the dosages suggested.
Magnetic Resonance Imaging 0 Volume 8, Number 5, 1990
unteer obtained using GRASS 50/15/40”, 1 mM Gd-DTPA, Fig. 8. (A)-(B) Axial images of the lower abdomen of a male VOll and 20% soybean oil emulsified in water. Notice the uniform enh rancement of the distal small bowel without significant dilutional effect.
Our new concept of a MRI oral contrast agent is to combine a paramagnetic agent with an oil emulsion. Our prototype agent is a mixture of corn oil, ice cream, milk, and Geritol. (Geritol is a commercially available dietary supplement which contains in each l/2 fluid ounce: 50 mg ferric ammonium citrate, 2.5 mg thiamine, 2.5 mg riboflavin, 50 mg niacinamide, 2 mg panthenol, 0.5 mg pyridoxine, 0.75 mg cyanocobalamin, 25 mg methionine, 50 mg choline bitartrate, and 12% v/v of alcohol.) With this prototype, all of the criteria for an ideal oral MRI contrast agents were satisfied. We have also shown that a variety of different combinations of paramagnetic agents and oils can work very well as oral MRI contrast agents. In conclusion, we believe that our new concept forms the basis for making many different products by varying the paramagnetic agent involved and the ingredients of the oil emulsions. This family of compounds can then be used as MRI GI contrast agents.
Chem. Phys. Med. NMR 16:123-128;
1. Li, K.C.P.; Tart, R.P.; Storm, B.; RoIfes, R.; Ang, P.; Ros, P.R. MRI oral contrast agents: Comparative study of five potential agents in humans. Proceedings of the Eighth Annual Meeting of the Society of Magnetic Resonance in Medicine, Amsterdam, August 1989; p. 791.
2. Burnett, K.R.; Goldstein, E.J.; Wolf, G.L.; Sen, S.; Mamourian, A.C. The oral administration of MnCI,: A potential alternative to i.v. injection for tissue contrast enhancement in magnetic resonance imaging. 1984.
1984.
Wesbey, G.E.; Brasch, R.C.; Goldberg, H.I.; Engelstad, B.L.; Moss, A.A. Dilute oral iron solutions as gastrointestinal contrast agents for magnetic resonance imaging: initial clinical experience. Magn. Reson. Imaging 3:57-64; 1985. Runge, V.M.; Stewart, R.G.; Clanton, J.A.; Jones, M.M.; Lukehart, C.M.; Partain, C.L.; James, A.E., Jr. Work in Progress. Potential oral and intravenous paramagnetic NMR contrast agents. Radiology 147:789-791; 1983.
6.
7.
8.
REFERENCES
Magn. Reson. Imaging 12:307-314;
Mamourian, A.C.; Burnett, K.R.; Goldstein, E.J.; Wolf, G.L.; Kressel, H.Y.; Baum, S. Proton relaxation enhancement in tissue due to ingested manganese chloride: Time course and dose response in the rat. Physiol.
9.
Laniado, M.; Kornmesser, W.; Hamm, B.; Clauss, W.; Weinmann, H.; Felix, R. MR imaging of the gastrointestinal tract: Value of Gd-DPTA. AJR 150:817-821; 1988. Widder, D. J.; Edelman, R.R.; Grief, W.L.; Monda, L. Magnetite albumin suspension: a superparamagnetic oral MR contrast agent. AJR 149:839-843; 1987. Hahn, P.F.; Stark, D.D.; Sanjay, S.; Lewis, J.M.; Wittenberg, J.; Ferrucci, J.T. Ferrite particles for bowel contrast in MR imaging: Design issues and feasibility studies. Radiology 164:37-41; 1987. Mattrey, R.F. Perfluorocytlbromide: A new contrast agent for CT, sonography, and MR imaging. AJR 152: 247-252;
1989.
10. Mattrey, R.F.; Hajek, P.C.; Gylys-Morin, V.M.; Baker, L.L.; Martin, J.; Long, D.C.; Long, D.M. Perfluorochemicals as gastrointestinal contrast agents for MR imaging: Preliminary studies in rats and humans. AJR 148:1259-1263;
1987.
