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Systemic Reactions*
SYSTEMIC REACTIONS* Τ θ TOPICAL EPINEPHRINE AND PHENYLEPHRINE R I C H A R D K. L A N S C H E ,
M.D.
La Jolla, California
Interest in the topical use of 2% (levo) epinephrine in the medical management of open-angle glaucoma has recently increased. A considerable literature attests to its use fulness and apparent safety. Some mention has been made of mild and easily controlled adverse reaction around the eye after its in stillation, but there has been only scant ref erence to serious systemic reactions in re cent years. This paper reports on the his tories of two patients who had alarming and potentially serious systemic toxic reactions following the topical use of 2% epinephrine or 10% phenylephrine in their eyes. CASE REPORTS CASE 1
Mrs. B, aged 40 years, sought consultation in March, 1963. She was suffering from acute and chronic chalazia of the right upper and lower eyelids. She reported that a number of such chalazia had been excised recently (under local anesthesia) by another physician. On four visits within the first 12 days under my care, it was necessary to excise, drain and curette about eight new chalazia, with rather considerable resultant bleeding. When a large chalazion developed at the outer third of the right lower lid two days later, prepara tion and procedure for its excision were carried out exactly as they had been previously, except that use of Glaucon® (2% epinephrine hydrochloride) was added. The right eye was anesthetized with topical 0.5% Ophthetic® (proparcaine hydrochloride 2.7 mg), followed by a drop of 4% Xylocaine® (lidocaine hydrochloride 2.7 mg). Half a cc of 1% Xylocaine® (5 mg) without added epineph rine was injected around the chalazion through the skin and conjunctival routes. Next, two drops of Glaucon® (a total of 2.7 mg epinephrine hydrochloride) were instilled in the lower cul-de-sac in order to prevent bleeding. Within one-half to one minute after instillation of the epinephrine, the patient became faint and pale and had to be placed in the supine position. Her blood pressure was recorded as 230 mm Hg, her pulse at 130 per minute. She was perspiring profusely and may have been unconscious. In a From the Department Scripps Memorial Hospital.
of
Ophthalmology,
few minutes she spoke of a severe headache in the occipital area. After about 15 minutes she felt able to have the excision completed. Routine post operative care was given. She returned 20 days later with another chala zion, this time on the right upper eyelid. It was excised, drained and curetted without use of epi nephrine, and without incident. After about six months, this patient's eyelids were normal. She seemed to have no more chalazia nor any other trouble with her eyes. CASE 2
Mr. G, aged 57 years, sought consultation in December, 1963. He had had diabetes mellitus for about 12 years, with complications of diabetic neuropathy, arteriosclerosis obliterans and diabetic oculopathy, with glaucoma secondary to rubeosis iridis. Ocular examination disclosed that his vision in each eye was reduced to counting fingers. The anterior chambers were deep, the corneas were steamy and too edematous to allow a view of the retinas. The epithelium was disrupted and consid erable rubeosis was visible on each iris, slightly greater on the left eye than on the right. By applanation tonometry, tension was shown to be 50 mm Hg in the right eye and 75 mm Hg in the left. Immediately after the tensions were measured, two drops of 4% pilocarpine (10.6 mg) were instilled in each eye to lessen this tension. Since the patient's glaucoma was of secondary wide-angle type and the redness was considerable, a drop of Glaucon® was instilled in each eye (equal to 2.7 mg of epinephrine). Both eyes were still anesthetized. Within a half or one minute after instillation of the Glaucon,® the patient began to tremble and perspire, saying that he was going