Feasibility and safety of inducing modest hypothermia in awake patients with acute stroke through surface cooling: A case-control study: the Copenhagen Stroke Study. Effect of paracetamol (acetaminophen) on body temperature in acute ischemic stroke: a double-blind, randomized phase II clinical trial. Forced-air warming is no more effective than conventional methods for raising postoperative core temperature after cardiac surgery. Admitting acute ischemic stroke patients to a stroke care monitoring unit versus a conventional stroke unit: a randomized pilot study. Cooling for Acute Ischemic Brain Damage (COOL AID): a feasibility trial of endovascular cooling. Acetaminophen for altering body temperature in acute stroke: a randomized clinical trial. Cooling for acute ischemic brain damage (cool aid): an open pilot study of induced hypothermia in acute ischemic stroke. A phase II study of moderate hypothermia in severe brain injury. Trends in acute ischemic stroke trials through the 20th century.
Hypothermia reduces neuronal damage in animal stroke models. Whether hypothermia is neuroprotective in patients with acute stroke remains to be clarified. In this case-control study, we evaluated the feasibility and safety of inducing modest hypothermia by a surface cooling method in awake patients with acute stroke.
                We prospectively included 17 patients (cases) with stroke admitted within 12 hours from stoke onset (mean 3.25 hours). They were given hypothermic treatment for 6 hours by the "forced air" method, a surface cooling method that uses a cooling blanket with a flow of cool air (10 degrees C). Pethidine was given to treat compensatory shivering. Cases were compared with 56 patients (controls) from the Copenhagen Stroke Study matched for age, gender, initial stroke severity, body temperature on admission, and time from stroke onset to admission. Blood cytology, biochemistry, ECGs, and body temperature were monitored during hypothermic treatment. Multiple regression analyses on outcome were performed to examine the safety of hypothermic therapy.
                Body temperature decreased from t(0)=36.8 degrees C to t(6)=35.5 degrees C (P:<0.001), and hypothermia was present until 4 hours after therapy (t(0)=36.8 degrees C versus t(10)=36.5 degrees C; P:=0.01). Mortality at 6 months after stroke was 12% in cases versus 23% in controls (P:=0. 50). Final neurological impairment (Scandinavian Stroke Scale score at 6 months) was mean 42.4 points in cases versus 47.9 in controls (P:=0.21). Hypothermic therapy was not a predictor of poor outcome in the multivariate analyses.
                Modest hypothermia can be achieved in awake patients with acute stroke by surface cooling with the "forced air" method, in combination with pethidine to treat shivering. It was not associated with a poor outcome. We suggest a large, randomized clinical trial to test the possible beneficial effect of induced modest hypothermia in unselected patients with stroke. Body temperature is a strong predictor of outcome in acute stroke. However, it is unknown whether antipyretic treatment leads to early and clinically worthwhile reduction of body temperature in patients with acute stroke, especially when they have no fever. The main purpose of this trial was to study whether early treatment of acute ischemic stroke patients with acetaminophen (paracetamol) reduces body temperature.
                Seventy-five patients with acute ischemic stroke confined to the anterior circulation were randomized to treatment with either 500 mg (low dose) or 1000 mg (high dose) acetaminophen or with placebo, administered as suppositories 6 times daily during 5 days. Body temperatures were measured with a rectal electronic thermometer at the start of treatment and after 24 hours and with an infrared tympanic thermometer at 2-hour intervals during the first 24 hours and at 6-hour intervals thereafter. The primary outcome measure was rectal temperature at 24 hours after the start of treatment.
                Treatment with high-dose acetaminophen resulted in 0.4 degrees C lower body temperatures than placebo treatment at 24 hours (95% CI 0.1 degrees C to 0.7 degrees C). The mean reduction from baseline temperature with high-dose acetaminophen was 0.3 degrees C (95% CI 0 degrees C to 0.6 degrees C) higher than that in placebo-treated patients. Treatment with low-dose acetaminophen did not result in lower body temperatures. After 5 days of treatment, no differences in temperature were found between the placebo and the high- or low-dose acetaminophen groups.
                Treatment with a daily dose of 6000 mg acetaminophen may result in a small, but potentially beneficial, decrease in body temperature shortly after ischemic stroke, even in normothermic and subfebrile patients. Further studies should determine whether this effect is reproducible and whether early reduction of body temperature leads to improved outcome. To determine whether postoperative forced-air warming of cardiac bypass patients in the intensive care unit (ICU) results in faster rate of warming and improved outcomes compared with more conventional ICU warming methods.
                Prospective randomized effectiveness study.
                Three hundred fifty-bed university-affiliated hospital.
                Sixty consenting randomized patients from a consecutive series of 84 patients undergoing routine adult cardiac surgery.
