Editorial Comments
15
Editorial Comments
Thrombosis: A Sequel to Phlebography? A Note from the Editors
The high incidence of postphlebographic deep-vein thrombosis as assessed by the 125I-fibrinogen uptake test provoked concern when first reported by Albrechtsson and Olsson in 1976 (Lancet 1:723-724, 1976). The current paper by these authors represents both a more detailed presentation of their results and an extension of the inquiry to a consideration of the effect of contrast medium osmolality on the development of complications. Because of the important implications of Albrechtsson and Olsson's findings, and because of their controversial nature, we have asked three investigators to comment on their own experiences with postphlebographic complications i H.L. Abrams
E. Zeitler
Comment 1
Two years ago in surveying our experiences in 20,000 phlebographic examinations, we found that a local thrombophlebitis, usually extending for 5 cm but in some cases reaching 20 cm in length, was frequently found in the superficial vein into which the injection was made [3]. This complication was so clinically insignificant that we did not tally its incidence, but we estimate that it occurred in about 20% of the cases. No treatment was required, and patients were simply informed that they were experiencing a harmless side effect and not a real complication. We have never registered a clinically manifest thrombosis of the deep veins, even though it is almost impossible that we could have failed to notice such a complication: Tyrol is such a small country that we are able to keep close track of our patients. No more than 40 ml of 45% meglumine diatrizoate (Angiografin) is ever used. Before phlebography, we inject 5,000 IU of heparin; after the procedure sodium chloride solution is administered, the leg is greatly elevated, and the patient is ordered to move it. Later the leg is bandaged and the patient is asked to walk around for two hours. After learning of Albrechtsson and Olsson's results, we regretted that we could not re-examine a large group of patients with normal radiologic results five days later using the xzsI-fibrinogen uptake test; after stating that the venous x-ray results were totally normal, we would not know how to explain to these patients the necessity for such an examination. However, we have been informed about such examinations
performed by other radiologists who have precisely observed our preventive measures. In these cases, very few instances of positive 125I-fibrinogen results have been found, despite the sensitivity of the test. While it was apparent that small thrombi in the deep veins could not be avoided totally, as a result of our preventive measures they did not develop into clinically manifest thrombi. Albrechtsson has told me, in a personal communication, that he did not perform preventive measures, as he felt that the damage to the intima was caused immediately after the injection of the contrast medium and, therefore, any such measure would come too late. We think that this is only partially correct. Our results prove that ,it is possible to keep small deep-vein thrombi localized in most cases. Such thrombi will be absorbed within a few days. This finding corresponds totally with the results of earlier animal experiments by Payling-Wright [4] and others. Nevertheless, we find cause for unease on other grounds. Gottlob [1, 2] has proved recently that the venous valves are especially sensitive to damage. Even if the amount of injected substance is kept sufficiently low that no venous thrombosis can develop, nevertheless, small mural thrombi may still develop in the sinus of the valve. Th'e valves apparently continue to function normally, and the small thrombi are soon absorbed. However, after 20 days the valves shrink and become insufficient. We now know also that contrast medium often remains in the sinus of the valve for 2-3 minutes, and it would seem doubtful that this circumstance is always harmless. We have all been taught that valves undergo regressive changes
16
Editorial Comments
over time, and it has been thought that this was a physiologic process. The recent studies by Leu have shown, however, that the valves never shrink physiologically with age; such a development is, without exception, the result of small mural thrombosis (H.J. Leu, personal communication). In conclusion, we believe that our preventive measures are adequate to avoid the thrombotic complications found by A1brechtsson and Olsson, but we feel that they may not be sufficient to prevent completely slight damage to the valves.