to faint. He was immediately placed in the supine position. His blood pressure was recorded as 230 mm Hg; his pulse was found to be 130 and regular. Aspir in was given for the headache and the blood pressure was recorded every 30 seconds. In about 15 minutes the pressure had returned from 230 mm Hg to its former level of 135/85, and the pulse had declined from 130 to 85. Instillation of 4% pilocarpine was continued ; in three hours the tension in the right eye was reduced to 18 mm Hg and that in the left eye was reduced to 60 mm Hg. He was then hospital ized for surgery and, 24 hours later, a retrociliary nonpenetrating cyclodiathermy was performed on the left eye. After six days the tension had decreased to 15 mm Hg in each eye. Further treatment consisted of Daranide® (dichlorphena-
95
RICHARD K. LANSCHE
96
mide) SO mg morning and night, by mouth, and 4% pilocarpine in each eye four times a day. Nearly two months later, at one of the routine examinations, the patient's vision was found to be 20/600 in the right eye and 20/70 m the left one. The right eye had severe rubeosis iridis, a small hyphema, corneal edema, conjunctival redness and pressure of 70 mm Hg. In contrast, the left eye was white, its cornea was clear, with scarcely any rubeosis, had a small pupil and the pressure was 25 mm Hg. Instillation of 4% pilocarpine in the right eye was continued at intervals of approxi mately 20 minutes but, three hours later, the ten sion had changed very little. At this time, and shortly following applanation tonometry, it was decided to dilate the pupil of the left eye for closer inspection of the retina. Therefore a drop of 10% phenylephrine (6.6 mg) was instilled in it. Within a minute after this single instillation in an eye that was not then red, though still anesthetized from the preceding tonom etry, the patient turned pale and became faint, while his blood pressure rose to 220 mm Hg. His pulse increased to 120 a minute, he began to per spire profusely and to suffer a severe occipital headache, without chest pain. A quantity of 0.5% pilocarpine was immediate ly instilled in his left eye to wash away any re maining phenylephrine. This unexpected reaction to phenylephrine was not so long or so severe as the one associated with Glaucon® already described but it was nevertheless alarming. It was decided to hospitalize the patient for surgery on the right eye. A retrociliary cyclodiathermy was performed 24 hours later. The im mediate and long-term results of this surgery were not so satisfactory as those after operation on the left eye. In addition, one month later he was found to have chronic myeloginous leukemia. DISCUSSION
in the presence of conjunctival hyperemia, or where the epithelium is anesthetized and only slightly damaged, allows a relatively large amount of that agent to be absorbed into the blood stream—almost as quickly as if it had been given subcutaneously. The most likely explanation for the sys temic reactions that have been described would seem to be systemic intoxication from sudden introduction of a specific agent into the blood. It seems possible that certain pa tients may have lowered degrees of toler ance for sympathomimetic drugs during various illnesses or during treatment with some agents, notably, certain antidepressant drugs that inhibit the enzyme monamine oxidase. It might have been possible to demon strate in these two patients the presence or absence of normal tolerance for sympatho mimetic drugs. If 0.3 cc. of 1:1000 solution of epinephrine (0.3 mg) had been injected sub cutaneously into each patient some time later, or 0.01 cc of 1% phenylephrine (1 mg) in the second case, and no systemic reaction had occurred, the failure to react might have been accepted as demonstrating normal tol erance. Since such testing was not carried out, it is impossible to state with certainty that lowered tolerance for epinephrine or phenylephrine was a factor in these inci dents.
