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Tongue angioedema after long-term use of ACE inhibitors
Case Renorts Tongue Angioedema of ACE Inhibitors
Long-term
Dionysios E. Kyrmizakis, MD, DDS, Chariton E. Papadakis, Emmanuel J. Fountoulakis, MD, Antonios D. Liolios, MD, and John G. Skoulas, MD
(Editorial Comment: This manuscript is important because the angiotensin-converting enzyme inhibitors used in the treatment of hypertension and congestive heart failure may be related to this dangerous side effect.)
Angioedema is a potentially life-threatening condition that is characterized by indurated, well-demarcated and often erythematous edema. Usually one or more areas of the head and neck (face, lips, tongue, and larynx) are involved. Milton, followed 6 years later by Quincke, described the first cases in 1876. Hereditary angioedema is a well-documented, clinical entity that has been attributed to deficiency or dysfunction of the C, esterase inhibit0r.l Acquired angioedema could be secondary to several factors, among which angiotensin-converting enzyme (ACE) inhibitors are considered to be the most common, accounting for 35% of the acquired cases.2 Since the mid-1980s, ACE inhibitors have been used widely for treatment of hypertension, congestive heart failure, and diabetic nephropathy,3 resulting in an increased incidence of angioedema cases. Given the efficacy of ACE inhibitors and the rarity of serious side effects associated with their use, it is expected that the incidence of angioedema will further From the Ear, Nose, and Throat Department, Venizelion General Hospital, Heraklion, Crete, Greece, the Ear, Nose, and Throat Deoartment. Universitv Hospital, Heraklion, Crete, Greece; and the Department of Medicine, 401 General Army Hospital, Athens, Greece. Address reprint requests to Dionysios E. Kyrmizakis, MD, DDS, St Nikolaidi 33, Heraklion, Crete 71305, Greece. Copyright o 1998 by W.B. Saunders Company 0196-0709/98/l 906-0009$8.00/O 394
American
Journal
of Otolatyngology,
MD,
increase in the future.4 Another reason for the increase of angioedema cases is the rise of life expectancy in western societies. The number of elderly patients being treated with ACE inhibitors has grown as a consequence of the increasing size of the elderly population, resulting in more patients being treated for hypertension and congestive heart failure. CASE REPORTS Case 1 A 68-year-old woman weighing 75 kg (160 lb) came to our emergency department with complaints of severe tongue edema to the extent that her tongue was protruding outside her mouth. There was no respiratory distress. The ear, nose, and throat examination revealed a symmetrically enlarged, nontender tongue. Because of the edema, it was not possible to visualize the hypopharynx and the larynx with indirect laryngoscopy. Auscultation of the neck was negative for stridor and the soft-tissue lateral cervical radiograph revealed a patent upper respiratory tract. The patient was given a dose of epinephrine (0.4 mg subcutaneously), and the same dosage was repeated 20 minutes later. The patient was also given dexamethasone (16 mg by intravenous [IV] bolus). The edema improved 4 hours later, and it completely resolved in 36 hours. Steroids were administered for 7 days, initially by IV and then orally. The steroids were then gradually tapered off. After a detailed history was taken, it was found that the patient had had four episodes of angioedema in the past 6 months. The previous episodes were milder, and they were treated successfully at the local health center. Seven months earlier, the patient was started on a course of captopril (25 mg three times a day) for hypertension. One month after taking captopril, the patient had her first episode of angioedema. The patient never had an
Vol 19, No 6 (November-December),
1998:
pp 394-396
TONGUE
ANGIOEDEMA
AFTER
USE
OF ACE
395
INHIBITORS
episode of angioedema before she started taking the ACE inhibitor. The patient was discharged 4 days later. and she was instructed to ston takine the ACE inhibitor. A list of medications Lontaimng ACE inhibitors was given to the patient. After consulting her cardiologist, her treatment was changed to a beta-blocker-and a diuretic. The oatient was followed every month for 6 months,*and was free of angioedema episodes.
