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Clinical characteristics of angiotensinconverting enzyme inhibitor-induced angioedema
CASE REPORT angioedema; angiotensin-converting enzyme inhibitor
Clinical Characteristics of AngiotensinConverting Enzyme Inhibitor-Induced Angioedema We present the cases of two patients with angiotensin-converting enzyme (ACE) inhibitor-induced angioedema that required intubation for lifethreatening airway compromise. This side effect has been previously reported with all ACE inhibitors, but its incidence and potential for a fatal outcome m a y not be fully appreciated. A review of the literature reveals 227 reports of this reaction with an overall incidence of approximately 0.1% to 0.2%. The etiology is nonimmunogenic and thought to be related to accentuated bradykinin activity There is no clinical profile that identifies patients at increased risk for this side effect. There are unique clinical characteristics to this idiosyncratic reaction: angioedema m a y suddenly occur even though the drug has been well tolerated for months or years; s y m p t o m s m a y regress spontaneously while the patient continues the medication, erroneously prompting an alternative diagnosis; the pathology has a special predilection for the tongue, a circumstance that renders orotracheal and nasotracheal intubation difficult; s y m p t o m s m a y progress rapidly despite aggressive medical therapy, necessitating emergency airway procedures; and a rebound phenomenon following successful medical therapy has been described. We recommend intensive medical treatment before angioedema is severe enough to thwart standard methods to ensure a protected airway, Once even minor angioedema is attributed to an ACE inhiMtor, an alternative class of antihypertensive medication should be chosen. I n d i v i d u a l s w i t h a history of idiopathic angioedema probably should not be given ACE inhibitors. [Roberts JR, Wuerz RC: Clinical characteristics of angiotensin-converting e n z y m e inhibitor-induced angio~ edema. Ann Emerg Med May 1991;20:555-558.]
James R Roberts, MD Richard C Wuerz, MD Philadelphia, Pennsylvania From the Department of Emergency Medicine and Division of Toxicology, Mercy Catholic Medical Center; and the Department of Emergency Medicine, The Medical College of Pennsylvania, Philadelphia. Received for publication October 4, 1990. Accepted for publication November 26, 1990. Address for reprints: James R Roberts, MD, Misericordia Hospital, Department of Emergency Medicine, 54th and Cedar Avenue, Philadelphia, Pennsylvania 19143.
INTRODUCTION Since the 1980s, angiotensin-converting enzyme (ACE} inhibitors have been widely used as effective antihypertensive agents and for the treatm e n t of congestive heart failure. Overall, these drugs have a relatively good clinical safety profile, but numerous side effects, including chronic cough, rhinitis, azotemia, skin rash, nephrotic syndrome, hypotension, arthralgia, hypokalemia, and agranulocytosis, have been reported, l-3 Only recently, however, has the potential been recognized for these drugs to cause severe life-threatening angioedema as a result of airway compromise. 4-m Angioedema has been related to all available ACE inhibitors (captopril, enalapril maleate, and ]isinopril), and there is a bold~type warning in the Physician's Desk Reference emphasizing this side effect. However, many physicians either are still unaware of the association or do not recognize the potential for a fatal outcome. A recent review of ACE inhibitor reactions classified angioedema as "usually mild" and stated that it "clears with discontinuation of the drug. 'q3 There are a number of unusual, characteristic clinical aspects of the angioedema associated with ACE inhibitors, and these vagaries may account for this lack of awareness. We report the cases of two patients with severe life-threatening angioedema associated with enalapril and captopril. The literature is also reviewed to further characterize and emphasize the specific clinical features of this important side effect. Based on our experience and these reports, we offer recommendations for treatment.
20:5 May 1991
Annals of Emergency Medicine
555/119
ANGIOEDEMA Roberts & Wuerz
FIGURE 1A&B. M a s s i v e t o n g u e swelling and drooling in patient 1. FIGURE 2. Successful airway secured with blind nasotracheal intubation in patient 1. Note rapid progression of soft-tissue swelling of the neck, which was not present on initial presentation.
