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Conjugated Estrogens in Cataract Surgery: A Negative Report
426
Y. KUROSE, T. W. SERY AND I. H. LEOPOLD
4. McCoy, G. A., and Leopold, I. H.: Intraocular penetration of oleoandomycin. Am. J. Ophth., 48:666, 1959. 5. Furgiuele, F. P., Sery, T. W., and Leopold, I. H.: New antibiotics: Their intraocular penetration. Am.J. Ophth., 50:614, 1960. 6. Pryor, J. G., Apt, L., and Leopold, I. H. : Intraocular penetration of vancomycin. AMA Arch. Ophth., 67:608, 1962. 7. Teng, P., and Johnson, B. A.: Experimental intracisternal injection of polymyxin. B. Neurology, 3:831, 1953.
CONJUGATED ESTROGENS IN CATARACT SURGERY: A NEGATIVE REPORT RUSSELL H. WATT,
M.D.
Marshalltown, Iowa INTRODUCTION
This study was initiated in an attempt to determine whether conjugated estrogens are of value in the prevention of hyphema. Be cause of the variability of experimental and traumatic hyphema, it was decided to study the effects of conjugated estrogens on the bleeding that occurs during and after cata ract surgery. Conjugated estrogens have been used for several years because of their alleged value in reducing operative bleeding. They are ob tained from pregnant mares' urine and con sist of a complex of amorphous steroids. Goldberg1 reported 63 cases of traumatic hyphema. Of the 41 treated "conservatively" with bedrest and binocular patching, 12 (29 percent) developed secondary hyphema and eight eventually became "blind." The other 22 patients received the same treatment plus oral and intravenous Premarin. There were no secondary hyphemas in this group and apparently no "blindness." Utilizing rabbits and a few humans, Lewis 2 · 3 concluded that Premarin infusion 90 minutes before surgery reduced intraocu lar and extraocular bleeding. The mode of action of conjugated estro gens is poorly understood and much of the work in this field is conflicting. Both intravascular 4 ' 5 and extravascular mechanisms have been claimed. In a nice bit of research, Schiff and Burn 8 demonstrated that intra
venous Premarin increased the amount of polymerization of the perivascular mucopolysaccharides. It was theorized that these changes would strengthen the vascular bed and be "valuable" in capillary types of bleed ing. TECHNIQUE
A double-blind study was performed upon 200 consecutive cataract patients. One hun dred patients received conjugated estrogen* (Group A ) , and 100 received a placebo (Group B ) . The drugs were administered in a random fashion. Patients in Group A received one ampule of Premarin (20 mg.) intravenously 90 minutes prior to surgery and again 12 hours later. The following day Premarin tablets (1.25 mg.) were started orally, three times daily, and continued for one week. Group B patients received placebo injections and tab lets. It was decided that no patient should be omitted from this study for systemic causes, such as diabetes or hypertension. The second eyes of patients who had bi lateral cataract surgery (five to seven days later) were not recorded because these pa tients were still receiving medication for the first operation. One patient in Group B re fused the tablets after the fifth day. No hyphema developed in this patient. Four surgeons of comparable ability par* Premarin and placebo supplied by Ayerst Lab oratories, New York.
CONJUGATED ESTROGENS IN CATARACT SURGERY ticipated in the study. Our operative routine is as follows: preoperative medication con sists of a sedative (barbiturate or chloral hydrate), tranquilizer (Phenergan), and meperidine (Demerol). The majority of the operations are done under local anesthesia consisting of the Van Lint and retrobulbar injection of two-percent Lidocaine, with hyaluronidase and 1:1,000 adrenalin. An occa sional patient had general anesthesia, pri marily because of inability to co-operate under local. All eyes receive five minutes of preoperative massage. Limbus-based flaps are used and the corneal-scleral incision with keratome and scissors is performed. All cases have three preplaced corneal-scleral catgut sutures and usually two postplaced sutures. Iris surgery is usually an iridotomy or a nonbasal sector iridectomy, superiorly. Occasionally the iris is dialyzed or a pe ripheral iridectomy is made. Arruga forceps, Verhoeff forceps and a Bell erisophake are used interchangeably. Sometimes alpha chymotrypsin is used, especially in patients un der 50 years of age. Penicillin is injected subconjunctivally at the termination of the procedure. The patients are ambulated later the same day. All eyes are observed daily. In this study, the primary observation was the presence or absence of a postoperative hyphema. In addition the hyphemas were graded as follows: Class I, barely visible; Class II, one third of chamber filled; Class III, one third to two thirds chamber filled; Class IV, complete hyphema. The secondary observation was the degree of operative bleeding from the conjunctiva, episclera and iris. This bleeding was graded as follows: Class I, no bleeding; Class II, mild bleeding that did not interfere with the operation; Class III, moderate bleeding of nuisance value; Class IV, marked bleeding that definitely interfered with performing the operation. We found this classification rather difficult to determine with precision and there was some variability in interpreta tion among the surgeons. Occasionally small amounts of blood were
427
Penale
Years
0-9
10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89 90-99
Fig. 1 (Watt). Distribution of patients and hyphema by decades (Group A).