The three incidents described in these two REVIEW OF LITERATURE cases had the following in common : ( 1 ) use of topical anesthesia; (2) conjunctival hyAnesthesiologists and pharmacologists peremia associated with chalazia (in one are, of course, familiar with systemic toxic case), and with acute secondary glaucoma reactions to vasoconstrictor drugs employed (in one case) ; (3) a breach in the corneal by topical or local routes, and ophthal epithelium (following applanation tonome mologists have commented on them in past try once and caused by heightened ocular years. A brief summary of data assembled tension once). On two occasions two drops in an incomplete search of the literature on of 2 % epinephrine (2.7 mg or the equivalent the subject may be of interest. of 2.7 cc of 1:1000 epinephrine) were instil Use of 1% or 2% epinephrine solution as a led and on one occasion one drop of 10% medication for treatment of glaucoma was phenylephrine (6.7 mg) was instilled. introduced into the United States about It would seem that combining a sym 1920 (having originated in Germany). pathomimetic agent with a topical anesthetic Gradle1 recorded a case in which slightly
REACTION TO EPINEPHRINE AND PHENYLEPHRINE more than 0.5 ce. of 1:1000 solution of epi nephrine, injected into the subconjunctival tissues, caused such a severe systemic reac tion that the conjunctiva had to be incised and the excess material washed away. Post 2 regularly anesthetized eyes with 1% holocaine before instilling levo-glaucosan or 2% epinephrine bitartrate; yet he mentions that a patient fainted after 1% solution of epi nephrine was instilled. Although Howell3 found no report in the literature (to 1934) of any death attribut able to use of epinephrine in the eye, he pointed out that this drug is rapidly ab sorbed from the conjunctival sac and may cause alarming symptoms in susceptible per sons. He reported one incident. Weiner and Alvis4 also recognized the potential danger of systemic toxic reaction when concentrated epinephrine preparations are used about the eye, remarking that un pleasant systemic effects could be expected occasionally, no matter how the drug is used. Beckman5 advised extreme caution in using epinephrine when tonometry or a local anesthetic has made the conjunctival epi thelium abnormally permeable, the reason being that the amount of epinephrine ab sorbed into the circulation from a concen trated solution may cause the blood pressure to rise dangerously. Becker and Shaffer8 declared that, on the basis of the tonogram of a patient showing cardiac irregularities, it would be unwise to continue a 2% solution of epinephrine. Ferguson 7 recalls encountering patients who had anginal attacks associated with topical application of 2% epinephrine. Gardner et al8 emphasized that the prede cessors of epinephrine, levo-glaucosan and glaucosan, were no longer much used, partly owing to the undesirable reactions of some hypertensive patients to them. Furthermore, systemic reactions have also followed parenteral administration of epinephrine. Flexner and Schneider9 and Keeney10 reported that a young normal-tensive patient developed
97
subarachnoid hemorrhage in one instance and hemiplegia in another after subcuta neous injections of 0.5 cc of 1:1000 epi nephrine solution (0.5 mg). Freeman 11 reviewed reports on 11 pa tients who had fatal reactions and three whose reactions were not fatal, to whom epinephrine had been administered by parenteral routes. He also stated that he had given 10 mg of piperoxan intravenously to a patient to whom 5 mg of epinephrine had been administered intramuscularly and that, thereby, he had undoubtedly saved the pa tient's life. He referred to the figures in the British Pharmacopeia, that the maximum therapeutic dosage of epinephrine by subcu taneous route is 0.5 mg (0.5 cc of 1:1000 solution) ; the maximum tolerated dosage is 7 to 8 mg, and the minimum lethal dosage is 4 mg. Many authors 5 · 12 ' 13 state that adverse sys temic reactions to epinephrine are due al most entirely to accumulation of high levels in the blood. They also observe that toxic manifestations can exactly duplicate those observed in the early stimulatory phase en countered in reaction to a local anesthetic, and, as a result, the local anesthetic is often wrongly blamed for what is really an unde sirable effect of the vasoconstrictor admin istered along with it. They considered that prolonged and severe palpitations and head aches are almost pathognomonic of toxic reactions to vasoconstrictors. Systemic reactions to typical phenylephrine used in the eye are also recorded. In 1956, McReynolds, Havener and Hen derson14 reported a patient who suffered a subarachnoid hemorrhage after a cotton pack soaked with 10% phenylephrine was applied to one of his eyes. Therefore, they studied the effects on blood pressure in 100 cases in which a topical application of 10% phenylephrine had been given to hyper tensive patients; only six of this series of 100 patients had resulting higher pressure and it was never greater than 10 mm Hg.
