Angiotensin-converting Enzyme Inhibitor Angioedema Research Articles

Acute angioedema in Cape Town emergency centres and a suggested algorithm to simplify and improve management.

Angioedema is the most common acute allergic presentation to emergency centres (EC), with hospitalisation rates increasing in high-income countries. Angioedema can complicate with life-threatening laryngeal obstruction. There are no local data; therefore, we aimed to characterise acute angioedema cases presenting to ECs and develop a simple management algorithm. To characterise the clinical presentation, management and outcomes of acute angioedema cases presenting to ECs. Based on these findings, we developed a management algorithm for acute angioedema to improve the care of acute angioedema in South Africa (SA). We conducted a retrospective folder review of all patients admitted to Groote Schuur Hospital (tertiary) and Mitchells Plain District Hospital (secondary) ECs from 1 June 2018 to 31 June 2020. Using ICD-10 coding, folders of adults ≥18 years with possible angioedema presenting to the ECs were screened. An allergist extracted demographics, medical history, management and outcome data for each angioedema event. A total of 142acute angioedema episodes were included, with a median (interquartile range) age of 42 (28- 58) years, and 62% of patients were female. The majority (124/142, 87%) of acute angioedema EC presentations involved swelling above the shoulders, with airway involvement in 20(14%) patients, with two patients requiring intubation. Nineteen (13%) patients required admission, with five (26%) admitted to high care/intensive care. Drug-induced angioedema was the most common cause, with 64/142 (45%) linked to a known offending drug, 42/64 (65.6%) being angiotensin-converting enzyme inhibitor (ACE-I). Critical information to guide angioedema management, including past personal/family allergy history, and duration of angioedema prior to EC visit, was not recorded in 64.7% and 37.8% of EC records, respectively. Unnecessary treatment with corticosteroids or antihistamines occurred in 19/53 (36%) and 16/53 (30%) cases with bradykinin-mediated angioedema ACE-I angioedema and hereditary angioedema). Overall, only 36/142 (25%) of angioedema patients were connected to allergy care. Angioedema is the most common allergy presentation to two ECs in Cape Town, SA. Bradykinin-mediated angioedema secondary to ACE-I therapy is the single most common offender, and was not appropriately managed in more than a third of cases. Based on these findings, we have developed a management algorithm that easily stratifies patients into bradykinin or mast cell-mediated angioedema with a step-by-step management approach that is applicable to the SA context. Ongoing awareness and education on allergy emergencies are required to ensure accurate diagnosis of less common causes of angioedema (particularly bradykinin-mediated angioedema) and linkage to allergy specialist care.

Hospitalizations due to Angioedema without Urticaria in a Portuguese Center: Five Year Retrospective Study.

Hospitalizations due to angioedema are important especially in debilitating or life-threatening situations. The aim of thisstudy was to evaluate the frequency and etiology of angioedema without urticaria in hospital admissions. The admissions between 2009 and 2013 in Centro Hospitalar Lisboa Norte with a diagnosis grouped under theICD9 codes of angioedema were retrospectively analysed. The episodes of angioedema with urticaria were excluded. The admissionswere categorized into 2 groups: A - hospitalizations motivated by the angioedema; B - hospitalizations in which the angioedema wasan incidental finding. There were 169 hospitalizations (52% females, 96% adults, mean age 52 ± 20.8 years), distributed by 23 hospital departments,51% in the Immunoallergology department. The mean annual angioedema admission rate was 72/100 000. In 68% of the cases,angioedema was the cause for the admission; in 32% an incidental finding. In 38% there was upper airway involvement. The etiologieswere: hereditary angioedema in 24%, angiotensin converting enzyme inhibitor induced angioedema in 31%, idiopathic angioedema in21%, thrombolysis induced angioedema in 13%, nonsteroidal anti-inflammatory drug-induced angioedema in 5%. The main etiology was angiotensin converting enzyme inhibitor angioedema, followed by hereditary angioedema andthrombolysis induced angioedema, and these findings concur with the international literature. The mean annual angioedema admission rate was 72/100 000 and there was airway involvement in 38% of hospitalizations.

