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Use of subcutaneous terbutaline to reverse peripheral ischemia
Therapeutics
Use of Subcutaneous Terbutaline to Reverse Peripheral Ischemia PETER A. STIER, MD,* MARK P. BOGNER, MD,I" KEVIN WEBSTER, MD,:I: JERROLD B. LEIKIN, MD,§ ANTHONY BURDA, RPH§ Four cases are presented, one involving extravasation of a dopamine and dobutamine solution in the arm and three involving accidental digital injection of epinephrine into the thumb. In three cases, local infiltration of terbutaline resulted in dramatic reversal of vasospasm and ischemia. In the remaining case the use of terbutaline resulted in minor clinical improvement. These are the first reported cases involving the successful treatment of peripheral ischemia with subcutaneous terbutaline. This experience suggests that terbutaline may be an effective alternative for treatment of peripheral ischemia when phentolamine is not available. (Am J Emerg ied 1999;17:91-94. Copyright © 1999 by W.B. Saunders Company) Terbutaline is a selective [32 agonist most commonly administered by inhalation or subcutaneous injection for relief of bronchospasm secondary to acute exacerbation of asthma. [32-adrenoreceptor agonists produce effects on smooth muscle and skeletal muscle. These include bronchodilation, relaxation of uterine musculature, and vasodilation of peripheral arteries. 1-4 Although the vasodilatory effects of [32 agonists have been previously described, 1 there is no report in the literature of these agents being used to reverse peripheral ischemic effects of extravasated vasoconstrictive agents. 1-25 In 1957, Zucker 26 reported the first successful treatment of soft-tissue ischemia caused by accidental norepinephrine extravasation with phentolamine. Since that time, phentolamine has become the drug of choice for such cases. Unfortunately there is a current shortage of phentolamine (Regitine; CibaGeneva Pharmaceuticals, Ciba-Geigy Corporation, Summit, NJ), and hospital pharmacies may not have sufficient stock of this product for adequate treatment of peripheral ischemia (written communication, Ciba-Geigy Corporation, July 8, 1996). We present four cases: one From *Department of Emergency Medicine, Methodist Hospital, Indianapolis, IN; and 1-Emergency Medicine, University of Chicago Hospitals, 1:Emergency Department, Resurrection Medical Center, and §Illinois Poison Center and Rush Presbyterian St. Luke's Medical Center, Chicago, IL. Manuscript received June 18, 1997, returned July 9, 1997; revision received August 12, 1997, accepted August 22, 1997. Presented at the North American Congress of Clinical Toxicology, September 1997, St. Louis, MO. Address reprint requests to Dr Leikin, Rush Presbyterian St Luke's Medical Center, 1653 W Congress Parkway, Chicago, IL 60612. Key Words: Extravasation, terbutaline. Copyright © 1999 by W.B. Saunders Company 0735-6757/99/1701-0028510.00/0
involving extravasation of a dopamine and dobutamine solution into the arm, and three involving accidental digital injection of epinephrine into the thumb. Local infiltration of terbntaline resulted in dramatic reversal of vasospasm and ischemia in three of the cases. In the remaining case, subcutaneous injection of terbutaline resulted in slight improvement of blood flow to the finger. CASE REPORTS Patient 1 A 65-year-old man with a history of congestive heart failure and renal failure was admitted to the intensive care unit for myocardial infarction and started on a dopamine and dobutamine infusion for hypotension. The intravenous infusion was promptly discontinued when the dorsum of the hand and wrist was noted to be pale and swollen. After discovering that there was no phentolamine available, the hospital's pharmacist notified our poison control center and the decision was made to try subcutaneous terbutaline. A solution containing 1 mg terbutaline in i0 mL normal saline was prepared and 10 mL was infiltrated into the subcutaneous tissue of the blanched areas 1 hour after noticing the extravasation. Almost immediately the infiltrated areas became hyperemic with return of normal skin color. There were no untoward effects from the administration of terbutaline, and the hand was normal at time of discharge from the hospital 12 days later. Patient 2 A 13-year-old girl presented to the emergency department (ED) approximately 20 minutes after accidentally discharging an epinephrine autoinjector into the pad of her right thumb. Physical examination revealed an adolescent girl who appeared distressed about the injury. On examination, vital signs were as follows: temperature 98.1°F; blood pressure, 170/70 mm Hg; pulse, 104 beats/rain; and respirations, 22 breaths/rain. Her general physical examination was unremarkable. The patient's right thumb was cool, pale, and demonstrated decreased capillary refill to the nail bed. The finger had diminished range of motion secondary to pain. Two-point discrimination and soft touch sensation were intact. There was severe local pain and pallor extending to the proximal wrist. As in the first case, the hospital had no available phentolamine and the physician caring for the patient was advised by our poison center to attempt injection of local subcutaneous terbutaline. Approximately 1~/2 hours after the original injury, 3 mL of a solution of terbutaline, 1 mg in 10 mL normal saline, was injected subcutaneously into the original puncture site. The thumb pad 91
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AMERICAN JOURNAL OF EMERGENCY MEDICINE • Volume 17, Number 1 • January 1999
became progressively pink during injection, and within 2 to 3 minutes an area of hyperemia developed around the injection site. About 10 minutes later, nitroglycerin ointment was also applied over the entire digit. Significant symptomatic improvement and return of normal skin color had already occurred. Within 30 minutes the thumb had completely returned to normal color and warmth, and the patient was discharged with instructions to follow up with a hand surgeon. Telephone follow-up 1 month later found no adverse long-term sequelae.
