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Angio-oedema Caused by Angiotensin-converting Enzyme Inhibitor Therapy
Tanabe, Yoshimura, Mishima
Asian J Oral Maxillofac Surg 2005;17(3):183-185. CASE REPORT
Angio-oedema Caused by Angiotensin-converting Enzyme Inhibitor Therapy Shinji Tanabe, Yasuro Yoshimura, Koichi Mishima Department of Oral and Maxillofacial Surgery, Shimane University School of Medicine, Izumo City, Shimane, Japan
Abstract This report is of an 83-year-old woman with a history of hypertension who had recurrent swelling of the tongue, oral floor, and lower lip. Angiotensin-converting enzyme inhibitor therapy was strongly suspected to be the cause of the swelling. Discontinuation of therapy resulted in disappearance of the swelling without recurrence. Key words: Angiotensin-converting enzyme inhibitors, Bradykinin, Edema, Hypertension, Oral manifestations
Introduction Angiotensin-converting enzyme (ACE) inhibitors are antihypertensive agents that are recommended for the following indications: heart failure, post–myocardial infarction, coronary disease, diabetes, chronic renal disease, and recurrent stroke.1 There is substantial evidence to support the effectiveness of ACE inhibitors for organ protection, and they are the most commonly used drugs for this indication after calcium channel blockers. Side effects of ACE inhibitors frequently include coughing (1% to 20%),2-4 but the occurrence of oedema is rare (<1%).2-6 It is possible that dentists and oral surgeons will be the first to recognise angio-oedema associated with ACE inhibitors, as the oral region is a common site of occurrence.
Japan, on 2 April 2002 with a history of swelling of the tongue, oral floor, and lower lip. The initial swelling had disappeared prior to the patient’s consultation at the clinic. At 3:00 pm on 6 May 2002, the swelling reappeared in the tongue, oral floor, lower lip, and submandibular region, and gradually increased. At clinical examination performed at 4:30 pm on the same day, the patient’s tongue was markedly swollen and protruded to the extent that she was unable to close her mouth, and there was severe swelling of the floor of the mouth floor, lip, and submandibular region (Figure 1). No other part of the body was
This report is of a patient with extensive angiooedema of the tongue, lower lip, oral floor, and submandibular region, for which treatment with an ACE inhibitor was the suspected cause.
Case Report An 83-year-old woman with essential hypertension who was taking enalapril 5 mg daily presented to the Department of Oral and Maxillofacial Surgery, Shimane University School of Medicine, Shimane, Correspondence: Shinji Tanabe, Department of Oral and Maxillofacial Surgery, Shimane University School of Medicine, 89-1 Enya-cho, Izumo City, Shimane 693-8501, Japan. Tel: (81 853) 202 301, Fax: (81 853) 202 299; E-mail: [email protected]
© Asian 2005J Asian Oral Maxillofac Association Surg of Oral Vol 17, andNo Maxillofacial 3, 2005 Surgeons.
Figure 1. Prominent swelling of the tongue, lower lip, and right submandibular region.
183
Angiotensin-converting Enzyme Inhibitor–induced Angio-oedema
Oedema
Consultation at hospital Appearance Reappearance of oedema and return to hospital of oedema
Chlorpheniramine 1 ml intravenous bolus Treatment
Hydrocortisone 100 mg intravenous bolus 5 February 2002
16:00
17:00
18:00
19:00
1 2 April 2002
6 7 8 9 10 11 12 13 14 15 May 2002
August 2003
No recurrence
Oedema
Hydrocortisone 100 mg continuous intravenous infusion 15:00
Present
6 May
20:00
21:00
Administration
14 May
Enalapril 5 mg/day Appearance Consultation of oedema at hospital
Amlodipine besylate 5 mg/day
Resolution of oedema
Figure 2. Clinical course of angio-oedema on the day of presentation and treatment.
Figure 3. Clinical course of recurrent angio-oedema from first occurrence to the present.
affected. According to her medical history, she had been taking enalapril since February 2002. Organ damage secondary to hypertension was not evident. She had no history of allergy.
The oedema diminished rapidly and had disappeared 3 hours later (Figure 2).
