Early restricted oxygen therapy after resuscitation from cardiac arrest (ER-OXYTRAC): protocol for a stepped-wedge cluster randomised controlled trial.

INTRODUCTION: Cardiac arrest is a critical condition, and patients often experience postcardiac arrest syndrome (PCAS) even after the return of spontaneous circulation (ROSC). Administering a restricted amount of oxygen in the early phase after ROSC has been suggested as a potential therapy for PCAS; however, the optimal target for arterial partial pressure of oxygen or peripheral oxygen saturation (SpO2) to safely and effectively reduce oxygen remains unclear. Therefore, we aimed to validate the efficacy of restricted oxygen treatment with 94%-95% of the target SpO2 during the initial 12 hours after ROSC for patients with PCAS. METHODS AND ANALYSIS: ER-OXYTRAC (early restricted oxygen therapy after resuscitation from cardiac arrest) is a nationwide, multicentre, pragmatic, single-blind, stepped-wedge cluster randomised controlled trial targeting cases of non-traumatic cardiac arrest. This study includes adult patients with out-of-hospital or in-hospital cardiac arrest who achieved ROSC in 39 tertiary centres across Japan, with a target sample size of 1000. Patients whose circulation has returned before hospital arrival and those with cardiac arrest due to intracranial disease or intoxication are excluded. Study participants are assigned to either the restricted oxygen (titration of a fraction of inspired oxygen with 94%-95% of the target SpO2) or the control (98%-100% of the target SpO2) group based on cluster randomisation per institution. The trial intervention continues until 12 hours after ROSC. Other treatments for PCAS, including oxygen administration later than 12 hours, can be determined by the treating physicians. The primary outcome is favourable neurological function, defined as cerebral performance category 1-2 at 90 days after ROSC, to be compared using an intention-to-treat analysis. ETHICS AND DISSEMINATION: This study has been approved by the Institutional Review Board at Keio University School of Medicine (approval number: 20211106). Written informed consent will be obtained from all participants or their legal representatives. Results will be disseminated via publications and presentations. TRIAL REGISTRATION NUMBER: UMIN Clinical Trials Registry (UMIN000046914).

Uric acid and neurological disease: a narrative review.

Hyperuricemia often accompanies hypertension, diabetes, dyslipidemia, metabolic syndrome, and chronic renal disease; it is also closely related to cardiovascular disease. Moreover, several epidemiological studies have linked hyperuricemia and ischemic stroke. However, uric acid may also have neuroprotective effects because of its antioxidant properties. An association between low uric acid levels and neurodegenerative diseases has been suggested, which may be attributed to diminished neuroprotective effects as a result of reduced uric acid. This review will focus on the relationship between uric acid and various neurological diseases including stroke, neuroimmune diseases, and neurodegenerative diseases. When considering both the risk and pathogenesis of neurological diseases, it is important to consider the conflicting dual nature of uric acid as both a vascular risk factor and a neuroprotective factor. This dual nature of uric acid is important because it may help to elucidate the biological role of uric acid in various neurological diseases and provide new insights into the etiology and treatment of these diseases.

Levetiracetam versus fosphenytoin as a second-line treatment after diazepam for adult convulsive status epilepticus: a multicentre non-inferiority randomised control trial.

OBJECTIVE: Status epilepticus (SE) is an emergency condition for which rapid and secured cessation is crucial. Although fosphenytoin (FPHT) is recommended as a second-line treatment, levetiracetam (LEV) reportedly has similar efficacy, but higher safety. Therefore, we herein compared LEV with FPHT in adult SE. METHODS: We initiated a multicentre randomised control trial in emergency departments with adult patients with convulsive SE. Diazepam was initially administered, followed intravenously by FPHT at 22.5 mg/kg or LEV at 1000-3000 mg. The primary outcome was assigned as the seizure cessation rate within 30 min of the administration of the study drug. RESULTS: A total of 176 adult patients with SE were enrolled (82 FPHT and 94 LEV), and 3 were excluded from the full analysis set. Seizure cessation rates within 30 min were 83.8% (67/80) in the FPHT group and 89.2% (83/93) in the LEV group. The difference in these rates was 5.5% (95% CI -4.7 to 15.7, p=0.29). The non-inferiority of LEV to FPHT was confirmed with p<0.001 by the Farrington-Manning test. No significant differences were observed in the seizure recurrence rate or intubation rate within 24 hours. Serious adverse events developed in three patients in the FPHT group and none in the LEV group (p=0.061). CONCLUSION: The efficacy of LEV was similar to that of FPHT for adult SE following the administration of diazepam. LEV may be recommended as a second-line treatment for SE along with phenytoin/FPHT. TRIAL REGISTRATION NUMBER: jRCTs031190160.