CASE REPORTS Case 1 A 60-year-old woman presented to the emergency department with the sudden o n s e t of swelling of the tongue, inability to speak clearly, and i n a b i l i t y to s w a l l o w her saliva. T h r o u g h a relative, it was determined that the patient had been prescribed enalapril (10 mg twice daily) for approximately two years for the treatment of essential hypertension. She had experienced two previous episodes of minor tongue and lip swelling that had not been attributed to the medication. Because she had continued to take the medication and the symptoms had abated spontaneously, it was assumed that the prior episodes were the result of an undetermined food allergy. When the patient arose on the morning of presentation, she rapidly developed in, creasing tongue and neck swelling that progressed into the inability to swallow saliva and mild dyspnea. The patient's medical history was remarkable for adult-onset diabetes mellitus not requiring medical therapy and moderate hypertension that was well controlled with the ACE inhibitor. She had no known allergies to drugs, asthma, hay fever, or eczema. She had taken the same dosage of enalapril on a daily basis for two years, and the last dose had been 12 hours before admission. On e x a m i n a t i o n , t h e p a t i e n t ' s blood pressure was 180/95 m m Hg; pulse, 110; respirations, 28; and tympanic membrane temperature, 37.2 C. She could speak only in a muffled unintelligible voice and was drooling saliva continuously. She appeared in m o d e r a t e respiratory distress and kept pointing to her tongue and neck. The skin was warm, and she exhibited mild diaphoresis without cyanosis. There was no obvious stridor, although she did have noisy respirations because of the pooling of secretions in the throat. The tongue was markedly swollen and protruded. 120/556
Minimal submental edema was also noted (Figure 1). Treatment included 0.3 mg epinephrine subcutaneously every 20 minutes for three doses, 300 mg cime t i d i n e IV, 250 m g m e t h y l p r e d nisolone IV, and 50 mg diphenhydramine IV for two doses. There was no response to this antiallergic treatment, and the soft-tissue swelling of the neck gradually increased. Because of the patient's inability to control her secretions and increasing respiratory difficulty, attempts were made to pass a nasotracheal tube over a fiberoptic bronchoscope. Fiberoptic intubation was unsuccessful because of inability to visualize the important landmarks. After shrinkage of the nasal mucosa with Neosynephrine ® nasal spray, a lubricated nasal trumpet airway was carefully inserted in an attempt to atraumatically dilate the n a s a l p a s s a g e b e f o r e b l i n d nasotracheal intubation. Preparations also were made for emergency cricothyrotomy, but fortunately the first attempt at blind nasotracheal intubation was successful (Figure 2). The patient was placed on humidified oxygen and admitted to the ICU. She was treated with dexamethasone; during the next two to three days, the swelling gradually decreased. Extubation was possible on the third hospital day with only minimal tongue swelling persisting. She was discharged five days later in a completely asymptomatic state and cautioned not to use ACE inhibitors. No further follow-up was available. Case 2 A 49-year-old man presented to the ED w i t h increasing facial and lip e d e m a during the p r e v i o u s eight hours. He had been prescribed proAnnals of Emergency Medicine
pranolol, hydrochlorothiazide, and 50 mg captopril twice daily for hypertension. None of the medications or dosages had been changed recently, and he had been taking captopril for more than one year. He had no history of angioedema, asthma, other allergies, or unusual exposures to unusual food or new medications. He had no history of previous angioedema. The presenting vital signs were blood pressure of 190/120 m m Hg; pulse, 84; and respirations, 28. Examination revealed gross edema of the lips and face. Tongue swelling was not initially present, but it rapidly developed within one hour. While in the ED, the patient began to experience hoarseness and increasing shortness of breath. He was given IV 50 mg diphenhydramine twice and 250 mg methylprednisolone without improvement. After shrinkage of the nasal mucosa, blind nasotracheal intubation was performed successfully on the first attempt. The patient was treated with IV corticosteroids, improved over the next 18 hours, and was extubated and 20:5 May 1991
ANGIOEDEMA Roberts & Wuerz
TABLE. Review of literature relating angioederna to the use of ACE inhibitors ACE Inhibitor* Treatmenl
Reference/Year
Patients/Clinical Symptoms
Jett14/1984 Suarez et alS/1989
First report of angioedema 55-year-old man/facial edema; 49-year-old woman/facial edema and agraoulocytesis 19 cases of angioedema;one case of urticaria in addition to angioedema Postmarketing survey: 38 cases reviewed; 138 additional cases identified 6 cases 1984 - 1986
Wood and Manns/1987 Slater et al3/1988 Barna et aW1989
Cameron and Higginsl/1989 15 cases Giannoccaro et alW1989 Smith and MorganW1989 Werber and PincusW1989
Chin and Buchan9/1990 Orfan et a116/1990
65-year-old man/facial edema, progressing to airway obstruction 63-year-old man/buccal and lip edema 57-year-old woman/tongue swelling; 52-year-old woman/intraoratand submandibular edema 67-year-old woman/progressedto airway obstruction Four cases of angioedema in patients with previous idiopathic angioedema
C C C
Outcome
Antihistaminesand hydrocortisone Diphenhydramineand steroids NA
Resolvedwith medical therapy Recovered Died of sepsis
E,C
NA
NA
E,C
NA
C,E
NA
Four deaths, three intubations, and one tracheostomy ? Not reported; one patient required tracheostomy No deaths Died: surgical airway obtained when unable to intubate Recovered Recovered without the need for airway control
L E
NA Diphenhydramineand steroids
E E
NA Steroids Antihistamines
E
Epinephrine, diphenhydramine, and Recovered; required nasotracheal steroids intubation Antihistamines,corticosteroids, and epi- All recovered with medical therapy nephrine
E,L
*E, enalaprfl; C, captopril; L, lisinopril
