Bruce C. Nisbet, MD, MEd, and Robert E. O'Conner, MD, MPH, Christiana Care Health System, Newark, Del
Bruce C. Nisbet, MD, MEd
Resident
Robert E. O'Conner, MD, MPH
Director
Emergency Medicine Residency Program
Department of Emergency Medicine
Christiana Care Health System
Newark, Del
Angiotensin-converting-enzyme (ACE) inhibitor?induced angioedema is a well-described and potentially lethal condition that affects between 0.1% and 0.2% of patients who are using ACE inhibitors.1 The majority of cases occur within 2 months of starting ACE inhibition therapy, but angioedema may be seen at any time during the course of treatment.2 The presentation is typically dramatic, with swelling of the lips, tongue, and larynx.
Case Presentation
A 48-year-old man with a history of hypertension, newly diagnosed heart failure, hypercholesterolemia, and bipolar disorder was rushed to the hospital by ambulance. His chief complaint was shortness of breath, which had started the previous day and had become progressively worse. He also complained of chest "heaviness," sweating, anxiety, light-headedness, and "tight and swollen" skin. He said that his tongue felt swollen and that he "could not talk right." His wife reported that he had been acting "bizarrely" today. The patient said he felt "cross-eyed." He had been experiencing muscle cramps, for which he had been drinking orange juice and eating bananas. He denied any new skin lesions or itching. He had seen his cardiologist on the previous day for his newly diagnosed heart failure, at which time he was started on furosemide (Lasix) and lisinopril (Zestril). The patient stated that he had been urinating less frequently since yesterday.
He smoked 1 to 2 packs of cigarettes daily and was formerly a heavy alcohol user, but he denied current use of alcohol or illegal drugs. He had been taking his medicines—oral valproic acid (Depakene, Depakote), quetiapine (Seroquel), hydrocodone/acetaminophen, furosemide, and lisinopril—as instructed and denied any other drug ingestion or overdose.
Physical examination revealed an anxious man in mild respiratory distress. His triage vital signs were: temperature, 36.9°C; heart rate, 91 beats/min; respiratory rate, 24 breaths/min; blood pressure (BP), 82/42 mm Hg; oxygen saturation, 89% on room air, which increased to 97% on 5 L/min via nasal cannula. Despite his tachypnea, he was able to speak in complete sentences. His cranial nerves were grossly intact. The lips and tongue appeared normal, without gross swelling. He had no stridor or jugular venous distension. Lungs were clear to auscultation. The rest of the examination was significant only for diffuse nonpitting edema.
Initial management, in addition to oxygenation, included a 1-L bolus of normal saline (after which his BP increased to 95/63 mm Hg), intravenous (IV) dexamethasone 5 mg, and IV diphenhydramine 25 mg.
An electrocardiogram showed a normal sinus rhythm of 92 beats/min, without ST-segment or T-wave abnormalities. Chest radiography demonstrated borderline cardiomegaly, but without infiltrate or cephalization (Figure). Laboratory results included: blood urea nitrogen, 42 mg/dL; creatinine, 3.0 mg/dL (baseline measured 1 month earlier, 1.0 mg/dL); N-terminal pro-brain natriuretic peptide (pro-BNP), 54 pg/mL (normal, 300 pg/mL); creatine kinase, 1594 U/L (normal, 40-250 U/L); creatine kinase?myocardial band fraction was within normal limits; troponin <0.01 ng/mL. Serum valproate level was 41 μg/mL (therapeutic, 50-100 μg/mL).
The patient was admitted to the cardiac step-down unit with a diagnosis of ACE inhibitor?induced angioedema and acute renal failure, based on the recent initiation of lisinopril therapy, the nonpitting edema on his arms and legs, the normal electrocardiography and chest radiography findings, and the cardiac enzyme and pro-BNP levels. Over the next 36 hours, he had an uneventful recovery, with normalization of BP, oxygenation, and renal function. His discharge diagnoses were ACE inhibitor?related angioedema, acute renal failure believed to be secondary to lisinopril-induced hypotension, and alcoholic cardiomyopathy. His discharge medications were atenolol (Tenormin), furosemide, quetiapine, and valproate.
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| Figure—Posteroanterior (left) and lateral (right) chest radiographs demonstrating borderline cardiomegaly, without infiltrate or cephalization. |
Discussion
Angioedema is characterized by the extravasation of fluid into the interstitial tissues. It can be activated either by mast cells or by another mechanism not involving mast cells. Causes of mast-cell?activated angioedema include:
- Immunoglobulin E?mediated allergic reactions (eg, to food, drugs, bee stings)
- Direct mast-cell release (associated with substances such as radiocontrast agents)
- Immune complex?mediated reactions (eg, to a transfusion)
- Abnormal arachidonic-acid metabolism (eg, adverse reaction to aspirin).
Mast-cell?mediated angioedema is almost invariably associated with urticaria and/or pruritus, because the cutaneous mast cell is located in the superficial dermis. Angioedema not mediated by mast cells involves the deeper dermis and subcutaneous tissues and may occur in the absence of urticaria or pruritus. The 2 most common causes of angioedema that is not associated with mast cells are the use of ACE inhibitors and genetics (ie, C1 complement deficiency).
The angiotensin-converting enzyme promotes both the generation of angiotensin II and the degradation of bradykinin (a potent vasodilator). ACE inhibitors are thought to cause angioedema by increasing the levels of bradykinin.