Patient 3 A 39-year-old woman was referred to the ED by our poison center after accidentally discharging an epinephrine autoinjector into the pad of her right thumb. The triage nurse was notified and we recommended the conventional treatment using phentolamine. On arrival to the ED, the patient's vital signs were as follows: temperature, 98.4°F; blood pressure, 139/101 mm Hg; regular pulse of 70 beats/min with occasional premature ventricular contractions; and respirations, 18 breaths/rain. Her general physical exam was um-emarkable. The patient's fight thumb was cool, pale, and demonstrated decreased capillary refill to the nail bed. There was also an area of blue discoloration on the thumb pad measuring approximately 0.25 cm in diameter. The patient complained of severe local pain at the injection site but maintained full range of motion. Our poison center was notified that there was no available phentolamine, and a staff member who was unaware of our previous cases recommended nitropaste and a warm compress to the affected area. By this time, approximately 2 hours had elapsed since the time of accidental injection. The authors were notified of the situation 15 minutes later. There had been no apparent resolution of symptoms up to this moment. Again the decision was made to administer subcutaneous terbutaline. This time, however, the attending physician was advised to dilute 1 mg terbutaline in 1 mL normal saline and inject 0.5 mL subcutaneously into the original puncture site. Immediately following the injection, the blanching resolved and there was return of the normal pink color of skin. Despite the dramatic improvement of symptoms, the attending physician elected to administer a second dose of nitropaste and terbutaline. There were no significant changes after the second dose. The patient was observed for 1 hour after the second dose and then discharged. At the time of discharge the thumb had normal color and warmth, but remained tender and had slightly decreased capillary refill (less than 3 seconds).
Patient 4 A 31-year-old nurse presented to the ED approximately 6 hours after accidentally discharging an epinephrine autoinjector into the pad of her right thumb. Vital signs were as follows: blood pressure, 134/72 mm Hg; pulse, 89 beats/rain; and respirations, 16 breaths/ latin. Her general physical examination was unremarkable. The patient's right thumb was cool, pale, and demonstrated decreased capillary refill to the nail bed. There was a visible puncture site with a small area of surrounding ecchymosis on the volar aspect of the thumb approximately 1 cm proximal to the tip. The finger had full range of motion but there was severe local pain. Two-point discrimination and soft touch sensation were diminished. Upon recommendation by the poison center, a 1:1 dilution of terbutaline was prepared (0.5 mg/mL), and 1 mL was injected subcutaneously into the original puncture site. Within a few minutes, the patient reported minimal relief of pain and a slight improvement in sensation. A slight increase in skin color was noted by the attending physician. Another identical dose of terbutaline was given 15 minutes after the initial dose. Continuous monitoring of vital signs showed no significant changes. After 1 hour of
observation there were no signs of ischemic progression. A hand surgeon was contacted and the patient was given an injection of phentolamine by method of digital block. There was immediate remm of normal skin color and capillary refill. The patient was discharged 1 hour later with full recovery of sensation.
DISCUSSION The current treatment of choice for peripheral ischemic events secondary to the extravasation or accidental injection of e~-adrenergic agents is local infiltration with phentolarnine at a dose of 5 nag in 9 m L normal saline. 4,18,27 Alternative methods that have been used previously with variable success include warm water immersion, amyl nitrite inhalations, metacarpal nerve block, intravenous chlorpromazine. intravenous nitroprnsside, and use o f topical nitroglycerin paste, m,17,24Although we found two case reports that demonstrated successful treatment of a dopamine-induced peripheral ischemia with topical nitroglycerin, other attempts have failed. 1°,13J7,21 A study investigating vasodilating agents to reverse vasoconstriction found that nitroglycerin effectively reverses vasoconstriction from intravenously injected catecholamines; phentolamine, however, was more effective in increasing capillary blood flow to the fingertip. 8 Phentolamine is the only agent proven effective in reversing distal extremity vasoconstriction, ischemia, and pain from local infiltration of catecholamines. Our experience with these four cases suggests that terbutaline may be an effective alternative treatment in such cases. Vascular smooth muscle contains three types of adrenergic receptors; a l , [32, and to a lesser extent, a2. 