- Email: [email protected]
Salpix: A New Approach to the Ideal Radiopaque Medium for Hysterosalpingography
Salpix A New Approach to the Ideal Radiopaque Medium for Hysterosalpingography
I. C. Rubin, M.D., Ernest Myller, M.D., and Carl G. Hartman, Ph.D.
were made to visualize the uterine cavitv (hysterography) and the lumen of the fallopian tubes (salpingography) by means of intrauterine injection of Collargol, reported independently by Cary and Rubin in 1914, many improvements have been advocated. Beginning with different solutions containing halogen salts,12 • 13 • 26 there followed the development of iodized oils, of which Lipiodol is representative of the entire group of substances combining iodine with oils of various kinds. Lipiodol was first proposed by Sicard and Forestier for general use and by Heuser for application in gynecology.s, s, 15, 16, 33, 37, 38, 42 When the organic iodine-containing compounds such as U roselectan, Hippuran, and Diodrast were developed for urologic x-ray diagnosis, many gynecologists soon adopted these in their original form or in some modification thereof. 11 • 14 • 18 • 24 • 31 The newer contrast media combine a watersoluble organic iodine compound with a vehicle to enhance the viscosity. Among these combinations may be mentioned Skiodan combined with acacia and Rayopaque with polyvinyl alcohol; most recently carboxymethylcellulose and dextran have been employed to increase the viscosity in this manner, the last-named especially in Sweden and Switzerland. These contrast media have all had the same objective; that of avoiding an oil residue in the female genital tract. SINCE THE FIRST ATTEMPTS
From the Department of Obstetrics and Gynecology, Mt. Sinai Hospital, New York 29, New York, and the Ortho Research Foundation, Raritan, New Jersey. 357
358
RUBIN ET AL.
[Fertility & Sterility
Iodized oils have been employed many times by two of the present authors until the deleterious effects of the oils were discovered in 1927. 27 • 28 The harmful results of iodized oil combinations as used in the investigation of sterility may be summarized as follows:
1. Retention in obstructed fallopian tubes. If the tubes have been nonpatulous, no apparent damage is suffered by the patient. If, however, the tubes have been partially patent, the iodized oil is trapped by virtue of its viscosity, its very slow absorption, and its failure to mix with the tubal secretions. Retained for varying lengths of time within the constricted lumen, the oil may, and in some cases actually does, set up a foreign body reaction leading to granuloma formation and complete tubal obstruction. The first observation of such oil retention in the fallopian tubes was reported by Rubin in 192727 and published in 1928. 28 Other reports of tubal irritation soon followed.2o, 21, 24, 29, 32, 33 2. Multiple cyst formation. A second undesirable sequel of the intrauterine injection of iodized oil is the long periods of time that spillage into the peritoneal cavity remains, 4· 7 • 19 • 32 · 33 setting up multiple cyst formations, which it is well to avoid even though such peritoneal reaction may not interfere with conception. Many gynecologists do not favor, or are unenthusiastic concerning, the use of iodized oil for salpingography, fearing injury to the cilia. 3. Oil embolism. Of less frequent occurrence, 1 but more serious when it occurs, is the intravasation of iodized oil into the uterine veins and thence into the systemic circulation. 1 • 2· 6 • 23 · 44 Also to be reckoned with is the introduction of the oil into the myometrium-especially in cases of adenomyosiswhere the iodized oil remains for a long time, with or without inciting inflammatory processes. These clinical and pathologic observations have led to renewed efforts at making available a radiopaque substance which has the following properties: ( 1) it should be dense enough to cast clean shadows; ( 2) it should pass through the fallopian tubes slowly enough tn be filmed; ( 3) it should be sufficiently viscous so that strictures of the tubal lumen may be accurately visualized; ( 4) and finally the material injected should be resorbed within a few hours, leaving no trace behind in the tubes or in the peritoneal cavity, yet offering the possibility of making a complete and positive diagnosis in a relatively short time. In this connection the well-known fact need
Vol. 4, No.5, 1953]
SALPIX
359
hardly be mentioned that when iodized oils are used, a 24-hour film is indispensable to establish tubal nonpatency or high-grade tubal strictures. The four criteria have been fully met in Salpix.
DESCRIPTION Chemical and Physical Properties The present paper deals with a radiopaque medium, Salpix, which is a combination of a solution of polyvinylpyrrolidone (P.V.P. ), the basis of a well-known blood extender, to which has been added sodium acetrizoate. The widely used blood substitute P.V.P. 9 has been selected as a suitable agent to impart to the acetrizoate, a compound of high x-ray opacity, the needed viscosity and tissue adhesiveness. Sodium acetrizoate has a high iodine content ( 65.8 per cent), as may be seen from the following formula: 0
II
C-0-Na
I)~ I I
II
0
I
I-N-C-CH3 ""/ I
I
H
The chemical name of this compound is sodium 3-acetylamino-2,4,6triiodo benzoate. Salpix is an amber-colored mixture. Its viscosity at 37° C. is approximately 200 centipoise. It contains 54 per cent sodium acetrizoate. It is stable on storage at 50° C. for six months, and will permit autoclaving without loss of its desirable properties. It is subjected to the usual controls for sterility and pyrogenicity.
Historical Note It is of interest to recall that the first trials with uterine injection of radiopaque substances were made upon the human female on purely empirical grounds. Cary's first injections of CollargoJ.were made without prior animal experimentation and Rubin had made only anatomic studies and injections of collargol in the rabbit before applying the method clinically. Soon after, in preparation of the clinical use of oxygen insuffiation through the uterus, Rubin injected the dog's uterine vein with an amount of oxygen equal to that recommended for the clinical diagnosis of tubal patency.
RUBIN ET AL.
360
[Fertility & Sterility
In retrospect there is no doubt that the new venture was concerned only with the anatomic feasibility and the physical realizability of the radiopaque agent. Untoward effects were only appreciated after some clinical trial with various substances employed in hysterosalpingography. This early and empirical method has since been abandoned and replaced by scientific experimental controls, which were instituted for example in the case of viscorayopaque ( Rayopaque). This substance appeared to satisfy the desiderata of viscosity as well as absence of residue, but proved to have an irritant action, in many cases for some minutes and occasionally longer. As the manufacture of this product was discontinued, the opportunity proffered by the Ortho Research Foundation was welcomed to develop another radiopaque substance having the desirable properties of Rayopaque without its disadvantages. The blood substitute polyvinylpyrrolidone as the viscosity-rendering vehicle and the organic iodine component acetrizoate have both been subjected to modern experimental controls to determine their desirability for clinical trial. Toxicity of P.V.P. and Sodium Acetrizoate
Since the nontoxicity of each component of Salpix has been amply demonstrated,9· 14 it might have been assumed that the combination of the two would also be nontoxic. Nevertheless this was not taken for granted. Special tests were made to study Salpix for possible irritation and toxicity. These tests consisted of injecting it into monkeys, rabbits, dogs, and rats, intravenously, intraperitoneally (by direct abdominal puncture and by way of the uterus), subcutaneously, and by gavage. The tests are presented in outline as follows:
Experiments with Monkeys. Thirty experiments were made on 13 monkeys; of these animals 2 were used four times; 2 three times; 4 twice, and eight once. In all experiments x-ray films were taken. Three monkeys each received 5 cc. of Salpix intravenously; none showed the slightest reaction or symptom. In 5 experiments the uterus was entered and injected from below by the technics of Rubin and Morse; 35 six times the uterus was injected successfully from without, i.e., through the abdominal wall, because the approach from below is sometimes extremely difficult. Three times a laparotomy was done and the uterus injected. Nine intraperitoneal injections were made to test toxicity and rate of absorption.