                One group of patients received usual patient care, which includes warm blankets and overhead heat lamps. Patients in the other group were placed under forced-air warming devices on arrival in the ICU. Sixty consenting patients (30 in each group) were randomly assigned to one or the other method of warming. The remaining 24 patients refused randomization and self-selected a treatment group.
                Results are presented for the randomized groups. Core temperature, measured by pulmonary artery catheter thermistor, increased in both groups at the rate of 0.25 degree C per hour. No statistically or clinically significant differences were found between the group for whom the warming device was used and the standard care group in the incidence of postoperative cardiac arrhythmia, duration of time in the ICU, or any other clinical variable.
                There is no evidence from this study to warrant use of forced-air warming devices for the care of postoperative cardiac surgical patients in the ICU. Pathophysiological considerations and observational studies indicate that elevated body temperature, hypoxia, hypotension, and cardiac arrhythmias in the acute phase of ischemic stroke may aggravate brain damage and worsen outcome.
                Both units were organized with the same standard care and multidisciplinary approach to nursing and rehabilitation. A blinded observer assessed functional outcome at 3 months with the modified Rankin scale (mRS) and Barthel Index (BI). End points were (1) poor outcome, defined as either mRS > or =4 or BI <60 or the need for institutional care and (2) mortality.
                Fifty-four patients meeting the inclusion criteria were randomized. The groups were well matched for baseline characteristics, stroke subtype, stroke severity, vascular risk factors, and prognostic factors. Poor outcome was seen in 7 (25.9%) patients in the SCMU group and in 13 (48.1%) in the SU group (P=0.16). Mortality was lower in the SCMU group than in the SU group (1 [3.7%] vs 7 [25.9%]; odds ratio, 0.11 [95% CI, 0.02 to 0.96], P=0.05).
                This pilot study suggests that admission of acute stroke patients to an SCMU may reduce mortality and poor outcome. A larger trial is required to confirm these findings. To report results of a randomized pilot clinical feasibility trial of endovascular cooling in patients with ischemic stroke.
                Forty patients with ischemic stroke presenting within 12 hours of symptom onset were enrolled in the study. An endovascular cooling device was inserted into the inferior vena cava of those randomized to hypothermia. A core body temperature of 33 degrees C was targeted for 24 hours. All patients underwent clinical assessment and MRI initially, at days 3 to 5 and days 30 to 37.
                Eighteen patients were randomized to hypothermia and 22 to receive standard medical management. Thirteen patients reached target temperature in a mean of 77 +/- 44 minutes. Most tolerated hypothermia well. Clinical outcomes were similar in both groups. Mean diffusion-weighted imaging (DWI) lesion growth in the hypothermia group (n = 12) was 90.0 +/- 83.5% compared with 108.4 +/- 142.4% in the control group (n = 11) (NS). Mean DWI lesion growth in patients who cooled well (n = 8) was 72.9 +/- 95.2% (NS).
                Induced moderate hypothermia is feasible using an endovascular cooling device in most patients with acute ischemic stroke. Further studies are needed to determine if hypothermia improves outcome. Mild alterations in temperature have prominent effects on ischemic cell injury and stroke outcome. Elevated core body temperature (CBT), even if mild, may exacerbate neuronal injury and worsen outcome, whereas hypothermia is potentially neuroprotective. The antipyretic effects of acetaminophen were hypothesized to reduce CBT.
                This was a randomized, controlled clinical trial at 2 university hospitals. Patients were included if they had stroke within 24 hours of onset of symptoms, National Institutes of Health Stroke Scale (NIHSS) score > or =5, initial CBT <3 8.5 degrees C, and white blood cell count < 12 600 cells/mm(3); they were excluded if they had signs of infection, severe medical illness, or contraindication to acetaminophen. CBT was measured every 30 minutes. Patients were randomized to receive acetaminophen 650 mg or placebo every 4 hours for 24 hours. The primary outcome measure was mean CBT during the 24-hour study period; the secondary outcome measure was the change in NIHSS.
                Thirty-nine patients were randomized. Baseline CBT was the same: 36.96 degrees C for acetaminophen versus 36.95 degrees C for placebo (P=0.96). During the study period, CBT tended to be lower in the acetaminophen group (37.13 degrees C versus 37.35 degrees C), a difference of 0.22 degrees C (95% CI, -0.08 degrees C to 0.51 degrees C; P=0.14). Patients given acetaminophen tended to be more often hypothermic <36.5 degrees C (OR, 3.4; 95% CI, 0.83 to 14.2; P=0.09) and less often hyperthermic >37.5 degrees C (OR, 0.52; 95% CI, 0.19 to 1.44; P=0.22). The change in NIHSS scores from baseline to 48 hours did not differ between the groups (P=0.93).