present in the anterior chamber at the ter mination of the operation. These cases were carefully recorded to avoid confusion with early postoperative hyphema. RESULTS
The general character of the two groups was quite similar. In Group A there were 48 males and 52 females (fig. 1), while in Group B there were 49 males and 51 fe males (fig. 2). The youngest patient in the entire series was 17 years of age and the oldest 95 years. Amazingly, there were 13 eyes in each group that developed postoperative hyphema. These are classified in Table 1. Most of the
RUSSELL H. WATT
428
TABLE 1 THE DISTRIBUTION OF HYPHEMA IN CATARACT SURGERY
Hyphema
Group A Group B
Class I
Class II
10 11
2 1
C l a s s i l i Class IV 0 0
1 1
TABLE 2 T H E DISTRIBUTION OF OPERATIVE BLEEDING IN CATARACT SURGERY
Operative Bleeding
Group A Group B
Class I
Class II
3 1
34 31
Class III Class IV 44 49
19 10
nificant variation either (table 2). Alpha chymotrypsin was used in 21 cases in Group A and 25 cases in Group B. Since this enzyme is said to retard wound healing, it is interesting to see that three hyphemas occurred in each group. All were Class I in Group A, and there was one each in Classes I, II, and IV in Group B. SUMMARY Years
0-9 10-19 20-29 30-39 40-49 50-59 60.69 70-79 80-89 90-99
Fig. 2 (Watt). Distribution of patients and hyphema by decades (Group B). hyphemas were present on postoperative day one (eight in Group A and eight in Group B), and the others on days two and three. This varies from the usual report of post operative hyphema which describes them as occurring on days five to seven. One patient in Group A developed a Class I hyphema on postoperative day seven. This hyphema dis appeared within 24 hours. The degree of operative bleeding did not result in any sig-
A double-blind study was performed to determine the effects of systemic adminis tration of conjugated estrogens upon opera tive and postoperative bleeding in cataract surgery. One hundred patients received in travenous Premarin on the day of surgery and oral Premarin for the following seven days. In addition, 100 patients received a placebo in the same manner. No significant difference in the postopera tive hyphema or in the operative bleeding occurred in these two groups. 309 East Church Street.
REFERENCES
1. Goldberg, J. L.: Conjugated estrogens in the prevention of secondary hyphema after ocular trauma. AMA Arch. Ophth., 63:1001, 1960. 2. Lewis, E. L. : Control of ocular hemorrhage with intravenous conjugated estrogens. EENT Monthly, 37:393 (June) 19S8. 3. Lewis, E. L.: Premarin in intraocular surgery. EENT Monthly, 38:215 (Mar.) 1959.
CONJUGATED ESTROGENS IN CATARACT SURGERY
429
4. Johnson, J. F.: Changes in plasma prothrombin, Ac-globulin and antithrombin concentration follow ing intravenous administration of estrogens. Proc. Soc. Exper. Biol. & Med., 94:92, 1957. 5. McGowen, Bunker, Goldstein and Estes: Effect of conjugated estrogens on the coagulation mecha nism. J.A.M.A., 11:175 (Mar. 18) 1961. 6. Schiff, M. and Burn, H. F.: The effect of intravenous estrogens on ground substance. Read before the 109th annual meeting A.M.A., Miami Beach, Fla., June 17, 1960.
INITIAL GLAUCOMA T H E R A P Y W I T H P H O S P H O L I N E IODIDE* RALPH Z. LEVENE,
M.D.