Vol. 4, No.5, 1953]
SALPIX
361
In 4, the vagina only was injected. None of the 13 monkeys showed the least sign of irritation or toxicity. Experiments with Dogs and Rabbits. A dog was injected subcutaneously with 5 cc. of Salpix. At autopsy the next day no sign of irritation was discernible at the injected area. Another dog received subcutaneously 2 cc. of Salpix in the right and left scapula and the right and left gluteal regions; no reaction was noted. A third dog licked the site of injection of 5 cc. of Salpix from time to time for about an hour, otherwise showing no symptoms. Four rabbits injected with 5 cc. of Salpix intravenously showed no symptoms of discomfort or irritation whatever. A fifth rabbit was treated as follows: 5 cc. of Salpix was injected intravenously; 5 minutes later, the right renal pelvis and ureter and left renal pelvis were visualized on the x-ray film; the liver was mottled, the lobules being outlined. Mter 30 minutes there were the same findings, much material showing in the bladder. In 50 minutes, both ureters were visualized, and the bladder was seen to be dilated and full of Salpix. In 80 minutes another intravascular injection of 2.5 cc. of Salpix was made. The findings were the same as before. No symptoms appeared. Table 1 summarizes the findings after animal experiments. Summary of Toxicity Experiments
The observations derived from animal experiments with Salpix may be summarized as follows: 1. Mter intravenous injection, Salpix rapidly leaves the blood stream by way of the kidneys. It remains in the uterine lumen of the monkey up to one or two hours for reasons stated below, but spillage into the peritoneal cavity is eliminated within an hour. 2. The longer retention of Salpix in the monkey uterus as compared with the human uterus requires a note of explanation. In Macaca mulatta there is in the region of the cervix uteri a colliculus which pushes the cervical lumen dorsally, like a ball valve, rendering the already narrow passage circuitous and the emptying of the uterus more difficult. It is apparent, too, that because of the obstructing colliculus, insertion of a cannula from below is practically impossible without surgery. The surgical technic required to overcome the cervical obstruction to a uterine cannula was developed by Rubin and Morse. It consists of cutting through the lateral cervix walls and bypassing the colliculus. By pulling apart the cervical lips, the uterine can-
[Fertility & Sterility
RUBIN ET AL.
362
nula can then be directly inserted into the uterus and injection successfully accomplished. That the colliculus blocks the discharge of uterine contents has been repeatedly observed by one of the authors (C. G. H.), who noted that the monkey uterus is much slower to expel its contents (a small dead embryo, for example) than is the human uterus. In a few clinical cases with TABLE 1. Animal
Rate of Absorption of Salpix: Results after Animal Experiments Residue
In;ection Amount (cc.)
Route of In;ection
Place
Time (min.)
Observation
Rabbits Monkeys #29 #26 #2
5
intravenous
bladder
60
no other residue
5
5 5
bladder bladder bladder bladder bladder
60
#11 #8
intravenous intravenous intraperitoneal intraperitoneal intraperitoneal
#30
3
intraperitoneal
bladder
#8
3
intraperitoneal
#21
3 3
no other residue no other residue no other residue no other residue faint streaks in abdominal cavity no other residue bladder empty no other residue bladder empty slight residue in uterus body cavity clear, good outline of uterus, much Salpix in bladder no residue
#8
#20 #24
#21
5 3
3 2.3 3
3
75 60 60 60 80 24 hr.
30
24 hr. 90 bladder into uterus uterus filled, spillage uterus and bladder 60 through tubes into body cavity
pelvis (by error) and uterus uterus filled, spillage through tubes into body cavity uterus filled, spillage through tubes into body cavity
24 hr.
120 24 hr.
30
no
residue in body cavity no residue uterus well outlined, no residue in body cavity
cervical stenosis Salpix was retained within the uterus for about a half-hour before it was evacuated. 3. As Salpix can safely be injected intravenously, its accidental entry into the blood stream during and after uterosalpingography is neither attended or followed by the harmful results which are, unfortunately, sometimes noted after intravasation of oil into the uterine vein causing fat embolism.
Vol. 4, No. 5, 1953]
SALPIX
363
CLINICAL OBSERVATIONS AND EVALUATION
Salpix has been employed by the senior author in uterotubal injection on more than 350 patients. The clinical use of Salpix has in his hands been more satisfactory than that of previously available opaque substances. Practically none of the patients experienced the mild to severe abdominal pain which attends or follows injection of iodized oils and solutions of organic iodine compounds hitherto used, including Rayopaque. It has been a pleasant experience to see the patients leave the office without the slightest discomfort after injection of SalpL'<. When other iodated compounds were used it was necessary to premedicate the patients because many complained of pelvic pains and other signs of peritoneal irritation lasting from a few minutes to a few hours on occasion. Although no permanent sequelae were noted after other water-soluble contrast media, the immediate reaction after injection was a disadvantage that needed to be overcome. These observations have raised the question of what accounts for the absence of subjective discomfort after Salpix. The explanation appears to be the following: Schubert has shown that P.V.P. reduces the toxicity of various compounds. He observes that P.V.P. serves, in the case of toxic dyes, to work the dyes out of blood plasma and tissues and to divert them from the liver to the kidneys, hence hastening their excretion, and acting much like human albumin binding. The virtually complete nontoxicity of Salpix may be due to the protective action of P.V.P. as well as to its rapid absorption and excretion-rapid enough to reduce irritation; slow enough to enable the examining physician to make a conclusive diagnosis of intrauterine lesions and of tubal patency or nonpatency. It is also true that sodium acetrizoate is stable and gives off no free iodine, which would, of course, cause peritoneal irritation. Hysterosalpingography has been employed to determine radiographically the first proximal point of tubal obstruction in cases which had previously been demonstrated by uterotubal insufflation to have nonpatent tubes and in whom surgical restoration was contemplated. In this connection it should again be emphasized, as the senior author has emphasized many times before, that for the determination of tubal patency, nonpatency, and partial patency, reliance may be placed first and foremost upon uterotubal insufflation. For those who prefer to resort to hysterosalpinography as a method of diagnosing tubal patency, the use of Salpix serves to reduce the hazards and
364
RUBIN ET AL.