RICHARD K. LANSCHE
98
ACKNOWLEDGMENT These same authors also investigated the I wish to thank Dr. Richard Farr of the Scripps effects of topical 10% phenylephrine in pa Clinic and Research Foundation for assistance in tients who were undergoing surgery to cor the preparation of this paper. rect strabismus; there was no instance of elevation of blood pressure higher than 10 REFERENCES mm Hg. 1. Gradle, H. S. : The use of adrenalin in in Schepens15 noted that applying phenyl creased intraocular pressure. Am. J, Ophth., ephrine alone to the cornea may cause such 7:851-858 (Nov.) 1924. reactions as nervousness, violent heart beat, 2. Post, L. T. : Laevo-glaukosan and epineph severe occipital headache, nausea and vomit rine bitartrate in treatment of glaucoma. Arch. ing. Heath 16 even applied 3 mg of phenyle Ophth., 11:187-193 (Jan.) 1934. 3. Howell, S. C. : Action of epinephrine on phrine powder to the cornea of a dog and normal human eye; use of stronger solutions for recorded an increase of 50 mm H g in sys instillation. Arch. Ophth., 12:833-841 (Dec.) 1934. tolic blood pressure, lasting more than two 4. Weiner, M., and Alvis, B. Y. : The use of con centrated epinephrine preparations in glaucoma, hours. iritis and related conditions. Am. J. Ophth., There is no need to avoid the topical use 20:497-504, 1937. of 2% epinephrine or 10% phenylephrine in 5. Beckman, H. : Drugs : Their Nature, Action cases in which it is clearly needed. But ob and Use. Philadelphia, Saunders, 1958, p. 345. 6. Becker, B., and Shaffer, R. N. : Diagnosis viously some precautions must be taken ; one and Therapy of the Glaucomas. St. Louis, Mosby, must know how and where these agents are 1961. to be used, what amount is safe and under 7. Ferguson, W. J. : Personal communication. what circumstances they must be avoided 8. Garner, L. L., Johnstone, W. W., Ballintine, E. altogether. In certain cases, a preliminary J., and Carroll, M. E. : Effect of 2.0% levo-rotary epinephrine on the intraocular pressure of test might act as a safeguard.
SUMMARY
Three incidents of serious systemic toxic reaction in two patients after topical appli cation of two drops of 2% epinephrine (2.7 mg) or one drop of 10% phenylephrine (6.7 mg) to eyes that had been previously an esthetized and affected by conjunctival hyperemia or some disruption of the corneal epithelium are reported. The reaction was characterized by severe occipital headache, palpitation, hypertension (up to 230 mm H g systolic), paleness, acceleration of heart beat, trembling and excessive perspiration. Some of the literature concerning such reac tions was reviewed. A method was descri bed for differentiating reactions attributable to a low degree of tolerance on the part of the patient from those resulting from ex ceedingly high blood levels of either of these drugs. 7946 Ivanhoe Avenue (92037).
the glaucomatous eye. Arch. Ophth., 62:230-238 (Aug.) 1959. 9. Flexner, M., and Schneider, B. : Subarachnoid hemorrhage following injection of epineph rine. Ann. Inter. Med., 12:876-882 (Dec.) 1938. 10. Keeney, E. L. : Hemiplegia following injec tion of epinephrine hydrochloride. JAMA, 112:2131-2132 (May 27) 1939. 11. Freedman, B. J. : Accidental adrenaline overdosage and its treatment with piperoxan. Lancet, 2:575-578 (Sept. 17) 1955. 12. Sadove, M. S., Wyant, G. M., Gittelson, L. A., and Kretchmer, H. E. : Classification and management of reactions to local anesthetic agents. JAMA, 148:17-22 (Jan. 5) 1952. 13. Drill, V. A. (editor) : Pharmacology in Medicine. New York, McGraw-Hill, 1958, ed. 2, chap. 26, p. 12. 14. McReynolds, W. U., Havener, W. H., and Henderson, J. W. : Hazards of use of sympathomimetic drugs in ophthalmology. Arch. Ophth., 56:176-179 (Aug.) 1956. 15. Schepens, C. L. : Progress in detachment surgery. Tr. Am. Acad. Ophth. Otolaryng., 55:607-615 (July-Aug.) 1951. 16. Heath, P. : Neosynephrine hydrochloride : Some uses and effects in ophthalmology. Arch. Ophth., 16:839-846 (Nov.) 1936.