Air Pollution and Angioedema.

To identify environmental factors that may precipitate angioedema. Case series with chart review. An urban tertiary care medical center. After institutional review board approval was obtained, a chart review of all patients who presented to Temple University Hospital with angioedema from January 2012 to December 2014 was performed. Patient demographics and hospital course were gathered. Environmental data on the dates of presentation, including precipitation, humidity, and air pollution, were obtained from regional Environmental Protection Agency online data banks and used for statistical analysis. In total, 408 patients, representing 450 episodes of angioedema, met the inclusion criteria for the study. Most patients were female (58%), African American (74%), and on an angiotensin-converting enzyme inhibitor (ACE-I) upon presentation (61%). Days with unhealthy levels of air pollution were associated with an increased likelihood of angioedema presentation (odds ratio [OR], 1.82; confidence interval [CI], 1.01-3.30; P = .046). Subgroup analysis revealed that elevated ground-level ozone was the primary air pollutant significantly associated with angioedema presentations (OR, 4.95; CI 1.92-12.76; P = .0009). Higher ground-level ozone was also associated with ACE-I angioedema presentations (P = .017) but not with non-ACE-I angioedema presentations (P = .86). Air quality was not predictive of angioedema severity or need for intubation. Angioedema is a complex, multifactorial disease resulting in potentially life-threatening complications. This is the first study to demonstrate that higher levels of air pollution, specifically ground-level ozone, are associated with significantly increased rates of angioedema episodes, although not severity.

ACE in the Hole: Angiotensin-Converting Enzyme Inhibitor-Induced Angioedema as a Cause of Recurrent Abdominal Pain

As one of the most prescribed medications in the United States, angiotensin-converting-enzyme inhibitors (ACEI) have a 0.1-0.7% risk of angioedema. Oropharyngeal angioedema is well known and rarer is angioedema of the GI tract, which can present with nonspecific signs of abdominal pain, nausea, or vomiting. We report a case of angioedema of the small bowel in a patient with recurrent abdominal pain and small bowel segmental thickening of the jejunum. A 58-year-old African American woman with a history of hypertension on lisinopril presented with recurrent abdominal pain in the mid-abdomen associated with vomiting and diarrhea. Symptoms would resolve with supportive treatment and she had several admissions for the same complaint over the past year. On exam she was afebrile with normal vitals and a mildly tender but soft abdomen. Laboratory data was remarkable for mild leukocytosis (12.4 WBC/mm3) with normal eosinophils. Infectious workup was negative and she had a normal C-reactive protein level. CT imaging showed segmental thickening of the proximal jejunum with trace ascites. A push enteroscopy was performed that revealed slightly edematous mucosa with erosions. Pathology from the biopsies showed focal areas of eosinophils. Autoimmune antibodies including ANCA, anti-transglutaminase antibodies, and c1-esterase inhibitor testing were negative. Lisinopril was discontinued with resolution of her symptoms and a diagnosis of ACEI small bowel angioedema was made. ACEI small bowel angioedema is a rare side effect of ACEI therapy and can occur at any time during therapy with an ACEI. The diagnosis is made when other more likely causes are ruled out and symptoms resolve on cessation of the drug. Eosinophilic gastritis is an important differential diagnosis but ACEI small bowel angioedema will not present with systemic eosinophilia. Risk factors for ACEI angioedema include female gender, age 40-70, and African American race. C1-esterase inhibitor levels are normal and the jejunum is most commonly affected with associated ascites. The biochemical increase in bradykinin by inhibition of the angiotensin-converting-enzyme is thought to be responsible for the angioedema. Given how common ACEI therapy is prescribed, clinicians should be aware of this potential side effect in a patient taking an ACEI with unexplained recurrent abdominal pain and segmental small bowel wall thickening.2542_A Figure 1. Abdominal CT imaging showing segmental thickening and edema of the jejunum and trace ascites.2542_B Figure 2. Push enteroscopy showing a mildly edematous jejunum.2542_C Figure 3. Jejunal biopsies showing no granulomas and focal areas of eosinophils.

