Orolingual bradykinin angioedema after tissue plasminogen activator in acute stroke – treatment with or without C1-esterase inhibitor

Summary

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manu­script met the ICMJE “uniform requirements” for biomedical papers.

Dear Editor,

The aim of this report is to compare the treatment of a bradykinin-induced orolingual angioedema (BiA) after recombinant tis­sue plasminogen activator (rtPA) adminis­tration in two ischemic stroke patients, and to show how C1-esterase inhibitor (C1-INH) reduces the risk of hypoxia from an obstruction in BiA.

Orolingual angioedema is a sudden com­plication, a rapid progres­sion of swel­ling, which can cause acute upper obstruction of the airways with the risk of acute hypoxia. Angioedema can occur for a variety of reasons, one of which is rtPA used in acute ischemic stroke patients. The incidence of angioedema after alteplase administration in ischemic stroke varies, with 7.9% be­­ing the highest reported in a study by Hurford et al [1].

From a pathophysiological point of view, acute swel­l­­ing of skin and subcutaneous tis­sue in angioedema occurs due to two dif­ferent mechanisms (Fig. 1). Histamine-in­duced angioedema is usual­ly al­lergy-related and can be treated with antihist­a­mines, steroids and adrenalin administration. In contrast, BiA can­not be treated by the aforementioned drugs, since its develop­ment is based on dif­ferent bio­chemical pathways. However, it can be treated with C1-INH. The BiA mechanism is based on bradykinin induc­­ing vasodilatation and increased endothelial permeability after be­­ing released from high-molecular-weight kininogen by the action of plasma kal­likrein. Angiotensin-converting enzyme (ACE) inhibitors reduce bradykinin degradation and this explains why the risk of BiA development is increased among people tak­­ing ACE inhibitors [1– 3].

Acute hypoxia in acute ischemic stroke patients can worsen morbidity and mortality due to secondary brain damage. This complication therefore neces­sitates urgent treatment [4– 5]. In our neurocritical care unit dur­­ing the period 2014– 2016, out of 489 ischemic stroke patients who received alteplase, angioedema occur­red in two cases (0.4%), both of whom had BiA and had been us­­ing ACE inhibitors for arterial hypertension (AH). The edema in these patients did not respond to clas­sic al­lergy ther­apy. The BiA of the first patient was resolved with an urgent video-as­sisted orotracheal intubation without C1-INH, while the second patient received C1-INH. This treatment was made available in our neurocritical care after the first dramatic situation.

The case reports are reported with written consent for publication.

Patient 1 without C1-INH –  a 78-year-oldwoman with a history of AH trea­t­­ed for 2 years with ACE inhibitors and no known al­lergies or BiA was admitted with severe aphasia and right-sided hemiparesis (3/ 5). Her admis­sion National Institutes of Health Stroke Scale (NIHSS) was 13. Brain CT showed no apparent acute ischemic or hemor­rhagic lesion, CT angiography showed no ves­sel occlusion so intravenous alteplase (75 mg) administration was started 150 min after the onset of symp­toms. After 110 min, she suddenly developed severe orolingual and airway edema (Fig. 2A) which did not respond to adrenalin, steroids and antihistamines. Urgent video-as­sisted oro­tracheal intubation took place without any complications. The patient underwent 18 h of ventilation until edema resolution and was extubated without dif­ficulties. Her neurological status partial­ly improved (NIHSS 6) upon discharge.

Patient 2 with C1-INH –  a 77-year-old woman with a history of AH treated for 3 years with ACE inhibitors and no known al­lergies or BiA was admitted with dysarthria and right-sided faciobrachial paresis (NIHSS 4). Brain CT showed no apparent ischemic or hemor­rhagic lesion, CT angiography showed embolic material in the distal branch of the middle cerebral artery. Intravenous alteplase was started 180 min after the onset of symp­toms (70 mg). Her neurological deficit progres­sed after 30 min (NIHSS 10). Alteplase administration was stopped. No changes could be detected on the urgent brain CT, so alteplase was restarted. After 70 min, the development of a right-sided upper lip, face and neck edema was noted (Fig. 2B). Rapid progres­sion led to dyspnea and dysphagia. Administration of adrenalin, steroids and antihistamines was inef­fective, so C1-INH (complement C1-esterase inhibitor Berinert®, 1500 international units) was applied. A very prompt resolution (30 min) of dysphagia and dyspnea was observed fol­lowed by gradual edema regres­sion (Fig. 2C), and no orotracheal intubation was neces­sary. She experienced almost a full neurological recovery (NIHSS 1) upon discharge.

Serious al­lergic reactions (anaphylaxis) after thrombolytic ther­apy with rtPA have been observed dur­­ing the treatment of acute ischemic stroke and Hurford even reported a 7.9% incidence of this complication after alteplase administration in ischemic stroke patients [1]. Upon onset of angioedema, we should bear in mind that angioedema can occur as a result of two dif­ferent mechanisms, histamine or BiA as shown in Fig 1. These dif­ferent mechanisms giv­­ing rise to angioedema require dif­ferent treatments. Al­lergy-related angioedema can be treated by antihistamines, steroids and adrenalin administration. In contrast, BiA can be treated by C1-INH. This medication was also used in a minority of cases in the Hurford΄s study. Therefore, from a practical viewpoint, when the usual al­lergy treatments are inef­fective, and in addition when the patient is us­­ing ACE inhibitors, we might consider BiA.

BiA is a sudden life-threaten­­ing com­plication due to the rapid progres­sion of swel­l­­ing caus­­ing acute obstruction of the airways. In order to prevent hypoxia, this complication must be resolved quickly by an expert physician who is skil­led in perform­­ing video-as­sisted orotracheal intubation to avoid the last pos­sible solution of a coniopuncture. Our first case report shows that although the patient was succes­sful­ly intubated, without complications or hypoxia, we felt the need to pay attention to this is­sue and to keep C1-INH available for acute use in our neurocritical care unit. We were therefore able to ef­fectively administer it to our second presented patient with BiA, who did not need intubation.

Even though our neurocritical care unit has a much lower incidence of orolingual angioedema than in the literature, we wanted to draw attention to this serious complication after alteplase treatment in acute stroke patients in neurocritical care. The question remains why our incidence of angioedema is so low in comparison with the Hurford΄s study, but in any case, orolingual angioedema is a risk factor for acute hypoxia, since it can be a fatal complication and therefore neces­sitates urgent treat­ment. When the usual anti-al­lergic measures are inef­fective, and in addition the patient is us­­ing ACE inhibitors, BiA should be suspected and C1-INH can be considered for treatment of angioedema in order to avoid urgent endotracheal intubation or emergency cricothyroidotomy.

Accepted for review: 15. 10. 2017

Accepted for print: 5. 3. 2018

MUDr. Věra Špatenková, Ph.D.

Neurocenter, Neurointensive Care Unit

Regional Hospital Liberec

Husova 10

46063 Liberec

Czech Republic

e-mail: vera.spatenkova@nemlib.cz