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A New, Nonirritating Opaque Medium for Uterosalpingography
A NEW, NONIRRITATING OPAQUE :MEDIUM FOR UTEROSALPINGOGRAPHY
II. EUMINATION OF ACACIA R. H. McCLELLAN, M.D., PAuL TrTus, M.D., R. E. TAFEL, M.D., AND E. C. LORY, PH.D., PITTSBURGH, PA. (From the John C. Olivl!'r Memorial Research Foundation and the Department of Obstetrics and Gynecology, St. Margaret Memorial Hospital)
HE use of iodized oils in the x-ray visualization of the uterus and T Fallopian tubes is occasionally :followed by troublesome :r::eactwns. Following· its injection,
acute ''chemical'' salpingitis, parametritic masses, and occasional allergic reactions have been reported. It has recently been shown by our group1 • 2 that a solution of mono-iodoinethane sulphonate of sodium (skiodan) with acacia is a nonirritati~g .medium for uterosalpingography. Skiodan is not irritating to the JJ,terus and tubes. It is rapidly eliminated from the body through the urine and does not liberate free or inorganic iodine. ;;. These studies did not show, however, the effect of the acacia used as a vehicle nor whether the acacia was eliminated. That a knowledge of the effect and fate of acacia is important is pointed out in the literature by several investigators3 - 5 who have shown that acacia when injected in large doses intravenously causes damage to the liver. Others6 express the clinical view, ho\vever, that, ''long continued presence of acacia within the body without apparent harmful effects demonstrates anew its innoeuous character in man.'' \Ve wished to be certain, in addition, that the acacia would not become encysted in the peritoneal cavity, as is so often the case with iodized oil injected :for uterosalpingography. To complete the study of the effect of, and the :fate of, skiodan-acaeia, a series of experiments was devised to study the action of the acacia upon the uterus, tubes, and peritoneum, if any, and to determine its fate upon injection into the female internal genitalia and the peritoneum. 1 SUMMARY OF EXPERIMEN'rS
Our experiments with acacia fall into three parts; iirst, a determination of the local or general effect of the injection of acacia into the genitalia and peritoneum of female rabbits, second, a study of the blood and urine thereafter for acacia, and third, chemical and microscopic studicH of the livers of rabbits so injected.
1. Loca:t and General Effects Three rabbits were injected with varying amounts of acacia in different ways. Rabbit 101 received 2 c.c. of 20 per cent acacia in the uterus and tubes following the technique used in our preceding experiments.2 There was no immediate reaction of any kind. After thirty-two days this rabbit was killed and the peritoneum and internal genitalia carefully examined. There was no evidence of the acacia in the peritoneum or genitalia, nor was there any evidence of inflammation or irritation. The liver was examined and found grossly to be normal. Rahbit 102 received 5 c.c. of
495
496
AMJ<;RIUAX JOUR:-
20 per cent acacia directly into the peritmwum. 'flterc wa ~ 110 illnltediate rew:tion and after twenty-five days this rabbit wa~ killed. 'l'he gToHS pxamination of perito · neum and liver did not show any eviclene(' of irritat ive rd'fed. R.abhit lll:l re~eived (i.6 e.c. of 30 per (~ent aeaeia direc tly into the peritoneum anu was killed seven~rhaps the best indication of the presence of acacia in urine.
A.
B.
c.
Fig. 1.-A , Rabbit 101 live r thirty -two days a fter injection o f 0.4 gm. of acac ia: B, Rabbit 10 2 liver tw enty-five days after injection of 1.0 gm. of acacia; C, Rabbit 103 liver seven d ays a fter injection of 2.Q gm. of acacia.
It was found (see 'l'able I ) that minute amounts of aeacia could be detected in the urine at intervals of from 6 to 108 hours after injection. It was concluded that if acacia is excreted in the urine it must be in only small amounts and perhaps over a very long period of time as was found by Andersch and Gibson. 3 For studies of acacia in the blood the oxidimetric method of Keith, Power and Wakefield6, 9 was cmployt>d, using 95 per ct>nt flthyl akohol as the precipitating agent. In the fir~t two rabbits we Wl're disappointed not to find the suHpected large amounts of acacia in the blood but. upon reading the work of Putnam1o we realized that we were not sampling the blood early enough to pick up the higher levels of the acacia (see Table I ) . Rabbit 103 showed that the level of acacia reached a maximum at about six hours after injection and rapidly f ell to approximately normal in less than seventy-two hours.