discharged after an ears, nose, and throat evaluation demonstrated no sequelae. The final diagnosis was captopril-induced angioedema. DISCUSSION The overall incidence of angioedema associated with use of ACE inhibitors has been estimated to be 0.1% to 0.2%. .3 This side effect was first reported by Jett in 1984; 14 since then, at least 89 additional cases have been reported (Table). Slater et al reported but did not characterize an additional 138 cases, a These authors characterized angioedema as "life threatening" in 22% of cases in which the details were available. The etiology of angioedema is unclear. It is probably not an immunologic mechanism but rather a biochemical phenomenon mediated through the kallikrein-kinin system. ACE inhibitors have been demonstrated to decrease the metabolism of bradykinin, a potent vasodilator that also increases vascular permeability. ~5 There also may be other unknown genetic or environmental factors that c o n t r i b u t e to this idiosyncratic response. ACE inhibitor antibodies have not been demonstrated, and it is unlikely that the reaction is IgE mediated. Urticaria without angioedema has 20:5 May 1991
been attributed to ACE inhibitors. ACE inhibitor-induced angioedema is different from hereditary angioedema because normal C-1 esterase inhibitor activity has been documented in patients affected with this complication. 9 Although no specific clinical profile or predisposing factors have been identified, individuals with a history of idiopathic angioedema or urticaria may be at increased risk and probably should not be treated with ACE i n h i b i t o r s . 16 P a t i e n t s w i t h angioedema do not appear to have higher incidence rates of food or drug allergy, asthma, hay fever, or eczema. ACE inhibitor-induced angioedema has a peculiar predilection for the head and neck region, particularly the tongue and lips. Edema of the periorbital, buccal, laryngeal, gener~ alized facial, neck, and subglottic areas has been described; the limbs are usually spared. Large doses of ACE inhibitors may be more likely to precipitate angioedema, but there is no clear evidence of a dose-response relationship, and angioedema often occurs with standard dosing regimens. About two thirds of the reactions occur within hours of initiation of treatment or during the first week of maintenance therapy. 3 Curiously, however, angioedema may occur at any time during the use of Annals of Emergency Medicine
ACE inhibitors. Serious l i f e - t h r e a t e n i n g consequences may develop precipitously even if the patient has tolerated the drug for many years. 9 Numerous authors also have e m p h a s i z e d that minor angioedema may occur during drug use yet s p o n t a n e o u s l y abate without therapy while the unaware patient continues to take the medication. Such a scenario would probably confuse the issue of etiology of the angioedema and easily cause the patient or physician to attribute the side effect to another cause, such as food allergy, insect stings, or other drug reactions. It is particularly important to note that because angioedema often affects the tongue, it may be impossible for the patient to verbalize symptoms or give a medical history. In addition, massive glossal edema can prohibit or hamper successful orotracheal or nasotracheal intubation that may be required for airway control. Both the precipitation and prog r e s s i o n of a n g i o e d e m a are unpredictable. Although many cases resolve s p o n t a n e o u s l y or are easily reversed with standard antiallergic drug therapy, progression may be rapid enough and the drug may be resistant enough to cause fatal airway compromise. 557/121
ANGIOEDEMA Roberts & Wuerz
In our first patient, the angioedema was totally resistant to very aggressive medical therapy that would have been expected to be effective against allergic or anaphylactoid reactions. In a report of a fatal case, Giannoccaro et al emphasized that angioedema may initially respond to drug therapy, yet rebound to an even more serious degree, m The management of ACE inhibitor-induced angioedema may be as simple as stopping the medication, but the gamut of medical intervention ranges from drug therapy to intubation or a surgical procedure to secure an airway, lz Once far advanced, angioedema is unlikely to be r e s p o n s i v e to e p i n e p h r i n e , antihistamines, or corticosteroids. The use of inhaled racemic epinephrine has not been reported, but it may be helpful. Significant soft-tissue edema can make oral intubation impossible or render nasotracheal i n t u b a t i o n problematic or even dangerous if bleeding or vomiting is precipitated before the airway is protected. If the soft tissues of neck are involved, cricothyrotomy may also be technically m o r e d i f f i c u l t . F i b e r o p t i c bronchoscopic nasal intubation or retrograde intubation over a guide wire p a s s e d t h r o u g h the c r i c o t h y r o i d membrane may be options for airway control if the physician is skilled in these procedures. The fatal potential of ACE inhibitor-induced angioedema necessitates a careful drug history in all patients with this symptom. ACE inhibitors should be considered the cause of angioedema whenever it occurs in patients taking these drugs. The fact that symptoms have occurred after years of uneventful ACE inhibitor
122/558
use should not dissuade the physician from associating these drugs with the reaction. We agree w i t h C h i n and B u c h a n t h a t p a t i e n t s should never receive any ACE inhibitor after even a mild or easily reversed episode of angioedema. 9 Medical t h e r a p y of progressive angioedema should be aggressive; failing a rapid response, mechanical methods to secure an airway should be undertaken before massive edema complicates oral or nasal intubation or surgical procedures. Patients who r e s p o n d to i n i t i a l drug t h e r a p y should be observed carefully for a possible rebound phenomenon. We emphasize the need for early intubation or cricothyrotomy or tracheostomy if signs of impending airway obstruction are present, and we caution against relying on medication to totally reverse the pathology.