At examination, the patient was alert, with a blood pressure of 196/108 mm Hg, a regular pulse of 91 beats per minute, and percutaneous oxygen saturation of 97%. Laboratory findings were unremarkable, except for a slight increase in C-reactive protein (0.4 mg/dl). Table 1 shows the laboratory values on the day of admission and after cessation of the ACE inhibitor. A clinical diagnosis of orofacial angio-oedema was made. Hydrocortisone 200 mg was administered immediately, followed by chlorpheniramine 5 mg. Component
6 May 2002
14 May 2002
Normal range
Immunoglobulin G (mg/dl)
1346.0
1313.0
870 -1700
Immunoglobulin A (mg/dl)
416.0
410.0
110 - 410
Immunoglobulin M (mg/dl)
164.0
157.0
35 - 220
Immunoglobulin E (IU/ml)
188.8
179.5
<380
C1-inhibitor (%)
129.0
100.0
80 - 125
C3 (mg/dl)
139.0
133.0
63 - 134
C4 (mg/dl)
26.0
26.0
13 - 36
CH50 (IU/ml)
46.5
36.9
30 - 45
0.4
0.2
C-reactive protein (mg/dl)
<0.2
Table 1. Laboratory values on the day of administration for angiooedema and after cessation of the angiotensin-converting enzyme inhibitor.
184
The ACE inhibitor therapy was strongly suspected to be the cause of the swelling. Administration of the ACE inhibitor was stopped and amlodipine besylate 5 mg/day was administered from 14 May 2002 after consultation with the patient’s physician (Figure 3). There has been no recurrence of the oedema.
Discussion There are 2 different types of reaction that may cause angio-oedema: one is hereditary and is related to deficiency of C1-esterase inhibitor7 and the other results from a drug reaction or allergy.5 The occurrence of angio-oedema induced by ACE inhibitors is an example of the latter type. Heredity and drug allergy were ruled out as causes of the oedema in this patient because the medical and family history revealed no significant allergies or angio-oedema. C1-esterase inhibitor, C3 and C4 were normal. Furthermore, no oedema occurred after discontinuation of the ACE inhibitor, so the ACE inhibitor was strongly suspected to be the cause. Patch and provocative tests with ACE inhibitors may have been useful for differential diagnosis. Angio-oedema induced by ACE inhibitors was first reported by Slater et al in 1988,5 and has been estimated to be less than 1%.2-6 Common sites of ACE Asian J Oral Maxillofac Surg Vol 17, No 3, 2005
Tanabe, Yoshimura, Mishima
Bradykinin
Angiotensinconverting enzyme inhibitor
The augmentation of bradykinin
Stop Stop
Angiotensinconverting enzyme
Vasodilation and increased vascular permeability
Angio-oedema The metabolite of bradykinin
Figure 4. Pathogenesis of angio-oedema caused by angiotensin-converting enzyme inhibitors.2-6
inhibitor–associated angio-oedema include the face, lips, tongue, and oropharyngeal and laryngeal areas.8 Although the majority of cases have been reported to occur within the first 3 weeks of the start of therapy,2,3,5,6,9 angio-oedema occurring after several months of ACE inhibitor treatment have been reported.3,6,9 The patient described here had an initial episode of angio-oedema 2 months after the start ACE inhibitor therapy. The pathogenesis of angio-oedema associated with ACE inhibitors is believed to be related to the augmentation of bradykinin activity, which causes inflammation, vasodilation, and increased vascular permeability. Bradykinin is metabolised to an inactive moiety by 2 proteases, kininase I (carboxypeptidase N) and kininase II (ACE). Development of angiooedema in patients receiving ACE inhibitors may be due to accumulation of tissue bradykinin levels due to the decrease in the degradation of bradykinin (Figure 4).2-6 Whether or not the augmentation of bradykinin activity is the sole mechanism of angio-oedema associated with ACE inhibitors remains unclear. When an ACE inhibitor is suspected to be a cause of angio-oedema, administration of the ACE inhibitor should be immediately terminated.3 It is generally thought that angio-oedemas associated with ACE inhibitors resolves within 72 hours after the ACE
Asian J Oral Maxillofac Surg Vol 17, No 3, 2005
inhibitor is stopped.2,4,5 Intubation and/or tracheostomy may be required to relieve respiratory distress for patients with vocal cord oedema, or to overcome airway obstruction in an acute severe episode.2,3 Administration of antihistamine, glucocorticoid, and epinephrine is effective.3 The incidence of angio-oedema induced by ACE inhibitors is low. However, it is likely that the chance of encountering patients with angio-oedema associated with ACE inhibitors will increase because of the increasing number of patients being treated with ACE inhibitors. In addition, common sites of angio-oedema associated with ACE inhibitors include the oral region.