2,14 Stimulation of % and a2 postsynaptic receptors results in vasoconstriction, whereas ~2 receptor activation promotes peripheral vasodilation. Epinephrine causes vasoconstriction of arterioles by stimulating primarily a receptors. Dopamine binds to dopamine, [3, and c~ receptors, but the degree of stimulation of each receptor type depends on the dose of the drug? 8 Usually high doses of dopamine, > 1 0 gg/kg/min, are necessary to affect binding to % receptors. Patients with preexisting vascular damage however, can have o~ effects at much lower doses, ranging from 1 to 1.5 ~g/kg/min. 2s The primary mechanism by which extravasation of catecholamines causes tissue necrosis is by constriction of smooth muscle around capillaries resulting in ischemia secondary to impaired circulation. Since the phenomenon of vasospasm is usually reversible, it is thought that the duration of extravasation is more important than the concentration of vasopressor administered. 19,2° Additional clinical and anatomic factors could affect the extent of ultimate damage to tissue from prolonged ischemia and may help the clinician predict the outcome. The most c o m m o n examples include the presence of peripheral vascular disease, dramatic changes in blood pressure, and the extent of surface area infused with the offending agent. Pharmacologic reversal of peripheral vasoconstriction and ischemia requires a locally acting agent with the capacity to induce vasodilation. Antagonism of a l receptor with locally injected phentolamine has been proven effective in such cases and is the preferred method o f treatment, Theoretically speaking, any agent with [32-adrenergic characteristics should cause selective vasodilation. Even in the presence of agents with antagonistic effects it is unlikely that
STIER ET AL • SUBCUTANEOUS TERBUTALINE FOR PERIPHERAL ISCHEMIA
any systemic drugs being taken by a patient would reach sufficient tissue levels to affect the efficacy of a locally infiltrated agent. [3-adrenergic reversal was first described by Cohen and Coffman 3 in a study reporting fingertip vasodilation after intraarterial isoproterenol. We chose to use terbutaline in these cases because of its availability in an injectable form and low potential for side effects due to its selectivity for [~a receptors. Skeletal muscle tremor is the most common adverse effect of the 132 agonists. Other more serious side effects, including an'hythmias and myocardial ischemia, are usually only seen in patients with underlying cardiovascular disease or those taking certain medications, including theophylline, monoamine oxidase inhibitors, and tricyclic antidepressants. 28 A 1:10 dilution was recommended in the first case to provide the maximum recommended dose of terbutaline with enough diluent to adequately cover the affected area with infiltration of antidote. We decided that more localized ischemia in distal extremities such as the finger would be better treated with a smaller volume of fluid to decrease the tissue pressure and subsequent compression of vasculature; therefore we recommended a 1:1 dilution for the last three cases. In the second case, however, a misunderstanding between the triage nurse and the poison center resulted in the administration of a 1:10 dilution of terbutaline instead. Fortunately, it worked well. The management of peripheral ischemia involves continuous monitoring of the affected area for signs of reperfusion or progression of ischemia. Most clinicians use the appearance of skin color, temperature, neurosensory function, and, sometimes, Doppler ultrasound to assess peripheral skin perfusion. These are the parameters used in the cases we describe and seem to be adequate for monitoring the status of an ischemic body part. A study by Joyce et al, 29 however, reports that pulse oximetry works as a quick and simple noninvasive method of monitoring peripheral circulation. Its application was reported by Schumer and Friedman, 3° who described a case in which pulse oximetry was used in the evaluation and treatment of a near-amputation of a digit. We believe that pulse oximetry would be especially well suited for use in EDs to monitor ischemic digits. The ultimate endpoint for reperfusion is the alleviation of symptoms. It was the lack of phentolamine that led to the use of terbutaline as an alternative. There have been several reports describing deficiencies in antidote stocking. 31-36The surveys sent to hospital pharmacists by previous investigators did not, however, include phentolamine on the list of antidotes evaluated. We investigated the availability of phentolamine (Regitine; CibaGeneva Pharmaceuticals, Ciba-Geigy Corporation, Summit, NJ) and discovered that it was initially affected by an FDA inspection and has been distributed on a limited-supply basis since June, 1995. A letter sent to hospital pharmacies by the manufacturer indicated that requests for shipments of Regitine would only be processed if there was an emergency/life-threatening medical need (written communication, Ciba-Geigy Corporation, July 8, 1996). The product would be supplied at no cost but may take up to 48 hours to deliver. Based on our experience in these cases, terbutaline is an effective alternative to phentolamine for the treatment of
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peripheral vasospasm and ischemia. According to Ellenhorn's toxicology text, 4 the recommended treatment involves the use of a 24-gauge needle for subcutaneous injection, beginning at the periphery of the blanched areas and moving inward in a pin-cushion fashion. In our experience, however, a 27-gauge needle is just as efficacious and better tolerated by the patient. Further experience with terbutaline will delineate its optimum dose and method of injection in these clinical situations.