New York One of the major aims of glaucoma therapy is the control of intraocular pressure at all times. The usual practice is to begin with the standard miotic pilocarpine and to reserve the stronger medications for those cases that are not controlled on pilocarpine. Reports on one of the more recent stronger medications, Phospholine Iodide (echothiophate iodide), indicate that this drug is more efficacious in controlling tension than the usual glaucoma medications.1·2 In the treatment of glaucoma one can never be certain that tension control exists at all times despite repeated and frequent ex amination. In this regard, the probability of round-the-clock tension control should be greater with the use of the more powerful medications and their use as an initial medi cation should be considered. METHOD
Phospholine Iodide and pilocarpine were tested on 59 open-angle glaucoma and sus pected patients from the Bellevue Glaucoma Clinic. New open-angle patients were ran domly divided into two groups and received either pilocarpine (two percent, four times daily) or Phospholine Iodide (0.12S per cent twice daily). They were followed every two to three months for periods up to 30 months with a minimum follow-up of three months. More than half of the patients were * From the Department of Ophthalmology, New York University Medical School. This investigation was supported by the Health Research Council, City of New York, Grant Number U-1020.
followed for over 15 months. Particular care was taken to check whether or not the patient used the medications as prescribed. If the patient stated that, for one reason or an other, he had not used the medication for that clinic visit, the tensions were not in cluded in the results. The patients in both groups were arbitrarily graded as to severity by their pretreatment tension peaks or out flow facility. Control was defined in terms of a limiting tension peak and absence of glaucomatous field loss during treatment. RESULTS
In 30 patients started on pilocarpine, four either stopped the drug within three months or did not return to clinic. In 29 patients started on Phospholine Iodide, 10 either stopped the drug within three months or did not return to clinic. Many complained of the usual miotic side-effects, such as headache, browache or blurring of vision. Table 1 lists the comparative results of the two drugs. The patients are graded into four groups by their pretreatment tension peaks. Tension control during treatment is defined as a tension peak less than 25 mm. Hg for all groups except the least severe group, where a tension peak less than 20 mm. H g was re quired. In the 25-29 mm. Hg tension group, the number of successes with the Phospholine Iodide treatment was significantly greater than the number with pilocarpine (p<0.05 chi square). There are no significant differ ences in the other three groups. No glaucomatous field loss was encountered in any group.
Y. KUROSE, T. W. SERY AND I. H. LEOPOLD
4. McCoy, G. A., and Leopold, I. H.: Intraocular penetration of oleoandomycin. Am. J. Ophth., 48:666, 1959. 5. Furgiuele, F. P., Sery, T. W., and Leopold, I. H.: New antibiotics: Their intraocular penetration. Am.J. Ophth., 50:614, 1960. 6. Pryor, J. G., Apt, L., and Leopold, I. H. : Intraocular penetration of vancomycin. AMA Arch. Ophth., 67:608, 1962. 7. Teng, P., and Johnson, B. A.: Experimental intracisternal injection of polymyxin. B. Neurology, 3:831, 1953.
CONJUGATED ESTROGENS IN CATARACT SURGERY: A NEGATIVE REPORT RUSSELL H. WATT,
M.D.
Marshalltown, Iowa INTRODUCTION
This study was initiated in an attempt to determine whether conjugated estrogens are of value in the prevention of hyphema. Be cause of the variability of experimental and traumatic hyphema, it was decided to study the effects of conjugated estrogens on the bleeding that occurs during and after cata ract surgery. Conjugated estrogens have been used for several years because of their alleged value in reducing operative bleeding. They are ob tained from pregnant mares' urine and con sist of a complex of amorphous steroids. Goldberg1 reported 63 cases of traumatic hyphema. Of the 41 treated "conservatively" with bedrest and binocular patching, 12 (29 percent) developed secondary hyphema and eight eventually became "blind." The other 22 patients received the same treatment plus oral and intravenous Premarin. There were no secondary hyphemas in this group and apparently no "blindness." Utilizing rabbits and a few humans, Lewis 2 · 3 concluded that Premarin infusion 90 minutes before surgery reduced intraocu lar and extraocular bleeding. The mode of action of conjugated estro gens is poorly understood and much of the work in this field is conflicting. Both intravascular 4 ' 5 and extravascular mechanisms have been claimed. In a nice bit of research, Schiff and Burn 8 demonstrated that intra
venous Premarin increased the amount of polymerization of the perivascular mucopolysaccharides. It was theorized that these changes would strengthen the vascular bed and be "valuable" in capillary types of bleed ing. TECHNIQUE
A double-blind study was performed upon 200 consecutive cataract patients. One hun dred patients received conjugated estrogen* (Group A ) , and 100 received a placebo (Group B ) . The drugs were administered in a random fashion. Patients in Group A received one ampule of Premarin (20 mg.) intravenously 90 minutes prior to surgery and again 12 hours later. The following day Premarin tablets (1.25 mg.) were started orally, three times daily, and continued for one week. Group B patients received placebo injections and tab lets. It was decided that no patient should be omitted from this study for systemic causes, such as diabetes or hypertension. The second eyes of patients who had bi lateral cataract surgery (five to seven days later) were not recorded because these pa tients were still receiving medication for the first operation. One patient in Group B re fused the tablets after the fifth day. No hyphema developed in this patient. Four surgeons of comparable ability par* Premarin and placebo supplied by Ayerst Lab oratories, New York.