Case 2 A 76-year-old man weighing 84 kg (181 lb) was referred to our Ear, Nose, and Throat department from another hospital because of severe tongue edema. Clinical examination revealed a severely enlarged tongue obstructing the upper airway, causing mild respiratory distress. We checked the patency of the larynx with a flexible endoscope through the nose. The edema did not expand to the larynx. The patient had tachypnea and tachycardia, but not orthopnea. He had normal arterial blood gases. The patient was started on methylprednisolone (125 mg IV every 8 hours), and received a single dose of epinephrine (0.4 mg) subcutaneously. The steroids were administered orally and tapered off in the following 7 days. The patient’s history revealed that this case was his third episode of tongue angioedema in the past 7 months. The two previous episodes were milder and were treated symptomatically in other hospitals. He was started on lisinopril26 mg administered every day orally 8 months ago for hypertension. Forty days later, he had his first episode of angioedema. The patient was discharged 4 days after complete resolution of his symptoms and was instructed to avoid ACE inhibitors. A list of the medications containing ACE inhibitors was given to the patient. The patient was followed every month. During the s-month follow-up, he was free of symptoms.
DISCUSSION ACE inhibitors are widely used medications for the treatment of hypertension, diabetic nephropathy, and congestive heart failure. The most common side effects are hypotension (usually after the first dose), renal dysfunction, hyperkalemia, and nonproductive cough. Rarely, angioedema (0.1% to 0.2 %), hepatotoxicity, dysgeusia, teratogenesis (if given during pregnancy), rash, proteinuria, and neutropenia may occur.4 Angioedema is divided into two categories: hereditary (congenital) and acquired (Table 1).5 In everyday clinical practice, ACE inhibitors are the most common cause of acquired angioedema. Biochemical rather than immunologic factors probably cause this form of angioedema.
TABLE 1.
Types
of Angioedema
Congenital Cl esterase Cl esterase
inhibitor inhibitor
(hereditary deficiency dysfunction
angioedema) (85%) (15%)
Acquired Cl esterase inhibitor deficiency B-cell lymphoma Connective tissue diseases Development of Cl esterase inhibitor autoantibodies Allergic type I hypersensitivity Parasites, food additives, drugs Chemical histamine releasers Morphine, codeine, iodinated contrast media Physical stimuli Extremes of temperature, sunlight, vibration Angiotensin-converting enzyme inhibitors Miscellaneous (rare) Systemic capillary leak syndrome Urticaria pigmentosa Idiopathic
ACE is produced in the lungs; it converts angiotensin I to angiotensin II, a powerful vasoconstrictive agent. ACE, which is also known as kininase II, metabolizes bradykinin, a potent vasodilating substance. ACE inhibitors increase the level of bradykinin and prolong its action. They also decrease angiotensin II and aldosterone levels. The combination of the aforementioned mechanisms leads to local or generalized vasodilatation, followed by fluid extravasation into the subcutaneous tissues, causing tissue edema and angioedema. 6,7 Microscopically, subcutaneous tissue vasodilatation, diffuse edema, and moderate inflammatory cell infiltration characterize angioedema. The most common area of angioedema is the head and necke8 The usual presentation is a hard-demarcated, extensive edema that is localized primarily at the face, lips, and tongue. It is usually erythematous, and it could evolve into laryngeal edema, upper airway obstruction, and death. Rarely, angioedema can be localized at the hands, feet, and abdominal viscera. In the abdominal viscera, it angioedema can present as abdominal pain. The most important step in diagnosing angioedema secondary to ACE inhibitors is the precise history. When hereditary or allergic angioedema is suspected, a measurement of Cl esterase inhibitors, C4, total and specific immunoglobulin (Ig)E, and performance of specific skin tests will help to establish the
KYRMIZAKIS
396