Characteristics of patients who received helicopter emergency medical services in Japan from 2012 to 2019: a retrospective analysis of data from Tochigi Prefecture.

BACKGROUND: Helicopter Emergency Medical Services (HEMS) has been in operation in Japan since 2001, allowing patients almost anywhere in the nation to receive on-scene emergency treatment from physicians. However, there is insufficient literature on the characteristics of the patients who use Japanese HEMS. Thus, this study aimed to investigate the overall characteristics of patients receiving HEMS care within a single prefecture in Japan. METHODS: We retrospectively analyzed the data of 5163 patients-in Tochigi Prefecture-who received HEMS care from 2012 to 2019. Descriptive statistics were used to analyze the following aspects of care: diagnosis, severity, background characteristics, geographical and environmental variables, immediate pre-hospital intervention, transportation type, and short-term clinical outcomes. RESULTS: Among 7370 HEMS requests received during the study period, treatment was provided to 5163 patients (1.8 cases per day; 3489 men [67.6%]). Nearly 55% (n = 2856) of patients were aged above 60 years. Age peaks were observed at 0-9 years and 60-69 years. The median distance from the base hospital to the site was 26.7 km. The age-standardized rate of HEMS treatment was 30.3 patients per 100,000 people. Cases of trauma and cardiovascular diseases were the most common (65.3%). Most individuals aged 0-9 years and 60-69 years had neurological disease (seizures accounted for 80.5% of this group) and cardiovascular disease, respectively. The number of patients was similar across all four seasons. After immediate pre-hospital intervention, 81.6% of patients receiving HEMS care were transferred by the helicopter ambulance (53.4% and 28.2% to the base hospital and to other hospitals, respectively). Overall, 56.6% of patients receiving HEMS care were transferred to the base hospital, and the short-term recovery rate was above 75%. Intravenous drip and oxygen administration were the most common pre-hospital interventions (93.1% and 72.7%, respectively). CONCLUSIONS: This study is the first to describe the overall characteristics of HEMS patients using comprehensive data of all HEMS patients in one prefecture in Japan. Further research using both local- and national-level data is needed to accelerate the understanding of the benefits of HEMS.

Phenytoin versus other antiepileptic drugs as treatments for status epilepticus in adults: a systematic review and meta-analysis.

AIM: Status epilepticus (SE) is a life-threatening neurological emergency. There is insufficient evidence regarding which antiepileptic therapy is most effective in patients with benzodiazepine-refractory convulsive SE. Therefore, this study aimed to evaluate intravenous phenytoin (PHT) and other intravenous antiepileptic medications for SE. METHODS: We searched PubMed, the Cochrane Central Register of Controlled Trials, and Igaku Chuo Zasshi for published randomized controlled trials (RCTs) in humans up to August 2019. We compared outcomes between intravenous PHT and other intravenous medications. The important primary composite outcomes were the successful clinical cessation of seizures, mortality, and neurological outcomes at discharge. The reliability of the level of evidence for each outcome was compared using the Grading of Recommendations Assessment, Development, and Evaluation approach. RESULTS: A total of 1,103 studies were identified from the databases, and 10 RCTs were included in the analysis. The ratio of successful clinical seizure cessation was significantly lower (risk ratio [RR] 0.89; 95% confidence interval [CI], 0.82-0.97) for patients treated with intravenous PHT than with other medications. When we compared mortality and neurological outcomes at discharge, we observed no significant differences between patients treated with PHT and those treated with other medications. The RRs were 1.07 (95% CI, 0.55-2.08) and 0.91 (95% CI, 0.72-1.15) for mortality and neurological outcomes at discharge, respectively. CONCLUSIONS: Our findings showed that intravenous PHT was significantly inferior to other medications in terms of the cessation of seizures. No significant differences were observed in mortality or neurological outcomes between PHT and other medications.

Characteristics of Emergency Neurological Patients Who Were Transported by Helicopter Emergency Medical Services in Tochigi, Japan.