[Fertility & Sterility
sequelae of radiopaque fluids to a minimum. That is the chief virtue of this new medium. It is taken for granted that the physician employing Salpix, like many other similar contrast media, will have familiarized himself with the interpretation of the radiographic pictures, the details of which cannot be entered into here.* Although the major interest in Salpix is its usefulness in detecting important intrauterine lesions such as polypi, submucous myomas, and cervical strictures both before and after the menopause, the presence of endometrial carcinoma is demonstrated by Salpix, at least as well as by any of the iodized oils hitherto extensively employed for hysterosalpingography without sharing their disadvantages. 34 Although the importance of these conditions has been attested by innumerable reports in the literature, the value of routine hysterography as a preoperative diagnostic measure in myomectomy and even more importantly in the diagnosis of endometrial carcinoma has not been appreciated. The former will presently be discussed in a forthcoming monograph; the latter was first suggested in a discussion at the 1942 meeting of the American Gynecological Society of Sheffey's paper on malignancy subsequent to irradiation of the uterus for benign conditions. 32 It has also recently been the subject of a special communication at the Congress at Morocco in April, 1952. Since then, several cases have been encountered, one of which is recorded herewith. Case 1 Mrs. E. G., 43 years old, a nullipara and nulligravida, consulted one of the present authors (I. C. R.) on November 14, 1952, with the complaint of sporadic bleeding for the past year, after a two-year period of amenorrhea, which she had considered to be her menopause. On physical examination, her uterus was found not to be appreciably enlarged, but a small amount of dark, somewhat clotted blood escaped from the cervix. Several days later, when she was not bleeding, a hysterogram showed many small irregular filling defects along the right border of the uterine cavity and especially abundant in the lower uterine segment (Fig. 1). The picture was strongly suggestive of carcinoma, but a positive diagnosis could not be made because of the possible presence of blood clots. A suction endometrial biopsy was, therefore, done immediately following the hysterogram. The material submitted was hydrolized. A second endometrial biopsy was reported as carcinoma. The patient was operated upon by Mr. V. B. Green-Armytage in London, England, on December 12, 1952. A total hysterectomy * For the reader who desires detailed information on this particular subject, reference may be made to Uterotubal Insufflation by I. C. Rubin. St. Louis, Mo., Mosby, 1947.
Vol. 4, No.5, 1953]
SALPIX
365
with bilateral salpingo-oophorectomy was done for endometrial carcinoma (Fig. 2).
Of especial interest in this case is that two vaginal smears taken in New York City and examined at a cancer detection center were reported as negative and third vaginal smear taken in London was also reported as negative.
Fig. 1.
Hysterogram showing filling defects in uterine cavity.
Furthermore, as the first endometrial biopsy was not conclusive, a second one was insisted upon because of the appearance of the hysterogram. The value of x-ray visualization with Salpix in this particular case needs no further comment, except to emphasize the fact that by its aid the entire configuration of the uterine cavity could be visualized; not only those areas which happen to be within the range of the suction curet. Four additional case reports show the application of x-ray visualization with Salpix to various gynecologic conditions.
RUBIN ET AL.
366
[Fertility & Sterility
Case 2 Y. B., 67 years old, complained of staining for the past thirteen months. Menopause was at 50 years of age. The size of the uterus could not be established by vaginal examination owing to an obese abdominal wall. A polyp of the cervix had been removed at the office of her family physician two years ago, following
1~3
Fig. 2.
14 1
Gross specimen of uterus and tubes.
which staining stopped for eleven months. A Papanicolaou smear, taken at the New York Hospital, was negative. Although the hysterogram was not characteristic of carcinoma it showed a large lesion in the uterine cavity which demanded operative intervention (Fig. 3). This was done and a uterine carcinoma was demonstrable in the extirpated specimen and by histologic examination.
Case 3 R. L., 53 years old, complained of menometrorrhagia for the previous six months. On one occasion the bleeding was very profuse. After hysterectomy the
Vol. 4, No. 5, 1953]
SALPIX
367
uterus was found to be enlarged by multiple fibroids to the size of a three months' gestation. The pathologists' report was fibroids and adenomyosis (Fig. 4).
Case 4 D. 0., a 35-year-old nullipara, had been married for five years. Her chief complaint was sterility (Fig. 5).
3
4
5
6
Fig. 3. A widely dilated uterine cavity with large shadow defect indicating an intrauterine tumor. Fig. 4. An irregular, dilated uterine cavity with spicules of various sizes and shapes projecting from the endometrial surface into the myometrium, and typical of adenomyosis. Shadow defects indicating the presence of small polyps and a cornual submucous myoma were also present. Fig. 5. Two uterine cavities, the left being the better developed. The tubes are both patent to Salpix. The large mass with a central defect corresponding to the cervix is the vaginal tampon saturated with Salpix spontaneously evacuated from the uterus. Fig. 6. A well-developed uterus, dextroverted, with both tubes patent to Salpix. The uterine cavity shows no abnormality.
368
[Fertility & Sterility
RUBIN ET AL.
Case 5 Z. A., 30 years old, had a child 3 years of age. She complained of infertility of two years' duration (Fig. 6).
SUMMARY A new water-soluble radiopaque medium has been described composed of polyvinylpyrrolidone (P.V.P.) with sodium acetrizoate and designated Salpix.* This has the properties of radiopacity and viscosity which are best suited for hysterosalpingography. Sharing the advantages of iodized oils and none of their disadvantages, this new contrast medium is also superior to the other water-soluble combinations of iodine with viscosity-increasing substances because its use is neither attended nor followed by pelvic irritation. Salpix possesses perfect tolerability. A special advantage over iodized oils is the possibility of diagnosing tubal obstruction from one x-ray exposure, avoiding the expense and inconvenience to the patient of a second exposure within 24 hours as is necessary where iodized oil is used. Another advantage is that within one or at most two hours it is absorbed, leaving no trace thereafter, in contrast to iodized oils which are frequently trapped at constricted points in the tubal lumen, hence causing foreign body granuloma and total obstruction where only partial and remediable obstruction was present before the hysterosalpingography. Adequate experimental evidence and clinical experience in over 350 cases in which Salpix has been used have demonstrated that it represents the nearest approach to the ideal x-ray contrast medium for use in hysterography per se and for hysterosalpingography. REFERENCES 1. BANK,
J.
Complications
of
hysterosalpingography.
Acta
obst.
et
gynec.
scandinav. 29:383, 1950.