3. Chemical and Micro~copi.c Stu.dies of Liver8 Several investigators3-5 have pointed out that the liver is damaged following intravenous use of relatively large amounts of acacia. We felt that we must know if acacia injected into the female internal genitals and peritoneum in the recommended dosage would have a like effect. Rabbits were injected with amounts corresponding t.o 4 to 20 times the amounts usually used in the human being for uterosalpingography. These rabbits were killed at thirty-two, twenty-five, and
MCCLELLAN ET AL.: TABLE
RABBI'l'
I.
1.0 gm.
103
2.0 gm.
497
DETERMINATION OF ACACIA IN BLOOD AND URINE
ACACIA INJECTED
102
OPAQUE MEDIUM FOR UTEROSALPINGOGRAPHY
TABLE
URINE TIME AFTER INJECTION
36 60 84 108 12 36 42 62 6 24 72 !I.
hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr.
BLOOD
ACACIA BIAL 'S TEST
Trace None Trace Trace Trace None None Trace None None Trace
TIME AFTER INJECTION
ACACIA IN BLOOD SERUM
c.c.
84 hr. 48 hr. 96 3 6 24 72
hr. hr. hr. hr. hr.
13.1 mg./100 c.c. 18.0 mg./100 c.c.
e. c. c.c. c.c.
c.c.
DETERMINATION OF ACACIA IN LIVER MICROSCOPIC SECTION LIVER
seven days after injection of acacia. In Rabbit 101 the injection was made into the uterus and tubes while in the remaining two rabbits the acacia was placed directly into the peritoneum. The livers were examined in situ in the gross and were found to present a normal appearance as to shape, size, margins, and surfaces. They were immediately removed from the body and a portion placed in ZRnker's fixative for mieroscopic study and a second portion taken for quantitative estimation of the amount of acacia therein. For this analysis the method of Youngbergs as used by Andersch and Gibsons was employed. The amount of furfural producing material, calculated as acacia, in all three livers was just above that given by Andersch and Gibsons as normal (Table II). '!'he microscopic study of these livers did not show the destruction and swelling of liver parenchyma as found by others following intravenous injection of larger amounts of acacia,3-5 and it was felt that all sections represent essentially normal histology. SUM.M.ARY
1. Experimental data indicate that acacia injected in the amounts used in uterosalpingography does not irritate the internal genitalia or peritoneum in rabbits. 2. Acacia does not remain in the peritoneum but is rapidly taken up and appears in the blood stream within three hours following its injection. The maximum level of acacia in the blood is reached within six hours, and it has almost disappeared from the blood in seventy-two hours. 3. We could not prove that acacia is excreted in the urine. It has been shown by Andersch and Gibson that in bile fistula dogs, acacia appears within six hours in the bile, and it is most likely that the bile is the means by which it leaves the body. 4. Microscopic studies of the livers up to thirty-two days after injection of more than ten times the amount of acacia used in human uterosalpingography did not show liver damage.
498
AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY
5. The amount of furfural producing material, calculated as acaeia, in the liver was just abo\·e that saill to hr nm·mul. coxcr.r~JoN
Our previous findings show that flkiodan produe.(•s satisfactory x-ray shadows, and further is nonirritating to the tissues and is rapidl:r eliminated from the body. Our presrnt findings show that acacia is nonirritating, is not retained in the peritoneum and does not eause liver damage. We conelude that skiodan-;waeia in nterosalpingography is harmless in the amounts used and is. thPrefnre, to lw preferred to the older opaque media (iodized oils). The materials for this inv(•stigation Chemi<'al Co., New York.
