DHC was the first-line therapy for patients with large hemispheric infarcts. However, those patients who declined DHC were then counseled about the use of TH as an alternative treatment option. Written informed consent was obtained from all caregivers prior to patient enrollment into TH treatment. This investigation was approved by the institutional review board.

We retrospectively reviewed the clinical and radiographic data from elderly patients aged 60 years or older who were diagnosed with a large acute hemispheric infarction and were treated with TH between February 2011 and August 2012. Seoul National University Bundang Hospital’s stroke data registry was used for analysis. Patients were enrolled if they met all of the following criteria: age ≥60 years, with acute ischemic stroke, hospital admission within 12 hours of stroke symptom onset, and initial National Institutes of Health Stroke Scale (NIHSS) score >10. Specific neuroimaging criteria included the following: large hemispheric infarction involving more than two-thirds of the MCA territory, involvement of the basal ganglia on diffusion-weighted magnetic resonance imaging scans within 12 hours of symptom onset, and parenchymal hypodensity involving more than two-thirds of the MCA territory with a midline shift evident on computed tomography (CT) scans within 72 hours of onset.

Patients were ineligible if they demonstrated any of the following exclusion criteria: severe cardiac dysarrhythmia or a corrected QT (QTc) interval >450 ms, platelet count <75,000/mm³, known coagulopathy (prothrombin time international normalized ratio >1.3) or active bleeding, severe sepsis and septic shock, preexisting illness with a life expectancy of <6 months, previous modified Rankin Scale (mRS) score >4, concurrent monoamine oxidase inhibitor usage, or pregnancy [21].

We reviewed clinical data, including patient demographics, diagnosis, Trial of ORG 10172 in Acute Stroke Treatment classification, vascular risk factors (hypertension, diabetes mellitus, hyperlipidemia, smoking, previous stroke, and previous cardiac disorders including arrhythmia), stroke severity as measured by NIHSS score at baseline and discharge, and long-term functional outcome 3 months following treatment as measured by the mRS.

Radiologic data included an initial magnetic resonance imaging scan on admission and follow-up computed tomography (CT) scans before and after TH. The follow-up CT scans were used to detect any hemorrhagic transformation and to quantify the magnitude of the midline shift 1 day and 3 days after completing TH. Hemorrhagic transformation was categorized into four different subtypes (hemorrhagic infarction 1 or 2, and parenchymal hemorrhage 1 or 2) according to the European Cooperative Acute Stroke Study I and II criteria [22,23]. The progression of cerebral edema was quantified by measuring lateral displacement of the calcified pineal gland from the midline on CT scans [24].

Physiological data included heart rate, blood pressure, and body temperature, which were measured every hour. Timeline data consisted of admission and discharge date, stroke onset, time of symptom onset to TH initiation, and time to target temperature. Laboratory data included white blood cell count, hematocrit and hemoglobin levels, platelet count, electrolytes (sodium, potassium, chloride, and phosphate), glucose, creatinine, albumin, creatinine kinase, aspartate transaminase, alanine transaminase, prothrombin time, activated partial thromboplastin time, and arterial blood gas. Urinalysis, electrocardiography, and chest radiography were also performed. Daily chest radiographs and microbiological pancultures (urine, blood, and sputum) were reviewed for infection status. Adverse events were adapted from the National Acute Brain Injury Study [25], which included cardiovascular complications, infections, electrolyte imbalances, and bleeding complications or coagulopathies, pulmonary edema, and liver function abnormalities.

Neurological deficits on admission and discharge were assessed using the NIHSS score. The functional status of each patient was assessed 3 months after treatment using mRS scoring. All clinical assessments were recorded by cerebrovascular neurologists. Complications arising from TH were recorded to determine safety and feasibility outcomes.

All patients were admitted to the neurological intensive care unit and treated according to the standardized institutional hypothermia protocol after obtaining informed consent. Patients were cooled with an external cooling device using cold water-circulating wrapping garments (Arctic Sun Temperature Management System; Medivance, Louisville, CO, USA) and subsequent use of 500 mL to 1 L of cold (4.0°C) saline infused intravenously within 30 to 60 minutes after enrollment. Core temperature was measured with an esophageal probe. After the core temperature reached the target temperature of 33°C, the Arctic Sun system automatically maintained the target temperature by regulating the temperature of the circulating water. Core temperature was continuously monitored and was recorded every hour. Invasive monitoring equipment, such as an arterial line or a central venous line, was used for those who needed close hemodynamic monitoring.