References 1. Gottlob, R.: Postthrombotische Ver/inderungen an Venenklappen im Tierexperiment. Virchows Arch. 358:249-258, 1973 2. Gottlob, R. : Untersuchungen an den obersten Klappen der Vena sapherm magna bei Varizen. Zentralbl. Clair. 100:1306-1315, 1975 3. May, R.: Thrombophlebitis nach Phlebographie. Vasa 6:169, 1977 4. Payling-Wright: In: Phlebographie der unteren Extremitfit. Kiinstliche Thrombose bei experimentellen Tieruntersuchungen, edited by R. May. Stuttgart, Thieme, 1973, p. 141
Innsbruck, Austria
R. May Krankenhaus der Kreuzschwestern
Comment 2
The article by Albrechtsson and Olsson from the University Hospital in Lund, Sweden, describes the experience gained with two different contrast media when used for lower extremity phlebography. The results are very interesting inasmuch as they show that the new non-ionic contrast agent metrizamide (Amipaque) reduces significantly the number of undesirable side effects and complications. In particular, a significant reduction in the number of positive 125Ifibrinogen uptake tests was noted in comparison to the findings after the use of a more conventional water-soluble contrast agent (meglumine calcium metrizoate [Isopaque Cerebral]). Most remarkable, among other interesting data, was that venograms performed with metrizamide did not induce an unequivocally positive fibrinogen test in any instance in a subgroup of patients, who had been shown to be free of thrombosis at the time of phlebography. This was in sharp contrast to the sizable number of positive fibrinogen tests found in a similar subgroup of patients in whom the same examination was performed with conventional contrast media. These results are in support of previous studies, including our own, which suggested that the physical
and chemical properties of the contrast agent are the main determinants of the undesirable side effects. Realizing that a complete and qualitatively acceptable phlebographic examination of the lower extremity requires relatively large contrast volumes and a long contact time, we had designed a prospective study in order to evaluate the incidence of complications [1]. As is common experience in such efforts, we found a much higher complication rate than we had anticipated based on general clinical impressions. We also found that diluting the water-soluble conventional contrast agent (meglumine diatrizoate and sodium diatrizoate [Renografin]) from 60% to 45% resulted in a significant drop in all types of side effects without diminishing the diagnostic accuracy of the examination. Realizing that such precautions reduced but did not eliminate the risk of complications, we have also used in our subsequent research the rather sensitive 12si_fibrinogen Uptake test and have found that even with our improved technique the fibrinogen test was positive in 9% of the patients, most of whom were shown by repeat phlebography to have either superficial- or deep-vein thrombosis. These disturbing findings constituted a strong impetus to explore the use of other contrast agents that combined a high iodine content with lower osmolality. Among these metrizamide was seriously considered because of its well-documented properties, but our more than two-year-old efforts met two apparently insurmountable obstacles. Firstly, this very promising new contrast agent had not, and as yet has not, been given approval by the United States Food and Drug Administration for clinical use in the United States. Secondly, we were discouraged by the manufacturers themselves, because the large volumes required for leg phlebography would result in an unacceptably high price for the examination. Undoubtedly, the favorable results by Albrechtsson and Olsson should again initiate new efforts to overcome these obstacles. As is obvious from the presentation, Albrechtsson and Olsson's study was not performed in a randomized fashion, nor was it performed prospectively during the entire span of time during which the examinations were done. Although the results are very convincing because of the obvious differences between groups, a randomized and well-controlled prospective study design would be a prerequisite for future evaluations that aim at the elaboration of more subtle differences such as one might expect to exist between the non-ionic metrizamide and diluted conventional contrast agents. Such a study would be of great importance in predicting the beneficial effects one could expect from a conversion to a new, but unfortunately rather costly, contrast agent.