2. BLOOMFffiLD, ALICE
Six cases of venous intravasation following intrauterine Lipiodol injections. ]. Obst. & Gynaec. Brit. Emp. 53:345, 1946. 3. BRANDT, P., and DuBois, J. Conclusion d'une serie de 200 hysterosalpingraphies practiques pour sterilite. Bull. Fed. soc. gynec. et obst. 1:349, 1949. 4. BRowN, W. E., JENNINGS, AGNES F., and BRADBURY, J. T. The absorption of radiopaque substances in hysterosalpingography. Am. ]. Obst. & Gynec. 58:1041, 1949. "'Developed by the Ortho Research Foundation, Raritan, N.
J.
Vol. ,4, No.5, 1953]
5. CARY, W. H. 6.
7. 8. 9. 10. II. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28.
SALPIX
369
Note on determination of patency of fallopian tubes by the use of collargol and the x-ray shadow. Am. /. Obst. 69:462, 1914. EISER, D., and GOLDSTEIN, J. Lipiodol intravasation during uterosalpingography. Radiology 45:603, 1945. FINKBEINER, H. Hysterosalpingography with oil or water soluble contrast media. Deutsche med. Wchnschr. 77:1627, 1952. FRAZIER, C. H. The use of iodized rapeseed oil ( campiodol) for roentgenographic exploration. Am. /. Surg. 89:801, 1929. GENERAL ANILINE AND FILM CoRP. P.V.P. (Polyvinylpyrrolidone). New York, 1954. HEUSER, C. Lipiodol in the diagnosis of pregnancy. Lancet 2:4, 1925; Brit. /. Radial. 31:110, 1926. }EFFERISS, D. Hysterosalpingography employing a water soluble contrast medium. f. Obst. & Gynaec. Brit. Emp. 55:271, 1940. KENNEDY, W. T. A method of keeping fallopian tubes open. Am. ]. Obst. & Gynec. 3:607, 1922. KENNEDY, W. T. Radiography of closed fallopian tubes. Am. f. Obst. & Gynec. 6:12, 1923. MALLINCKRODT CHEMICAL WoRKS, Professional Information, "Sterile Solution Uroken Sodium 30% and Uroken Sodium 70%." St. Louis, Mo., 1952. MATHIEU, A. Lipiodol as a diagnostic aid in fibromata of female genital tract. Am. ]. Surg. 6:720, 1929. MATHIEU, A. Hysterosalpingography by means of iodized rapeseed oil. Am. f. Surg. 14:634, 1931. MoRSE, A. H., and RuBIN, I. C. The pharmacodynamic effects of certain oxytocics upon tubal contractions in the rhesus monkey. Surg., Gynec. & Obst. 71:620, 1940. NEUHAUS, DoROTHY, CHRISTMAN, A. J., and LEWIS, H. B. Evaluation of some iodine-containing organic compounds as x-ray contrast media. Proc. Soc. Exper. Biol. & Med. 78:313, 1951. NIELSEN, P. H. Injuries caused by hysterosalpingography. Acta obst. et gynec. scandinav. 26:265, 1946. NovAK, J. Salpingographie oder Tubendurchblasung. Zentralbl. Gyniik. 54: 3013, 1930. NovAK, J. Salpingographie und Tubendurchblasung. Zentralbl. Gyniik. 55: 1449, 1931. PALMER, A. Lipiodol "F" for use in hysterosalpingography. Fertil. & Steril. 3:210, 1952. PLATT, A. Intravasation of Lipiodol during uterosalpingography. Ohio State M. ]. 43:821, 1947. RIEs, E. Effect of Lipiodol injection on the tubes. Am. f. Obst. & Gynec. 17:728, 1929. RoBECCHI, E., and TEm, A. The use of water-soluble viscous contrast media for hysterosalpingography. Minerva ginec. 4:141, 1952 (Abstr. in f. Obst. & Gynaec. Brit. Emp. 59:911, 1952). RuBIN, I. C. Roentgen diagnosis of tumor with the aid of intrauterine collargol injections. Zentralbl. Gyniik. 38:658, 1914. RuBIN, I. C. Paper presented at the Thirteenth Meeting of the Radiological Society of North America, Dec. I, 1927. RUBIN, I. C. Diagnostic use of intrauterine iodized oil injection combined with
370
29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44.
RUBIN ET AL
[Fertility & Sterility
the x-rays as compared to peruterine carbon dioxide insufflation. Radiology 11: 115, 1928. RuBIN, I. C. Subphrenic collection of Lipiodol following injection into the fallopian tube: With observations on reverse gravitation of pelvic exudates and the genito-phrenic syndrome in women. Am. ]. Obst. & Gynec. 31:230, 1936. RuBIN, I. C. Retention of Lipiodol in fallopian tubes with special reference to occlusive effect in cases of permeable stricture. New York State]. Med. 36:1089, 1936. RuBIN, I. C. Use of soluble x-ray opaque media in gynecology. M. Rec. 152: 212, 1940. RuBIN, I. C. Discussion to Scheffey, L. C.: Malignancy subsequent to irradiation of the uterus for benign conditions. Tr. Am. Gynec. Soc. 67:313, 1942. RuBIN, I. C. Uterotubal Insufflation. St. Louis, Mo., Mosby, 1947. RuBIN, I. C. Comparison of carbon dioxide and opaque media in the diagnosis of tubal patency. Fertil. & Steril. 3:179, 1952. RuBIN, I. C., and MoRSE, A. H. Comparative value of radiopaque substances used in uterosalpingography. Am. ]. Roentgenol. 41:527, 1939. ScHUBERT, R. Neue Wege der Entgiftung durch Infusion niedermolekularen Kollidonfrakfionen. Deutsche. med. Wchnschr. 73:551, 1948. SEYMOUR, FRANCES I. The importance of diagnostic uterosalpingography in gynecology. M. Woman's ]., Sept. 1939. SEYMOUR, FRANCES I. A simple method of tubal insufflation treatment for sterility. M. Woman's]., May 3, 1938. SICARD, J. A., and FoRESTIER, J. Iodized oil as contrast medium in radioscopy. Bull. et mem. Soc. med. hOp. Paris 46:463, 1922. SICARD, J. A., and SoLAL, D'ORAN Accidents consecutifs au injection intrauterine de Lipiodol. Bull. et rruim. Soc. nat. de Chir. 54:1423, 1928. WEIR, W. C., and WEIR, D. R. Therapeutic value of salpingograms in infertility. Fertil. & Steril. 2:514, 1951. WEISMAN, A. I. Incidence of residual intraperitoneal iodochlorol after hysterosalpingography. Fertil. & Steril. 3:290, 1952. WHITE, MARGARET MooRE Errors in technique and interpretation of hysterosalpingography and tubal insufflation. ]. Obst. & Gynaec. Brit. Emp. 58:573, 1951. WILLIAMS, E. R. Venous intravasation during uterosalpingography. Brit. ]. Radiol. 17:13, 1944.
Tel-Aviv Institute for Research and Treatment of Infertility The Municipal Hospital Hadassah, Tel-Aviv, Israel, has established an Institute for Research and Treatment of Infertility as a subunit of the gynecologic and obstetric departments (Dr. I. G. Asherman, Director). The institute will be under the direction of Dr. Charles A. Joel.