diagnosis. Angioedema secondary to ACE inhibitors may appear from several hours to 2 years after initiation of treatment.g The severity of the angioedema does not appear to be related to dosage. The initial therapeutic step is to secure the patency of the upper airway. Depending on the severity of the obstruction and the physician’s experience, medications, standard intubation, intubation with the use of a flexible bronchoscope, cricothyroidotomy, or tracheotomy may be used.2 The patient should be given oxygen, epinephrine (0.01 mg/kg) subcutaneously; maximum dosage 0.5 mg for persons more than 50 kg (110 lb); the dosage may be repeated in 20 minutes) and high doses of steroids (usually dexamethasone) IV. Several authors recommend inhalations with nebulized racemic epinephrine. It should be emphasized that the mechanism causing angioedema secondary to ACE inhibitors is not the same mechanism causing allergic angioedema, and that the ACE inhibitors have a prolonged half life. Consequently, the standard treatment for allergic reactions (epinephrine, steroids, and antihistamines) may not be as effective. Steroids should also be used for a prolonged period to avoid recurrence. In everyday practice, angioedema secondary to ACE inhibitors is usually diagnosed after several episodes. The reason for this practice is that the initial episodes are underestimated, and the involved physicians (family practitioners, cardiologists, internists, and otolaryngologists) are unaware of the association. After an initial episode, the patient is usually treated symptomatically while continuing to take the offending medication, risking a more severe (and potentially lethal) episode in the
ET AL
future.lO When the diagnosis is established or even suspected, the patient should cease taking the responsible medication and be treated for hypertension or congestive heart failure with alternative agents. The fact that diuretics, calcium channel blockers, or p-blockers might also cause angioedema should also not be forgotten.ll The patient should be given written instructions on how to avoid all medications containing ACE inhibitors. These precautions are particularly important, given that the use of ACE inhibitors is expected to rise in the future. REFERENCES 1. Donaldson VH, Evans RR: A biochemical abnormality in hereditary angioneurotic edema: Absence of serum inhibitor C1 esterase. Am J Med 35:37-44,1963 2. Megerian CA, Arnold JE, Berger M: Angioedema: 5 Years experience, with a review of the disorder’s presentation and treatment. Laryngoscope 102:256-260, 1992 3. Jett GK: Captopril-induced angioedema. Ann Emerg Med 13:489-490,1984 4. Alderman CP: Adverse effects of the angiotensinconverting enzyme inhibitors. Ann Pharmacother 30:5561,1996 5. Pracy JPM, McGlashan JA, Walsh RM, et al: Angioedema secondary to angiotensin-converting inhibitors. J Laryngol Otol108:696-698, 1994 6. Suarez M, Ho PW, Johnson ES, et al: Angioneurotic edema, agranulocytosis and fatal septicemia following captopril therapy. Am J Med 81:336-338,1986 7. Fuller RW, Warren JB, McCuster M, et al: Effect of enalapril on the skin response to bradykinin in man. Br J Clin Pharmacol23:88-90, 1987 8. Haddad A, Frenkiel S, Small P: Angioedema of the head and neck. J Otolaryngol14:14-16, 1985 9. Chin HL, Buchan DA: Severe angioedema after longterm use of an angiotensin-converting enzyme inhibitor. Ann Int Med 112:312-313, 1990 10. Orfan N, Patterson R, Dykewicz MS: Severe angioedema related to ACE inhibitors in patients with idiopathic angioedema. JAMA 264:1287-1289,199O 11. Hedner T, Saamuelson 0, Lindholm L, et al: Precipitation of angioedema by antihypertensives drugs. J Hypertension 9:S360-S361,1991 (suppl)
Long-term
Dionysios E. Kyrmizakis, MD, DDS, Chariton E. Papadakis, Emmanuel J. Fountoulakis, MD, Antonios D. Liolios, MD, and John G. Skoulas, MD
(Editorial Comment: This manuscript is important because the angiotensin-converting enzyme inhibitors used in the treatment of hypertension and congestive heart failure may be related to this dangerous side effect.)
Angioedema is a potentially life-threatening condition that is characterized by indurated, well-demarcated and often erythematous edema. Usually one or more areas of the head and neck (face, lips, tongue, and larynx) are involved. Milton, followed 6 years later by Quincke, described the first cases in 1876. Hereditary angioedema is a well-documented, clinical entity that has been attributed to deficiency or dysfunction of the C, esterase inhibit0r.l Acquired angioedema could be secondary to several factors, among which angiotensin-converting enzyme (ACE) inhibitors are considered to be the most common, accounting for 35% of the acquired cases.2 Since the mid-1980s, ACE inhibitors have been used widely for treatment of hypertension, congestive heart failure, and diabetic nephropathy,3 resulting in an increased incidence of angioedema cases. Given the efficacy of ACE inhibitors and the rarity of serious side effects associated with their use, it is expected that the incidence of angioedema will further From the Ear, Nose, and Throat Department, Venizelion General Hospital, Heraklion, Crete, Greece, the Ear, Nose, and Throat Deoartment. Universitv Hospital, Heraklion, Crete, Greece; and the Department of Medicine, 401 General Army Hospital, Athens, Greece. Address reprint requests to Dionysios E. Kyrmizakis, MD, DDS, St Nikolaidi 33, Heraklion, Crete 71305, Greece. Copyright o 1998 by W.B. Saunders Company 0196-0709/98/l 906-0009$8.00/O 394