Authors' Reply
17
Reference
1. Bettman, M.A., Paulin, S.: Leg phlebography: The incidence, nature and modification of undesirable side effects. Radiology 122:101-104, 1977
Boston, Mass. 02115
S. Paulin Harvard MedicalSchool Beth Israel Hospital
Comment 3
It is well known that ascending phlebography with concentrated contrast media is painful and causes local superficial phlebitis at the injection site and, in rare cases, even skin necrosis if paravasation occurs. These adverse effects are mainly due to the hyperosmolality of the solution, which is five to seven times higher than that of human blood. Because of this fact we have, for the past six years, been using a sodium-free contrast medium (meg/umine diatrizoate [Angiografin]), which we dilute with bidistilled water to a 40% or 45% solution that has an iodine content of, respectively, 188 mg/ml or 212 mg/ml. This dilution, which is sufficient for good contrast in the venous system up to the pelvic veins, makes phlebography a painless procedure even in deep venous thrombosis. On average, the injection volume is 100 ml, given at a flow rate of 0.5 ml/sec. After the examination, which lasts from three to four minutes, phlebography is initiated with 5000 IU of heparinized saline, thus flushing the veins with 100 ml. If no deep venous thrombosis is found, an elastic bandage is applied, and the patient is encouraged to walk. We have been satisfied with this technique since, except for a 2-3-cm-long superficial phlebitis at the
injection site in 15% of the cases, we have had no serious side effects while performing about 900 examinations a year. In particular, a clinically relevant postphlebographic thrombosis has never been noted. We have been further encouraged by a series of 89 patients who suffered from deep venous thrombosis and were rephlebographed after six days for the control of the therapeutic effect of heparin. In 88% the phlebographic pattern was unchanged, in 9% formerly occluded veins were recanalized, and in only 3% could a further growth of thrombi be seen. When evaluating metrizamide for phlebography and comparing it to our diluted conventional ionic contrast medium in the same patients we combined phlebography and the radiofibrinogen test. One patient with formerly open veins had an increased uptake over the calf after 48 hours. Repeat phlebography showed some small thrombi in the soleus veins. After treatment with heparin and marcumar, the radiofibrinogen test became negative within another 48 hours. The work of Albrechtsson and Olsson shows that serious side effects can be caused by concentrated contrast media. To the best of our knowledge and experience, these complications can be avoided by dilution of the contrast medium and the other prophylactic measures described above. But it must be borne in mind that even a 40% meglumine diatrizoate solution still has an osmolality almost three times higher than that of blood. There is no doubt that a contrast medium isotonic with blood would be preferable if available at an acceptable price. The development and marketing of new substances may solve the problem in the near future.
Basel, Switzerland
H.-E. Schmitt Angib-Radiologische Abteilung der Universit/it Kantonsspital
Authors'Reply Our study was performed with the contrast concentrations and doses that have been used in our clinic for the past 10 years and that are used in most Swedish hospitals. The study was originally designed as a comparison between diagnostic tests for thrombosis, but after examination of about 60 patients, it was redesigned as a prospective investigation of contrast media complications. We also performed a small randomized study, which showed the same differences between the contrast media.
We and Drs. May, Paulin, and Schmitt all agree that it is the high osmolality of phlebographic contrast media that causes the thrombotic complications. However, in studies in which the contrast medium was diluted to 45%, Bettman and Paulin [1] also found a significant, although lower, incidence of complications. Further dilution of contrast media is probably impossible without loss of too much information. Dose reduction might also be expected to reduce the frequency ofpostphlebographic thrombosis. However, to
18
our knowledge a study to test this premise has not been performed by any other investigators; in our work no correlation between complication rate and contrast volume was found. In our study we did not employ any prophylactic methods to prevent thrombotic complications, but such techniques could, of course, reduce the number of complications. However, other studies ([1, 2] and J.J. Cranley, personal communication) have shown that a single dose of heparin after the examination does not prevent postphlebographic thrombosis. If the primary deleterious effect of the contrast medium is an inflammatory reaction in the vessel wall, with secondary thrombosis - a process that occurs over a considerable span of time - it would be surprising if a single infusion of heparin, with its short duration of activity, would prevent the side effects. The only truly satisfactory phlebographic contrast medium would be a substance isotonic to blood and
Author's Reply
available at an acceptable price. Today there is only one substance, metrizamide (Amipaque), which is of the proper osmolality; it, however, is costly. We therefore believe that it is essential at this time to avoid unnecessary examinations, use contrast media with as low osmolality as possible, and reduce contrast volume as much as is practicable.