I. C. Rubin, M.D., Ernest Myller, M.D., and Carl G. Hartman, Ph.D.
were made to visualize the uterine cavitv (hysterography) and the lumen of the fallopian tubes (salpingography) by means of intrauterine injection of Collargol, reported independently by Cary and Rubin in 1914, many improvements have been advocated. Beginning with different solutions containing halogen salts,12 • 13 • 26 there followed the development of iodized oils, of which Lipiodol is representative of the entire group of substances combining iodine with oils of various kinds. Lipiodol was first proposed by Sicard and Forestier for general use and by Heuser for application in gynecology.s, s, 15, 16, 33, 37, 38, 42 When the organic iodine-containing compounds such as U roselectan, Hippuran, and Diodrast were developed for urologic x-ray diagnosis, many gynecologists soon adopted these in their original form or in some modification thereof. 11 • 14 • 18 • 24 • 31 The newer contrast media combine a watersoluble organic iodine compound with a vehicle to enhance the viscosity. Among these combinations may be mentioned Skiodan combined with acacia and Rayopaque with polyvinyl alcohol; most recently carboxymethylcellulose and dextran have been employed to increase the viscosity in this manner, the last-named especially in Sweden and Switzerland. These contrast media have all had the same objective; that of avoiding an oil residue in the female genital tract. SINCE THE FIRST ATTEMPTS
From the Department of Obstetrics and Gynecology, Mt. Sinai Hospital, New York 29, New York, and the Ortho Research Foundation, Raritan, New Jersey. 357
358
RUBIN ET AL.
[Fertility & Sterility
Iodized oils have been employed many times by two of the present authors until the deleterious effects of the oils were discovered in 1927. 27 • 28 The harmful results of iodized oil combinations as used in the investigation of sterility may be summarized as follows:
1. Retention in obstructed fallopian tubes. If the tubes have been nonpatulous, no apparent damage is suffered by the patient. If, however, the tubes have been partially patent, the iodized oil is trapped by virtue of its viscosity, its very slow absorption, and its failure to mix with the tubal secretions. Retained for varying lengths of time within the constricted lumen, the oil may, and in some cases actually does, set up a foreign body reaction leading to granuloma formation and complete tubal obstruction. The first observation of such oil retention in the fallopian tubes was reported by Rubin in 192727 and published in 1928. 28 Other reports of tubal irritation soon followed.2o, 21, 24, 29, 32, 33 2. Multiple cyst formation. A second undesirable sequel of the intrauterine injection of iodized oil is the long periods of time that spillage into the peritoneal cavity remains, 4· 7 • 19 • 32 · 33 setting up multiple cyst formations, which it is well to avoid even though such peritoneal reaction may not interfere with conception. Many gynecologists do not favor, or are unenthusiastic concerning, the use of iodized oil for salpingography, fearing injury to the cilia. 3. Oil embolism. Of less frequent occurrence, 1 but more serious when it occurs, is the intravasation of iodized oil into the uterine veins and thence into the systemic circulation. 1 • 2· 6 • 23 · 44 Also to be reckoned with is the introduction of the oil into the myometrium-especially in cases of adenomyosiswhere the iodized oil remains for a long time, with or without inciting inflammatory processes. These clinical and pathologic observations have led to renewed efforts at making available a radiopaque substance which has the following properties: ( 1) it should be dense enough to cast clean shadows; ( 2) it should pass through the fallopian tubes slowly enough tn be filmed; ( 3) it should be sufficiently viscous so that strictures of the tubal lumen may be accurately visualized; ( 4) and finally the material injected should be resorbed within a few hours, leaving no trace behind in the tubes or in the peritoneal cavity, yet offering the possibility of making a complete and positive diagnosis in a relatively short time. In this connection the well-known fact need
Vol. 4, No.5, 1953]
SALPIX
359
hardly be mentioned that when iodized oils are used, a 24-hour film is indispensable to establish tubal nonpatency or high-grade tubal strictures. The four criteria have been fully met in Salpix.
DESCRIPTION Chemical and Physical Properties The present paper deals with a radiopaque medium, Salpix, which is a combination of a solution of polyvinylpyrrolidone (P.V.P. ), the basis of a well-known blood extender, to which has been added sodium acetrizoate. The widely used blood substitute P.V.P. 9 has been selected as a suitable agent to impart to the acetrizoate, a compound of high x-ray opacity, the needed viscosity and tissue adhesiveness. Sodium acetrizoate has a high iodine content ( 65.8 per cent), as may be seen from the following formula: 0
II
C-0-Na
I)~ I I
II
0
I
I-N-C-CH3 ""/ I
I
H
The chemical name of this compound is sodium 3-acetylamino-2,4,6triiodo benzoate. Salpix is an amber-colored mixture. Its viscosity at 37° C. is approximately 200 centipoise. It contains 54 per cent sodium acetrizoate. It is stable on storage at 50° C. for six months, and will permit autoclaving without loss of its desirable properties. It is subjected to the usual controls for sterility and pyrogenicity.
Historical Note It is of interest to recall that the first trials with uterine injection of radiopaque substances were made upon the human female on purely empirical grounds. Cary's first injections of CollargoJ.were made without prior animal experimentation and Rubin had made only anatomic studies and injections of collargol in the rabbit before applying the method clinically. Soon after, in preparation of the clinical use of oxygen insuffiation through the uterus, Rubin injected the dog's uterine vein with an amount of oxygen equal to that recommended for the clinical diagnosis of tubal patency.
RUBIN ET AL.
360
[Fertility & Sterility
In retrospect there is no doubt that the new venture was concerned only with the anatomic feasibility and the physical realizability of the radiopaque agent. Untoward effects were only appreciated after some clinical trial with various substances employed in hysterosalpingography. This early and empirical method has since been abandoned and replaced by scientific experimental controls, which were instituted for example in the case of viscorayopaque ( Rayopaque). This substance appeared to satisfy the desiderata of viscosity as well as absence of residue, but proved to have an irritant action, in many cases for some minutes and occasionally longer. As the manufacture of this product was discontinued, the opportunity proffered by the Ortho Research Foundation was welcomed to develop another radiopaque substance having the desirable properties of Rayopaque without its disadvantages. The blood substitute polyvinylpyrrolidone as the viscosity-rendering vehicle and the organic iodine component acetrizoate have both been subjected to modern experimental controls to determine their desirability for clinical trial. Toxicity of P.V.P. and Sodium Acetrizoate
Since the nontoxicity of each component of Salpix has been amply demonstrated,9· 14 it might have been assumed that the combination of the two would also be nontoxic. Nevertheless this was not taken for granted. Special tests were made to study Salpix for possible irritation and toxicity. These tests consisted of injecting it into monkeys, rabbits, dogs, and rats, intravenously, intraperitoneally (by direct abdominal puncture and by way of the uterus), subcutaneously, and by gavage. The tests are presented in outline as follows:
Experiments with Monkeys. Thirty experiments were made on 13 monkeys; of these animals 2 were used four times; 2 three times; 4 twice, and eight once. In all experiments x-ray films were taken. Three monkeys each received 5 cc. of Salpix intravenously; none showed the slightest reaction or symptom. In 5 experiments the uterus was entered and injected from below by the technics of Rubin and Morse; 35 six times the uterus was injected successfully from without, i.e., through the abdominal wall, because the approach from below is sometimes extremely difficult. Three times a laparotomy was done and the uterus injected. Nine intraperitoneal injections were made to test toxicity and rate of absorption.
