Edaravone is a widely used treatment for patients with cerebral infarction and, in most cases, edaravone-induced side effects are mild. However, edaravone-related adverse reactions have been receiving increasing attention.

We treated three patients with acute cerebral infarction who died following treatment with edaravone. Edaravone is a widely used treatment for patients with cerebral infarction and, in most cases, edaravone-induced side effects are mild. However, edaravone-related adverse reactions have been receiving increasing attention.

Our cases highlight the importance of educating clinicians regarding the new edaravone-induced clinical syndromes of cerebral infarction as potentially fatal adverse drug reactions. Considering that no laboratory or confirmatory test exists to diagnose edaravone-induced death from cerebral infarction, clinicians’ knowledge is the key element in recognizing this phenomenon.

Edaravone is a clinically effective neuroprotective agent and a free radical scavenger that can capture hydroxyl radicals. It was approved for marketing in Japan and China in 2001 and 2005, respectively. Initially indicated for protection against ischemic brain damage, the indications for edaravone have gradually expanded to the treatment of amyotrophic lateral sclerosis[1-5]. However, owing to its widespread clinical application, adverse reactions due to edaravone have also received increasing attention[6-8]. In the earliest randomized controlled trial of edaravone for ischemic stroke treatment, 4 patients in the edaravone and 5 patients in the blank control groups died out of the 125 cases in each group. In the edaravone group, all deaths were caused by cerebral infarction; while in the control group, three patients died of cardiac arrest, pneumonia, and depression suicide, and two patients died of cerebral hernia caused by edema, worsened cerebral infarction, pneumonia, and disseminated intravascular coagulation (DIC) caused by cirrhosis[6]. In 2007, Japanese scholars reported that one patient with cerebral infarction treated with edaravone experienced severe adverse reactions. The patient presented with a sudden disturbance of consciousness and shock 12 d after hospitalization[6]. In 2018, we observed three patients who died of sudden worsening of acute cerebral infarction during treatment with edaravone, which was suspected to be the cause of death.

Case 1: Acute cerebral infarction, respiratory failure, and pneumonia.

Case 2: Hypertension, diabetes mellitus, and cerebral infarction.

Case 3: Hypertension, DIC, and cerebral infarction.

Case 1: The following drugs were prescribed: Aspirin (100 mg once a day)[7,8], atorvastatin (20 mg once a day)[8,9], edaravone (30 mg twice a day), and Ginkgo biloba extract[10,11]. On the sixth day after admission, the patient developed dyspnea and showed decreased oxygen saturation. The patient was transferred to the intensive care unit (ICU) for tracheal intubation and mechanical ventilation. Multiple ecchymoses were observed on the patient’s body. DIC was diagnosed based on blood coagulation results, and low-molecular weight heparin (0.2 mL twice a day), tranexamic acid (500 mg once a day), fresh frozen plasma (400 mL), and cryoprecipitate (6 U) were administered to the patient. Blood coagulation status improved gradually after treatment. The patient’s respiratory condition improved after receiving ceftizoxime, and she was released from the ventilator.

Case 2: The patient received aspirin (100 mg once a day)[7,8], atorvastatin (20 mg once a day)[8,9], edaravone (30 mg twice a day), Ginkgo biloba extract[10-13], and ceftizoxime (2 g three times a day) to treat the lung infection. Insulin was pumped intravenously based on increased blood glucose levels.

Case 3: The patient was administered clopidogrel bisulfate (75 mg once a day), atorvastatin (20 mg once a day)[8,9], edaravone (30 mg twice a day), and ozagrel extract.

Case 1: On the tenth day after admission, the patient experienced sudden cardiac and respiratory arrest. After external chest compressions and mechanical ventilation, her heartbeat and breathing were restored. However, two further cardiac arrests occurred, and the patient died after the last attempt at resuscitation failed.

Case 2: On the third day after admission, the patient's consciousness improved into a lethargic state. However, on the fifth day after admission, the patient lapsed into a deep coma and his heart rate gradually decreased. Resuscitation attempts were ultimately unsuccessful.

Case 3: The twisted corner of the mouth rapidly improved. However, sudden cardiac arrest occurred. The heartbeat was restored after external chest compressions, and the patient was alert again. During transfer to the ICU, his heart rate slowed down to 20 beats/min but was restored after external chest compressions. A bedside tracheotomy was performed due to difficulties with orotracheal intubation. Bleeding at the cutting site and urethral bleeding occurred. The coagulation function showed prothrombin time 15.3 s, increased prothrombin time ratio 1.30, increased international normalized ratio 1.31, decreased prothrombin activity 65.2%, activated partial thromboplastin time 32.6 s, thrombin time 18.1 s, and increased D-dimer > 76 mg/L. Fresh frozen plasma (400 mL), cryoprecipitate (6 U), and red blood cell suspension (2 U) were administered to the patient. Compression and carbazochrome sodium sulfonate injection were performed to stop the bleeding, which improved. However, six days after admission, the patient experienced cardiac arrest and died.