REFERENCES
SUMMARY
10. Giannoccaro PJ, Wallace GJ, Higginson LAJ, et al: Fatal angioedema associated with enalapril. Can J CardioI 1989;5:335-336.
We describe the cases of two patients who had tolerated ACE inhibitots for many months without ill effects until they suddenly developed life-threatening angioedema of the upper airway, necessitating tracheal i n t u b a t i o n . N e i t h e r p a t i e n t responded to standard drug therapy that usually reverses allergic reactions. The potential for patients taking ACE inhibitors to develop serious angioedema is stressed. Physicians are urged to withhold this class of drugs from all patients who develop even mild angioedema during therapy and to consider this drug reaction in all patients with angioedema. Once angioedema develops, patients should be monitored aggressively and treated, as this is a potentially fatal complication.
Annals of Emergency Medicine
1. Cameron HA, Higgins TJC: Clinical experience with lisinoprii: Observations on safety and tolerability. J Hzlm Hypertens 1989;3:177-186. 2. Weber MA: Safety issues during antihypertensive treatment with angiotensin converting enzyme inhibitots. A m J Med 1988;84:16-23. 3. Slater EE, Merrill DD, Guess HA, et al: Clinical profile of angioedema associated with angiotensin converting enzyme inhibition. JAMA 1988;260:967-970. 4. Barna JS, Prable MAS, Abedi E: Report of angioedema secondary to hypertension medications. Va Med 1989; 116:147. 5. Wood SM, Mann RD: Angioedema and urticaria associated with angiotensin converting enzyme inhibitors. Br Med J 1987;294:91-92. 6. Self F, Bates GJ, Drake-Lee A: Severe angioneurotic edema causing acute airway obstruction. J R Soc Med 1988;81:544~545. 7. Singer DRJ, MacGregor GA: Angioneurotic edema associated with two angiotensin converting enzyme inhibitors. Br Med J 1986;293:1243. 8. Suarez M, Wan Lye Ho P, Johnson ES: Angioneurotic edema, agranulocytosis, and fatal septicemia following captopril therapy. A m J Med 1989;81:336-338. 9. Chin HL, Buchan DA: Severe angioedema after long term use of an angiotensin-converting enzyme inhibitor. Ann Intern Med 1990;112:312-313.
11. Smith ME, Morgan MT: Angioedema of the head and neck and angiotensin-converting enzyme inhibitots. Otolaryngof Head Neck Surg 1989;101:93-95. 12. Werber JL, Pincus RL: Oropharyngeal angioedema associated with the use of angiotensin-converting enzyme inhibitors. OtolaryngoI Head Neck Stzrg 1989; 101:96-98. 13. O'Hollaren MT, Porter GA: Angiotensin converting enzyme inhibitors and the allergist. A n n AHergy 1990;64:503. 14. Jett KG: Captopril-induced angioedema (letter). Ann Emerg Med 1984;13:489-490. 15. Anderson MW, DeShazo RD: Studies of the mechanism of ACE inhibitor-associated angioedema: The effect of an ACE inhibitor on Cutaneo vs responses to bradykinin, codeine, and histamine. J Aller Clfn Immunol 1990;85:856. 16. Orfan N, Patterson R, Dykewicz MS: Severe anglo ~ edema related to ACE inhibitors in patients with a history of idiopathic angioedema. JAMA 1990;264:1287. 17. Long TM: Atraumatie nasopharyngeaI intubation for upper airway obstruction. Anesthesia 1988;43: 510-511.