REFERENCES 1. Abboud FM, Eckstein JW, Zimmerman BG: Venous and arterial responses to stimulation of beta adrenergic receptors. Am J Physiel 1965;209:383-389 2. Abramson DI: Neural regulation of cutaneous circulation. Adv Biol Skin 1972; 12:207-233 3. Cohen RA, Coffman JD: f3-adrenergic vasodilator mechanism in the finger. Circ Res 1981 ;49:1196-1201 4. Ellenhorn MJ: Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning (ed 2). Baltimore, MD, Williams & Wilkins, 1996 5. Aycock BG, Hawtof DB, Moody SB: Treatment of peripheral ischemia secondary to lidocaine containing epinephrine. Ann Plast Surg 1989;23:27-30 6. Boltax RS, Dineen JP, Scarpa FJ: Gangrene resulting from infiltrated dopamine solution. N Engl J Med 1977;296:823 (letter) 7. Coakley J: Nitroglycerin ointment for dopamine-induced peripheral ischemia. Lancet 1983;2:633 (letter) 8. Coffman JD, Cohen RA: Intra-arterial vasodilator agents to reverse human finger vasoconstriction. Clin Pharmacol Ther 1987;41 : 574-579 9. Cooper BE: High dose phentolamine for extravasation of pressers. Clin Pharm 1989;8:689 (letter) 10. Denkler KA, Cohen BE: Reversal of dopamine extravasation injury with topical nitroglycerine ointment. Plas Reconstru Surg 1989;84:811-813 11. Deshmukh N, Tolland JT: Treatment of accidental epinephrine injection in a finger. J Emerg Med 1989;7:408 (letter) 12. Ebels T J, Homan van der Heide JN: Dopamine induced ischemia. Lancet 1977;2:762 (letter) 13. Gibbs NM, Oh TE: Nitroglycerin ointment for dopamine induced peripheral digital ischemia. Lancet 1983;2:290 (letter) 14. Lefkowitz RJ, Hoffman BB, Taylor P: Neurotransmission (the autonomic and somatic motor nervous systems). In Gilman AG, Goodman LS (eds): The Pharmacological Basis of Therapeutics (ed 3). New York, NY, Macmillan Publishing Co, Inc, 1996, pp 104-140 15. Green SI, Smith JW: Dopamine gangrene. N Engl J Med 1976;294:114 (letter) 16. Greenlaw CW, Null LW: Dopamine induced ischemia. Lancet 1977;2:555 (letter) 17. Hinterberger JW, Kintzi HE: Phentolamine reversal of epinephrine induced digital vasospasm. Arch Fam Med 1994;3:193-195 18. Leikin JB, Paloucek FP: Poisoning and Toxicology Handbook (ed 2). Hudson, OH, Lexicomp, 1996-1997 19. Lynch DJ, Key JC, White RR: Management and prevention of infiltration and extravasation injury. Surg Clin North Am 1979;59:939949 20. Maguire WM, Reisdorff EJ, Smith D, Wiegenstein JF: Epinephrine induced vasospams reversed by phentolamine digital block. Am J Emerg Med 1990;8:46-47 21. McCauley WA, Gerace RV, Scilley C: Treatment of accidental digital injection of epinephrine. Ann Emerg Med 1991 ;20:665-668 22. Roberts JR, Kfisanda TJ: Accidental intraarterial injection of epinephrine treated with phentolamine. Ann Emerg Med 1980;18:424425 23. Siwy BK, Sadavoe AM: Acute management of dopamine infiltration injury with Regitine. Plast Reconstruct Surg 1987;80:610612
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24. Valdes ME: Post-dopamine ischemia treated with chlorpromazine. N Engl J Med 1976;295:1081-1082 (letter) 25. Upton J, Mullikan JB, Murray JE: Major intravenous extravasation injuries. Am J Surg 1979;137:497-506 26. Zucker G: Use of phentolamine to prevent necrosis due to levarterenol. JAMA 1957; 163:1477-1479 27. Kulig K: Extravasation injury (management/treatment protocol). In Rumack BH, Hess AJ, Gelman CR (eds): POISINDEX® System. Englewood, CO, MICROMEDEX, Inc, 1997 28. Hoffman BB, Lefkowitz RJ: Catecholamines, sympathomimetic drugs, and adrenergic receptor antagonists. In Gilman AG, Goodman LS: The Pharmacological Basis of Therapeutics (ed 3). New York, NY, Macmillan Publishing Co, Inc, 1996, pp 211-213 29. Joyce WP, Walsh K, Gough DB, et ah Pulse oximetry: A new non-invasive assessment of peripheral arterial occlusive disease. Br J Surg 1990;77:1115-1117 30. Schumer E, Friedman FD: Pulse oximetry for vascular monitoring. 1995;13:753-755
31. Freeman G: Is your pharmacy sufficiently stocked? Lack of key supplies is a liability risk. Healthcare Risk Management 1997;19: 1-12 32. Woolf AD, Chrisathus K: On-site availability of selected antidotes: Results of a survey of Massachusetts Hospitals. Am J Emerg Med 1997;15:62-66 33. Chyka PA, Conner HG. Availability of antidotes in rural and urban hospitals in Tennessee. Am J Hosp Pharm 1994;51:1346-1348 34. Dart RC, Stark Y, Fulton B, et ah Insufficient stocking of poisoning antidotes in hospital pharmacies. JAMA 1996;276:15081510 35. Parker DP, Dart RC, McNally JT: Critical deficiencies in the treatment of toxicologic emergencies: Antidote stocking in Arizona hospitals. Vet Hum Toxico11990;32:376 (abstr) 36. Kanatani MS, Kearney TE, Levin RH, Heard SE: Treatment of toxicologic emergencies--Antidote preparedness: An evaluation of Bay area hospital pharmacies and its impact on emergency planning. Vet Hum Toxico11992;34:319 (abstr)