In Japan, reports on the association of individual characteristics, and geographical distance and time with clinical outcomes for neurological emergencies involving helicopter emergency medical services (HEMS) are scarce. Using Tochigi HEMS data (2010-2018), we assessed the characteristics of 1,170 emergency neurological patients (e.g., stroke, neurotrauma, and seizure) at the base hospital, which covered 58% of all HEMS patients in the prefecture. After initial treatment in the emergency room, emergency physicians confirmed the clinical outcomes of each patient compared to those at the incident sites (recovery/non-recovery). We calculated the geographic distance from the base hospital to each incident site, and estimated and adjusted odds ratios (aOR) and 95% confidence intervals (CI) for non-recovery against distance. The mean distance between the incident site and base hospital was 22.0 ± 11.7 km, and 77.4% of patients recovered following initial treatment. Two peak age groups were observed among emergency neurological diseases, including seizures in patients who were aged < 5 years and stroke and neurotrauma in patients who were aged 70-80 years. The percentages of stroke, traumatic head and brain injury, and seizure were 35.8%, 29.2%, and 22.8%, respectively. The incidence of stroke (aOR = 11.8, 95% CI 6.86-20.3) and neurotrauma (aOR = 4.86, 95% CI 2.78-8.51) independently predicted a poor prognosis. However, no significant association was observed with the distance from the base hospital. Therefore, in the Tochigi prefecture, geographical disparities may not affect the short-term prognosis of patients with neurological emergencies who were transported by HEMS.

Levetiracetam versus fosphenytoin as a second-line treatment after diazepam for status epilepticus: study protocol for a multicenter non-inferiority designed randomized control trial.

BACKGROUND: Status epilepticus (SE) is an emergency condition for which rapid and secured cessation is important. Phenytoin and fosphenytoin, the prodrug of phenytoin with less severe adverse effects, have been recommended as second-line treatments. However, fosphenytoin causes severe adverse events, such as hypotension and arrhythmia. Levetiracetam reportedly has similar efficacy and higher safety for SE; however, evidence to support its use for adult SE is lacking. In the present study, a non-inferiority designed multicenter randomized controlled trial (RCT) is being conducted to compare levetiracetam with fosphenytoin after diazepam as a second-line treatment for SE. METHODS: This multicenter, prospective, and open-label RCT is conducted in emergency departments. Between December 23, 2019, and March 31, 2023, 176 patients with convulsive SE transported to an emergency room will be randomized into a fosphenytoin group and levetiracetam group at a ratio of 1:1. The definition of SE is "continuous seizures longer than 5 min or discrete seizures longer than 2 min with intervening consciousness disturbance." In both groups, diazepam is initially administered at 1-20 mg, followed by intravenous fosphenytoin at 22.5 mg/kg or intravenous levetiracetam at 1000-3000 mg. The primary outcome is the seizure cessation rate within 30 min. Seizure recurrence within 24 h, severe adverse events, and intubation rate within 24 h are secondary outcomes. DISCUSSION: The present study was approved and conducted as an initiative study of the Japanese Association for Acute Medicine. If non-inferiority is identified, the society will pursue an application for the national health insurance coverage of levetiracetam for SE via a public knowledge-based application. TRIAL REGISTRATION: Japan Registry of Clinical Trials jRCTs031190160 . Registered on December 13, 2019.

Comparison of diazepam and lorazepam for the emergency treatment of adult status epilepticus: a systemic review and meta-analysis.

Status epilepticus (SE) is a life-threatening medical and neurological emergency. Prompt recognition and treatment are essential to stop the seizure and improve patient outcomes. To elucidate which benzodiazepine should be used as the first-line treatment, a systemic search of the PubMed, Cochrane Central Register of Controlled Trials, and Igaku Chuo Zasshi databases was carried out to identify randomized controlled trials (RCTs) comparing i.v. administration of lorazepam and diazepam used for adult SE. The certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation approach. Only two RCTs were finally analyzed among 2182 papers extracted. The SE definitions, inclusion criteria, and doses of the drugs differed in the two studies. Of 204 patients included, 103 and 101 patients were allocated to the lorazepam and diazepam groups, respectively. The pooled risk ratio (RR) and confidence interval (CI) for lorazepam treatment on seizure cessation (two RCTs, n = 204) showed a significantly superior effect of lorazepam over diazepam (RR, 1.24; 95% CI, 1.03-1.49). No statistically significant relationship was found for mortality (two RCTs, n = 204) (RR 0.43; 95% CI, 0.43-6.90), poor neurological outcome (one RCT, n = 134) (RR, 1.10; 95% CI, 0.59-2.04), hypotension (one RCT, n = 70) (RR, 2.68; 95% CI, 0.11-63.61), and respiratory depression (two RCTs, n = 204) (RR, 1.07; 95% CI, 0.48-2.48). The certainty of the evidence was rated as very low. The results of this meta-analysis of RCTs showed that i.v. lorazepam was better than i.v. diazepam for the cessation of adult SE.