20:5 May 1991
Clinical Characteristics of AngiotensinConverting Enzyme Inhibitor-Induced Angioedema We present the cases of two patients with angiotensin-converting enzyme (ACE) inhibitor-induced angioedema that required intubation for lifethreatening airway compromise. This side effect has been previously reported with all ACE inhibitors, but its incidence and potential for a fatal outcome m a y not be fully appreciated. A review of the literature reveals 227 reports of this reaction with an overall incidence of approximately 0.1% to 0.2%. The etiology is nonimmunogenic and thought to be related to accentuated bradykinin activity There is no clinical profile that identifies patients at increased risk for this side effect. There are unique clinical characteristics to this idiosyncratic reaction: angioedema m a y suddenly occur even though the drug has been well tolerated for months or years; s y m p t o m s m a y regress spontaneously while the patient continues the medication, erroneously prompting an alternative diagnosis; the pathology has a special predilection for the tongue, a circumstance that renders orotracheal and nasotracheal intubation difficult; s y m p t o m s m a y progress rapidly despite aggressive medical therapy, necessitating emergency airway procedures; and a rebound phenomenon following successful medical therapy has been described. We recommend intensive medical treatment before angioedema is severe enough to thwart standard methods to ensure a protected airway, Once even minor angioedema is attributed to an ACE inhiMtor, an alternative class of antihypertensive medication should be chosen. I n d i v i d u a l s w i t h a history of idiopathic angioedema probably should not be given ACE inhibitors. [Roberts JR, Wuerz RC: Clinical characteristics of angiotensin-converting e n z y m e inhibitor-induced angio~ edema. Ann Emerg Med May 1991;20:555-558.]
James R Roberts, MD Richard C Wuerz, MD Philadelphia, Pennsylvania From the Department of Emergency Medicine and Division of Toxicology, Mercy Catholic Medical Center; and the Department of Emergency Medicine, The Medical College of Pennsylvania, Philadelphia. Received for publication October 4, 1990. Accepted for publication November 26, 1990. Address for reprints: James R Roberts, MD, Misericordia Hospital, Department of Emergency Medicine, 54th and Cedar Avenue, Philadelphia, Pennsylvania 19143.
INTRODUCTION Since the 1980s, angiotensin-converting enzyme (ACE} inhibitors have been widely used as effective antihypertensive agents and for the treatm e n t of congestive heart failure. Overall, these drugs have a relatively good clinical safety profile, but numerous side effects, including chronic cough, rhinitis, azotemia, skin rash, nephrotic syndrome, hypotension, arthralgia, hypokalemia, and agranulocytosis, have been reported, l-3 Only recently, however, has the potential been recognized for these drugs to cause severe life-threatening angioedema as a result of airway compromise. 4-m Angioedema has been related to all available ACE inhibitors (captopril, enalapril maleate, and ]isinopril), and there is a bold~type warning in the Physician's Desk Reference emphasizing this side effect. However, many physicians either are still unaware of the association or do not recognize the potential for a fatal outcome. A recent review of ACE inhibitor reactions classified angioedema as "usually mild" and stated that it "clears with discontinuation of the drug. 'q3 There are a number of unusual, characteristic clinical aspects of the angioedema associated with ACE inhibitors, and these vagaries may account for this lack of awareness. We report the cases of two patients with severe life-threatening angioedema associated with enalapril and captopril. The literature is also reviewed to further characterize and emphasize the specific clinical features of this important side effect. Based on our experience and these reports, we offer recommendations for treatment.
20:5 May 1991
Annals of Emergency Medicine
555/119
ANGIOEDEMA Roberts & Wuerz
FIGURE 1A&B. M a s s i v e t o n g u e swelling and drooling in patient 1. FIGURE 2. Successful airway secured with blind nasotracheal intubation in patient 1. Note rapid progression of soft-tissue swelling of the neck, which was not present on initial presentation.
