Case
A 49-year-old man with a history of hypertension, for which he was taking aspirin, carvedilol, hydralazine, and nifedipine, presented to the ED with complaints of left-sided weakness that started 3 hours before he came to the ED. Initial vital signs were: blood pressure, 158/90 mm Hg; heart rate, 74 beats/min; respiratory rate, 18 breaths/min; and temperature, 98°F. Oxygen saturation was 100% on room air, and a finger-stick glucose test was 106 mg/dL.
Physical examination revealed slowed speech with mild dysarthria, mild left facial droop, 2/5 strength in all muscle groups in the left upper and lower extremities, and decreased sensation to light touch on the left side. The patient also had left-sided sensory neglect and an abnormal gait, and dragged his left foot on the floor when walking. The rest of his examination was normal.
The stroke team was activated, and the patient was immediately transferred to the ED radiology department for imaging studies. A noncontrast head computed tomography (CT) was negative for any acute intracranial hemorrhage or cerebral edema. A CT angiogram (CTA) also was performed, which revealed atherosclerosis but no arterial occlusion. Based on these findings and the existing protocol, the patient received an intravenous (IV) bolus of tissue plasminogen activator (tPA). Approximately 17 minutes after tPA administration, the patient developed left-sided upper and lower lip swelling. There was no voice change, tongue swelling, or uvular deviation.
What is the differential diagnosis of swelling of the lip?
The differential diagnoses for lip swelling includes trauma, allergic reaction, and angioedema (hereditary, or angiotensin converting enzyme inhibitor [ACEI]-induced). The patient in this case denied any trauma to the lip, and no bleeding was noted from the lip; however, his entire left lip (upper and lower) was swollen. He was not taking any ACEIs or angiotensin-receptor blockers (ARBs). He also denied a family history of angioedema or any prior similar episodes. The patient further denied exposure to any new medications, foods, or other substances and had no respiratory distress, urticaria, or other findings consistent with an allergy.
What are the common adverse effects of tPA?
The only US Food and Drug-approved pharmacological treatment for ischemic stroke is tPA (also known as IV rtPA). Tissue plasminogen activator hydrolyzes plasminogen to plasmin, which exerts a fibrinolytic effect. Based on the ability of tPA to lyse thrombus, it is also a standard therapy for hemodynamically unstable patients with confirmed pulmonary embolism, as well as for patients with myocardial infarction in whom percutaneous intervention is contraindicated or unavailable. Despite the beneficial effects of tPA, significant adverse effects are associated with the drug. For example, thrombolysis may result in conversion of an ischemic stroke into a hemorrhagic event, resulting in generalized bleeding from mucosal surfaces.
The increase in plasmin may play a role in the development of angioedema by activating the kinin pathway, leading to the formation of the vasodilator bradykinin (Figure). Plasmin also activates the complement system and leads to the production of anaphylatoxins C3a, C4a, and C5a, which also cause mast cell degranulation and histamine release.1
When does post-tPA angioedema occur?
In the few published case reports available, tPA-induced angioedema was shown to typically occur in the stroke distribution (which was attributed to the left-sided swelling in this patient).2 Following tPA administration, the onset of angioedema reportedly varies from as early as 10 to 15 minutes from initiation until about 1 hour postinfusion. The short half-life of tPA (approximately 7 minutes)2 limits the outer- time window for the initial development of angioedema, but progression can continue well beyond this timeframe.
What is the treatment for tPA-induced angioedema?
The first priority of acute management of angioedema is discontinuation of the inciting substance, if possible—in this case, the tPA infusion.3 Assessment and maintenance of a patent airway are of utmost concern. Patients with posterior oropharyngeal effects or who are progressing should be admitted to an intensive care unit (ICU) for observation.4-6
Endotracheal Intubation. Providers should have a low threshold for endotracheal intubation, which should ideally be performed in any patient at risk for airway compromise.4 Due to the extensive airway swelling that can occur in the setting of angioedema, airway intervention should optimally be performed by an available clinician with the most skill and experience in this area. It is wise to be prepared to utilize advanced airway techniques, if available, including fiberoptic laryngoscopy or potentially cricothyrotomy.
Figure
Histamine Agonists. Standard therapy for patients who develop angioedema should include histamine antagonists, such as diphenhydramine (H1 antagonist) and famotidine (H2 antagonist) along with corticosteroids. Although these therapies are unlikely to be helpful in the treatment of tPA-induced angioedema, the difficulty in excluding allergic angioedema and the low risk of adverse effects associated with these medications support their use.
Fresh Frozen Plasma. Fresh frozen plasma (FFP) should be considered for patients who have a history of hereditary angioedema. Fresh frozen plasma contains enzymes that degrade bradykinin. Although FFP has been used successfully in the treatment of ACEI-induced angioedema, its use (or benefit) in tPA-related cases is not clear.
Icatibant. A selective bradykinin B2-receptor antagonist, icatibant has been used to treat patients with ACEI-induced angioedema because of its effects on bradykinin receptors. Comparison of the efficacy of icatibant to the prevailing treatment strategy of diphenhydramine, famotidine, and methylprednisolone found a shorter time to symptom relief with icatibant.7 However, icatibant is extremely expensive ($23,000/30 mg). As previously mentioned, based on its similar mechanism of action, lower cost, and safety profile, FFP can be given (off label) in this situation.
Case Conclusion
The patient was given diphenhydramine, famotidine, and methylprednisolone, but did not show any improvement. His upper/lower lip swelling continued to worsen, and 30 minutes after the onset of angioedema, he was unable to open his mouth more than 1 cm.
Multiple attempts to perform awake fiberoptic intubation failed due to inadequate sedation; however, intubation was successfully performed following light sedation. The patient self-extubated in the ICU on hospital day 3, and the angioedema had progressively decreased. Angioedema and weakness completely resolved by hospital day 4, and he was discharged home on hospital day 7.