This prospective, single-center RCT was approved by the Ethics Committee of Xuanwu Hospital Capital Medical University, Beijing. Written informed consent was obtained from all patients or their designated surrogates. The trial was registered in the Chinese Clinical Trial Registry (registration number: ChiCTR-TRC-12002698).
All patients with acute ischemic stroke from July 2010 to June 2016 in Department of Neurology, Xuanwu Hospital Capital Medical University were screened for eligibility. Patients were eligible if they met all of the following criteria: (1) aged 18 to 80 years old, (2) acute unilateral ischemic stroke <48 hours prior to presentation, (3) infarction involving at least two-thirds of the middle cerebral artery (MCA) territory on cranial computed tomography or magnetic resonance imaging, (4) a reduced level of consciousness indicated by a National Institutes of Health Stroke Scale (NIHSS) item 1a score ≥1, and (5) able to undergo DC within 48 hours after symptom onset.
Patients were excluded if they met any of the following criteria: (1) premorbid mRS score >2; (2) secondary hemorrhage involving more than one-third of the infarction territory with a space-occupying effect; (3) a Glasgow Coma Scale (GCS) without a verbal response item score of <6; (4) rapidly improving symptoms; (5) both pupils fixed and dilated; (6) simultaneous other brain lesion, including tumors and contralateral or infratentorial infarctions; (7) platelet count <75000/mm3; (8) severe coagulopathy or cardiac, liver or kidney disease; (9) vasospastic disease, hematological disease with increased risk of thrombosis or paramyotonia congenita; (10) sepsis; (11) premorbid treatment with a monoamine oxidase inhibitor or an allergy to pethidine; (12) inferior vena cava fistula or a filter in its place, a mass near the inferior vena cava, or a height of <1.5 m; (13) pregnancy; or (14) a life expectancy <6 months.
Enrolled patients were randomly assigned to the following three groups: DC group, DC plus head surface cooling group (DCSC group) and DC plus endovascular hypothermia group (DCEH group), according to a previously generated randomization scheme. A randomly selected number was folded and sealed in an envelope before the initiation of the study. The allocation ratio was 1:1:1. These envelopes were opened by an investigator who was not involved in patient screening, treatment, data collection or analysis.
Standard Medical Treatment
All patients included in the study received standard medical treatment. Patients were admitted into the neurointensive care unit (NCU) immediately after enrollment. Standard medical treatment was initiated as soon as possible. The standard medical treatment is shown in Table 1.
All included patients received DC first as soon as possible. DC consisted of a large hemicraniectomy and a duraplasty. The bone flap with a diameter of at least 12 cm, which included temporal, frontal, parietal, and some occipital bones, was removed. The dura was opened, and a dural patch made of a dura substitute was placed into the incision and secured. Resection of infarcted brain tissue was forbidden.
Patients allocated to the DCSC group were sustained using ice caps that were placed around the head. The ice cap was worn 24 hours a day for 7 days. The systematic temperature was sustained normothermia.
Patients randomized to the DCEH group were treated with endovascular hypothermia. Hypothermia was initiated as soon as possible after DC. A maximal cooling rate was applied using a target bladder temperature of 34°C. Hypothermia was maintained for a minimum of 24 hours and could be prolonged to 72 hours according to the physician’s discretion. The rewarming process was controlled and raised 0.5°C every 12 h. In the event of deterioration as a result of rebound ICP, the rewarming process was intermittent until the patient regained a stable status. The time course for rewarming varied from 24 and 72 hours.
The temperature of the patients in the DC group was sustained between 36.5 and 37.5°C to maintain normothermia.
The patient characteristics included age, sex, comorbidities (such as hypertension, coronary heart disease, atrial fibrillation, hyperlipidemia, valvular dysfunction, diabetes mellitus and stroke), radiological data (affected hemisphere and infarcted area), stroke severity at enrollment (GCS score, NIHSS score and Acute Physiology And Chronic Health Evaluation II score), transtentorial herniation, the administration of thrombolysis, antiplatelet or anticoagulants or defibrinogen and the time interval from symptom onset to DC procedure.
The laboratory data included the erythrocyte count, leukocyte count, platelet count, hemoglobin level, international normalized ratio, thrombin time, prothrombin time, activated partial thromboplastin time, fibrinogen, total bilirubin, alanine aminotransferase, aspertate aminotransferase, creatine kinase, creatinine, urea, glucose, total protein, albumin, sodium, potassium, magnesium, calcium, phosphonium, amylase, lipase, lactate, and arterial blood gas. The tests were run every 12 hours in the DCEH group and every other day in the DC and DCSC group. Chest radiography, electrocardiogram and deep venous ultrasound were also performed every 3 days in all groups.
We also observed severe complications, including hemorrhagic transformation, recurrent infarction, transtentorial herniation post-DC, intracranial hemorrhage or infection post-DC, severe arrhythmia resulting hemodynamic disorder, heart failure (New York Heart Association class IV), hypotension (systolic blood pressure <90 mmHg), pulmonary embolism, gastrointestinal bleeding requiring a blood transfusion (hemoglobin <7 g/L), gastric retention (gastric residual >250 mL), refractory hiccup, acute pancreatitis, acute liver injury, acute kidney injury, platelet <50×109/L, disseminated intravascular coagulation, infection (e.g., catheter-related infection, bacteremia, sepsis, pneumonia and urinary infection), severe electrolyte disorder (blood sodium >160 or <125 mmol/L, blood potassium >6.5 or <2.5 mmoL/L), stress hyperglycemia (>11.1 mmol/L), hypoalbuminemia (<30 g/L), and lower extremity deep vein thrombosis.
The primary outcomes were all-cause mortality and mRS score at 6 months after symptom onset. An investigator who was not involved in the randomization, treatment or analysis performed the follow-up by calling the patients or surrogates after 6 months. A mRS 0–3 was regarded as a good neurological outcome. Secondary outcomes indicated complications.
No similar results were found before the study was designed. Based on data from a previous open study of hypothermia in stroke patients, the sample size was calculated to 252 assuming that the difference of the mean mRS of groups was 1 and that the standard deviation was 2 (α=0.05; β=0.10). Because of the slow recruitment, the study was terminated early after a period of 6 years and we are planning a multicenter RCT in China.
Statistic Package for Social Science (SPSS) 25.0 (SPSS Inc., Chicago, Illinois, USA) was used for statistical analyses. Continuous covariates are presented as the mean±SD or the median (range), as appropriate. Categorical covariates are presented as counts and proportions. Comparisons between the three groups were performed using a two-tailed Kruskal-Wallis H test for continuous covariates and the Pearson’s chi-square test for categorical covariates, as appropriate. All tests were two-tailed, and the level of significance was set to a p-value <0.05.