CASE REPORTS Case 1 A 60-year-old woman presented to the emergency department with the sudden o n s e t of swelling of the tongue, inability to speak clearly, and i n a b i l i t y to s w a l l o w her saliva. T h r o u g h a relative, it was determined that the patient had been prescribed enalapril (10 mg twice daily) for approximately two years for the treatment of essential hypertension. She had experienced two previous episodes of minor tongue and lip swelling that had not been attributed to the medication. Because she had continued to take the medication and the symptoms had abated spontaneously, it was assumed that the prior episodes were the result of an undetermined food allergy. When the patient arose on the morning of presentation, she rapidly developed in, creasing tongue and neck swelling that progressed into the inability to swallow saliva and mild dyspnea. The patient's medical history was remarkable for adult-onset diabetes mellitus not requiring medical therapy and moderate hypertension that was well controlled with the ACE inhibitor. She had no known allergies to drugs, asthma, hay fever, or eczema. She had taken the same dosage of enalapril on a daily basis for two years, and the last dose had been 12 hours before admission. On e x a m i n a t i o n , t h e p a t i e n t ' s blood pressure was 180/95 m m Hg; pulse, 110; respirations, 28; and tympanic membrane temperature, 37.2 C. She could speak only in a muffled unintelligible voice and was drooling saliva continuously. She appeared in m o d e r a t e respiratory distress and kept pointing to her tongue and neck. The skin was warm, and she exhibited mild diaphoresis without cyanosis. There was no obvious stridor, although she did have noisy respirations because of the pooling of secretions in the throat. The tongue was markedly swollen and protruded. 120/556
Minimal submental edema was also noted (Figure 1). Treatment included 0.3 mg epinephrine subcutaneously every 20 minutes for three doses, 300 mg cime t i d i n e IV, 250 m g m e t h y l p r e d nisolone IV, and 50 mg diphenhydramine IV for two doses. There was no response to this antiallergic treatment, and the soft-tissue swelling of the neck gradually increased. Because of the patient's inability to control her secretions and increasing respiratory difficulty, attempts were made to pass a nasotracheal tube over a fiberoptic bronchoscope. Fiberoptic intubation was unsuccessful because of inability to visualize the important landmarks. After shrinkage of the nasal mucosa with Neosynephrine ® nasal spray, a lubricated nasal trumpet airway was carefully inserted in an attempt to atraumatically dilate the n a s a l p a s s a g e b e f o r e b l i n d nasotracheal intubation. Preparations also were made for emergency cricothyrotomy, but fortunately the first attempt at blind nasotracheal intubation was successful (Figure 2). The patient was placed on humidified oxygen and admitted to the ICU. She was treated with dexamethasone; during the next two to three days, the swelling gradually decreased. Extubation was possible on the third hospital day with only minimal tongue swelling persisting. She was discharged five days later in a completely asymptomatic state and cautioned not to use ACE inhibitors. No further follow-up was available. Case 2 A 49-year-old man presented to the ED w i t h increasing facial and lip e d e m a during the p r e v i o u s eight hours. He had been prescribed proAnnals of Emergency Medicine
pranolol, hydrochlorothiazide, and 50 mg captopril twice daily for hypertension. None of the medications or dosages had been changed recently, and he had been taking captopril for more than one year. He had no history of angioedema, asthma, other allergies, or unusual exposures to unusual food or new medications. He had no history of previous angioedema. The presenting vital signs were blood pressure of 190/120 m m Hg; pulse, 84; and respirations, 28. Examination revealed gross edema of the lips and face. Tongue swelling was not initially present, but it rapidly developed within one hour. While in the ED, the patient began to experience hoarseness and increasing shortness of breath. He was given IV 50 mg diphenhydramine twice and 250 mg methylprednisolone without improvement. After shrinkage of the nasal mucosa, blind nasotracheal intubation was performed successfully on the first attempt. The patient was treated with IV corticosteroids, improved over the next 18 hours, and was extubated and 20:5 May 1991
ANGIOEDEMA Roberts & Wuerz
TABLE. Review of literature relating angioederna to the use of ACE inhibitors ACE Inhibitor* Treatmenl
Reference/Year
Patients/Clinical Symptoms
Jett14/1984 Suarez et alS/1989
First report of angioedema 55-year-old man/facial edema; 49-year-old woman/facial edema and agraoulocytesis 19 cases of angioedema;one case of urticaria in addition to angioedema Postmarketing survey: 38 cases reviewed; 138 additional cases identified 6 cases 1984 - 1986
Wood and Manns/1987 Slater et al3/1988 Barna et aW1989
Cameron and Higginsl/1989 15 cases Giannoccaro et alW1989 Smith and MorganW1989 Werber and PincusW1989
Chin and Buchan9/1990 Orfan et a116/1990
65-year-old man/facial edema, progressing to airway obstruction 63-year-old man/buccal and lip edema 57-year-old woman/tongue swelling; 52-year-old woman/intraoratand submandibular edema 67-year-old woman/progressedto airway obstruction Four cases of angioedema in patients with previous idiopathic angioedema
C C C
Outcome
Antihistaminesand hydrocortisone Diphenhydramineand steroids NA
Resolvedwith medical therapy Recovered Died of sepsis
E,C
NA
NA
E,C
NA
C,E
NA
Four deaths, three intubations, and one tracheostomy ? Not reported; one patient required tracheostomy No deaths Died: surgical airway obtained when unable to intubate Recovered Recovered without the need for airway control
L E
NA Diphenhydramineand steroids
E E
NA Steroids Antihistamines
E
Epinephrine, diphenhydramine, and Recovered; required nasotracheal steroids intubation Antihistamines,corticosteroids, and epi- All recovered with medical therapy nephrine
E,L
*E, enalaprfl; C, captopril; L, lisinopril