M.D.
La Jolla, California
Interest in the topical use of 2% (levo) epinephrine in the medical management of open-angle glaucoma has recently increased. A considerable literature attests to its use fulness and apparent safety. Some mention has been made of mild and easily controlled adverse reaction around the eye after its in stillation, but there has been only scant ref erence to serious systemic reactions in re cent years. This paper reports on the his tories of two patients who had alarming and potentially serious systemic toxic reactions following the topical use of 2% epinephrine or 10% phenylephrine in their eyes. CASE REPORTS CASE 1
Mrs. B, aged 40 years, sought consultation in March, 1963. She was suffering from acute and chronic chalazia of the right upper and lower eyelids. She reported that a number of such chalazia had been excised recently (under local anesthesia) by another physician. On four visits within the first 12 days under my care, it was necessary to excise, drain and curette about eight new chalazia, with rather considerable resultant bleeding. When a large chalazion developed at the outer third of the right lower lid two days later, prepara tion and procedure for its excision were carried out exactly as they had been previously, except that use of Glaucon® (2% epinephrine hydrochloride) was added. The right eye was anesthetized with topical 0.5% Ophthetic® (proparcaine hydrochloride 2.7 mg), followed by a drop of 4% Xylocaine® (lidocaine hydrochloride 2.7 mg). Half a cc of 1% Xylocaine® (5 mg) without added epineph rine was injected around the chalazion through the skin and conjunctival routes. Next, two drops of Glaucon® (a total of 2.7 mg epinephrine hydrochloride) were instilled in the lower cul-de-sac in order to prevent bleeding. Within one-half to one minute after instillation of the epinephrine, the patient became faint and pale and had to be placed in the supine position. Her blood pressure was recorded as 230 mm Hg, her pulse at 130 per minute. She was perspiring profusely and may have been unconscious. In a From the Department Scripps Memorial Hospital.
of
Ophthalmology,
few minutes she spoke of a severe headache in the occipital area. After about 15 minutes she felt able to have the excision completed. Routine post operative care was given. She returned 20 days later with another chala zion, this time on the right upper eyelid. It was excised, drained and curetted without use of epi nephrine, and without incident. After about six months, this patient's eyelids were normal. She seemed to have no more chalazia nor any other trouble with her eyes. CASE 2
Mr. G, aged 57 years, sought consultation in December, 1963. He had had diabetes mellitus for about 12 years, with complications of diabetic neuropathy, arteriosclerosis obliterans and diabetic oculopathy, with glaucoma secondary to rubeosis iridis. Ocular examination disclosed that his vision in each eye was reduced to counting fingers. The anterior chambers were deep, the corneas were steamy and too edematous to allow a view of the retinas. The epithelium was disrupted and consid erable rubeosis was visible on each iris, slightly greater on the left eye than on the right. By applanation tonometry, tension was shown to be 50 mm Hg in the right eye and 75 mm Hg in the left. Immediately after the tensions were measured, two drops of 4% pilocarpine (10.6 mg) were instilled in each eye to lessen this tension. Since the patient's glaucoma was of secondary wide-angle type and the redness was considerable, a drop of Glaucon® was instilled in each eye (equal to 2.7 mg of epinephrine). Both eyes were still anesthetized. Within a half or one minute after instillation of the Glaucon,® the patient began to tremble and perspire, saying that he was going to faint. He was immediately placed in the supine position. His blood pressure was