Vol. 4, No.5, 1953]
SALPIX
361
In 4, the vagina only was injected. None of the 13 monkeys showed the least sign of irritation or toxicity. Experiments with Dogs and Rabbits. A dog was injected subcutaneously with 5 cc. of Salpix. At autopsy the next day no sign of irritation was discernible at the injected area. Another dog received subcutaneously 2 cc. of Salpix in the right and left scapula and the right and left gluteal regions; no reaction was noted. A third dog licked the site of injection of 5 cc. of Salpix from time to time for about an hour, otherwise showing no symptoms. Four rabbits injected with 5 cc. of Salpix intravenously showed no symptoms of discomfort or irritation whatever. A fifth rabbit was treated as follows: 5 cc. of Salpix was injected intravenously; 5 minutes later, the right renal pelvis and ureter and left renal pelvis were visualized on the x-ray film; the liver was mottled, the lobules being outlined. Mter 30 minutes there were the same findings, much material showing in the bladder. In 50 minutes, both ureters were visualized, and the bladder was seen to be dilated and full of Salpix. In 80 minutes another intravascular injection of 2.5 cc. of Salpix was made. The findings were the same as before. No symptoms appeared. Table 1 summarizes the findings after animal experiments. Summary of Toxicity Experiments
The observations derived from animal experiments with Salpix may be summarized as follows: 1. Mter intravenous injection, Salpix rapidly leaves the blood stream by way of the kidneys. It remains in the uterine lumen of the monkey up to one or two hours for reasons stated below, but spillage into the peritoneal cavity is eliminated within an hour. 2. The longer retention of Salpix in the monkey uterus as compared with the human uterus requires a note of explanation. In Macaca mulatta there is in the region of the cervix uteri a colliculus which pushes the cervical lumen dorsally, like a ball valve, rendering the already narrow passage circuitous and the emptying of the uterus more difficult. It is apparent, too, that because of the obstructing colliculus, insertion of a cannula from below is practically impossible without surgery. The surgical technic required to overcome the cervical obstruction to a uterine cannula was developed by Rubin and Morse. It consists of cutting through the lateral cervix walls and bypassing the colliculus. By pulling apart the cervical lips, the uterine can-
[Fertility & Sterility
RUBIN ET AL.
362
nula can then be directly inserted into the uterus and injection successfully accomplished. That the colliculus blocks the discharge of uterine contents has been repeatedly observed by one of the authors (C. G. H.), who noted that the monkey uterus is much slower to expel its contents (a small dead embryo, for example) than is the human uterus. In a few clinical cases with TABLE 1. Animal
Rate of Absorption of Salpix: Results after Animal Experiments Residue
In;ection Amount (cc.)
Route of In;ection
Place
Time (min.)
Observation
Rabbits Monkeys #29 #26 #2
5
intravenous
bladder
60
no other residue
5
5 5
bladder bladder bladder bladder bladder
60
#11 #8
intravenous intravenous intraperitoneal intraperitoneal intraperitoneal
#30
3
intraperitoneal
bladder
#8
3
intraperitoneal
#21
3 3
no other residue no other residue no other residue no other residue faint streaks in abdominal cavity no other residue bladder empty no other residue bladder empty slight residue in uterus body cavity clear, good outline of uterus, much Salpix in bladder no residue
#8
#20 #24
#21
5 3
3 2.3 3
3
75 60 60 60 80 24 hr.
30
24 hr. 90 bladder into uterus uterus filled, spillage uterus and bladder 60 through tubes into body cavity
pelvis (by error) and uterus uterus filled, spillage through tubes into body cavity uterus filled, spillage through tubes into body cavity
24 hr.
120 24 hr.
30
no
residue in body cavity no residue uterus well outlined, no residue in body cavity
cervical stenosis Salpix was retained within the uterus for about a half-hour before it was evacuated. 3. As Salpix can safely be injected intravenously, its accidental entry into the blood stream during and after uterosalpingography is neither attended or followed by the harmful results which are, unfortunately, sometimes noted after intravasation of oil into the uterine vein causing fat embolism.
Vol. 4, No. 5, 1953]
SALPIX
363
CLINICAL OBSERVATIONS AND EVALUATION
Salpix has been employed by the senior author in uterotubal injection on more than 350 patients. The clinical use of Salpix has in his hands been more satisfactory than that of previously available opaque substances. Practically none of the patients experienced the mild to severe abdominal pain which attends or follows injection of iodized oils and solutions of organic iodine compounds hitherto used, including Rayopaque. It has been a pleasant experience to see the patients leave the office without the slightest discomfort after injection of SalpL'<. When other iodated compounds were used it was necessary to premedicate the patients because many complained of pelvic pains and other signs of peritoneal irritation lasting from a few minutes to a few hours on occasion. Although no permanent sequelae were noted after other water-soluble contrast media, the immediate reaction after injection was a disadvantage that needed to be overcome. These observations have raised the question of what accounts for the absence of subjective discomfort after Salpix. The explanation appears to be the following: Schubert has shown that P.V.P. reduces the toxicity of various compounds. He observes that P.V.P. serves, in the case of toxic dyes, to work the dyes out of blood plasma and tissues and to divert them from the liver to the kidneys, hence hastening their excretion, and acting much like human albumin binding. The virtually complete nontoxicity of Salpix may be due to the protective action of P.V.P. as well as to its rapid absorption and excretion-rapid enough to reduce irritation; slow enough to enable the examining physician to make a conclusive diagnosis of intrauterine lesions and of tubal patency or nonpatency. It is also true that sodium acetrizoate is stable and gives off no free iodine, which would, of course, cause peritoneal irritation. Hysterosalpingography has been employed to determine radiographically the first proximal point of tubal obstruction in cases which had previously been demonstrated by uterotubal insufflation to have nonpatent tubes and in whom surgical restoration was contemplated. In this connection it should again be emphasized, as the senior author has emphasized many times before, that for the determination of tubal patency, nonpatency, and partial patency, reliance may be placed first and foremost upon uterotubal insufflation. For those who prefer to resort to hysterosalpinography as a method of diagnosing tubal patency, the use of Salpix serves to reduce the hazards and
364
RUBIN ET AL.