Novel clinical features of nonconvulsive status epilepticus.

Nonconvulsive status epilepticus (NCSE) has rapidly expanded from classical features such as staring, repetitive blinking, chewing, swallowing, and automatism to include coma, prolonged apnea, cardiac arrest, dementia, and higher brain dysfunction, which were demonstrated mainly after the 2000s by us and other groups. This review details novel clinical features of NCSE as a manifestation of epilepsy, but one that is underdiagnosed, with the best available evidence. Also, we describe the new concept of epilepsy-related organ dysfunction (Epi-ROD) and a novel electrode and headset which enables prompt electroencephalography.

Recurrent juvenile ischemic stroke caused by bow hunter's stroke revealed by carotid duplex ultrasonography.

Bow hunter's stroke (BHS) is a rare cause of vertebrobasilar insufficiency due to rotational vertebral artery (VA) occlusion associated with head turning. We report a juvenile patient presenting with recurrent ischemic stroke caused by BHS, which was revealed by carotid duplex ultrasonography. Carotid duplex ultrasonography performed in the neutral position showed normal findings. However, disappearance of end-diastolic blood flow of contralateral VAs was observed with head rotation. Digital subtraction angiography confirmed occlusion at C1/2 levels in the VA contralateral to the head rotation, bilaterally. Importantly, our patient did not recognize the association of head rotation and previous episodes of stroke. We suggest that BHS should be considered in patients with cryptogenic stroke occurring in the vertebrobasilar artery territory.

Postpartum migraines: a long-term prospective study.

OBJECTIVE: There are many reports regarding the course of migraines during pregnancy. However, the prevalence and characteristics of migraines during the postpartum period have not been adequately investigated. We prospectively investigated the patients suffering from migraines over a long postpartum period in an obstetrics department in Japan. METHODS: We investigated the course of migraines experienced during the postpartum period by patients in a postnatal ward. The patients were surveyed during the first postpartum week and 1, 3, 6 and 12 months after delivery. The patients were provided a headache diary to assess medication use and migraine attack frequency, severity (the faces pain scale) and duration. RESULTS: The migraine remission rate was 63%, 83% and 85% during the first, second and third trimesters, respectively. No patient experienced a worsening of headaches during pregnancy. Headache recurrence during the first month after delivery was more frequent in the patients >30 years of age than in those ≤30 years of age (p<0.05). The percentage of women experiencing recurrence at 1, 3, 6 and 12 months after delivery was 63%, 75%, 78% (n=60) and 87.5% (n=40), respectively. In breastfeeding patients, the rates were 50%, 65.8%, 71.1% and 91.7% and in bottle feeding patients, the rates were 86.4%, 90.9%, 95.5% and 81.3%, respectively. CONCLUSION: We found that 85% of the patients with migraines experience remission during pregnancy and that more than 50% experience recurrence during the first month after delivery. Until six months after delivery, breastfeeding is associated with a lower recurrence rate than bottle feeding.

Evaluation of olfaction in patients with migraine using an odour stick identification test.

AIMS: Peculiar characteristics of migraine headaches include the arousal of olfaction during the attacks and osmophobia. We performed an olfactory test to evaluate the association between olfaction and migraines. METHODS: We evaluated olfactory dysfunction in 80 migraine patients (31 experienced migraines with aura (MWA), 49 migraine without aura (MWOA)) and 30 healthy controls. Participants were assessed for concurrent osmophobia. Olfaction was evaluated using an odour stick identification test (OSIT), in which participants were asked to identify various odours during a migraine-free period. The degree of offensiveness of each odour was also evaluated. RESULTS: Sixty-three percent of migraine patients were found to have concurrent osmophobia (MWA 71%; MWOA 57%). The percentages of migraine patients and controls who correctly identified test odours were 91% (92%, MWA; 89%, MWOA) and 92%, respectively. Perfume, rose and Japanese cypress odours were more offensive to migraine patients than to controls. All test odours were found to be more offensive to MWA than to MWOA patients. CONCLUSIONS: The OSIT showed certain odours to be highly offensive to migraine patients even when they were not experiencing migraine headaches. More attention should be paid to odours that are perceived to be offensive by migraine patients, particularly those with MWA.