Angioedema Following tPA Administration for Acute Cerebrovascular Accident
The use of thrombolytic medications for the treatment of acute ischemic cerebral infarctions has dynamically altered stroke care. However, there are both major and minor side effects associated with its use—most notably major bleeding, which led to strict inclusion and exclusion criteria governing the administration of this medication class. One less recognized but potentially serious complication is angioedema secondary to tissue plasminogen activator (tPA). Our case emphasizes the importance of early recognition of this clinical syndrome as it relates to airway compromise and potential respiratory failure in patients who are treated with tPA.
Case
A 70-year-old woman with a history of diabetes and hypertension and a remote history of breast cancer, nonhemiplegic migraines, and hypothyroidism presented to the ED with complaints of aphasia and right-sided paralysis, with onset 2 hours prior. Regarding the patient’s medication history, she had been taking lisinopril for hypertension.
Upon assessment, the patient was awake and alert and her vital signs were normal and stable, but she was aphasic, unable to accurately phonate, and was not able to move her right arm or leg against gravity. Her sensation appeared intact, and she had mild facial asymmetry with inability to raise the right corner of her mouth; her tongue had midline protrusion.
An emergent computed tomography (CT) scan of the head demonstrated mild brain atrophy and minimal low attenuation within the cerebral hemispheric white matter—most noticeably within the subcortical region of the left frontal lobe, consistent with small vessel ischemia. There was no evidence of acute intracranial hemorrhage, midline shift, or focal mass effect, and no convincing CT evidence for acute large vessel, cortical-based infarction.
The patient was determined to be an appropriate candidate for tPA, and was consented in the usual fashion. Within 15 minutes of administration of intravenous (IV) tPA, her symptoms improved, the aphasia resolved, and she was able to lift her right arm and leg against gravity and verbally communicate. Approximately 30 minutes following the resolution of her neurological symptoms, however, the patient was noted to have bleeding around a tooth socket, which was controlled with gauze and pressure. She subsequently began to complain of swelling on her right inferior lip without acute airway compromise. Over the next 10 to 15 minutes, she began to develop tongue swelling and feelings of dyspnea without wheezing.
The patient’s airway was reassessed and was classified as a Mallampati class IV. Anesthesia services were consulted for an emergent, awake intubation for airway protection. She was medicated with midazolam IV, as well as atomized lidocaine and lidocaine gargle for local anesthesia. The patient was successfully intubated awake using a flexible fiber optic technique. She was admitted to the medical intensive care unit for further monitoring, where she was treated with IV methylprednisolone, famotidine, and diphenhydramine. She was extubated the following day, had a relatively uncomplicated hospital course, and was discharged on hospital day 5 with improvement in her speech and right-sided weakness.
Discussion
The risk of angioedema associated with tPA administration has been previously described, with an estimated rate of 1.3 to 5.1%.1-3 Studies have shown the risk of developing angioedema is significantly increased in the setting of concomitant use of an angiotensin converting enzyme inhibitor (ACE-I); CT studies have also shown evidence of frontal and insular ischemia, with an odds radio of 13.6 and 9.1, respectively.2 Our patient was on lisinopril and had early signs of ischemia in the frontal lobe on initial CT scan, which likely increased her risk for angioedema.
How tPA Can Trigger Angioedema
The development of angioedema after administration of tPA has a well-described biochemical basis. Angioedema has been linked to the local vasodilatory effects of bradykinin, mast cell degranulation, and histamine release from activation of the complement pathway.4 Tissue plasminogen activator may trigger both of these pathways. It is a serine protease that cleaves plasminogen to plasmin; the plasmin in turn cleaves fibrin, resulting in the desired thrombolytic effects.5 Plasmin can cause mast cell degranulation through conversion of C3 to C3a and through activation of the complement pathway through conversion of C1 to C1a.6
Studies have shown tPA to have low antigenicity, and activation of this pathway is most likely secondary to direct proteolytic effects as opposed to antibody complexes.7 In a study by Bennett et al,6 tPA was shown to significantly increase C3a, C4a, and C5a serum levels when given in the setting of myocardial infarction (MI). It has also been shown to activate and increase serum kallikrein, which cleaves high-molecular weight kininogen to bradykinin, a potent vasodilator.8,9