Use of Subcutaneous Terbutaline to Reverse Peripheral Ischemia PETER A. STIER, MD,* MARK P. BOGNER, MD,I" KEVIN WEBSTER, MD,:I: JERROLD B. LEIKIN, MD,§ ANTHONY BURDA, RPH§ Four cases are presented, one involving extravasation of a dopamine and dobutamine solution in the arm and three involving accidental digital injection of epinephrine into the thumb. In three cases, local infiltration of terbutaline resulted in dramatic reversal of vasospasm and ischemia. In the remaining case the use of terbutaline resulted in minor clinical improvement. These are the first reported cases involving the successful treatment of peripheral ischemia with subcutaneous terbutaline. This experience suggests that terbutaline may be an effective alternative for treatment of peripheral ischemia when phentolamine is not available. (Am J Emerg ied 1999;17:91-94. Copyright © 1999 by W.B. Saunders Company) Terbutaline is a selective [32 agonist most commonly administered by inhalation or subcutaneous injection for relief of bronchospasm secondary to acute exacerbation of asthma. [32-adrenoreceptor agonists produce effects on smooth muscle and skeletal muscle. These include bronchodilation, relaxation of uterine musculature, and vasodilation of peripheral arteries. 1-4 Although the vasodilatory effects of [32 agonists have been previously described, 1 there is no report in the literature of these agents being used to reverse peripheral ischemic effects of extravasated vasoconstrictive agents. 1-25 In 1957, Zucker 26 reported the first successful treatment of soft-tissue ischemia caused by accidental norepinephrine extravasation with phentolamine. Since that time, phentolamine has become the drug of choice for such cases. Unfortunately there is a current shortage of phentolamine (Regitine; CibaGeneva Pharmaceuticals, Ciba-Geigy Corporation, Summit, NJ), and hospital pharmacies may not have sufficient stock of this product for adequate treatment of peripheral ischemia (written communication, Ciba-Geigy Corporation, July 8, 1996). We present four cases: one From *Department of Emergency Medicine, Methodist Hospital, Indianapolis, IN; and 1-Emergency Medicine, University of Chicago Hospitals, 1:Emergency Department, Resurrection Medical Center, and §Illinois Poison Center and Rush Presbyterian St. Luke's Medical Center, Chicago, IL. Manuscript received June 18, 1997, returned July 9, 1997; revision received August 12, 1997, accepted August 22, 1997. Presented at the North American Congress of Clinical Toxicology, September 1997, St. Louis, MO. Address reprint requests to Dr Leikin, Rush Presbyterian St Luke's Medical Center, 1653 W Congress Parkway, Chicago, IL 60612. Key Words: Extravasation, terbutaline. Copyright © 1999 by W.B. Saunders Company 0735-6757/99/1701-0028510.00/0
involving extravasation of a dopamine and dobutamine solution into the arm, and three involving accidental digital injection of epinephrine into the thumb. Local infiltration of terbntaline resulted in dramatic reversal of vasospasm and ischemia in three of the cases. In the remaining case, subcutaneous injection of terbutaline resulted in slight improvement of blood flow to the finger. CASE REPORTS Patient 1 A 65-year-old man with a history of congestive heart failure and renal failure was admitted to the intensive care unit for myocardial infarction and started on a dopamine and dobutamine infusion for hypotension. The intravenous infusion was promptly discontinued when the dorsum of the hand and wrist was noted to be pale and swollen. After discovering that there was no phentolamine available, the hospital's pharmacist notified our poison control center and the decision was made to try subcutaneous terbutaline. A solution containing 1 mg terbutaline in i0 mL normal saline was prepared and 10 mL was infiltrated into the subcutaneous tissue of the blanched areas 1 hour after noticing the extravasation. Almost immediately the infiltrated areas became hyperemic with return of normal skin color. There were no untoward effects from the administration of terbutaline, and the hand was normal at time of discharge from the hospital 12 days later. Patient 2 A 13-year-old girl presented to the emergency department (ED) approximately 20 minutes after accidentally discharging an epinephrine autoinjector into the pad of her right thumb. Physical examination revealed an adolescent girl who appeared distressed about the injury. On examination, vital signs were as follows: temperature 98.1°F; blood pressure, 170/70 mm Hg; pulse, 104 beats/rain; and respirations, 22 breaths/rain. Her general physical examination was unremarkable. The patient's right thumb was cool, pale, and demonstrated decreased capillary refill to the nail bed. The finger had diminished range of motion secondary to pain. Two-point discrimination and soft touch sensation were intact. There was severe local pain and pallor extending to the proximal wrist. As in the first case, the hospital had no available phentolamine and the physician caring for the patient was advised by our poison center to attempt injection of local subcutaneous terbutaline. Approximately 1~/2 hours after the original injury, 3 mL of a solution of terbutaline, 1 mg in 10 mL normal saline, was injected subcutaneously into the original puncture site. The thumb pad 91
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AMERICAN JOURNAL OF EMERGENCY MEDICINE • Volume 17, Number 1 • January 1999
became progressively pink during injection, and within 2 to 3 minutes an area of hyperemia developed around the injection site. About 10 minutes later, nitroglycerin ointment was also applied over the entire digit. Significant symptomatic improvement and return of normal skin color had already occurred. Within 30 minutes the thumb had completely returned to normal color and warmth, and the patient was discharged with instructions to follow up with a hand surgeon. Telephone follow-up 1 month later found no adverse long-term sequelae.