W<'l'\'
gc"nHously furnisheu by the ·winthrop
HEFEHENCES Me~;ser, F. C.: AM. J. 0BS1'. (2) Idem: Ibid. 36: 889, 1938. (3) Andersch, M .. nnd Gibson, R. B.: J. Pharmacol. & Exper. 'l'herap. 52: 390, 1934. (4) Heckel, G. P., Erickson, C. C., Y'ldle, C. L., and Knutti, R. E.: J. Exper. Med. 67: 345, 1938. ( 5) Hall, W. K.: Proc. Soc. Exper. Biol. & Med. 38: 4!i, 1938. (6) Keith, N. M., Power, M. H., and Wnkefield, E. G.: Proc. Staff Meet., Mayo Clinic 10: 38, 1935. (7) Sumner, J. B.: J. Bioi. Chem. 65: 319, 1925. (8) Youngberg, G. E.: J. Biol. Chem. 73: 599, 1927. (9) Power, M. H., and ·wakefield, E. G.: .T. Bioi. Chem. 123: 665, 1938. (10) Putnam, T ..J.: Am .• 1. Physiol. 63: 548, 1923.
(1) Titus, P., Tnfel, R. J.;,, McClellan, R. H .• nnd
& GYNEC. 33: 164, 1937.
RELAXATION OF 'I'HE PELVIC lJIGAlVIENTS IN PREGNANT MONKEYS CARL
G.
HAwrMAN,
PH.D.,
AND WILLIAM
BAvriMORE,
::vrn.
L.
STRAus, .TR.,
PH.D.,
(From the Carnegie Lnbmatory of Embryology, the Johns Hopkins JJ:ledical School)
ROFOUND chauges occur in the pubic and sacroiliac joints in many of the lower mammals during the eourst> of gt>statinn. 'rhe horP monal control of the tissue metamorphoses involwd has been fairly well worked out. 1 An examination of modern textbooks of obstetrics 2 • 3 as well as the current literature on the subject indicates that pelvic relaxation in women is generally recognized. Most of the clinical literature coneerns cases of pathologic exaggeration of the process which may lead to separation of the pubic bones and eonsequent distressing symptoms. The pregnancy changes in the ligaments as a normal and physiologic process is also stressed or taken for gTanted. 'l'hus Kehrer 3 states that the motility of the pelvi(~ bones, by loosening of the joints, has not only a pathologie significance bnt above all a physiologic one; for it makes possible an increase in the diameter of the birth canal. DeLee 2 says that "in the human there is no doubt but that the joints soften, thicken and thus enlarge the cavity of the pelvis. The bones become more movable on each other . . . . " The relaxation of the pelvic ligaments has been noted in scores of eases in the rhesus monkey (Macaca mulatta) and in six specimens
II. EUMINATION OF ACACIA R. H. McCLELLAN, M.D., PAuL TrTus, M.D., R. E. TAFEL, M.D., AND E. C. LORY, PH.D., PITTSBURGH, PA. (From the John C. Olivl!'r Memorial Research Foundation and the Department of Obstetrics and Gynecology, St. Margaret Memorial Hospital)
HE use of iodized oils in the x-ray visualization of the uterus and T Fallopian tubes is occasionally :followed by troublesome :r::eactwns. Following· its injection,
acute ''chemical'' salpingitis, parametritic masses, and occasional allergic reactions have been reported. It has recently been shown by our group1 • 2 that a solution of mono-iodoinethane sulphonate of sodium (skiodan) with acacia is a nonirritati~g .medium for uterosalpingography. Skiodan is not irritating to the JJ,terus and tubes. It is rapidly eliminated from the body through the urine and does not liberate free or inorganic iodine. ;;. These studies did not show, however, the effect of the acacia used as a vehicle nor whether the acacia was eliminated. That a knowledge of the effect and fate of acacia is important is pointed out in the literature by several investigators3 - 5 who have shown that acacia when injected in large doses intravenously causes damage to the liver. Others6 express the clinical view, ho\vever, that, ''long continued presence of acacia within the body without apparent harmful effects demonstrates anew its innoeuous character in man.'' \Ve wished to be certain, in addition, that the acacia would not become encysted in the peritoneal cavity, as is so often the case with iodized oil injected :for uterosalpingography. To complete the study of the effect of, and the :fate of, skiodan-acaeia, a series of experiments was devised to study the action of the acacia upon the uterus, tubes, and peritoneum, if any, and to determine its fate upon injection into the female internal genitalia and the peritoneum. 1 SUMMARY OF EXPERIMEN'rS
Our experiments with acacia fall into three parts; iirst, a determination of the local or general effect of the injection of acacia into the genitalia and peritoneum of female rabbits, second, a study of the blood and urine thereafter for acacia, and third, chemical and microscopic studicH of the livers of rabbits so injected.