                Early administration of acetaminophen (3900 mg/d) to afebrile patients with acute stroke may result in a small reduction in CBT. Acetaminophen may also modestly promote hypothermia <36.5 degrees C or prevent hyperthermia >37.5 degrees C. These effects are unlikely to have robust clinical impact, and alternative or additional methods are needed to achieve effective thermoregulation in stroke patients. Hypothermia is effective in improving outcome in experimental models of brain infarction. We studied the feasibility and safety of hypothermia in patients with acute ischemic stroke treated with thrombolysis.
                An open study design was used. All patients presented with major ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score >15) within 6 hours of onset. After informed consent, patients with a persistent NIHSS score of >8 were treated with hypothermia to 32+/-1 degrees C for 12 to 72 hours depending on vessel patency. All patients were monitored in the neurocritical care unit for complications. A modified Rankin Scale was measured at 90 days and compared with concurrent controls.
                Ten patients with a mean age of 71.1+/-14.3 years and an NIHSS score of 19.8+/-3.3 were treated with hypothermia. Nine patients served as concurrent controls. The mean time from symptom onset to thrombolysis was 3.1+/-1.4 hours and from symptom onset to initiation of hypothermia was 6.2+/-1.3 hours. The mean duration of hypothermia was 47.4+/-20.4 hours. Target temperature was achieved in 3.5+/-1.5 hours. Noncritical complications in hypothermia patients included bradycardia (n=5), ventricular ectopy (n=3), hypotension (n=3), melena (n=2), fever after rewarming (n=3), and infections (n=4). Four patients with chronic atrial fibrillation developed rapid ventricular rate, which was noncritical in 2 and critical in 2 patients. Three patients had myocardial infarctions without sequelae. There were 3 deaths in patients undergoing hypothermia. The mean modified Rankin Scale score at 3 months in hypothermia patients was 3.1+/-2.3.
                Induced hypothermia appears feasible and safe in patients with acute ischemic stroke even after thrombolysis. Refinements of the cooling process, optimal target temperature, duration of therapy, and, most important, clinical efficacy, require further study. Forty-six patients with severe nonpenetrating brain injury [Glasgow Coma Scale (GCS) 4-7] were randomized to standard management at 37 degrees C (n = 22) and to standard management with systemic hypothermia to 32 to 33 degrees C (n = 24). The two groups were balanced in terms of age (Wilcoxon's rank sum test, p > 0.95), randomizing GCS (chi-square test, p = 0.54), and primary diagnosis. Cooling was begun within 6 h of injury by use of cooling blankets. Metocurine and morphine were given hourly during induction and maintenance of hypothermia. Rewarming was at a rate of 1 degree C per 4 h beginning 48 h after intravascular temperature had reached 33 degrees C. Muscle relaxants and sedation were continued until core temperature reached 35 degrees C. There were no cardiac or coagulopathy-related complications. Seizure incidence was lower in the hypothermia group (Fisher's exact text, p = 0.019). Sepsis was seen more commonly in the hypothermia group, but difference was not statistically significant (chi-square test). Mean Glasgow Outcome Scale (GOS) score at 3 months after injury showed an absolute increase of 16% (i.e., 36.4-52.2%) in the number of patients in the Good Recovery/Moderate Disability (GR/MD) category as compared with Severe Disability/Vegetative/Dead (SD/V/D) (chi-square test, p > 0.287). Based on evidence of improved neurologic outcome with minimal toxicity, we believe that phase III testing of moderate systemic hypothermia in patients with severe head injury is warranted. The advent of controlled clinical trials revolutionized clinical medicine over the course of the 20th century. The objective of this study was to quantitatively characterize developments in clinical trial methodology over time in the field of acute ischemic stroke.
                All controlled trials targeting acute ischemic stroke with a final report in English were identified through MEDLINE and international trial registries. Data regarding trial design, implementation, and results were extracted. A formal 100-point scale was used to rate trial quality.
                A total of 178 controlled acute stroke trials were identified, encompassing 73 949 patients. Eighty-eight trials involved neuroprotective agents, 59 rheological/antithrombotic agents, 26 agents with both neuroprotective and rheological/antithrombotic effects, and 5 a nonpharmacological intervention. Only 3 trials met conventional criteria for a positive outcome. Between the 1950s and 1990s, the number of trials per decade increased from 3 to 99, and mean trial sample size increased from 38 (median, 26) to 661 (median, 113). During 1980-1999, median time window allowed for enrollment decreased per half decade from 48 to 12 hours. Reported pharmaceutical sponsorship increased substantially over time, from 38% before 1970 to 68% in the 1990s. Trial quality improved substantially from a median score of 12 in the 1950s to 72 in the 1990s.
                Accelerating trends in acute stroke controlled trials include growth in number, sample size, and quality, and reduction in entry time window. These changes reflect an increased understanding of the pathophysiology of acute stroke, the imperative for treatment initiation within a critical time window, and more sophisticated trial design.
There is currently no evidence from randomised trials to support routine use of physical or pharmacological strategies to reduce temperature in patients with acute stroke. Large randomised clinical trials are needed to study the effect of such strategies.