discharged after an ears, nose, and throat evaluation demonstrated no sequelae. The final diagnosis was captopril-induced angioedema. DISCUSSION The overall incidence of angioedema associated with use of ACE inhibitors has been estimated to be 0.1% to 0.2%. .3 This side effect was first reported by Jett in 1984; 14 since then, at least 89 additional cases have been reported (Table). Slater et al reported but did not characterize an additional 138 cases, a These authors characterized angioedema as "life threatening" in 22% of cases in which the details were available. The etiology of angioedema is unclear. It is probably not an immunologic mechanism but rather a biochemical phenomenon mediated through the kallikrein-kinin system. ACE inhibitors have been demonstrated to decrease the metabolism of bradykinin, a potent vasodilator that also increases vascular permeability. ~5 There also may be other unknown genetic or environmental factors that c o n t r i b u t e to this idiosyncratic response. ACE inhibitor antibodies have not been demonstrated, and it is unlikely that the reaction is IgE mediated. Urticaria without angioedema has 20:5 May 1991
been attributed to ACE inhibitors. ACE inhibitor-induced angioedema is different from hereditary angioedema because normal C-1 esterase inhibitor activity has been documented in patients affected with this complication. 9 Although no specific clinical profile or predisposing factors have been identified, individuals with a history of idiopathic angioedema or urticaria may be at increased risk and probably should not be treated with ACE i n h i b i t o r s . 16 P a t i e n t s w i t h angioedema do not appear to have higher incidence rates of food or drug allergy, asthma, hay fever, or eczema. ACE inhibitor-induced angioedema has a peculiar predilection for the head and neck region, particularly the tongue and lips. Edema of the periorbital, buccal, laryngeal, gener~ alized facial, neck, and subglottic areas has been described; the limbs are usually spared. Large doses of ACE inhibitors may be more likely to precipitate angioedema, but there is no clear evidence of a dose-response relationship, and angioedema often occurs with standard dosing regimens. About two thirds of the reactions occur within hours of initiation of treatment or during the first week of maintenance therapy. 3 Curiously, however, angioedema may occur at any time during the use of Annals of Emergency Medicine
ACE inhibitors. Serious l i f e - t h r e a t e n i n g consequences may develop precipitously even if the patient has tolerated the drug for many years. 9 Numerous authors also have e m p h a s i z e d that minor angioedema may occur during drug use yet s p o n t a n e o u s l y abate without therapy while the unaware patient continues to take the medication. Such a scenario would probably confuse the issue of etiology of the angioedema and easily cause the patient or physician to attribute the side effect to another cause, such as food allergy, insect stings, or other drug reactions. It is particularly important to note that because angioedema often affects the tongue, it may be impossible for the patient to verbalize symptoms or give a medical history. In addition, massive glossal edema can prohibit or hamper successful orotracheal or nasotracheal intubation that may be required for airway control. Both the precipitation and prog r e s s i o n of a n g i o e d e m a are unpredictable. Although many cases resolve s p o n t a n e o u s l y or are easily reversed with standard antiallergic drug therapy, progression may be rapid enough and the drug may be resistant enough to cause fatal airway compromise. 557/121
ANGIOEDEMA Roberts & Wuerz
In our first patient, the angioedema was totally resistant to very aggressive medical therapy that would have been expected to be effective against allergic or anaphylactoid reactions. In a report of a fatal case, Giannoccaro et al emphasized that angioedema may initially respond to drug therapy, yet rebound to an even more serious degree, m The management of ACE inhibitor-induced angioedema may be as simple as stopping the medication, but the gamut of medical intervention ranges from drug therapy to intubation or a surgical procedure to secure an airway, lz Once far advanced, angioedema is unlikely to be r e s p o n s i v e to e p i n e p h r i n e , antihistamines, or corticosteroids. The use of inhaled racemic epinephrine has not been reported, but it may be helpful. Significant soft-tissue edema can make oral intubation impossible or render nasotracheal i n t u b a t i o n problematic or even dangerous if bleeding or vomiting is precipitated before the airway is protected. If the soft tissues of neck are involved, cricothyrotomy may also be technically m o r e d i f f i c u l t . F i b e r o p t i c bronchoscopic nasal intubation or retrograde intubation over a guide wire p a s s e d t h r o u g h the c r i c o t h y r o i d membrane may be options for airway control if the physician is skilled in these procedures. The fatal potential of ACE inhibitor-induced angioedema necessitates a careful drug history in all patients with this symptom. ACE inhibitors should be considered the cause of angioedema whenever it occurs in patients taking these drugs. The fact that symptoms have occurred after years of uneventful ACE inhibitor
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use should not dissuade the physician from associating these drugs with the reaction. We agree w i t h C h i n and B u c h a n t h a t p a t i e n t s should never receive any ACE inhibitor after even a mild or easily reversed episode of angioedema. 9 Medical t h e r a p y of progressive angioedema should be aggressive; failing a rapid response, mechanical methods to secure an airway should be undertaken before massive edema complicates oral or nasal intubation or surgical procedures. Patients who r e s p o n d to i n i t i a l drug t h e r a p y should be observed carefully for a possible rebound phenomenon. We emphasize the need for early intubation or cricothyrotomy or tracheostomy if signs of impending airway obstruction are present, and we caution against relying on medication to totally reverse the pathology.
