Benazepril

Study objective: To evaluate the incidence of airway compromise, clinical presentation and morbidity of angiotensin-converting enzyme inhibitor (ACEI)-related angioedema (AE).

Method: A retrospective chart review was conducted of all patients admitted to our hospital between 1996 and 2001 with the diagnosis of AE.

Results: A total of 70 charts on which a diagnosis of AE had been entered were reviewed. Of those, 45 patients (64%) had AE that was thought to be related to ACEI therapy. Of those 45 patients, 29 were women. The mean age was 62 years, and 41 (91%) were African-American. The duration of ACEI therapy before presentation varied from 1 day to 5 years postingestion. Twenty-one of 32 patients presented within 2 months of the initiation of therapy. The mean duration between the onset of symptoms and presentation to the hospital was 9 h. Lip and tongue swelling was seen in all patients. Pulmonary manifestations were noted in 17 of 45 patients (38%) [dyspnea 17 of 17 patients; stridor/respiratory failure, 5 of 17 patients; cough, 2 of 17 patients]. Dysphagia was noted in 9 of 45 patients, drooling of saliva in 8 of 45 patients, and pruritus in 6 of 45 patients. Ten of 45 patients had a history of AE. In five of those patients (50%), ACEI use was a presumed cause of the AE for the current hospital admission. Eighteen of 45 (40%) patients required ICU admission. The mean ICU length of stay was 2.2 days. Five of 45 patients required endotracheal intubation. The mean time spent receiving ventilation was 2.2 days. Discontinuation of the initiating agent and supportive care were the keys to therapy. All of our patients responded to supportive management, and there was no mortality.

Conclusion: Sixty-four percent of patients in this series had AE due to receiving an ACEI. The majority of the patients were African-American women. Most patients presented within 2 months of starting to receive the drug, although longer durations of therapy were not uncommon. Lip and tongue swelling was the most common airway manifestation. Based on our observations, the discontinuation of ACEI therapy and supportive management are the recommended approaches to therapy to prevent an untoward outcome.

Key words: airway obstruction; angioedema; angiotensin-converting enzyme inhibitors

Abbreviations: AA = African-American; ACEI = angiotensin-converting enzyme inhibitor: AE = angioedema; ARB = angiotensin receptor blocker; ED = emergency department; ENT = ear, nose, and throat; HAE = hereditary angioedema

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Angioedema (AE) is asymmetrical, nonpitting edema that occurs in the skin and mucus membranes. It often presents as facial swelling, but can progress to the tongue and supraglottic areas, resulting in airway compromise. Angiotensin-converting enzyme inhibitors (ACEIs) are one of the most common known causes of AE leading to airway compromise. (1,2) The incidence of ACEI-related AE has been reported to be between 0.1% and 0.2%. (3,4) Over the last few years, the use of ACEIs has increased, and it is currently estimated that > 40 million people are receiving therapy with ACEIs, which could lead to an increasing number of AE eases. (5) We evaluated the prevalence of airway compromise, clinical presentation, and morbidity of patients with ACEI-related AE at our institution over a 5-year period.

MATERIALS AND METHODS

Albert Einstein Medical Center is a 600-bed, tertiary care, institution with a large cardiology program (ie, cardiac catheterization program, heart surgical unit, and coronary care unit) that is affiliated with Thomas Jefferson University. It is located in urban Philadelphia and serves a predominantly African-American (AA) population.

A retrospective chart review was conducted on all patients who had been admitted to our hospital with a diagnosis code for AE from July 1996 to June 2001. We examined each chart to determine whether an ACEI could be the causative agent. All patients who developed AE while receiving ACEIs were presumed to have the diagnosis of ACEI-related AE. Patients with other explanations for AE (eg, new medications, infection, and food allergies) were grouped as having non-ACEI-related AE.

Demographic data, time of onset of symptoms to presentation, and any prior events were recorded. Particular attention was given to presenting signs, symptoms, and initial management in the emergency department (ED). The hospital course was reviewed for any morbidity and mortality.

RESULTS

A total of 125,843 patients was admitted to our hospital from July 1995 to June 2001. Seventy charts had the diagnosis code of AE, and these charts were reviewed for this study. Twenty-three cases were attributed to food allergy, antibiotics, and infection, and in 2 eases there was no obvious predisposing factor. Forty-five cases (64%) were thought to be related to ACEI therapy. Of those 45 patients, 29 (67%) were women. The mean age was 62 years, and 41 patients were AA (91%). On average, 64% of all inpatient admissions to our institution are for AAs. The duration of ACEI therapy prior to presentation varied from 1 day to 5 years postingestion. Twenty-one of 45 patients (47%) presented within 2 months of the initiation of therapy, while 11 patients (24%) received the drug for 6 months to 5 years. The duration of therapy was unclear in 13 cases (29%). The mean duration from the onset of symptoms and presentation to the hospital was 9 h (range, 1 to 48 h). Three patients (6.8%) presented > 24 h after the onset of symptoms.