[Fertility & Sterility
sequelae of radiopaque fluids to a minimum. That is the chief virtue of this new medium. It is taken for granted that the physician employing Salpix, like many other similar contrast media, will have familiarized himself with the interpretation of the radiographic pictures, the details of which cannot be entered into here.* Although the major interest in Salpix is its usefulness in detecting important intrauterine lesions such as polypi, submucous myomas, and cervical strictures both before and after the menopause, the presence of endometrial carcinoma is demonstrated by Salpix, at least as well as by any of the iodized oils hitherto extensively employed for hysterosalpingography without sharing their disadvantages. 34 Although the importance of these conditions has been attested by innumerable reports in the literature, the value of routine hysterography as a preoperative diagnostic measure in myomectomy and even more importantly in the diagnosis of endometrial carcinoma has not been appreciated. The former will presently be discussed in a forthcoming monograph; the latter was first suggested in a discussion at the 1942 meeting of the American Gynecological Society of Sheffey's paper on malignancy subsequent to irradiation of the uterus for benign conditions. 32 It has also recently been the subject of a special communication at the Congress at Morocco in April, 1952. Since then, several cases have been encountered, one of which is recorded herewith. Case 1 Mrs. E. G., 43 years old, a nullipara and nulligravida, consulted one of the present authors (I. C. R.) on November 14, 1952, with the complaint of sporadic bleeding for the past year, after a two-year period of amenorrhea, which she had considered to be her menopause. On physical examination, her uterus was found not to be appreciably enlarged, but a small amount of dark, somewhat clotted blood escaped from the cervix. Several days later, when she was not bleeding, a hysterogram showed many small irregular filling defects along the right border of the uterine cavity and especially abundant in the lower uterine segment (Fig. 1). The picture was strongly suggestive of carcinoma, but a positive diagnosis could not be made because of the possible presence of blood clots. A suction endometrial biopsy was, therefore, done immediately following the hysterogram. The material submitted was hydrolized. A second endometrial biopsy was reported as carcinoma. The patient was operated upon by Mr. V. B. Green-Armytage in London, England, on December 12, 1952. A total hysterectomy * For the reader who desires detailed information on this particular subject, reference may be made to Uterotubal Insufflation by I. C. Rubin. St. Louis, Mo., Mosby, 1947.
Vol. 4, No.5, 1953]
SALPIX
365
with bilateral salpingo-oophorectomy was done for endometrial carcinoma (Fig. 2).
Of especial interest in this case is that two vaginal smears taken in New York City and examined at a cancer detection center were reported as negative and third vaginal smear taken in London was also reported as negative.
Fig. 1.
Hysterogram showing filling defects in uterine cavity.
Furthermore, as the first endometrial biopsy was not conclusive, a second one was insisted upon because of the appearance of the hysterogram. The value of x-ray visualization with Salpix in this particular case needs no further comment, except to emphasize the fact that by its aid the entire configuration of the uterine cavity could be visualized; not only those areas which happen to be within the range of the suction curet. Four additional case reports show the application of x-ray visualization with Salpix to various gynecologic conditions.
RUBIN ET AL.
366
[Fertility & Sterility
Case 2 Y. B., 67 years old, complained of staining for the past thirteen months. Menopause was at 50 years of age. The size of the uterus could not be established by vaginal examination owing to an obese abdominal wall. A polyp of the cervix had been removed at the office of her family physician two years ago, following
1~3
Fig. 2.
14 1
Gross specimen of uterus and tubes.
which staining stopped for eleven months. A Papanicolaou smear, taken at the New York Hospital, was negative. Although the hysterogram was not characteristic of carcinoma it showed a large lesion in the uterine cavity which demanded operative intervention (Fig. 3). This was done and a uterine carcinoma was demonstrable in the extirpated specimen and by histologic examination.
Case 3 R. L., 53 years old, complained of menometrorrhagia for the previous six months. On one occasion the bleeding was very profuse. After hysterectomy the
Vol. 4, No. 5, 1953]
SALPIX
367
uterus was found to be enlarged by multiple fibroids to the size of a three months' gestation. The pathologists' report was fibroids and adenomyosis (Fig. 4).
Case 4 D. 0., a 35-year-old nullipara, had been married for five years. Her chief complaint was sterility (Fig. 5).
3
4
5
6
Fig. 3. A widely dilated uterine cavity with large shadow defect indicating an intrauterine tumor. Fig. 4. An irregular, dilated uterine cavity with spicules of various sizes and shapes projecting from the endometrial surface into the myometrium, and typical of adenomyosis. Shadow defects indicating the presence of small polyps and a cornual submucous myoma were also present. Fig. 5. Two uterine cavities, the left being the better developed. The tubes are both patent to Salpix. The large mass with a central defect corresponding to the cervix is the vaginal tampon saturated with Salpix spontaneously evacuated from the uterus. Fig. 6. A well-developed uterus, dextroverted, with both tubes patent to Salpix. The uterine cavity shows no abnormality.
368
[Fertility & Sterility
RUBIN ET AL.
Case 5 Z. A., 30 years old, had a child 3 years of age. She complained of infertility of two years' duration (Fig. 6).
SUMMARY A new water-soluble radiopaque medium has been described composed of polyvinylpyrrolidone (P.V.P.) with sodium acetrizoate and designated Salpix.* This has the properties of radiopacity and viscosity which are best suited for hysterosalpingography. Sharing the advantages of iodized oils and none of their disadvantages, this new contrast medium is also superior to the other water-soluble combinations of iodine with viscosity-increasing substances because its use is neither attended nor followed by pelvic irritation. Salpix possesses perfect tolerability. A special advantage over iodized oils is the possibility of diagnosing tubal obstruction from one x-ray exposure, avoiding the expense and inconvenience to the patient of a second exposure within 24 hours as is necessary where iodized oil is used. Another advantage is that within one or at most two hours it is absorbed, leaving no trace thereafter, in contrast to iodized oils which are frequently trapped at constricted points in the tubal lumen, hence causing foreign body granuloma and total obstruction where only partial and remediable obstruction was present before the hysterosalpingography. Adequate experimental evidence and clinical experience in over 350 cases in which Salpix has been used have demonstrated that it represents the nearest approach to the ideal x-ray contrast medium for use in hysterography per se and for hysterosalpingography. REFERENCES 1. BANK,
J.
Complications
of
hysterosalpingography.
Acta
obst.
et
gynec.
scandinav. 29:383, 1950.
2. BLOOMFffiLD, ALICE
Six cases of venous intravasation following intrauterine Lipiodol injections. ]. Obst. & Gynaec. Brit. Emp. 53:345, 1946. 3. BRANDT, P., and DuBois, J. Conclusion d'une serie de 200 hysterosalpingraphies practiques pour sterilite. Bull. Fed. soc. gynec. et obst. 1:349, 1949. 4. BRowN, W. E., JENNINGS, AGNES F., and BRADBURY, J. T. The absorption of radiopaque substances in hysterosalpingography. Am. ]. Obst. & Gynec. 58:1041, 1949. "'Developed by the Ortho Research Foundation, Raritan, N.
