Penumbral Rescue by normobaric O = O administration in patients with ischemic stroke and target mismatch proFile (PROOF): Study protocol of a phase IIb trial.

RATIONALE: Oxygen is essential for cellular energy metabolism. Neurons are particularly vulnerable to hypoxia. Increasing oxygen supply shortly after stroke onset could preserve the ischemic penumbra until revascularization occurs. AIMS: PROOF investigates the use of normobaric oxygen (NBO) therapy within 6 h of symptom onset/notice for brain-protective bridging until endovascular revascularization of acute intracranial anterior-circulation occlusion. METHODS AND DESIGN: Randomized (1:1), standard treatment-controlled, open-label, blinded endpoint, multicenter adaptive phase IIb trial. STUDY OUTCOMES: Primary outcome is ischemic core growth (mL) from baseline to 24 h (intention-to-treat analysis). Secondary efficacy outcomes include change in NIHSS from baseline to 24 h, mRS at 90 days, cognitive and emotional function, and quality of life. Safety outcomes include mortality, intracranial hemorrhage, and respiratory failure. Exploratory analyses of imaging and blood biomarkers will be conducted. SAMPLE SIZE: Using an adaptive design with interim analysis at 80 patients per arm, up to 456 participants (228 per arm) would be needed for 80% power (one-sided alpha 0.05) to detect a mean reduction of ischemic core growth by 6.68 mL, assuming 21.4 mL standard deviation. DISCUSSION: By enrolling endovascular thrombectomy candidates in an early time window, the trial replicates insights from preclinical studies in which NBO showed beneficial effects, namely early initiation of near 100% inspired oxygen during short temporary ischemia. Primary outcome assessment at 24 h on follow-up imaging reduces variability due to withdrawal of care and early clinical confounders such as delayed extubation and aspiration pneumonia. TRIAL REGISTRATIONS: ClinicalTrials.gov: NCT03500939; EudraCT: 2017-001355-31.

[What's behind cerebellar dizziness? - News on diagnosis and therapy]. / Zerebellärer Schwindel, was steckt dahinter?

Vertigo and dizziness comprise a multisensory and multidisciplinary syndrome of different etiologies. The term "cerebellar vertigo and dizziness" comprises a heterogenous group of disorders with clinical signs of cerebellar dysfunction and is caused by vestibulo-cerebellar, vestibulo-spinal or cerebellar systems. About 10 % of patients in an outpatient clinic for vertigo and balance disorders suffer from cerebellar vertigo and dizziness. According to the course of the symptoms, one can considers 3 types: permanent complaints, recurrent episodes of vertigo and balance disorders, or an acute onset of complaints. The most common diagnoses in patients with cerebellar vertigo and dizziness were as follows: degenerative disease, hereditary forms and acquired forms. In a subgroup of patients with cerebellar vertigo, central cerebellar oculomotor dysfunction is indeed the only clinical correlate of the described symptoms. 81 % of patients with cerebellar vertigo suffer from permanent, persistent vertigo and dizziness, 31 % from vertigo attacks, and 21 % from both. Typical clinical cerebellar signs, including gait and limb ataxia or dysarthria, were found less frequently. Key to diagnosis is a focused history as well as a thorough clinical examination with particular attention to oculomotor function. Regarding oculomotor examination, the most common findings were saccadic smooth pursuit, gaze-evoked nystagmus, provocation nystagmus, rebound nystagmus, central fixation nystagmus, most commonly downbeat nystagmus, and disturbances of saccades. Thus, oculomotor examination is very sensitive in diagnosing cerebellar vertigo and dizziness, but not specific in distinguishing different etiologies. Laboratory examinations using posturography and a standardized gait analysis can support the diagnosis, but also help to estimate the risk of falls and to quantify the course and possible symptomatic treatment effects. Patients with cerebellar vertigo and dizziness should receive multimodal treatment.

Intravenous thrombolysis in acute ischemic stroke after antagonization of unfractionated heparin with protamine: case series and systematic review of literature.

Background and aims: Intravenous thrombolysis (IVT) is standard of care for disabling acute ischemic stroke (AIS) within a time window of ⩽ 4.5 h. Some AIS patients cannot be treated with IVT due to limiting contraindications, including heparin usage in an anticoagulating dose within the past 24 h or an elevated activated prothrombin time (aPTT) > 15 s. Protamine is a potent antidote to unfractionated heparin. Objectives: The objective of this study was to investigate the safety and efficacy of IVT in AIS patients after antagonization of unfractionated heparin with protamine. Methods: Patients from our stroke center (between January 2015 and September 2021) treated with IVT after heparin antagonization with protamine were analyzed. National Institutes of Health Stroke Scale (NIHSS) was used for stroke severity and modified Rankin Scale (mRS) for outcome assessment. Substantial neurological improvement was defined as the difference between admission and discharge NIHSS of ⩾8 or discharge NIHSS of ⩽1. Good outcome at follow-up after 3 months was defined as mRS 0-2. Safety data were obtained for mortality, symptomatic intracerebral hemorrhage (sICH), and for adverse events due to protamine. Second, a systematic review was performed searching PubMed and Scopus for studies and case reviews presenting AIS patients treated with IVT after heparin antagonization with protamine. The search was limited from January 1, 2011 to September 29, 2021. Furthermore, we conducted a propensity score matching comparing protamine-treated patients to a control IVT group without protamine (ratio 2:1, match tolerance 0.2). Results: A total of 16 patients, 5 treated in our hospital and 11 from literature, [65.2 ± 13.1 years, 37.5% female, median premorbid mRS (pmRS) 1 (IQR 1, 4)] treated with IVT after heparin antagonization using protamine were included and compared to 31 IVT patients [76.2 ± 10.9 years, 45% female, median pmRS 1 (IQR 0, 2)]. Substantial neurological improvement was evident in 68.8% of protamine-treated patients versus 38.7% of control patients (p = 0.028). Good clinical outcome at follow-up was observed in 56.3% versus 58.1% of patients (p = 0.576). No adverse events due to protamine were reported, one patient suffered sICH after secondary endovascular thrombectomy of large vessel occlusion. Mortality was 6.3% versus 22.6% (p = 0.236). Conclusion: IVT after heparin antagonization with protamine seems to be safe and, prospectively, may extend the number of AIS patients who can benefit from reperfusion treatment using IVT. Further prospective registry trials would be helpful to further investigate the clinical applicability of heparin antagonization.