References 1. Bettman, M.A., Paulin, S.: Leg phlebography: The incidence, nature and modification of undesirable side effects. Radiology 122:101-104, 1977 2. Crantey, J.J. : Venous thrombosis secondary to phlebography. In: Vascular Surgery, Vol. 2. Hagerstown, Maryland, Harper & Row Publishers, 1975, pp. 70-71
Lund, Sweden
U. Albrechtsson, C.G. Olsson University Hospital
15
Editorial Comments
Thrombosis: A Sequel to Phlebography? A Note from the Editors
The high incidence of postphlebographic deep-vein thrombosis as assessed by the 125I-fibrinogen uptake test provoked concern when first reported by Albrechtsson and Olsson in 1976 (Lancet 1:723-724, 1976). The current paper by these authors represents both a more detailed presentation of their results and an extension of the inquiry to a consideration of the effect of contrast medium osmolality on the development of complications. Because of the important implications of Albrechtsson and Olsson's findings, and because of their controversial nature, we have asked three investigators to comment on their own experiences with postphlebographic complications i H.L. Abrams
E. Zeitler
Comment 1
Two years ago in surveying our experiences in 20,000 phlebographic examinations, we found that a local thrombophlebitis, usually extending for 5 cm but in some cases reaching 20 cm in length, was frequently found in the superficial vein into which the injection was made [3]. This complication was so clinically insignificant that we did not tally its incidence, but we estimate that it occurred in about 20% of the cases. No treatment was required, and patients were simply informed that they were experiencing a harmless side effect and not a real complication. We have never registered a clinically manifest thrombosis of the deep veins, even though it is almost impossible that we could have failed to notice such a complication: Tyrol is such a small country that we are able to keep close track of our patients. No more than 40 ml of 45% meglumine diatrizoate (Angiografin) is ever used. Before phlebography, we inject 5,000 IU of heparin; after the procedure sodium chloride solution is administered, the leg is greatly elevated, and the patient is ordered to move it. Later the leg is bandaged and the patient is asked to walk around for two hours. After learning of Albrechtsson and Olsson's results, we regretted that we could not re-examine a large group of patients with normal radiologic results five days later using the xzsI-fibrinogen uptake test; after stating that the venous x-ray results were totally normal, we would not know how to explain to these patients the necessity for such an examination. However, we have been informed about such examinations
performed by other radiologists who have precisely observed our preventive measures. In these cases, very few instances of positive 125I-fibrinogen results have been found, despite the sensitivity of the test. While it was apparent that small thrombi in the deep veins could not be avoided totally, as a result of our preventive measures they did not develop into clinically manifest thrombi. Albrechtsson has told me, in a personal communication, that he did not perform preventive measures, as he felt that the damage to the intima was caused immediately after the injection of the contrast medium and, therefore, any such measure would come too late. We think that this is only partially correct. Our results prove that ,it is possible to keep small deep-vein thrombi localized in most cases. Such thrombi will be absorbed within a few days. This finding corresponds totally with the results of earlier animal experiments by Payling-Wright [4] and others. Nevertheless, we find cause for unease on other grounds. Gottlob [1, 2] has proved recently that the venous valves are especially sensitive to damage. Even if the amount of injected substance is kept sufficiently low that no venous thrombosis can develop, nevertheless, small mural thrombi may still develop in the sinus of the valve. Th'e valves apparently continue to function normally, and the small thrombi are soon absorbed. However, after 20 days the valves shrink and become insufficient. We now know also that contrast medium often remains in the sinus of the valve for 2-3 minutes, and it would seem doubtful that this circumstance is always harmless. We have all been taught that valves undergo regressive changes
16
Editorial Comments
over time, and it has been thought that this was a physiologic process. The recent studies by Leu have shown, however, that the valves never shrink physiologically with age; such a development is, without exception, the result of small mural thrombosis (H.J. Leu, personal communication). In conclusion, we believe that our preventive measures are adequate to avoid the thrombotic complications found by A1brechtsson and Olsson, but we feel that they may not be sufficient to prevent completely slight damage to the valves.