J.
Vol. ,4, No.5, 1953]
5. CARY, W. H. 6.
7. 8. 9. 10. II. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28.
SALPIX
369
Note on determination of patency of fallopian tubes by the use of collargol and the x-ray shadow. Am. /. Obst. 69:462, 1914. EISER, D., and GOLDSTEIN, J. Lipiodol intravasation during uterosalpingography. Radiology 45:603, 1945. FINKBEINER, H. Hysterosalpingography with oil or water soluble contrast media. Deutsche med. Wchnschr. 77:1627, 1952. FRAZIER, C. H. The use of iodized rapeseed oil ( campiodol) for roentgenographic exploration. Am. /. Surg. 89:801, 1929. GENERAL ANILINE AND FILM CoRP. P.V.P. (Polyvinylpyrrolidone). New York, 1954. HEUSER, C. Lipiodol in the diagnosis of pregnancy. Lancet 2:4, 1925; Brit. /. Radial. 31:110, 1926. }EFFERISS, D. Hysterosalpingography employing a water soluble contrast medium. f. Obst. & Gynaec. Brit. Emp. 55:271, 1940. KENNEDY, W. T. A method of keeping fallopian tubes open. Am. ]. Obst. & Gynec. 3:607, 1922. KENNEDY, W. T. Radiography of closed fallopian tubes. Am. f. Obst. & Gynec. 6:12, 1923. MALLINCKRODT CHEMICAL WoRKS, Professional Information, "Sterile Solution Uroken Sodium 30% and Uroken Sodium 70%." St. Louis, Mo., 1952. MATHIEU, A. Lipiodol as a diagnostic aid in fibromata of female genital tract. Am. ]. Surg. 6:720, 1929. MATHIEU, A. Hysterosalpingography by means of iodized rapeseed oil. Am. f. Surg. 14:634, 1931. MoRSE, A. H., and RuBIN, I. C. The pharmacodynamic effects of certain oxytocics upon tubal contractions in the rhesus monkey. Surg., Gynec. & Obst. 71:620, 1940. NEUHAUS, DoROTHY, CHRISTMAN, A. J., and LEWIS, H. B. Evaluation of some iodine-containing organic compounds as x-ray contrast media. Proc. Soc. Exper. Biol. & Med. 78:313, 1951. NIELSEN, P. H. Injuries caused by hysterosalpingography. Acta obst. et gynec. scandinav. 26:265, 1946. NovAK, J. Salpingographie oder Tubendurchblasung. Zentralbl. Gyniik. 54: 3013, 1930. NovAK, J. Salpingographie und Tubendurchblasung. Zentralbl. Gyniik. 55: 1449, 1931. PALMER, A. Lipiodol "F" for use in hysterosalpingography. Fertil. & Steril. 3:210, 1952. PLATT, A. Intravasation of Lipiodol during uterosalpingography. Ohio State M. ]. 43:821, 1947. RIEs, E. Effect of Lipiodol injection on the tubes. Am. f. Obst. & Gynec. 17:728, 1929. RoBECCHI, E., and TEm, A. The use of water-soluble viscous contrast media for hysterosalpingography. Minerva ginec. 4:141, 1952 (Abstr. in f. Obst. & Gynaec. Brit. Emp. 59:911, 1952). RuBIN, I. C. Roentgen diagnosis of tumor with the aid of intrauterine collargol injections. Zentralbl. Gyniik. 38:658, 1914. RuBIN, I. C. Paper presented at the Thirteenth Meeting of the Radiological Society of North America, Dec. I, 1927. RUBIN, I. C. Diagnostic use of intrauterine iodized oil injection combined with
370
29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44.
RUBIN ET AL
[Fertility & Sterility
the x-rays as compared to peruterine carbon dioxide insufflation. Radiology 11: 115, 1928. RuBIN, I. C. Subphrenic collection of Lipiodol following injection into the fallopian tube: With observations on reverse gravitation of pelvic exudates and the genito-phrenic syndrome in women. Am. ]. Obst. & Gynec. 31:230, 1936. RuBIN, I. C. Retention of Lipiodol in fallopian tubes with special reference to occlusive effect in cases of permeable stricture. New York State]. Med. 36:1089, 1936. RuBIN, I. C. Use of soluble x-ray opaque media in gynecology. M. Rec. 152: 212, 1940. RuBIN, I. C. Discussion to Scheffey, L. C.: Malignancy subsequent to irradiation of the uterus for benign conditions. Tr. Am. Gynec. Soc. 67:313, 1942. RuBIN, I. C. Uterotubal Insufflation. St. Louis, Mo., Mosby, 1947. RuBIN, I. C. Comparison of carbon dioxide and opaque media in the diagnosis of tubal patency. Fertil. & Steril. 3:179, 1952. RuBIN, I. C., and MoRSE, A. H. Comparative value of radiopaque substances used in uterosalpingography. Am. ]. Roentgenol. 41:527, 1939. ScHUBERT, R. Neue Wege der Entgiftung durch Infusion niedermolekularen Kollidonfrakfionen. Deutsche. med. Wchnschr. 73:551, 1948. SEYMOUR, FRANCES I. The importance of diagnostic uterosalpingography in gynecology. M. Woman's ]., Sept. 1939. SEYMOUR, FRANCES I. A simple method of tubal insufflation treatment for sterility. M. Woman's]., May 3, 1938. SICARD, J. A., and FoRESTIER, J. Iodized oil as contrast medium in radioscopy. Bull. et mem. Soc. med. hOp. Paris 46:463, 1922. SICARD, J. A., and SoLAL, D'ORAN Accidents consecutifs au injection intrauterine de Lipiodol. Bull. et rruim. Soc. nat. de Chir. 54:1423, 1928. WEIR, W. C., and WEIR, D. R. Therapeutic value of salpingograms in infertility. Fertil. & Steril. 2:514, 1951. WEISMAN, A. I. Incidence of residual intraperitoneal iodochlorol after hysterosalpingography. Fertil. & Steril. 3:290, 1952. WHITE, MARGARET MooRE Errors in technique and interpretation of hysterosalpingography and tubal insufflation. ]. Obst. & Gynaec. Brit. Emp. 58:573, 1951. WILLIAMS, E. R. Venous intravasation during uterosalpingography. Brit. ]. Radiol. 17:13, 1944.
Tel-Aviv Institute for Research and Treatment of Infertility The Municipal Hospital Hadassah, Tel-Aviv, Israel, has established an Institute for Research and Treatment of Infertility as a subunit of the gynecologic and obstetric departments (Dr. I. G. Asherman, Director). The institute will be under the direction of Dr. Charles A. Joel.