All patients treated with TH were intubated and adequately sedated. We adopted the Columbia University Anti-shivering Protocol [26], which included both universal and patient-specific therapies. Initially, acetaminophen (650 mg every 4 hours) and buspirone (30 mg every 8 hours) were used as anti-shivering agents, and a skin counter-warming system (Bear Hugger, Arizant Healthcare Inc.; Eden Prairie, MN, USA) was applied. If shivering developed, meperidine (50-100 mg bolus followed by 12.5-50 mg/h) or propofol infusions (75-300 mg/h) were used. If shivering persisted, a dexmedetomidine infusion (loading dose 1 µg/kg over 10 minutes, followed by an infusion of 0.3-1.5 µg/kg/h) was used, and finally, a continuous infusion of vecuronium (0.1 mg/kg/h) was administered for refractory shivering cases.

All patients underwent follow-up CT scans before and after TH to visually assess the degree of cerebral edema. After obtaining stable clinical and CT findings for 24 hours, a passive and slow rewarming process was initiated. The rate of rewarming was set at 0.1°C/h.

A total of 199 patients with MCA infarctions between February 2011 and August 2012 were screened. Thirty-four patients had malignant MCA infarctions. Five patients (15%) underwent DHC, 13 (38%) received conservative treatment, 16 (47%) were treated with TH, and 11 (32%) were eligible for our study. Baseline patient characteristics are summarized in Table 1. The median age was 76 (range, 64-82 years) and the median NIHSS score was 18 (range, 13-22) upon admission. Six (55%) of the 11 patients underwent intravenous or intra-arterial thrombolysis. Based on Trial of ORG 10,172 in Acute Stroke Treatment subtype classification, 6 (55%) of 11 patients had a cardioembolism, 3 (27%) had large artery atherosclerosis, and 2 (18%) were of undetermined etiology. One patient had two potential causes of stroke (large artery atherosclerosis and cardioembolism), and the other patient was not fully evaluated due to death (undetermined etiology, negative evaluation). Nine (82%) of 11 patients exhibited hypertension and 3 (27%) had previously experienced stroke. Premorbid mRS scores were 0 for 9 patients, 2 for 1 patient, and 3 for 1 patient. Hemorrhagic transformation was detected in 5 (45%) of 11 patients before the initiation of hypothermia, and 4 (80%) out of these 5 patients experienced an additional mass effect due to hemorrhagic transformation (parenchymal hemorrhage 1 or 2).

TH was initiated at a median of 30.3±23.0 hours after stroke onset (Table 2). The median time to reach core target temperature (33°C) after cold saline infusion was 4.0±2.4 hours. TH was maintained for a median of 76.7±57.1 hours (range, 46-254 hours).

The mean mRS score 3 months after treatment was 4.9±0.8 for all patients and 4.7±0.7 for survivors (Table 3). There were two deaths (18%) due to either progression of cerebral edema (case 2) or sudden cardiac arrhythmia after rewarming (case 10). One (9%) of the 11 patients treated with TH achieved a favorable functional outcome (mRS 3).

All patients who exhibited pineal gland displacement >5 mm on the first day of TH experienced poor outcomes (mRS 5 or 6) and the degree of the lateral displacement of the pineal gland was more significant in those who died (case 2: 12-mm pineal gland displacement). Two (33%) of 6 patients with <5 mm of pineal gland displacement exhibited an mRS of 3 or 4 three months after treatment, suggesting that the magnitude of pineal gland displacement on the first day of TH corresponded with mortality and functional outcome.

Shivering was observed in all TH patients (Table 4). Bradycardia was frequently noted during the cooling phase (45%, n=5), but was transient in nature and asymptomatic in all cases. Five patients (45%) who had preexisting atrial fibrillation developed further cardiac arrhythmias during hypothermia, 2 (18%) developed a non-sustained ventricular tachycardia, and 3 (27%) experienced atrial fibrillation with rapid ventricular responses. No patient required urgent anti-arrhythmic therapy. Hypotension was noted in 2 (18%) cases and was thought to be due to hypothermia-induced diuresis and relative intravascular volume depletion. Six (55%) patients developed pneumonia, but responded favorably to appropriate antibiotic therapies.

Electrolyte imbalances were detected in most patients during TH. Serum sodium was altered in 55% of patients (hypernatremia, n=5; hyponatremia, n=1). Hypokalemia was observed in 82% of patients (n=9) and 1 patient developed rebound hyperkalemia during the rewarming phase. Hypophosphatemia was also a common side effect (82%, n=9). Minor bleeding complications, such as hemoptysis (n=2) and hematuria (n=2), were observed, but were easily controlled. No major coagulopathy was induced by TH.