Patient 3 A 39-year-old woman was referred to the ED by our poison center after accidentally discharging an epinephrine autoinjector into the pad of her right thumb. The triage nurse was notified and we recommended the conventional treatment using phentolamine. On arrival to the ED, the patient's vital signs were as follows: temperature, 98.4°F; blood pressure, 139/101 mm Hg; regular pulse of 70 beats/min with occasional premature ventricular contractions; and respirations, 18 breaths/rain. Her general physical exam was um-emarkable. The patient's fight thumb was cool, pale, and demonstrated decreased capillary refill to the nail bed. There was also an area of blue discoloration on the thumb pad measuring approximately 0.25 cm in diameter. The patient complained of severe local pain at the injection site but maintained full range of motion. Our poison center was notified that there was no available phentolamine, and a staff member who was unaware of our previous cases recommended nitropaste and a warm compress to the affected area. By this time, approximately 2 hours had elapsed since the time of accidental injection. The authors were notified of the situation 15 minutes later. There had been no apparent resolution of symptoms up to this moment. Again the decision was made to administer subcutaneous terbutaline. This time, however, the attending physician was advised to dilute 1 mg terbutaline in 1 mL normal saline and inject 0.5 mL subcutaneously into the original puncture site. Immediately following the injection, the blanching resolved and there was return of the normal pink color of skin. Despite the dramatic improvement of symptoms, the attending physician elected to administer a second dose of nitropaste and terbutaline. There were no significant changes after the second dose. The patient was observed for 1 hour after the second dose and then discharged. At the time of discharge the thumb had normal color and warmth, but remained tender and had slightly decreased capillary refill (less than 3 seconds).
Patient 4 A 31-year-old nurse presented to the ED approximately 6 hours after accidentally discharging an epinephrine autoinjector into the pad of her right thumb. Vital signs were as follows: blood pressure, 134/72 mm Hg; pulse, 89 beats/rain; and respirations, 16 breaths/ latin. Her general physical examination was unremarkable. The patient's right thumb was cool, pale, and demonstrated decreased capillary refill to the nail bed. There was a visible puncture site with a small area of surrounding ecchymosis on the volar aspect of the thumb approximately 1 cm proximal to the tip. The finger had full range of motion but there was severe local pain. Two-point discrimination and soft touch sensation were diminished. Upon recommendation by the poison center, a 1:1 dilution of terbutaline was prepared (0.5 mg/mL), and 1 mL was injected subcutaneously into the original puncture site. Within a few minutes, the patient reported minimal relief of pain and a slight improvement in sensation. A slight increase in skin color was noted by the attending physician. Another identical dose of terbutaline was given 15 minutes after the initial dose. Continuous monitoring of vital signs showed no significant changes. After 1 hour of
observation there were no signs of ischemic progression. A hand surgeon was contacted and the patient was given an injection of phentolamine by method of digital block. There was immediate remm of normal skin color and capillary refill. The patient was discharged 1 hour later with full recovery of sensation.
DISCUSSION The current treatment of choice for peripheral ischemic events secondary to the extravasation or accidental injection of e~-adrenergic agents is local infiltration with phentolarnine at a dose of 5 nag in 9 m L normal saline. 4,18,27 Alternative methods that have been used previously with variable success include warm water immersion, amyl nitrite inhalations, metacarpal nerve block, intravenous chlorpromazine. intravenous nitroprnsside, and use o f topical nitroglycerin paste, m,17,24Although we found two case reports that demonstrated successful treatment of a dopamine-induced peripheral ischemia with topical nitroglycerin, other attempts have failed. 1°,13J7,21 A study investigating vasodilating agents to reverse vasoconstriction found that nitroglycerin effectively reverses vasoconstriction from intravenously injected catecholamines; phentolamine, however, was more effective in increasing capillary blood flow to the fingertip. 8 Phentolamine is the only agent proven effective in reversing distal extremity vasoconstriction, ischemia, and pain from local infiltration of catecholamines. Our experience with these four cases suggests that terbutaline may be an effective alternative treatment in such cases. Vascular smooth muscle contains three types of adrenergic receptors; a l , [32, and to a lesser extent, a2. 