References 1. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr. The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure. JAMA 2003;289:2560-2571. 2. Oike Y, Ogata Y, Higashi D, Matsumura T, Numata Y. Fatal angioedema associated with enalapril. Intern Med 1993;32:308-310. 3. Shionoiri H, Takasaki I, Hirawa N, Kihara M, Gotoh E, Sasaki T. A case report of angioedema during long-term (66 months) angiotensin converting enzyme inhibition therapy with enalapril. Jpn Circ J 1996;60:166-170. 4. Israili ZH, Hall WD. Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy. Ann Intern Med 1992;117:234-242. 5. Slater EE, Merrill DD, Guess HA, Roylance PJ, Cooper WD, Inman WH. Clinical profile of angioedema associated with angiotensin converting-enzyme inhibition. JAMA 1988;260:967-970. 6. Matsumura M, Haruki K, Kajinami K, Takada T. Angioedema likely related to angiotensin converting enzyme inhibitors. Intern Med 1993;32:424-426. 7. Osler W. Hereditary angioneurotic edema. Am J Med Sci 1888;95:362-367. 8. Wood SM, Mann RD, Rawlins MD. Angio-oedema and urticaria associated with angiotensin coverting enzyme inhibitors. Br Med J 1987;294:91-92. 9. Anderson MW, de Shazo RD. Studies of the mechanism of angiotensin-converting enzyme (ACE) inhibitor associated angioedema: the effect of an ACE inhibitor on cutaneous responses to bradykinin, codeine and histamine. J Allergy Clin Immunol 1990;85:856-858.
185
Asian J Oral Maxillofac Surg 2005;17(3):183-185. CASE REPORT
Angio-oedema Caused by Angiotensin-converting Enzyme Inhibitor Therapy Shinji Tanabe, Yasuro Yoshimura, Koichi Mishima Department of Oral and Maxillofacial Surgery, Shimane University School of Medicine, Izumo City, Shimane, Japan
Abstract This report is of an 83-year-old woman with a history of hypertension who had recurrent swelling of the tongue, oral floor, and lower lip. Angiotensin-converting enzyme inhibitor therapy was strongly suspected to be the cause of the swelling. Discontinuation of therapy resulted in disappearance of the swelling without recurrence. Key words: Angiotensin-converting enzyme inhibitors, Bradykinin, Edema, Hypertension, Oral manifestations
Introduction Angiotensin-converting enzyme (ACE) inhibitors are antihypertensive agents that are recommended for the following indications: heart failure, post–myocardial infarction, coronary disease, diabetes, chronic renal disease, and recurrent stroke.1 There is substantial evidence to support the effectiveness of ACE inhibitors for organ protection, and they are the most commonly used drugs for this indication after calcium channel blockers. Side effects of ACE inhibitors frequently include coughing (1% to 20%),2-4 but the occurrence of oedema is rare (<1%).2-6 It is possible that dentists and oral surgeons will be the first to recognise angio-oedema associated with ACE inhibitors, as the oral region is a common site of occurrence.
Japan, on 2 April 2002 with a history of swelling of the tongue, oral floor, and lower lip. The initial swelling had disappeared prior to the patient’s consultation at the clinic. At 3:00 pm on 6 May 2002, the swelling reappeared in the tongue, oral floor, lower lip, and submandibular region, and gradually increased. At clinical examination performed at 4:30 pm on the same day, the patient’s tongue was markedly swollen and protruded to the extent that she was unable to close her mouth, and there was severe swelling of the floor of the mouth floor, lip, and submandibular region (Figure 1). No other part of the body was
This report is of a patient with extensive angiooedema of the tongue, lower lip, oral floor, and submandibular region, for which treatment with an ACE inhibitor was the suspected cause.