American
Journal
of Otolatyngology,
MD,
increase in the future.4 Another reason for the increase of angioedema cases is the rise of life expectancy in western societies. The number of elderly patients being treated with ACE inhibitors has grown as a consequence of the increasing size of the elderly population, resulting in more patients being treated for hypertension and congestive heart failure. CASE REPORTS Case 1 A 68-year-old woman weighing 75 kg (160 lb) came to our emergency department with complaints of severe tongue edema to the extent that her tongue was protruding outside her mouth. There was no respiratory distress. The ear, nose, and throat examination revealed a symmetrically enlarged, nontender tongue. Because of the edema, it was not possible to visualize the hypopharynx and the larynx with indirect laryngoscopy. Auscultation of the neck was negative for stridor and the soft-tissue lateral cervical radiograph revealed a patent upper respiratory tract. The patient was given a dose of epinephrine (0.4 mg subcutaneously), and the same dosage was repeated 20 minutes later. The patient was also given dexamethasone (16 mg by intravenous [IV] bolus). The edema improved 4 hours later, and it completely resolved in 36 hours. Steroids were administered for 7 days, initially by IV and then orally. The steroids were then gradually tapered off. After a detailed history was taken, it was found that the patient had had four episodes of angioedema in the past 6 months. The previous episodes were milder, and they were treated successfully at the local health center. Seven months earlier, the patient was started on a course of captopril (25 mg three times a day) for hypertension. One month after taking captopril, the patient had her first episode of angioedema. The patient never had an
Vol 19, No 6 (November-December),
1998:
pp 394-396
TONGUE
ANGIOEDEMA
AFTER
USE
OF ACE
395
INHIBITORS
episode of angioedema before she started taking the ACE inhibitor. The patient was discharged 4 days later. and she was instructed to ston takine the ACE inhibitor. A list of medications Lontaimng ACE inhibitors was given to the patient. After consulting her cardiologist, her treatment was changed to a beta-blocker-and a diuretic. The oatient was followed every month for 6 months,*and was free of angioedema episodes.
Case 2 A 76-year-old man weighing 84 kg (181 lb) was referred to our Ear, Nose, and Throat department from another hospital because of severe tongue edema. Clinical examination revealed a severely enlarged tongue obstructing the upper airway, causing mild respiratory distress. We checked the patency of the larynx with a flexible endoscope through the nose. The edema did not expand to the larynx. The patient had tachypnea and tachycardia, but not orthopnea. He had normal arterial blood gases. The patient was started on methylprednisolone (125 mg IV every 8 hours), and received a single dose of epinephrine (0.4 mg) subcutaneously. The steroids were administered orally and tapered off in the following 7 days. The patient’s history revealed that this case was his third episode of tongue angioedema in the past 7 months. The two previous episodes were milder and were treated symptomatically in other hospitals. He was started on lisinopril26 mg administered every day orally 8 months ago for hypertension. Forty days later, he had his first episode of angioedema. The patient was discharged 4 days after complete resolution of his symptoms and was instructed to avoid ACE inhibitors. A list of the medications containing ACE inhibitors was given to the patient. The patient was followed every month. During the s-month follow-up, he was free of symptoms.
DISCUSSION ACE inhibitors are widely used medications for the treatment of hypertension, diabetic nephropathy, and congestive heart failure. The most common side effects are hypotension (usually after the first dose), renal dysfunction, hyperkalemia, and nonproductive cough. Rarely, angioedema (0.1% to 0.2 %), hepatotoxicity, dysgeusia, teratogenesis (if given during pregnancy), rash, proteinuria, and neutropenia may occur.4 Angioedema is divided into two categories: hereditary (congenital) and acquired (Table 1).5 In everyday clinical practice, ACE inhibitors are the most common cause of acquired angioedema. Biochemical rather than immunologic factors probably cause this form of angioedema.
TABLE 1.