2,14 Stimulation of % and a2 postsynaptic receptors results in vasoconstriction, whereas ~2 receptor activation promotes peripheral vasodilation. Epinephrine causes vasoconstriction of arterioles by stimulating primarily a receptors. Dopamine binds to dopamine, [3, and c~ receptors, but the degree of stimulation of each receptor type depends on the dose of the drug? 8 Usually high doses of dopamine, > 1 0 gg/kg/min, are necessary to affect binding to % receptors. Patients with preexisting vascular damage however, can have o~ effects at much lower doses, ranging from 1 to 1.5 ~g/kg/min. 2s The primary mechanism by which extravasation of catecholamines causes tissue necrosis is by constriction of smooth muscle around capillaries resulting in ischemia secondary to impaired circulation. Since the phenomenon of vasospasm is usually reversible, it is thought that the duration of extravasation is more important than the concentration of vasopressor administered. 19,2° Additional clinical and anatomic factors could affect the extent of ultimate damage to tissue from prolonged ischemia and may help the clinician predict the outcome. The most c o m m o n examples include the presence of peripheral vascular disease, dramatic changes in blood pressure, and the extent of surface area infused with the offending agent. Pharmacologic reversal of peripheral vasoconstriction and ischemia requires a locally acting agent with the capacity to induce vasodilation. Antagonism of a l receptor with locally injected phentolamine has been proven effective in such cases and is the preferred method o f treatment, Theoretically speaking, any agent with [32-adrenergic characteristics should cause selective vasodilation. Even in the presence of agents with antagonistic effects it is unlikely that
STIER ET AL • SUBCUTANEOUS TERBUTALINE FOR PERIPHERAL ISCHEMIA
any systemic drugs being taken by a patient would reach sufficient tissue levels to affect the efficacy of a locally infiltrated agent. [3-adrenergic reversal was first described by Cohen and Coffman 3 in a study reporting fingertip vasodilation after intraarterial isoproterenol. We chose to use terbutaline in these cases because of its availability in an injectable form and low potential for side effects due to its selectivity for [~a receptors. Skeletal muscle tremor is the most common adverse effect of the 132 agonists. Other more serious side effects, including an'hythmias and myocardial ischemia, are usually only seen in patients with underlying cardiovascular disease or those taking certain medications, including theophylline, monoamine oxidase inhibitors, and tricyclic antidepressants. 28 A 1:10 dilution was recommended in the first case to provide the maximum recommended dose of terbutaline with enough diluent to adequately cover the affected area with infiltration of antidote. We decided that more localized ischemia in distal extremities such as the finger would be better treated with a smaller volume of fluid to decrease the tissue pressure and subsequent compression of vasculature; therefore we recommended a 1:1 dilution for the last three cases. In the second case, however, a misunderstanding between the triage nurse and the poison center resulted in the administration of a 1:10 dilution of terbutaline instead. Fortunately, it worked well. The management of peripheral ischemia involves continuous monitoring of the affected area for signs of reperfusion or progression of ischemia. Most clinicians use the appearance of skin color, temperature, neurosensory function, and, sometimes, Doppler ultrasound to assess peripheral skin perfusion. These are the parameters used in the cases we describe and seem to be adequate for monitoring the status of an ischemic body part. A study by Joyce et al, 29 however, reports that pulse oximetry works as a quick and simple noninvasive method of monitoring peripheral circulation. Its application was reported by Schumer and Friedman, 3° who described a case in which pulse oximetry was used in the evaluation and treatment of a near-amputation of a digit. We believe that pulse oximetry would be especially well suited for use in EDs to monitor ischemic digits. The ultimate endpoint for reperfusion is the alleviation of symptoms. It was the lack of phentolamine that led to the use of terbutaline as an alternative. There have been several reports describing deficiencies in antidote stocking. 31-36The surveys sent to hospital pharmacists by previous investigators did not, however, include phentolamine on the list of antidotes evaluated. We investigated the availability of phentolamine (Regitine; CibaGeneva Pharmaceuticals, Ciba-Geigy Corporation, Summit, NJ) and discovered that it was initially affected by an FDA inspection and has been distributed on a limited-supply basis since June, 1995. A letter sent to hospital pharmacies by the manufacturer indicated that requests for shipments of Regitine would only be processed if there was an emergency/life-threatening medical need (written communication, Ciba-Geigy Corporation, July 8, 1996). The product would be supplied at no cost but may take up to 48 hours to deliver. Based on our experience in these cases, terbutaline is an effective alternative to phentolamine for the treatment of
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peripheral vasospasm and ischemia. According to Ellenhorn's toxicology text, 4 the recommended treatment involves the use of a 24-gauge needle for subcutaneous injection, beginning at the periphery of the blanched areas and moving inward in a pin-cushion fashion. In our experience, however, a 27-gauge needle is just as efficacious and better tolerated by the patient. Further experience with terbutaline will delineate its optimum dose and method of injection in these clinical situations.