Case Report An 83-year-old woman with essential hypertension who was taking enalapril 5 mg daily presented to the Department of Oral and Maxillofacial Surgery, Shimane University School of Medicine, Shimane, Correspondence: Shinji Tanabe, Department of Oral and Maxillofacial Surgery, Shimane University School of Medicine, 89-1 Enya-cho, Izumo City, Shimane 693-8501, Japan. Tel: (81 853) 202 301, Fax: (81 853) 202 299; E-mail: [email protected]
© Asian 2005J Asian Oral Maxillofac Association Surg of Oral Vol 17, andNo Maxillofacial 3, 2005 Surgeons.
Figure 1. Prominent swelling of the tongue, lower lip, and right submandibular region.
183
Angiotensin-converting Enzyme Inhibitor–induced Angio-oedema
Oedema
Consultation at hospital Appearance Reappearance of oedema and return to hospital of oedema
Chlorpheniramine 1 ml intravenous bolus Treatment
Hydrocortisone 100 mg intravenous bolus 5 February 2002
16:00
17:00
18:00
19:00
1 2 April 2002
6 7 8 9 10 11 12 13 14 15 May 2002
August 2003
No recurrence
Oedema
Hydrocortisone 100 mg continuous intravenous infusion 15:00
Present
6 May
20:00
21:00
Administration
14 May
Enalapril 5 mg/day Appearance Consultation of oedema at hospital
Amlodipine besylate 5 mg/day
Resolution of oedema
Figure 2. Clinical course of angio-oedema on the day of presentation and treatment.
Figure 3. Clinical course of recurrent angio-oedema from first occurrence to the present.
affected. According to her medical history, she had been taking enalapril since February 2002. Organ damage secondary to hypertension was not evident. She had no history of allergy.
The oedema diminished rapidly and had disappeared 3 hours later (Figure 2).
At examination, the patient was alert, with a blood pressure of 196/108 mm Hg, a regular pulse of 91 beats per minute, and percutaneous oxygen saturation of 97%. Laboratory findings were unremarkable, except for a slight increase in C-reactive protein (0.4 mg/dl). Table 1 shows the laboratory values on the day of admission and after cessation of the ACE inhibitor. A clinical diagnosis of orofacial angio-oedema was made. Hydrocortisone 200 mg was administered immediately, followed by chlorpheniramine 5 mg. Component
6 May 2002
14 May 2002
Normal range
Immunoglobulin G (mg/dl)
1346.0
1313.0
870 -1700
Immunoglobulin A (mg/dl)
416.0
410.0
110 - 410
Immunoglobulin M (mg/dl)
164.0
157.0
35 - 220
Immunoglobulin E (IU/ml)
188.8
179.5
<380
C1-inhibitor (%)
129.0
100.0
80 - 125
C3 (mg/dl)
139.0
133.0
63 - 134
C4 (mg/dl)
26.0
26.0
13 - 36
CH50 (IU/ml)
46.5
36.9
30 - 45
0.4
0.2
C-reactive protein (mg/dl)
<0.2
Table 1. Laboratory values on the day of administration for angiooedema and after cessation of the angiotensin-converting enzyme inhibitor.
184
The ACE inhibitor therapy was strongly suspected to be the cause of the swelling. Administration of the ACE inhibitor was stopped and amlodipine besylate 5 mg/day was administered from 14 May 2002 after consultation with the patient’s physician (Figure 3). There has been no recurrence of the oedema.