Airway management constitutes the primary concern in the treatment of angioedema; tracheostomy may be required. The response of angioedema to antihistamines, steroids, and epinephrine depends on whether or not it is mast-cell mediated. Angioedema not associated with mast cells (which is typically the case with ACE inhibitor?related angioedema, as noted above) has not been shown conclusively to respond to steroids, antihistamines, or epinephrine, although the use of such agents will not cause harm. Withdrawing the offending ACE inhibitor should result in a resolution of symptoms within 24 to 48 hours.3 The infusion of fresh-frozen plasma has been successful in 2 cases of resistant, life-threatening ACE inhibitor?related angioedema.3,4
Our case illustrates a deviation from the typical presentation of ACE inhibitor?induced angioedema (Table). Although the patient complained of tongue swelling, no swelling was seen during the physical examination. In a case series describing 45 patients with ACE inhibitor?related angioedema, lip and tongue swelling were present in all cases.2
The presence of ACE inhibitor?induced angioedema without upper airway symptomatology as the chief complaint is unusual, although there have been reports of ACE inhibitor?induced angioedema of the stomach and intestine.5,6
Hypotension
The differential diagnosis of hypoxia and hypotension in a patient with known cardiomyopathy should include myocardial infarction, cardiogenic shock, and pulmonary embolism. In our patient, the medication history, including the initiation of lisinopril and furosemide therapy just hours before the onset of symptoms, was crucial to a timely diagnosis and allowed appropriate treatment. The normal electrocardiogram and chest radiograph, and the normal cardiac enzyme and pro-BNP values, confirmed the initial suspicion of ACE inhibitor?related angioedema, despite the absence of lip and tongue swelling. The pro-BNP value of 54 pg/mL fell well below the suggested cutoff of 300 pg/mL, which has been shown to be 99% sensitive for diagnosing acute decompensated heart failure.7
Patients with acute congestive heart failure tend to display pitting edema, deteriorate with aggressive fluid boluses and, unless in cardiogenic shock, have elevated BP—the opposite of what was observed in our patient. In addition, the absence of cardiomegaly or cephalization on our patient's chest radiograph would be unusual in acute congestive heart failure.
Renal failure
Our patient's acute renal failure was thought to be predominantly prerenal, as a result of the significant intravascular volume depletion secondary to the shift of fluid into the interstitium, which was responsible for the generalized nonpitting edema and the subjective complaint of "skin tightness." Nonpitting edema is characteristic of angioedema. Although the combination of diuretics and ACE inhibitors may precipitate an acute hypotensive event or even acute renal failure, it would not be associated with nonpitting edema.
Rather than having forced furosemide-induced diuresis, the patient reported that his urination had decreased considerably since beginning the medication. In fact, he said he had drunk a lot of orange juice and eaten several bananas in an attempt to self-treat his muscle cramps. To our knowledge, rhabdomyolysis is not a recognized complication of ACE inhibitor therapy. The increased creatine kinase level in our patient may have been related to the muscle cramping he was experiencing. It is unlikely that this degree of rhabdomyolysis played any significant role in his renal failure.
Conclusion
Our patient's hypotension, which was initially corrected with normal saline, as well as his renal function, improved dramatically over the next 24 hours. This improvement was most likely secondary to the lisinopril discontinuation. Because his angioedema was non?mast-cell mediated, the diphenhydramine and dexamethasone were probably of little benefit. The introduction of furosemide did not play a role in his condition. After discharge, he continued to take furosemide without any adverse reactions.
A presentation of ACE inhibitor?induced angioedema without upper airway involvement as the chief complaint is not common; it illustrates the importance of taking a detailed history, with particular attention to the medication review, including recent changes in medications and side effects. Adverse drug reactions represent a significant proportion of visits to the emergency department and may go unrecognized if not included in the differential diagnosis by emergency physicians.8
References
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Megerian CA, Arnold JE, Berger M. Angioedema: 5 years? experience, with a review of the disorder?s presentation and treatment. Laryngoscope.1992;102:256-260.
- Sondhi D, Lippmann M, Murali G. Airway compromise due to angiotensin-converting enzyme inhibitor-induced angioedema: clinical experience at a large community teaching hospital. Chest. 2004;126: 400-404.
- Warrier MR, Copilevitz CA, Dykewicz MS, et al. Fresh frozen plasma in the treatment of resistant angiotensin-converting enzyme inhibitor angioedema. Ann Allergy Asthma Immunol. 2004;92:573-575.
- Karim MY, Masood A. Fresh-frozen plasma as a treatment for life-threatening ACE-inhibitor angioedema. J Allergy Clin Immunol. 2002; 109:370-371.
- Schmidt TD, McGrath KM. Angiotensin-converting enzyme inhibitor angioedema of the intestine: a case report and review of the literature. Am J Med Sci. 2002;324:106-108.
- Shahzad G, Korsten MA, Blatt C, et al. Angiotensin-converting enzyme (ACE) inhibitor-associated angioedema of the stomach and small intestine: a case report. Mt Sinai J Med. 2006;73:1123-1125.
- Januzzi JL Jr, Camargo CA, Anwaruddin S, et al. The N-terminal Pro-BNP investigation of dyspnea in the emergency department (PRIDE) study. Am J Cardiol. 2005;95:948-954.
- Hohl CM, Robitaille C, Lord V, et al. Emergency physician recognition of adverse drug-related events in elder patients presenting to an emergency department. Acad Emerg Med. 2005;12:197-205.