REFERENCES
SUMMARY
10. Giannoccaro PJ, Wallace GJ, Higginson LAJ, et al: Fatal angioedema associated with enalapril. Can J CardioI 1989;5:335-336.
We describe the cases of two patients who had tolerated ACE inhibitots for many months without ill effects until they suddenly developed life-threatening angioedema of the upper airway, necessitating tracheal i n t u b a t i o n . N e i t h e r p a t i e n t responded to standard drug therapy that usually reverses allergic reactions. The potential for patients taking ACE inhibitors to develop serious angioedema is stressed. Physicians are urged to withhold this class of drugs from all patients who develop even mild angioedema during therapy and to consider this drug reaction in all patients with angioedema. Once angioedema develops, patients should be monitored aggressively and treated, as this is a potentially fatal complication.
Annals of Emergency Medicine
1. Cameron HA, Higgins TJC: Clinical experience with lisinoprii: Observations on safety and tolerability. J Hzlm Hypertens 1989;3:177-186. 2. Weber MA: Safety issues during antihypertensive treatment with angiotensin converting enzyme inhibitots. A m J Med 1988;84:16-23. 3. Slater EE, Merrill DD, Guess HA, et al: Clinical profile of angioedema associated with angiotensin converting enzyme inhibition. JAMA 1988;260:967-970. 4. Barna JS, Prable MAS, Abedi E: Report of angioedema secondary to hypertension medications. Va Med 1989; 116:147. 5. Wood SM, Mann RD: Angioedema and urticaria associated with angiotensin converting enzyme inhibitors. Br Med J 1987;294:91-92. 6. Self F, Bates GJ, Drake-Lee A: Severe angioneurotic edema causing acute airway obstruction. J R Soc Med 1988;81:544~545. 7. Singer DRJ, MacGregor GA: Angioneurotic edema associated with two angiotensin converting enzyme inhibitors. Br Med J 1986;293:1243. 8. Suarez M, Wan Lye Ho P, Johnson ES: Angioneurotic edema, agranulocytosis, and fatal septicemia following captopril therapy. A m J Med 1989;81:336-338. 9. Chin HL, Buchan DA: Severe angioedema after long term use of an angiotensin-converting enzyme inhibitor. Ann Intern Med 1990;112:312-313.
11. Smith ME, Morgan MT: Angioedema of the head and neck and angiotensin-converting enzyme inhibitots. Otolaryngof Head Neck Surg 1989;101:93-95. 12. Werber JL, Pincus RL: Oropharyngeal angioedema associated with the use of angiotensin-converting enzyme inhibitors. OtolaryngoI Head Neck Stzrg 1989; 101:96-98. 13. O'Hollaren MT, Porter GA: Angiotensin converting enzyme inhibitors and the allergist. A n n AHergy 1990;64:503. 14. Jett KG: Captopril-induced angioedema (letter). Ann Emerg Med 1984;13:489-490. 15. Anderson MW, DeShazo RD: Studies of the mechanism of ACE inhibitor-associated angioedema: The effect of an ACE inhibitor on Cutaneo vs responses to bradykinin, codeine, and histamine. J Aller Clfn Immunol 1990;85:856. 16. Orfan N, Patterson R, Dykewicz MS: Severe anglo ~ edema related to ACE inhibitors in patients with a history of idiopathic angioedema. JAMA 1990;264:1287. 17. Long TM: Atraumatie nasopharyngeaI intubation for upper airway obstruction. Anesthesia 1988;43: 510-511.
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