recorded as 230 mm Hg; his pulse was found to be 130 and regular. Aspir in was given for the headache and the blood pressure was recorded every 30 seconds. In about 15 minutes the pressure had returned from 230 mm Hg to its former level of 135/85, and the pulse had declined from 130 to 85. Instillation of 4% pilocarpine was continued ; in three hours the tension in the right eye was reduced to 18 mm Hg and that in the left eye was reduced to 60 mm Hg. He was then hospital ized for surgery and, 24 hours later, a retrociliary nonpenetrating cyclodiathermy was performed on the left eye. After six days the tension had decreased to 15 mm Hg in each eye. Further treatment consisted of Daranide® (dichlorphena-
95
RICHARD K. LANSCHE
96
mide) SO mg morning and night, by mouth, and 4% pilocarpine in each eye four times a day. Nearly two months later, at one of the routine examinations, the patient's vision was found to be 20/600 in the right eye and 20/70 m the left one. The right eye had severe rubeosis iridis, a small hyphema, corneal edema, conjunctival redness and pressure of 70 mm Hg. In contrast, the left eye was white, its cornea was clear, with scarcely any rubeosis, had a small pupil and the pressure was 25 mm Hg. Instillation of 4% pilocarpine in the right eye was continued at intervals of approxi mately 20 minutes but, three hours later, the ten sion had changed very little. At this time, and shortly following applanation tonometry, it was decided to dilate the pupil of the left eye for closer inspection of the retina. Therefore a drop of 10% phenylephrine (6.6 mg) was instilled in it. Within a minute after this single instillation in an eye that was not then red, though still anesthetized from the preceding tonom etry, the patient turned pale and became faint, while his blood pressure rose to 220 mm Hg. His pulse increased to 120 a minute, he began to per spire profusely and to suffer a severe occipital headache, without chest pain. A quantity of 0.5% pilocarpine was immediate ly instilled in his left eye to wash away any re maining phenylephrine. This unexpected reaction to phenylephrine was not so long or so severe as the one associated with Glaucon® already described but it was nevertheless alarming. It was decided to hospitalize the patient for surgery on the right eye. A retrociliary cyclodiathermy was performed 24 hours later. The im mediate and long-term results of this surgery were not so satisfactory as those after operation on the left eye. In addition, one month later he was found to have chronic myeloginous leukemia. DISCUSSION
in the presence of conjunctival hyperemia, or where the epithelium is anesthetized and only slightly damaged, allows a relatively large amount of that agent to be absorbed into the blood stream—almost as quickly as if it had been given subcutaneously. The most likely explanation for the sys temic reactions that have been described would seem to be systemic intoxication from sudden introduction of a specific agent into the blood. It seems possible that certain pa tients may have lowered degrees of toler ance for sympathomimetic drugs during various illnesses or during treatment with some agents, notably, certain antidepressant drugs that inhibit the enzyme monamine oxidase. It might have been possible to demon strate in these two patients the presence or absence of normal tolerance for sympatho mimetic drugs. If 0.3 cc. of 1:1000 solution of epinephrine (0.3 mg) had been injected sub cutaneously into each patient some time later, or 0.01 cc of 1% phenylephrine (1 mg) in the second case, and no systemic reaction had occurred, the failure to react might have been accepted as demonstrating normal tol erance. Since such testing was not carried out, it is impossible to state with certainty that lowered tolerance for epinephrine or phenylephrine was a factor in these inci dents.