Epidemiology of ACE Inhibitor Angioedema Utilizing a Large Electronic Health Record

Angiotensin-converting enzyme inhibitors (ACEIs) are a common cause of drug-induced angioedema in the United States. Most epidemiologic ACEI angioedema data are from large multicenter clinical trials. The objective of this study was to identify the incidence of and risk factors for ACEI angioedema using a large integrated electronic health record (EHR). We conducted a retrospective cohort study of all ACEI prescriptions in the outpatient setting of a large academic center between January 1, 2000, and September 30, 2008. We determined frequency, timing, and risk factors for ACEI angioedema within 5 years of prescription. All data were derived from EHR sources, with angioedema defined by EHR reactions of angioedema, swelling, edema, or lip, eye, face, tongue, throat or mouth swelling. Among 134,945 patients prescribed an ACEI, 0.7%(n= 888) developed angioedema during the subsequent 5 years. Sex was similar but patients who developed ACEI angioedema were younger (61.5 vs 62.7 years, P= .007). Patients with ACEI angioedema were more likely to have a history of nonsteroidal anti-inflammatory drug allergy compared with patients who did not develop angioedema (7.1% vs 4.2%, P < .001). We identified a 0.07% incidence of ACEI angioedema within 1 month of prescription and a 0.23% incidence during the first year. Incidence of angioedema was relatively constant annually over the subsequent 4 years (0.10%to 0.12%). The incidence of ACEI angioedema within a large EHR is consistent with large clinical trial data. We observed a persistent and relatively constant annual risk; however, angioedema risk factors and underlying genetic and pathophysiological mechanisms require further study.

ACE Inhibitor–Induced Angioedema

Angiotensin-converting enzyme inhibitors (ACEI) are commonly prescribed for blood pressure control and renal protection. ACEI angioedema is a common problem in patients who are taking ACEI, although, in most cases, the disorder is self-limited, and spontaneous episodes of apparently unprovoked angioedema stop with the discontinuation of the medication. In a subset of patients, hospitalization and even intubation are required for airway protection. The diagnosis is made clinically. There are no laboratory studies that establish the diagnosis. However, such investigations help exclude alternative diagnoses as the cause for the patient's presentation. Conventional treatment with regimens used to control allergic angioedema is ineffective in this condition. The mechanism of ACEI-induced angioedema is thought to be related to its effect on the kallikrein-kinin system. Kallikrein is a protease that converts high-molecular-weight kininogens into kinins, primarily bradykinin. Medications recently developed, primarily icatibant and ecallantide, to control hereditary angioedema, a disorder also associated with kallikrein-kinin activation, have been used to treat ACEI angioedema with some success. The efficacy of these agents and their optimal use remains to be established by randomized and placebo controlled trials.

Factors associated with hospitalization of patients with angiotensin-converting enzyme inhibitor‐induced angioedema