Types
of Angioedema
Congenital Cl esterase Cl esterase
inhibitor inhibitor
(hereditary deficiency dysfunction
angioedema) (85%) (15%)
Acquired Cl esterase inhibitor deficiency B-cell lymphoma Connective tissue diseases Development of Cl esterase inhibitor autoantibodies Allergic type I hypersensitivity Parasites, food additives, drugs Chemical histamine releasers Morphine, codeine, iodinated contrast media Physical stimuli Extremes of temperature, sunlight, vibration Angiotensin-converting enzyme inhibitors Miscellaneous (rare) Systemic capillary leak syndrome Urticaria pigmentosa Idiopathic
ACE is produced in the lungs; it converts angiotensin I to angiotensin II, a powerful vasoconstrictive agent. ACE, which is also known as kininase II, metabolizes bradykinin, a potent vasodilating substance. ACE inhibitors increase the level of bradykinin and prolong its action. They also decrease angiotensin II and aldosterone levels. The combination of the aforementioned mechanisms leads to local or generalized vasodilatation, followed by fluid extravasation into the subcutaneous tissues, causing tissue edema and angioedema. 6,7 Microscopically, subcutaneous tissue vasodilatation, diffuse edema, and moderate inflammatory cell infiltration characterize angioedema. The most common area of angioedema is the head and necke8 The usual presentation is a hard-demarcated, extensive edema that is localized primarily at the face, lips, and tongue. It is usually erythematous, and it could evolve into laryngeal edema, upper airway obstruction, and death. Rarely, angioedema can be localized at the hands, feet, and abdominal viscera. In the abdominal viscera, it angioedema can present as abdominal pain. The most important step in diagnosing angioedema secondary to ACE inhibitors is the precise history. When hereditary or allergic angioedema is suspected, a measurement of Cl esterase inhibitors, C4, total and specific immunoglobulin (Ig)E, and performance of specific skin tests will help to establish the
KYRMIZAKIS
396
diagnosis. Angioedema secondary to ACE inhibitors may appear from several hours to 2 years after initiation of treatment.g The severity of the angioedema does not appear to be related to dosage. The initial therapeutic step is to secure the patency of the upper airway. Depending on the severity of the obstruction and the physician’s experience, medications, standard intubation, intubation with the use of a flexible bronchoscope, cricothyroidotomy, or tracheotomy may be used.2 The patient should be given oxygen, epinephrine (0.01 mg/kg) subcutaneously; maximum dosage 0.5 mg for persons more than 50 kg (110 lb); the dosage may be repeated in 20 minutes) and high doses of steroids (usually dexamethasone) IV. Several authors recommend inhalations with nebulized racemic epinephrine. It should be emphasized that the mechanism causing angioedema secondary to ACE inhibitors is not the same mechanism causing allergic angioedema, and that the ACE inhibitors have a prolonged half life. Consequently, the standard treatment for allergic reactions (epinephrine, steroids, and antihistamines) may not be as effective. Steroids should also be used for a prolonged period to avoid recurrence. In everyday practice, angioedema secondary to ACE inhibitors is usually diagnosed after several episodes. The reason for this practice is that the initial episodes are underestimated, and the involved physicians (family practitioners, cardiologists, internists, and otolaryngologists) are unaware of the association. After an initial episode, the patient is usually treated symptomatically while continuing to take the offending medication, risking a more severe (and potentially lethal) episode in the
ET AL
future.lO When the diagnosis is established or even suspected, the patient should cease taking the responsible medication and be treated for hypertension or congestive heart failure with alternative agents. The fact that diuretics, calcium channel blockers, or p-blockers might also cause angioedema should also not be forgotten.ll The patient should be given written instructions on how to avoid all medications containing ACE inhibitors. These precautions are particularly important, given that the use of ACE inhibitors is expected to rise in the future. REFERENCES 1. Donaldson VH, Evans RR: A biochemical abnormality in hereditary angioneurotic edema: Absence of serum inhibitor C1 esterase. Am J Med 35:37-44,1963 2. Megerian CA, Arnold JE, Berger M: Angioedema: 5 Years experience, with a review of the disorder’s presentation and treatment. Laryngoscope 102:256-260, 1992 3. Jett GK: Captopril-induced angioedema. Ann Emerg Med 13:489-490,1984 4. Alderman CP: Adverse effects of the angiotensinconverting enzyme inhibitors. Ann Pharmacother 30:5561,1996 5. Pracy JPM, McGlashan JA, Walsh RM, et al: Angioedema secondary to angiotensin-converting inhibitors. J Laryngol Otol108:696-698, 1994 6. Suarez M, Ho PW, Johnson ES, et al: Angioneurotic edema, agranulocytosis and fatal septicemia following captopril therapy. Am J Med 81:336-338,1986 7. Fuller RW, Warren JB, McCuster M, et al: Effect of enalapril on the skin response to bradykinin in man. Br J Clin Pharmacol23:88-90, 1987 8. Haddad A, Frenkiel S, Small P: Angioedema of the head and neck. J Otolaryngol14:14-16, 1985 9. Chin HL, Buchan DA: Severe angioedema after longterm use of an angiotensin-converting enzyme inhibitor. Ann Int Med 112:312-313, 1990 10. Orfan N, Patterson R, Dykewicz MS: Severe angioedema related to ACE inhibitors in patients with idiopathic angioedema. JAMA 264:1287-1289,199O 11. Hedner T, Saamuelson 0, Lindholm L, et al: Precipitation of angioedema by antihypertensives drugs. J Hypertension 9:S360-S361,1991 (suppl)