Lip and tongue swelling were observed in all patients. Pulmonary manifestations were noted in 17 of 45 patients (38%) (dyspnea, 17 of 17 patients [100%]; stridor/respiratory failure, 5 of 17 patients [29%]; cough, 2 of 17 patients [12%]). Dysphagia was noted in 9 of 45 patients (20%), drooling of saliva in 8 of 45 patients (18%), and pruritus in 6 of 45 patients (13%). Twenty-two percent of patients (10 of 45 patients) had a history of AE. In 50% of these patients, ACEI use had been the presumed cause of the AE.

Fifteen of 45 patients received epinephrine in the ED, and in 3 patients a second dose was required. All patients received H1 blockers, methylprednisolone, and IV fluids in the ED, and 38 of 45 patients also received H2 blockers. All patients were monitored for respiratory, distress, BP, and oxygen saturation. Fifteen of 45 patients had the upper airway examined by an ear, nose, and throat (ENT) specialist in the ED. Eighteen of 45 patients (40%) required ICU admission, while the others were admitted to general medical floors. Five of 45 patients (11%) required endotracheal intubation, which constituted 28% of those admitted to the ICU. One of five intubated patients (20%) had a history of ACEI-related AE. The mean duration of ACEI use in patients requiring intubation was 12 days (range, 1 to 30 days). All of these patients presented with tongue swelling, shortness of breath, and stridor. Intubation was required for respiratory distress and airway compromise. Two patients were intubated orally, two were intubated nasally, and one required urgent cricothyrotomy. There were no significant complications other than oozing from the cricothyrotomy site in one patient. The mean time spent receiving ventilation was 2.2 days, and the mean ICU length of stay was 2.2 days (range, 1 to 7 days). The mean hospital LOS was 2.4 days (range, 1 to 8 days) [patients admitted to the ICU, 3 days (range, 1 to 8 days); patients admitted to general medical floors, 2 days (range, 1 to 5 days)].

One patient who required a cricothyrotomy had excessive bleeding from the cricothyrotomy site. None of the patients required reintubation. All of our patients responded to supportive management, and there was no mortality.

In our study, there was no statistically significant difference in the likelihood of one particular ACEI causing AE. Eleven of 45 cases were related to lisinopril use. Quinapril and enalapril were each associated with nine cases. Fosinopril was responsible for five cases, captopril for four cases, and benazepril for three cases. In four patients, the precise ACEI could not be determined. We noticed an increase in the number of cases of AE during the period of our study. It increased from 5 cases between 1995 and 1996 to 30 eases between 2000 and 2001. Figure 1 demonstrates that the rising numbers of AE cases, from July 1997 to June 2001 at our institution, were caused by a marked increase in ACEI-related AE.

[FIGURE 1 OMITTED]

DISCUSSION

ACEIs are routinely recommended for the treatment of hypertension, especially in the presence of left ventricular dysfunction and congestive heart failure. (6-10) ACEIs are also indicated for the treatment of proteinuria and diabetic nephropathy. (11,12) Thus, ACEIs are being used more frequently, in various patient populations, which may lead to more reported side effects, particularly AE.

AE is seen in 0.1 to 0.2% of patients receiving ACEIs. AE can vary from a mild swelling of the face to swelling of the tongue and supraglottic area leading to respiratory compromise. The use of an ACEI was the most common factor associated with AE in our study population. Other causes are secondary to allergic responses to exogenous substances such as foods (eg, shellfish and nuts), insect bites, and medications (eg, antibiotics, narcotics, nonsteroidal anti-inflammatory drugs, and angiotensin receptor blockers [ARBs]).

Even though the etiology of ACEI-related AE is not completely understood, the accumulation of bradykinin is thought to be one explanation. Bradykinin causes vasodilatation and capillary leakage leading to AE. (13,14) Figure 2 shows the mechanism of ACEI-related AE. It is not clear why only a few individuals develop AE. Possibly, there is a genetic deficiency of other bradykinin-metabolizing enzymes like carboxypeptidase-N and aminopeptidase-P. (15,16) These enzymes degrade bradykinin but are not affected by ACEIs. This may predispose these individuals to AE in the presence of ACEI, while patients with normal levels of carboxypeptidase-N and aminopeptidase-P do not get AE.