Angiotensin-converting enzyme inhibitor (ACE-I)-induced angioedema can be life-threatening without emergent intervention. The putative mediator is believed to be bradykinin, similar to hereditary angioedema, so these patients respond poorly to corticosteroids and antihistamines. This study was designed to determine characteristics and clinical outcomes of patients presenting to an emergency department (ED) with ACE-I angioedema. This was a retrospective chart review of 100 patients presenting to the ED from 2007 to 2008 with an ICD-9 code of 995.1 (angioedema) or 995.2 (drug-induced angioedema). Two hundred fifty-two patients with these ICD-9 codes were identified and placed in random order, and the first 100 meeting inclusion criteria were included. Statistical analysis was primarily descriptive. All 100 patients had an ICD-9 code of 995.1 (angioedema). Patients presented in every month, with spring months (April-June) having the most presentations (32%). The median age was 59 years, 75% were African American, and 66% were admitted to the hospital. Two patients (2%) required endotracheal intubation. Lisinopril was the most commonly prescribed ACE-I (84%). The most common symptom was moderate lip and tongue swelling (89%) followed by mild difficulty breathing (12%). Tongue swelling was significantly associated with admission. Time from symptom onset to ED presentation was not associated with need for admission. Concomitant medications did not differ between admitted and discharged patients. ACE-I angioedema is associated with significant morbidity and health care use because many patients require hospitalization, suggesting an unmet need for novel therapies targeted to treat this condition.

Prompt Reversal of Airway Obstruction Secondary to Angiotensin Converting Enzyme Inhibitor (ACEI) Induced Angioedema by Ecallantide: A Case Report

Fatal airway obstruction from ACEI angioedema has been described but effective therapy has not been established. Intubation is sometimes required for progressive airway compromise. Ecallantide is a kallikrein pathway blocker and may offer benefit in reversing ACEI induced angioedema.

Recurrent Takotsubo cardiomyopathy presenting with different morphologic patterns

ing intestinal angioedema: CT appearance. AJR Am J Roentgenol Dec 1993;161(6): 1215–6. [36] Orr KK, Myers JR. Intermittent visceral edema induced by long-term enalapril administration. Ann Pharmacother May 2004;38(5):825–7. [37] Spahn TW, Grosse-Thie W, Mueller MK. Endoscopic visualization of angiotensinconverting enzyme inhibitor-induced small bowel angioedema as a cause of relapsing abdominal pain using double-balloon enteroscopy. Dig Dis Sci May 2008;53(5):1257–60. [38] Byrne TJ, Douglas DD, Landis ME, Heppell JP. Isolated visceral angioedema: an underdiagnosed complication of ACE inhibitors?Mayo Clin Proc Nov 2000;75(11): 1201–4. [39] Troy DSKM. ACE inhibitor angioedema of the intestine: a case report and review of literature. Am J Med Sci 2002;324(2):106–8. [40] KarimMY, Masood A. Fresh-frozen plasma as a treatment for life-threatening ACEinhibitor angioedema. J Allergy Clin Immunol Feb 2002;109(2):370–1. [41] Warrier MRCC, Dykewicz MS, Slavin RG. Fresh frozen plasma in the treatment of resistant angiotensin converting enzyme inhibitor angioedema. Ann Allergy Asthma Immunol 2004(92):573–5. [42] Bas M, Adams V, Suvorava T, Niehues T, Hoffmann TK, Kojda G. Nonallergic angioedema: role of bradykinin. Allergy Aug 2007;62(8):842–56. [43] Shewan LG, Coats AJ. Ethics in the authorship and publishing of scientific articles. Int J Cardiol 2010;144:1–2.

Angioedema and angiotensin-converting enzyme inhibitors: Are demographics a risk?

The use of angiotensin-converting enzyme inhibitors (ACEI) has become the leading cause of acquired angioedema. Previous studies have suggested that certain patient populations may be at a higher risk for ACEI-induced angioedema. The objective of this study was to evaluate any demographic associations. A retrospective chart review. Angioedema patients from 1999 to 2004 treated at a tertiary care hospital were reviewed. Demographics, inciting factors, and comorbid conditions were examined. One hundred eighty-two patients met inclusion criteria. Sixty-three percent of patients with angioedema had ACEI triggers. Eighty-one percent of all ACEI angioedema occurred in black patients. Of all angioedema patients, 70% (95% confidence interval [CI], 62%-78%) of black patients noted an ACEI as the inciting agent compared with 44% (95% CI, 30%-59%) in other patient groups. Black patients were 3.03 times more likely to have angioedema from an ACEI than all other patient groups (95% CI, 1.54-5.94). This study represents the largest series of patients with angioedema. Although retrospective in nature, the data show that black patients are at a higher risk for ACEI-induced angioedema.