The three incidents described in these two REVIEW OF LITERATURE cases had the following in common : ( 1 ) use of topical anesthesia; (2) conjunctival hyAnesthesiologists and pharmacologists peremia associated with chalazia (in one are, of course, familiar with systemic toxic case), and with acute secondary glaucoma reactions to vasoconstrictor drugs employed (in one case) ; (3) a breach in the corneal by topical or local routes, and ophthal epithelium (following applanation tonome mologists have commented on them in past try once and caused by heightened ocular years. A brief summary of data assembled tension once). On two occasions two drops in an incomplete search of the literature on of 2 % epinephrine (2.7 mg or the equivalent the subject may be of interest. of 2.7 cc of 1:1000 epinephrine) were instil Use of 1% or 2% epinephrine solution as a led and on one occasion one drop of 10% medication for treatment of glaucoma was phenylephrine (6.7 mg) was instilled. introduced into the United States about It would seem that combining a sym 1920 (having originated in Germany). pathomimetic agent with a topical anesthetic Gradle1 recorded a case in which slightly
REACTION TO EPINEPHRINE AND PHENYLEPHRINE more than 0.5 ce. of 1:1000 solution of epi nephrine, injected into the subconjunctival tissues, caused such a severe systemic reac tion that the conjunctiva had to be incised and the excess material washed away. Post 2 regularly anesthetized eyes with 1% holocaine before instilling levo-glaucosan or 2% epinephrine bitartrate; yet he mentions that a patient fainted after 1% solution of epi nephrine was instilled. Although Howell3 found no report in the literature (to 1934) of any death attribut able to use of epinephrine in the eye, he pointed out that this drug is rapidly ab sorbed from the conjunctival sac and may cause alarming symptoms in susceptible per sons. He reported one incident. Weiner and Alvis4 also recognized the potential danger of systemic toxic reaction when concentrated epinephrine preparations are used about the eye, remarking that un pleasant systemic effects could be expected occasionally, no matter how the drug is used. Beckman5 advised extreme caution in using epinephrine when tonometry or a local anesthetic has made the conjunctival epi thelium abnormally permeable, the reason being that the amount of epinephrine ab sorbed into the circulation from a concen trated solution may cause the blood pressure to rise dangerously. Becker and Shaffer8 declared that, on the basis of the tonogram of a patient showing cardiac irregularities, it would be unwise to continue a 2% solution of epinephrine. Ferguson 7 recalls encountering patients who had anginal attacks associated with topical application of 2% epinephrine. Gardner et al8 emphasized that the prede cessors of epinephrine, levo-glaucosan and glaucosan, were no longer much used, partly owing to the undesirable reactions of some hypertensive patients to them. Furthermore, systemic reactions have also followed parenteral administration of epinephrine. Flexner and Schneider9 and Keeney10 reported that a young normal-tensive patient developed
97
subarachnoid hemorrhage in one instance and hemiplegia in another after subcuta neous injections of 0.5 cc of 1:1000 epi nephrine solution (0.5 mg). Freeman 11 reviewed reports on 11 pa tients who had fatal reactions and three whose reactions were not fatal, to whom epinephrine had been administered by parenteral routes. He also stated that he had given 10 mg of piperoxan intravenously to a patient to whom 5 mg of epinephrine had been administered intramuscularly and that, thereby, he had undoubtedly saved the pa tient's life. He referred to the figures in the British Pharmacopeia, that the maximum therapeutic dosage of epinephrine by subcu taneous route is 0.5 mg (0.5 cc of 1:1000 solution) ; the maximum tolerated dosage is 7 to 8 mg, and the minimum lethal dosage is 4 mg. Many authors 5 · 12 ' 13 state that adverse sys temic reactions to epinephrine are due al most entirely to accumulation of high levels in the blood. They also observe that toxic manifestations can exactly duplicate those observed in the early stimulatory phase en countered in reaction to a local anesthetic, and, as a result, the local anesthetic is often wrongly blamed for what is really an unde sirable effect of the vasoconstrictor admin istered along with it. They considered that prolonged and severe palpitations and head aches are almost pathognomonic of toxic reactions to vasoconstrictors. Systemic reactions to typical phenylephrine used in the eye are also recorded. In 1956, McReynolds, Havener and Hen derson14 reported a patient who suffered a subarachnoid hemorrhage after a cotton pack soaked with 10% phenylephrine was applied to one of his eyes. Therefore, they studied the effects on blood pressure in 100 cases in which a topical application of 10% phenylephrine had been given to hyper tensive patients; only six of this series of 100 patients had resulting higher pressure and it was never greater than 10 mm Hg.