[FIGURE 2 OMITTED]

In cases other than ACEI-related AE (ie, food-related cases), mast cell-mediated release of vasoactive mediators plays an important role. Urticaria and generalized pruritus is present in 90% of these cases. Urticaria, which is seen in some cases of ACEI-related AE, appears to be secondary to a true allergic reaction. (17)

The most common presenting symptom is lip and tongue swelling. These were seen in all of our patients presenting with AE. Urticaria and generalized pruritus are typically absent in ACEI-related cases. Other symptoms are dyspnea, cough, stridor, drooling of saliva, dysphagia, and abdominal pain. All of these symptoms are secondary to AE of respective organ systems.

The duration of ACEI use prior to the onset of AE may vary from months to years but is more commonly seen in patients who have recently begun to receive the drug. However, some patients with a history of ACEI-related AE, when therapy with an ACEI is restarted, may go weeks to months before they present with AE. There is no clear explanation for this, but it probably indicates that ACEI-related AE is not secondary to sensitization to the drug, perhaps due to low levels of bradykinin-metabolizing enzymes, which could be due to genetic or acquired factors.

There are no clear predisposing risk factors. In some studies, as well as in our own, there appears to be an increased risk of ACEI-related AE in patients of African origin. (18) Twenty-two percent of our patients had a history of AE. Thus, a history of AE could be a risk factor. ACEIs should not be used for treatment in patients with a history, of ACEI-related AE. Even ARBs are not safe in patients with a history of ACEI-related AE. (19-21)

As the exact mechanism of ACEI-related AE is not completely understood and initiating factors may not be known at the time of presentation, the management of AE should be prompt and aggressive. Discontinuation of the initiating agent and supportive care are the keys to therapy. Careful management of the airway is crucial as well. On presentation, these patients should be carefully examined for any evidence of respiratory compromise such as stridor, a markedly enlarged tongue, symptoms of dyspnea, acutely presenting dysphagia, and drooling of saliva. The decision of when to intubate should be made early based on standard physiologic criteria, recognizing that intubation may be difficult secondary to edema of the airway. Cricothyrotomy or emergency trachcostomy is required for maintenance of the airway if oropharyngeal and nasopharyngeal intubation fails. A careful ENT examination is recommended in all cases.

Fluid resuscitation and therapy with vasopressors may be required if the patient is hemodynamically unstable. Hypotension can be seen in severe cases secondary to the extravasation of large amounts of fluid into the extravascular space.

Patients presenting with respiratory symptoms should immediately receive 0.5 mL epinephrine (1:1000) subcutaneously. (22) The dose can be repeated in 15 to 20 min. Therapy with antihistamines and steroids should be started initially in all patients, as a true allergic reaction cannot be excluded. Although the role of epinephrine, antihistamines, and corticosteroids is controversial in non-mast cell-mediated AE (ie, ACEI-related AE and hereditary AE [HAE]), (17,23) these therapies can be safely used until the etiologic agent is identified and discontinued. Supportive management should continue until upper airway swelling has resolved. Intubated patients should have their airways examined by an ENT specialist prior to extubation. Once AE has resolved, patients can be safely discharged to home. We did not find any evidence to support continuing therapy with steroids or histamine blockers after hospital discharge. If there is high clinical suspicion for HAE or if the patient is not responding to supportive therapy, a workup for the diagnosis of HAE should be performed.

Patients who developed AE while taking an ACEI should be advised not to reinitiate their use. Physicians taking care of these patients should provide them with a written statement indicating that they had ACEI-related AE and that they should never be given an ACEI or ARB.

CONCLUSION

ACEIs play very important roles in the management of hypertension, congestive heart failure, and diabetes mellitus. With the increasing use of ACEIs, AE may become more frequent, so physicians should be wary of this when taking a history. Even though most cases present soon after the initiation of ACEI therapy, AE may occur after many years of therapy, occurring after 5 years of therapy in some patients in our study. Patients with any history of AE should avoid the use of ACEIs. The discontinuation of therapy with ACEIs and supportive management are the recommended approaches to therapy to prevent untoward outcomes.

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* From the Division of Pulmonary and Critical Care, Albert Einstein Medical Center, Philadelphia, PA.

This study was presented as a poster presentation tit CHEST 2002.

Manuscript received August 25, 2003; revision accepted March 16, 2004.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chestnet.org).

Correspondence to: Michael Lippmann, MD, FCCP, Head, Division of Pulmonary and Critical Care, Albert Einstein Medical Center, Klein Building, Suite 363, 5401 Old York Rd, Philadelphia, PA 19141; e-mail: lippmanm@einstein.edu

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