Airway management in angiotensin converting enzyme inhibitor related angioedema

To the Editor: In their review of the anaesthetic implications of angiotensin converting enzyme inhibitors (ACEI) and angioedema,1 Sarkar et al. review a limited variety of airway management techniques. Rai et al. describe five patients with ACEI related angioedema, all requiring emergency airway control.2 Four patients had a tracheostomy, and three of these were performed following awake fibreoptic intubation. Tracheal intubation in these cases may be difficult. In one series, two of 14 cases required emergency cricothyroidotomy following failed endotracheal intubation. The authors produced an airway management algorithm, which suggested fibreoptic intubation with emergency cricothyroidotomy or tracheostomy if trans-oral intubation fails.3 Our own experience of three patients with ACEI angioedema suggests that early pre-emptive cannula cricothyroidotomy is useful in this setting. We use the Ravussin cannula-over-needle technique (VBM, Sulz, Germany). Pre-emptive, precautionary cricothyroidotomy has been shown to be an effective “insurance policy” in a variety of airway pathologies.4 This allows immediate oxygenation and ventilation if the airway becomes further compromised, and provides an effective bridge to definitive management. If the patient can be oxygenated via a cannula cricothyroidotomy, then the airway can be secured by either an awake fibreoptic technique, direct laryngoscopy under general anesthesia, or by tracheostomy depending on the operator’s expertise. Once the airway has been secured, however, there is little to be gained in performing a tracheostomy, as airway edema from ACEI usually resolves within 48 hr.3

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Angiotensin converting enzyme inhibitor-induced angioedema more prevalent in transplant patients.

Angioedema in association with angiotensin converting enzyme inhibitor (ACEI) use is rare, but serious. Which patients are predisposed to the reaction and whether it involves an immune mechanism remain unclear. To determine the frequency of ACEI angioedema in immunosuppressed cardiac and renal transplant patients. This was a retrospective chart review of all adult cardiac (n = 156) and renal (n = 341) transplant patients followed at our hospital (years 1985 to 1995). Of 105 cardiac and 91 renal transplant patients on a combination of immunosuppressive and ACEI therapy, 5 (4.8%) cardiac and 1 (1%) renal patients developed angioedema. This prevalence of ACEI angioedema among cardiac and renal transplant patients is 24 times and 5 times higher, respectively, than that observed in the general population (0.1% to 0.2%). Reactions often appeared after prolonged ACEI use (average 19 months; range 3 days to 6.3 years). African-Americans were significantly more likely to experience ACEI-associated angioedema (P = .034), especially among the cardiac patients where 4 of 5 reactors were African-American. For unclear reasons, ACEI-induced angioedema (often late-onset) is more prevalent among immunosuppressed cardiac and renal transplant patients. Additionally, African-Americans are over-represented among those developing the reaction.

Predisposition to and Late Onset of Upper Airway Obstruction following Angiotensin-Converting Enzyme Inhibitor Therapy

Angioedema of the face and neck is a rare but potentially fatal complication of angiotensin-converting enzyme inhibitor (ACEI) use. We retrospectively reviewed five cases of ACEI angioedema seen at our institution over the past 2 1/2 years. Four of the cases occurred with enalapril and one with lisinopril. Onset of symptoms varied from two days to ten months. Importantly, three of the five patients had been receiving medication three months or longer, suggesting clinicians must consider this complication during long-term administration of these agents. Three of the five patients were markedly obese, had a history of previous face and neck surgery, or had been intubated in the past. Thus, we propose that previous manipulation or trauma of the upper airway, perhaps resulting in airway narrowing, may represent a risk factor for upper airway obstruction secondary to ACEI-induced angioedema.