1. Loca:t and General Effects Three rabbits were injected with varying amounts of acacia in different ways. Rabbit 101 received 2 c.c. of 20 per cent acacia in the uterus and tubes following the technique used in our preceding experiments.2 There was no immediate reaction of any kind. After thirty-two days this rabbit was killed and the peritoneum and internal genitalia carefully examined. There was no evidence of the acacia in the peritoneum or genitalia, nor was there any evidence of inflammation or irritation. The liver was examined and found grossly to be normal. Rahbit 102 received 5 c.c. of
495
496
AMJ<;RIUAX JOUR:-
20 per cent acacia directly into the peritmwum. 'flterc wa ~ 110 illnltediate rew:tion and after twenty-five days this rabbit wa~ killed. 'l'he gToHS pxamination of perito · neum and liver did not show any eviclene(' of irritat ive rd'fed. R.abhit lll:l re~eived (i.6 e.c. of 30 per (~ent aeaeia direc tly into the peritoneum anu was killed seven
A.
B.
c.
Fig. 1.-A , Rabbit 101 live r thirty -two days a fter injection o f 0.4 gm. of acac ia: B, Rabbit 10 2 liver tw enty-five days after injection of 1.0 gm. of acacia; C, Rabbit 103 liver seven d ays a fter injection of 2.Q gm. of acacia.
It was found (see 'l'able I ) that minute amounts of aeacia could be detected in the urine at intervals of from 6 to 108 hours after injection. It was concluded that if acacia is excreted in the urine it must be in only small amounts and perhaps over a very long period of time as was found by Andersch and Gibson. 3 For studies of acacia in the blood the oxidimetric method of Keith, Power and Wakefield6, 9 was cmployt>d, using 95 per ct>nt flthyl akohol as the precipitating agent. In the fir~t two rabbits we Wl're disappointed not to find the suHpected large amounts of acacia in the blood but. upon reading the work of Putnam1o we realized that we were not sampling the blood early enough to pick up the higher levels of the acacia (see Table I ) . Rabbit 103 showed that the level of acacia reached a maximum at about six hours after injection and rapidly f ell to approximately normal in less than seventy-two hours.
3. Chemical and Micro~copi.c Stu.dies of Liver8 Several investigators3-5 have pointed out that the liver is damaged following intravenous use of relatively large amounts of acacia. We felt that we must know if acacia injected into the female internal genitals and peritoneum in the recommended dosage would have a like effect. Rabbits were injected with amounts corresponding t.o 4 to 20 times the amounts usually used in the human being for uterosalpingography. These rabbits were killed at thirty-two, twenty-five, and
MCCLELLAN ET AL.: TABLE
RABBI'l'
I.
1.0 gm.
103
2.0 gm.
497
DETERMINATION OF ACACIA IN BLOOD AND URINE
ACACIA INJECTED
102
OPAQUE MEDIUM FOR UTEROSALPINGOGRAPHY
TABLE
URINE TIME AFTER INJECTION
36 60 84 108 12 36 42 62 6 24 72 !I.
hr. hr. hr. hr. hr. hr. hr. hr. hr. hr. hr.
BLOOD
ACACIA BIAL 'S TEST
Trace None Trace Trace Trace None None Trace None None Trace
TIME AFTER INJECTION
ACACIA IN BLOOD SERUM
c.c.
84 hr. 48 hr. 96 3 6 24 72
hr. hr. hr. hr. hr.
13.1 mg./100 c.c. 18.0 mg./100 c.c.
e. c. c.c. c.c.
c.c.