REFERENCES 1. Abboud FM, Eckstein JW, Zimmerman BG: Venous and arterial responses to stimulation of beta adrenergic receptors. Am J Physiel 1965;209:383-389 2. Abramson DI: Neural regulation of cutaneous circulation. Adv Biol Skin 1972; 12:207-233 3. Cohen RA, Coffman JD: f3-adrenergic vasodilator mechanism in the finger. Circ Res 1981 ;49:1196-1201 4. Ellenhorn MJ: Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning (ed 2). Baltimore, MD, Williams & Wilkins, 1996 5. Aycock BG, Hawtof DB, Moody SB: Treatment of peripheral ischemia secondary to lidocaine containing epinephrine. Ann Plast Surg 1989;23:27-30 6. Boltax RS, Dineen JP, Scarpa FJ: Gangrene resulting from infiltrated dopamine solution. N Engl J Med 1977;296:823 (letter) 7. Coakley J: Nitroglycerin ointment for dopamine-induced peripheral ischemia. Lancet 1983;2:633 (letter) 8. Coffman JD, Cohen RA: Intra-arterial vasodilator agents to reverse human finger vasoconstriction. Clin Pharmacol Ther 1987;41 : 574-579 9. Cooper BE: High dose phentolamine for extravasation of pressers. Clin Pharm 1989;8:689 (letter) 10. Denkler KA, Cohen BE: Reversal of dopamine extravasation injury with topical nitroglycerine ointment. Plas Reconstru Surg 1989;84:811-813 11. Deshmukh N, Tolland JT: Treatment of accidental epinephrine injection in a finger. J Emerg Med 1989;7:408 (letter) 12. Ebels T J, Homan van der Heide JN: Dopamine induced ischemia. Lancet 1977;2:762 (letter) 13. Gibbs NM, Oh TE: Nitroglycerin ointment for dopamine induced peripheral digital ischemia. Lancet 1983;2:290 (letter) 14. Lefkowitz RJ, Hoffman BB, Taylor P: Neurotransmission (the autonomic and somatic motor nervous systems). In Gilman AG, Goodman LS (eds): The Pharmacological Basis of Therapeutics (ed 3). New York, NY, Macmillan Publishing Co, Inc, 1996, pp 104-140 15. Green SI, Smith JW: Dopamine gangrene. N Engl J Med 1976;294:114 (letter) 16. Greenlaw CW, Null LW: Dopamine induced ischemia. Lancet 1977;2:555 (letter) 17. Hinterberger JW, Kintzi HE: Phentolamine reversal of epinephrine induced digital vasospasm. Arch Fam Med 1994;3:193-195 18. Leikin JB, Paloucek FP: Poisoning and Toxicology Handbook (ed 2). Hudson, OH, Lexicomp, 1996-1997 19. Lynch DJ, Key JC, White RR: Management and prevention of infiltration and extravasation injury. Surg Clin North Am 1979;59:939949 20. Maguire WM, Reisdorff EJ, Smith D, Wiegenstein JF: Epinephrine induced vasospams reversed by phentolamine digital block. Am J Emerg Med 1990;8:46-47 21. McCauley WA, Gerace RV, Scilley C: Treatment of accidental digital injection of epinephrine. Ann Emerg Med 1991 ;20:665-668 22. Roberts JR, Kfisanda TJ: Accidental intraarterial injection of epinephrine treated with phentolamine. Ann Emerg Med 1980;18:424425 23. Siwy BK, Sadavoe AM: Acute management of dopamine infiltration injury with Regitine. Plast Reconstruct Surg 1987;80:610612
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24. Valdes ME: Post-dopamine ischemia treated with chlorpromazine. N Engl J Med 1976;295:1081-1082 (letter) 25. Upton J, Mullikan JB, Murray JE: Major intravenous extravasation injuries. Am J Surg 1979;137:497-506 26. Zucker G: Use of phentolamine to prevent necrosis due to levarterenol. JAMA 1957; 163:1477-1479 27. Kulig K: Extravasation injury (management/treatment protocol). In Rumack BH, Hess AJ, Gelman CR (eds): POISINDEX® System. Englewood, CO, MICROMEDEX, Inc, 1997 28. Hoffman BB, Lefkowitz RJ: Catecholamines, sympathomimetic drugs, and adrenergic receptor antagonists. In Gilman AG, Goodman LS: The Pharmacological Basis of Therapeutics (ed 3). New York, NY, Macmillan Publishing Co, Inc, 1996, pp 211-213 29. Joyce WP, Walsh K, Gough DB, et ah Pulse oximetry: A new non-invasive assessment of peripheral arterial occlusive disease. Br J Surg 1990;77:1115-1117 30. Schumer E, Friedman FD: Pulse oximetry for vascular monitoring. 1995;13:753-755
31. Freeman G: Is your pharmacy sufficiently stocked? Lack of key supplies is a liability risk. Healthcare Risk Management 1997;19: 1-12 32. Woolf AD, Chrisathus K: On-site availability of selected antidotes: Results of a survey of Massachusetts Hospitals. Am J Emerg Med 1997;15:62-66 33. Chyka PA, Conner HG. Availability of antidotes in rural and urban hospitals in Tennessee. Am J Hosp Pharm 1994;51:1346-1348 34. Dart RC, Stark Y, Fulton B, et ah Insufficient stocking of poisoning antidotes in hospital pharmacies. JAMA 1996;276:15081510 35. Parker DP, Dart RC, McNally JT: Critical deficiencies in the treatment of toxicologic emergencies: Antidote stocking in Arizona hospitals. Vet Hum Toxico11990;32:376 (abstr) 36. Kanatani MS, Kearney TE, Levin RH, Heard SE: Treatment of toxicologic emergencies--Antidote preparedness: An evaluation of Bay area hospital pharmacies and its impact on emergency planning. Vet Hum Toxico11992;34:319 (abstr)