CONJUGATED ESTROGENS IN CATARACT SURGERY ticipated in the study. Our operative routine is as follows: preoperative medication con sists of a sedative (barbiturate or chloral hydrate), tranquilizer (Phenergan), and meperidine (Demerol). The majority of the operations are done under local anesthesia consisting of the Van Lint and retrobulbar injection of two-percent Lidocaine, with hyaluronidase and 1:1,000 adrenalin. An occa sional patient had general anesthesia, pri marily because of inability to co-operate under local. All eyes receive five minutes of preoperative massage. Limbus-based flaps are used and the corneal-scleral incision with keratome and scissors is performed. All cases have three preplaced corneal-scleral catgut sutures and usually two postplaced sutures. Iris surgery is usually an iridotomy or a nonbasal sector iridectomy, superiorly. Occasionally the iris is dialyzed or a pe ripheral iridectomy is made. Arruga forceps, Verhoeff forceps and a Bell erisophake are used interchangeably. Sometimes alpha chymotrypsin is used, especially in patients un der 50 years of age. Penicillin is injected subconjunctivally at the termination of the procedure. The patients are ambulated later the same day. All eyes are observed daily. In this study, the primary observation was the presence or absence of a postoperative hyphema. In addition the hyphemas were graded as follows: Class I, barely visible; Class II, one third of chamber filled; Class III, one third to two thirds chamber filled; Class IV, complete hyphema. The secondary observation was the degree of operative bleeding from the conjunctiva, episclera and iris. This bleeding was graded as follows: Class I, no bleeding; Class II, mild bleeding that did not interfere with the operation; Class III, moderate bleeding of nuisance value; Class IV, marked bleeding that definitely interfered with performing the operation. We found this classification rather difficult to determine with precision and there was some variability in interpreta tion among the surgeons. Occasionally small amounts of blood were
427
Penale
Years
0-9
10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89 90-99
Fig. 1 (Watt). Distribution of patients and hyphema by decades (Group A).
present in the anterior chamber at the ter mination of the operation. These cases were carefully recorded to avoid confusion with early postoperative hyphema. RESULTS
The general character of the two groups was quite similar. In Group A there were 48 males and 52 females (fig. 1), while in Group B there were 49 males and 51 fe males (fig. 2). The youngest patient in the entire series was 17 years of age and the oldest 95 years. Amazingly, there were 13 eyes in each group that developed postoperative hyphema. These are classified in Table 1. Most of the
RUSSELL H. WATT
428
TABLE 1 THE DISTRIBUTION OF HYPHEMA IN CATARACT SURGERY
Hyphema
Group A Group B
Class I
Class II
10 11
2 1
C l a s s i l i Class IV 0 0
1 1
TABLE 2 T H E DISTRIBUTION OF OPERATIVE BLEEDING IN CATARACT SURGERY
Operative Bleeding
Group A Group B
Class I
Class II
3 1
34 31
Class III Class IV 44 49
19 10
nificant variation either (table 2). Alpha chymotrypsin was used in 21 cases in Group A and 25 cases in Group B. Since this enzyme is said to retard wound healing, it is interesting to see that three hyphemas occurred in each group. All were Class I in Group A, and there was one each in Classes I, II, and IV in Group B. SUMMARY Years
0-9 10-19 20-29 30-39 40-49 50-59 60.69 70-79 80-89 90-99
Fig. 2 (Watt). Distribution of patients and hyphema by decades (Group B). hyphemas were present on postoperative day one (eight in Group A and eight in Group B), and the others on days two and three. This varies from the usual report of post operative hyphema which describes them as occurring on days five to seven. One patient in Group A developed a Class I hyphema on postoperative day seven. This hyphema dis appeared within 24 hours. The degree of operative bleeding did not result in any sig-
A double-blind study was performed to determine the effects of systemic adminis tration of conjugated estrogens upon opera tive and postoperative bleeding in cataract surgery. One hundred patients received in travenous Premarin on the day of surgery and oral Premarin for the following seven days. In addition, 100 patients received a placebo in the same manner. No significant difference in the postopera tive hyphema or in the operative bleeding occurred in these two groups. 309 East Church Street.