Discussion There are 2 different types of reaction that may cause angio-oedema: one is hereditary and is related to deficiency of C1-esterase inhibitor7 and the other results from a drug reaction or allergy.5 The occurrence of angio-oedema induced by ACE inhibitors is an example of the latter type. Heredity and drug allergy were ruled out as causes of the oedema in this patient because the medical and family history revealed no significant allergies or angio-oedema. C1-esterase inhibitor, C3 and C4 were normal. Furthermore, no oedema occurred after discontinuation of the ACE inhibitor, so the ACE inhibitor was strongly suspected to be the cause. Patch and provocative tests with ACE inhibitors may have been useful for differential diagnosis. Angio-oedema induced by ACE inhibitors was first reported by Slater et al in 1988,5 and has been estimated to be less than 1%.2-6 Common sites of ACE Asian J Oral Maxillofac Surg Vol 17, No 3, 2005
Tanabe, Yoshimura, Mishima
Bradykinin
Angiotensinconverting enzyme inhibitor
The augmentation of bradykinin
Stop Stop
Angiotensinconverting enzyme
Vasodilation and increased vascular permeability
Angio-oedema The metabolite of bradykinin
Figure 4. Pathogenesis of angio-oedema caused by angiotensin-converting enzyme inhibitors.2-6
inhibitor–associated angio-oedema include the face, lips, tongue, and oropharyngeal and laryngeal areas.8 Although the majority of cases have been reported to occur within the first 3 weeks of the start of therapy,2,3,5,6,9 angio-oedema occurring after several months of ACE inhibitor treatment have been reported.3,6,9 The patient described here had an initial episode of angio-oedema 2 months after the start ACE inhibitor therapy. The pathogenesis of angio-oedema associated with ACE inhibitors is believed to be related to the augmentation of bradykinin activity, which causes inflammation, vasodilation, and increased vascular permeability. Bradykinin is metabolised to an inactive moiety by 2 proteases, kininase I (carboxypeptidase N) and kininase II (ACE). Development of angiooedema in patients receiving ACE inhibitors may be due to accumulation of tissue bradykinin levels due to the decrease in the degradation of bradykinin (Figure 4).2-6 Whether or not the augmentation of bradykinin activity is the sole mechanism of angio-oedema associated with ACE inhibitors remains unclear. When an ACE inhibitor is suspected to be a cause of angio-oedema, administration of the ACE inhibitor should be immediately terminated.3 It is generally thought that angio-oedemas associated with ACE inhibitors resolves within 72 hours after the ACE
Asian J Oral Maxillofac Surg Vol 17, No 3, 2005
inhibitor is stopped.2,4,5 Intubation and/or tracheostomy may be required to relieve respiratory distress for patients with vocal cord oedema, or to overcome airway obstruction in an acute severe episode.2,3 Administration of antihistamine, glucocorticoid, and epinephrine is effective.3 The incidence of angio-oedema induced by ACE inhibitors is low. However, it is likely that the chance of encountering patients with angio-oedema associated with ACE inhibitors will increase because of the increasing number of patients being treated with ACE inhibitors. In addition, common sites of angio-oedema associated with ACE inhibitors include the oral region.
References 1. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr. The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure. JAMA 2003;289:2560-2571. 2. Oike Y, Ogata Y, Higashi D, Matsumura T, Numata Y. Fatal angioedema associated with enalapril. Intern Med 1993;32:308-310. 3. Shionoiri H, Takasaki I, Hirawa N, Kihara M, Gotoh E, Sasaki T. A case report of angioedema during long-term (66 months) angiotensin converting enzyme inhibition therapy with enalapril. Jpn Circ J 1996;60:166-170. 4. Israili ZH, Hall WD. Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy. Ann Intern Med 1992;117:234-242. 5. Slater EE, Merrill DD, Guess HA, Roylance PJ, Cooper WD, Inman WH. Clinical profile of angioedema associated with angiotensin converting-enzyme inhibition. JAMA 1988;260:967-970. 6. Matsumura M, Haruki K, Kajinami K, Takada T. Angioedema likely related to angiotensin converting enzyme inhibitors. Intern Med 1993;32:424-426. 7. Osler W. Hereditary angioneurotic edema. Am J Med Sci 1888;95:362-367. 8. Wood SM, Mann RD, Rawlins MD. Angio-oedema and urticaria associated with angiotensin coverting enzyme inhibitors. Br Med J 1987;294:91-92. 9. Anderson MW, de Shazo RD. Studies of the mechanism of angiotensin-converting enzyme (ACE) inhibitor associated angioedema: the effect of an ACE inhibitor on cutaneous responses to bradykinin, codeine and histamine. J Allergy Clin Immunol 1990;85:856-858.
185