References 1. Gottlob, R.: Postthrombotische Ver/inderungen an Venenklappen im Tierexperiment. Virchows Arch. 358:249-258, 1973 2. Gottlob, R. : Untersuchungen an den obersten Klappen der Vena sapherm magna bei Varizen. Zentralbl. Clair. 100:1306-1315, 1975 3. May, R.: Thrombophlebitis nach Phlebographie. Vasa 6:169, 1977 4. Payling-Wright: In: Phlebographie der unteren Extremitfit. Kiinstliche Thrombose bei experimentellen Tieruntersuchungen, edited by R. May. Stuttgart, Thieme, 1973, p. 141
Innsbruck, Austria
R. May Krankenhaus der Kreuzschwestern
Comment 2
The article by Albrechtsson and Olsson from the University Hospital in Lund, Sweden, describes the experience gained with two different contrast media when used for lower extremity phlebography. The results are very interesting inasmuch as they show that the new non-ionic contrast agent metrizamide (Amipaque) reduces significantly the number of undesirable side effects and complications. In particular, a significant reduction in the number of positive 125Ifibrinogen uptake tests was noted in comparison to the findings after the use of a more conventional water-soluble contrast agent (meglumine calcium metrizoate [Isopaque Cerebral]). Most remarkable, among other interesting data, was that venograms performed with metrizamide did not induce an unequivocally positive fibrinogen test in any instance in a subgroup of patients, who had been shown to be free of thrombosis at the time of phlebography. This was in sharp contrast to the sizable number of positive fibrinogen tests found in a similar subgroup of patients in whom the same examination was performed with conventional contrast media. These results are in support of previous studies, including our own, which suggested that the physical
and chemical properties of the contrast agent are the main determinants of the undesirable side effects. Realizing that a complete and qualitatively acceptable phlebographic examination of the lower extremity requires relatively large contrast volumes and a long contact time, we had designed a prospective study in order to evaluate the incidence of complications [1]. As is common experience in such efforts, we found a much higher complication rate than we had anticipated based on general clinical impressions. We also found that diluting the water-soluble conventional contrast agent (meglumine diatrizoate and sodium diatrizoate [Renografin]) from 60% to 45% resulted in a significant drop in all types of side effects without diminishing the diagnostic accuracy of the examination. Realizing that such precautions reduced but did not eliminate the risk of complications, we have also used in our subsequent research the rather sensitive 12si_fibrinogen Uptake test and have found that even with our improved technique the fibrinogen test was positive in 9% of the patients, most of whom were shown by repeat phlebography to have either superficial- or deep-vein thrombosis. These disturbing findings constituted a strong impetus to explore the use of other contrast agents that combined a high iodine content with lower osmolality. Among these metrizamide was seriously considered because of its well-documented properties, but our more than two-year-old efforts met two apparently insurmountable obstacles. Firstly, this very promising new contrast agent had not, and as yet has not, been given approval by the United States Food and Drug Administration for clinical use in the United States. Secondly, we were discouraged by the manufacturers themselves, because the large volumes required for leg phlebography would result in an unacceptably high price for the examination. Undoubtedly, the favorable results by Albrechtsson and Olsson should again initiate new efforts to overcome these obstacles. As is obvious from the presentation, Albrechtsson and Olsson's study was not performed in a randomized fashion, nor was it performed prospectively during the entire span of time during which the examinations were done. Although the results are very convincing because of the obvious differences between groups, a randomized and well-controlled prospective study design would be a prerequisite for future evaluations that aim at the elaboration of more subtle differences such as one might expect to exist between the non-ionic metrizamide and diluted conventional contrast agents. Such a study would be of great importance in predicting the beneficial effects one could expect from a conversion to a new, but unfortunately rather costly, contrast agent.