REFERENCES
1. Goldberg, J. L.: Conjugated estrogens in the prevention of secondary hyphema after ocular trauma. AMA Arch. Ophth., 63:1001, 1960. 2. Lewis, E. L. : Control of ocular hemorrhage with intravenous conjugated estrogens. EENT Monthly, 37:393 (June) 19S8. 3. Lewis, E. L.: Premarin in intraocular surgery. EENT Monthly, 38:215 (Mar.) 1959.
CONJUGATED ESTROGENS IN CATARACT SURGERY
429
4. Johnson, J. F.: Changes in plasma prothrombin, Ac-globulin and antithrombin concentration follow ing intravenous administration of estrogens. Proc. Soc. Exper. Biol. & Med., 94:92, 1957. 5. McGowen, Bunker, Goldstein and Estes: Effect of conjugated estrogens on the coagulation mecha nism. J.A.M.A., 11:175 (Mar. 18) 1961. 6. Schiff, M. and Burn, H. F.: The effect of intravenous estrogens on ground substance. Read before the 109th annual meeting A.M.A., Miami Beach, Fla., June 17, 1960.
INITIAL GLAUCOMA T H E R A P Y W I T H P H O S P H O L I N E IODIDE* RALPH Z. LEVENE,
M.D.
New York One of the major aims of glaucoma therapy is the control of intraocular pressure at all times. The usual practice is to begin with the standard miotic pilocarpine and to reserve the stronger medications for those cases that are not controlled on pilocarpine. Reports on one of the more recent stronger medications, Phospholine Iodide (echothiophate iodide), indicate that this drug is more efficacious in controlling tension than the usual glaucoma medications.1·2 In the treatment of glaucoma one can never be certain that tension control exists at all times despite repeated and frequent ex amination. In this regard, the probability of round-the-clock tension control should be greater with the use of the more powerful medications and their use as an initial medi cation should be considered. METHOD
Phospholine Iodide and pilocarpine were tested on 59 open-angle glaucoma and sus pected patients from the Bellevue Glaucoma Clinic. New open-angle patients were ran domly divided into two groups and received either pilocarpine (two percent, four times daily) or Phospholine Iodide (0.12S per cent twice daily). They were followed every two to three months for periods up to 30 months with a minimum follow-up of three months. More than half of the patients were * From the Department of Ophthalmology, New York University Medical School. This investigation was supported by the Health Research Council, City of New York, Grant Number U-1020.
followed for over 15 months. Particular care was taken to check whether or not the patient used the medications as prescribed. If the patient stated that, for one reason or an other, he had not used the medication for that clinic visit, the tensions were not in cluded in the results. The patients in both groups were arbitrarily graded as to severity by their pretreatment tension peaks or out flow facility. Control was defined in terms of a limiting tension peak and absence of glaucomatous field loss during treatment. RESULTS
In 30 patients started on pilocarpine, four either stopped the drug within three months or did not return to clinic. In 29 patients started on Phospholine Iodide, 10 either stopped the drug within three months or did not return to clinic. Many complained of the usual miotic side-effects, such as headache, browache or blurring of vision. Table 1 lists the comparative results of the two drugs. The patients are graded into four groups by their pretreatment tension peaks. Tension control during treatment is defined as a tension peak less than 25 mm. Hg for all groups except the least severe group, where a tension peak less than 20 mm. H g was re quired. In the 25-29 mm. Hg tension group, the number of successes with the Phospholine Iodide treatment was significantly greater than the number with pilocarpine (p<0.05 chi square). There are no significant differ ences in the other three groups. No glaucomatous field loss was encountered in any group.