DETERMINATION OF ACACIA IN LIVER MICROSCOPIC SECTION LIVER
seven days after injection of acacia. In Rabbit 101 the injection was made into the uterus and tubes while in the remaining two rabbits the acacia was placed directly into the peritoneum. The livers were examined in situ in the gross and were found to present a normal appearance as to shape, size, margins, and surfaces. They were immediately removed from the body and a portion placed in ZRnker's fixative for mieroscopic study and a second portion taken for quantitative estimation of the amount of acacia therein. For this analysis the method of Youngbergs as used by Andersch and Gibsons was employed. The amount of furfural producing material, calculated as acacia, in all three livers was just above that given by Andersch and Gibsons as normal (Table II). '!'he microscopic study of these livers did not show the destruction and swelling of liver parenchyma as found by others following intravenous injection of larger amounts of acacia,3-5 and it was felt that all sections represent essentially normal histology. SUM.M.ARY
1. Experimental data indicate that acacia injected in the amounts used in uterosalpingography does not irritate the internal genitalia or peritoneum in rabbits. 2. Acacia does not remain in the peritoneum but is rapidly taken up and appears in the blood stream within three hours following its injection. The maximum level of acacia in the blood is reached within six hours, and it has almost disappeared from the blood in seventy-two hours. 3. We could not prove that acacia is excreted in the urine. It has been shown by Andersch and Gibson that in bile fistula dogs, acacia appears within six hours in the bile, and it is most likely that the bile is the means by which it leaves the body. 4. Microscopic studies of the livers up to thirty-two days after injection of more than ten times the amount of acacia used in human uterosalpingography did not show liver damage.
498
AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY
5. The amount of furfural producing material, calculated as acaeia, in the liver was just abo\·e that saill to hr nm·mul. coxcr.r~JoN
Our previous findings show that flkiodan produe.(•s satisfactory x-ray shadows, and further is nonirritating to the tissues and is rapidl:r eliminated from the body. Our presrnt findings show that acacia is nonirritating, is not retained in the peritoneum and does not eause liver damage. We conelude that skiodan-;waeia in nterosalpingography is harmless in the amounts used and is. thPrefnre, to lw preferred to the older opaque media (iodized oils). The materials for this inv(•stigation Chemi<'al Co., New York.
W<'l'\'
gc"nHously furnisheu by the ·winthrop
HEFEHENCES Me~;ser, F. C.: AM. J. 0BS1'. (2) Idem: Ibid. 36: 889, 1938. (3) Andersch, M .. nnd Gibson, R. B.: J. Pharmacol. & Exper. 'l'herap. 52: 390, 1934. (4) Heckel, G. P., Erickson, C. C., Y'ldle, C. L., and Knutti, R. E.: J. Exper. Med. 67: 345, 1938. ( 5) Hall, W. K.: Proc. Soc. Exper. Biol. & Med. 38: 4!i, 1938. (6) Keith, N. M., Power, M. H., and Wnkefield, E. G.: Proc. Staff Meet., Mayo Clinic 10: 38, 1935. (7) Sumner, J. B.: J. Bioi. Chem. 65: 319, 1925. (8) Youngberg, G. E.: J. Biol. Chem. 73: 599, 1927. (9) Power, M. H., and ·wakefield, E. G.: .T. Bioi. Chem. 123: 665, 1938. (10) Putnam, T ..J.: Am .• 1. Physiol. 63: 548, 1923.
(1) Titus, P., Tnfel, R. J.;,, McClellan, R. H .• nnd
& GYNEC. 33: 164, 1937.
RELAXATION OF 'I'HE PELVIC lJIGAlVIENTS IN PREGNANT MONKEYS CARL
G.
HAwrMAN,
PH.D.,
AND WILLIAM
BAvriMORE,
::vrn.
L.
STRAus, .TR.,
PH.D.,
(From the Carnegie Lnbmatory of Embryology, the Johns Hopkins JJ:ledical School)
ROFOUND chauges occur in the pubic and sacroiliac joints in many of the lower mammals during the eourst> of gt>statinn. 'rhe horP monal control of the tissue metamorphoses involwd has been fairly well worked out. 1 An examination of modern textbooks of obstetrics 2 • 3 as well as the current literature on the subject indicates that pelvic relaxation in women is generally recognized. Most of the clinical literature coneerns cases of pathologic exaggeration of the process which may lead to separation of the pubic bones and eonsequent distressing symptoms. The pregnancy changes in the ligaments as a normal and physiologic process is also stressed or taken for gTanted. 'l'hus Kehrer 3 states that the motility of the pelvi(~ bones, by loosening of the joints, has not only a pathologie significance bnt above all a physiologic one; for it makes possible an increase in the diameter of the birth canal. DeLee 2 says that "in the human there is no doubt but that the joints soften, thicken and thus enlarge the cavity of the pelvis. The bones become more movable on each other . . . . " The relaxation of the pelvic ligaments has been noted in scores of eases in the rhesus monkey (Macaca mulatta) and in six specimens