Authors' Reply
17
Reference
1. Bettman, M.A., Paulin, S.: Leg phlebography: The incidence, nature and modification of undesirable side effects. Radiology 122:101-104, 1977
Boston, Mass. 02115
S. Paulin Harvard MedicalSchool Beth Israel Hospital
Comment 3
It is well known that ascending phlebography with concentrated contrast media is painful and causes local superficial phlebitis at the injection site and, in rare cases, even skin necrosis if paravasation occurs. These adverse effects are mainly due to the hyperosmolality of the solution, which is five to seven times higher than that of human blood. Because of this fact we have, for the past six years, been using a sodium-free contrast medium (meg/umine diatrizoate [Angiografin]), which we dilute with bidistilled water to a 40% or 45% solution that has an iodine content of, respectively, 188 mg/ml or 212 mg/ml. This dilution, which is sufficient for good contrast in the venous system up to the pelvic veins, makes phlebography a painless procedure even in deep venous thrombosis. On average, the injection volume is 100 ml, given at a flow rate of 0.5 ml/sec. After the examination, which lasts from three to four minutes, phlebography is initiated with 5000 IU of heparinized saline, thus flushing the veins with 100 ml. If no deep venous thrombosis is found, an elastic bandage is applied, and the patient is encouraged to walk. We have been satisfied with this technique since, except for a 2-3-cm-long superficial phlebitis at the
injection site in 15% of the cases, we have had no serious side effects while performing about 900 examinations a year. In particular, a clinically relevant postphlebographic thrombosis has never been noted. We have been further encouraged by a series of 89 patients who suffered from deep venous thrombosis and were rephlebographed after six days for the control of the therapeutic effect of heparin. In 88% the phlebographic pattern was unchanged, in 9% formerly occluded veins were recanalized, and in only 3% could a further growth of thrombi be seen. When evaluating metrizamide for phlebography and comparing it to our diluted conventional ionic contrast medium in the same patients we combined phlebography and the radiofibrinogen test. One patient with formerly open veins had an increased uptake over the calf after 48 hours. Repeat phlebography showed some small thrombi in the soleus veins. After treatment with heparin and marcumar, the radiofibrinogen test became negative within another 48 hours. The work of Albrechtsson and Olsson shows that serious side effects can be caused by concentrated contrast media. To the best of our knowledge and experience, these complications can be avoided by dilution of the contrast medium and the other prophylactic measures described above. But it must be borne in mind that even a 40% meglumine diatrizoate solution still has an osmolality almost three times higher than that of blood. There is no doubt that a contrast medium isotonic with blood would be preferable if available at an acceptable price. The development and marketing of new substances may solve the problem in the near future.
Basel, Switzerland
H.-E. Schmitt Angib-Radiologische Abteilung der Universit/it Kantonsspital
Authors'Reply Our study was performed with the contrast concentrations and doses that have been used in our clinic for the past 10 years and that are used in most Swedish hospitals. The study was originally designed as a comparison between diagnostic tests for thrombosis, but after examination of about 60 patients, it was redesigned as a prospective investigation of contrast media complications. We also performed a small randomized study, which showed the same differences between the contrast media.
We and Drs. May, Paulin, and Schmitt all agree that it is the high osmolality of phlebographic contrast media that causes the thrombotic complications. However, in studies in which the contrast medium was diluted to 45%, Bettman and Paulin [1] also found a significant, although lower, incidence of complications. Further dilution of contrast media is probably impossible without loss of too much information. Dose reduction might also be expected to reduce the frequency ofpostphlebographic thrombosis. However, to
18
our knowledge a study to test this premise has not been performed by any other investigators; in our work no correlation between complication rate and contrast volume was found. In our study we did not employ any prophylactic methods to prevent thrombotic complications, but such techniques could, of course, reduce the number of complications. However, other studies ([1, 2] and J.J. Cranley, personal communication) have shown that a single dose of heparin after the examination does not prevent postphlebographic thrombosis. If the primary deleterious effect of the contrast medium is an inflammatory reaction in the vessel wall, with secondary thrombosis - a process that occurs over a considerable span of time - it would be surprising if a single infusion of heparin, with its short duration of activity, would prevent the side effects. The only truly satisfactory phlebographic contrast medium would be a substance isotonic to blood and
Author's Reply
available at an acceptable price. Today there is only one substance, metrizamide (Amipaque), which is of the proper osmolality; it, however, is costly. We therefore believe that it is essential at this time to avoid unnecessary examinations, use contrast media with as low osmolality as possible, and reduce contrast volume as much as is practicable.
References 1. Bettman, M.A., Paulin, S.: Leg phlebography: The incidence, nature and modification of undesirable side effects. Radiology 122:101-104, 1977 2. Crantey, J.J. : Venous thrombosis secondary to phlebography. In: Vascular Surgery, Vol. 2. Hagerstown, Maryland, Harper & Row Publishers, 1975, pp. 70-71
Lund, Sweden
U. Albrechtsson, C.G. Olsson University Hospital