Edaravone is a newly developed free radical scavenger, and its administration has been used as a clinical therapeutic option for the management of cerebral infarction[6]. In this case, all three patients had acute cerebral infarction. Therefore, we selected edaravone as the therapeutic option for our patients.

The instructions for edaravone clearly suggest that caution should be exercised when using the drug in cardiac patients due to the risk of death[14]. When edaravone was prescribed to elderly patients with cerebral infarction, some experienced a sudden worsening of their condition or died of cardiac arrest[15]. Therefore, we suspected that edaravone may cause serious adverse reactions, although the reason for this remains unknown. Death in patients with cerebral infarction is commonly caused by cerebral hernias in the acute phase of cerebral edema and organ dysfunction resulting from infection accompanied by deterioration of the underlying heart disease[16,17]. This is a noteworthy aspect that should be emphasized, as the acute ischemic stroke etiology in the patients described may also be due to hematological disease[18]. However, in three cases, the patients’ condition deteriorated suddenly and they passed away soon after, which is different from the common cause of death we mentioned above. All these cases had the following characteristics: (1) Elderly patients (aged > 60-year-old); (2) patients with acute cerebral infarction but with a small infarct size, no increase in intracranial pressure, and no serious infection; (3) no history of coronary heart disease, no atrial fibrillation or heart failure, and no abnormal electrocardiography; (4) treatment with edaravone for 4-10 d; (5) rapid deterioration in the patients’ condition, including coagulation dysfunction, severe hepatic and renal damage, or sudden cardiac arrest; and (6) poor response to treatment and difficulty in recovering.

Edaravone has also been reported to cause coagulation dysfunctions. In Japan, approximately 400000 patients received edaravone within 4 years of its release in 2001. The registered adverse reactions were 477 cases, including hepatobiliary diseases (0.1%), renal urinary diseases (0.05%), and thrombocytopenia/DIC (0.02%)[5,6]. Both cases 1 and 3 showed coagulation dysfunction, which improved with plasma and cryoprecipitate infusion, and edaravone was discontinued. This suggests that coagulation dysfunction may have occurred before and after cardiac arrest in these aggravated conditions. Therefore, early detection and reasonable treatment of coagulation dysfunction are important. Patients showed tracheal hemorrhage after tracheotomy, massive urethral hemorrhage, and an abnormal coagulation index without a significant decline in platelets, which were in line with the serious adverse reactions of edaravone with a high risk of disseminated or diffuse intravascular coagulation.

Cardiac arrest occurred in all three patients during treatment with edaravone. In cases 2 and 3, cardiac arrest was the only manifestation of early exacerbation. Patients 1 and 3 were successfully resuscitated after short-term cardiac arrest, but all three patients ultimately had a worse prognosis. As none of the three patients had prior heart disease, the cardiac arrest could not be attributed to existing heart disease. Based on our clinical observations, other possible causes of the three deaths could be excluded, including concomitant medications such as aspirin, clopidogrel, atorvastatin, Ginkgo biloba extract, ozagrel extract, and ceftizoxime. There were no severe adverse reactions related to sudden cardiac arrest, and there were no warnings for the medications administered for patients with heart disease according to the instructions for these drugs. Therefore, these drugs are unlikely to cause disease progression or cardiac arrest. During this exacerbation, severe hepatic and renal function impairments were observed in case 3, which have been mentioned as severe adverse reactions caused by the edaravone. Therefore, sudden deterioration of the patients may be due to adverse drug reactions caused by edaravone. However, the cause-and-effect relationship between the three patients’ deaths and edaravone’s severe adverse reactions still requires confirmation.

In contrast, experimental animal studies have suggested that edaravone treatment improves hepatic injury following ischemia/reperfusion injury, partial hepatectomy, or endotoxin administration[19]. Other researchers have shown that edaravone has beneficial effects on kidney injury induced by ischemia/reperfusion or cisplatin[20-22]. It is possible that edaravone and edaravone-peroxy radicals, which are metabolic products of edaravone, are responsible for these adverse effects; however, the underlying mechanisms remain unclear. Further studies are required to determine the discrepancies between the protective effects observed in previous animal studies and the adverse effects observed in our patients.

In summary, these patients exhibited similar clinical characteristics. Although the characteristics of edaravone use that may lead to sudden death have not yet been identified, this series of cases represent a new clinical syndrome. Thus, further studies are needed to characterize the pathophysiology of this syndrome and determine the underlying causes.