RICHARD K. LANSCHE
98
ACKNOWLEDGMENT These same authors also investigated the I wish to thank Dr. Richard Farr of the Scripps effects of topical 10% phenylephrine in pa Clinic and Research Foundation for assistance in tients who were undergoing surgery to cor the preparation of this paper. rect strabismus; there was no instance of elevation of blood pressure higher than 10 REFERENCES mm Hg. 1. Gradle, H. S. : The use of adrenalin in in Schepens15 noted that applying phenyl creased intraocular pressure. Am. J, Ophth., ephrine alone to the cornea may cause such 7:851-858 (Nov.) 1924. reactions as nervousness, violent heart beat, 2. Post, L. T. : Laevo-glaukosan and epineph severe occipital headache, nausea and vomit rine bitartrate in treatment of glaucoma. Arch. ing. Heath 16 even applied 3 mg of phenyle Ophth., 11:187-193 (Jan.) 1934. 3. Howell, S. C. : Action of epinephrine on phrine powder to the cornea of a dog and normal human eye; use of stronger solutions for recorded an increase of 50 mm H g in sys instillation. Arch. Ophth., 12:833-841 (Dec.) 1934. tolic blood pressure, lasting more than two 4. Weiner, M., and Alvis, B. Y. : The use of con centrated epinephrine preparations in glaucoma, hours. iritis and related conditions. Am. J. Ophth., There is no need to avoid the topical use 20:497-504, 1937. of 2% epinephrine or 10% phenylephrine in 5. Beckman, H. : Drugs : Their Nature, Action cases in which it is clearly needed. But ob and Use. Philadelphia, Saunders, 1958, p. 345. 6. Becker, B., and Shaffer, R. N. : Diagnosis viously some precautions must be taken ; one and Therapy of the Glaucomas. St. Louis, Mosby, must know how and where these agents are 1961. to be used, what amount is safe and under 7. Ferguson, W. J. : Personal communication. what circumstances they must be avoided 8. Garner, L. L., Johnstone, W. W., Ballintine, E. altogether. In certain cases, a preliminary J., and Carroll, M. E. : Effect of 2.0% levo-rotary epinephrine on the intraocular pressure of test might act as a safeguard.
SUMMARY
Three incidents of serious systemic toxic reaction in two patients after topical appli cation of two drops of 2% epinephrine (2.7 mg) or one drop of 10% phenylephrine (6.7 mg) to eyes that had been previously an esthetized and affected by conjunctival hyperemia or some disruption of the corneal epithelium are reported. The reaction was characterized by severe occipital headache, palpitation, hypertension (up to 230 mm H g systolic), paleness, acceleration of heart beat, trembling and excessive perspiration. Some of the literature concerning such reac tions was reviewed. A method was descri bed for differentiating reactions attributable to a low degree of tolerance on the part of the patient from those resulting from ex ceedingly high blood levels of either of these drugs. 7946 Ivanhoe Avenue (92037).
the glaucomatous eye. Arch. Ophth., 62:230-238 (Aug.) 1959. 9. Flexner, M., and Schneider, B. : Subarachnoid hemorrhage following injection of epineph rine. Ann. Inter. Med., 12:876-882 (Dec.) 1938. 10. Keeney, E. L. : Hemiplegia following injec tion of epinephrine hydrochloride. JAMA, 112:2131-2132 (May 27) 1939. 11. Freedman, B. J. : Accidental adrenaline overdosage and its treatment with piperoxan. Lancet, 2:575-578 (Sept. 17) 1955. 12. Sadove, M. S., Wyant, G. M., Gittelson, L. A., and Kretchmer, H. E. : Classification and management of reactions to local anesthetic agents. JAMA, 148:17-22 (Jan. 5) 1952. 13. Drill, V. A. (editor) : Pharmacology in Medicine. New York, McGraw-Hill, 1958, ed. 2, chap. 26, p. 12. 14. McReynolds, W. U., Havener, W. H., and Henderson, J. W. : Hazards of use of sympathomimetic drugs in ophthalmology. Arch. Ophth., 56:176-179 (Aug.) 1956. 15. Schepens, C. L. : Progress in detachment surgery. Tr. Am. Acad. Ophth. Otolaryng., 55:607-615 (July-Aug.) 1951. 16. Heath, P. : Neosynephrine hydrochloride : Some uses and effects in ophthalmology. Arch. Ophth., 16:839-846 (Nov.) 1936.