Metoclopramide to Prevent Pneumonia in Patients With Stroke and a Nasogastric Tube: Data From the PRECIOUS Trial.

BACKGROUND: A randomized trial suggested that treatment with metoclopramide reduces the risk of pneumonia in patients with acute stroke and a nasogastric tube. We assessed whether this finding could be replicated in a post hoc analysis of the randomized PRECIOUS trial (Prevention of Complications to Improve Outcome in Elderly Patients With Acute Stroke). METHODS: PRECIOUS was an international, 3×2 partial-factorial, randomized controlled, open-label clinical trial with blinded outcome assessment assessing preventive treatment with metoclopramide, paracetamol, and ceftriaxone in patients aged ≥66 years with acute ischemic stroke or intracerebral hemorrhage and a National Institutes of Health Stroke Scale score ≥6. In the present study, we analyzed patients who had a nasogastric tube within 24 hours after randomization. Patients who were allocated to metoclopramide (10 mg TID) were compared with patients who were not. Treatment was started within 24 hours after symptom onset and continued for 4 days or until discharge if earlier. The primary outcome was pneumonia in the first week after stroke. The score on the modified Rankin Scale after 90 days was a secondary outcome and analyzed with ordinal logistic regression. RESULTS: From April 2016 through June 2022, a total of 1493 patients were enrolled with 1376 included in this analysis, of whom 1185 (86%) had ischemic stroke and 191 (14%) had intracerebral hemorrhage. The first day after randomization, 329 (23.9%) patients had a nasogastric tube, of whom 156 were allocated to metoclopramide and 173 to standard care. Metoclopramide was not associated with a reduction of pneumonia (41.0% versus 35.8%; adjusted odds ratio, 1.35 [95% CI, 0.79-2.30]) or with poor functional outcome (adjusted odds ratio, 1.07 [95% CI, 0.71-1.61]). CONCLUSIONS: In patients with stroke who had a nasogastric tube shortly after stroke onset, metoclopramide for 4 days did not reduce pneumonia or have an effect on the functional outcome.

Prevalence and 3-month follow-up of cerebrovascular MRI markers in hospitalized COVID-19 patients: the CORONIS study.

PURPOSE: To investigate the prevalence of cerebrovascular MRI markers in unselected patients hospitalized for COVID-19 (Coronavirus disease 2019), we compared these with healthy controls without previous SARS-CoV-2 infection or hospitalization and subsequently, investigated longitudinal (incidental) lesions in patients after three months. METHODS: CORONIS (CORONavirus and Ischemic Stroke) was an observational cohort study in adult hospitalized patients for COVID-19 and controls without COVID-19, conducted between April 2021 and September 2022. Brain MRI was performed shortly after discharge and after 3 months. Outcomes included recent ischemic (DWI-positive) lesions, previous infarction, microbleeds, white matter hyperintensities (WMH) and intracerebral hemorrhage and were analysed with logistic regression to adjust for confounders. RESULTS: 125 patients with COVID-19 and 47 controls underwent brain MRI a median of 41.5 days after symptom onset. DWI-positive lesions were found in one patient (1%) and in one (2%) control, both clinically silent. WMH were more prevalent in patients (78%) than in controls (62%) (adjusted OR: 2.95 [95% CI: 1.07-8.57]), other cerebrovascular MRI markers did not differ. Prevalence of markers in ICU vs. non-ICU patients was similar. After three months, five patients (5%) had new cerebrovascular lesions, including DWI-positive lesions (1 patient, 1.0%), cerebral infarction (2 patients, 2.0%) and microbleeds (3 patients, 3.1%). CONCLUSION: Overall, we found no higher prevalence of cerebrovascular markers in unselected hospitalized COVID-19 patients compared to controls. The few incident DWI-lesions were most likely to be explained by risk-factors of small vessel disease. In the general hospitalized COVID-19 population, COVID-19 shows limited impact on cerebrovascular MRI markers shortly after hospitalization.

Deferred Consent in an Acute Stroke Trial from a Patient, Proxy, and Physician Perspective: A Cross-Sectional Survey.

BACKGROUND: In some acute care trials, immediate informed consent is not possible, but deferred consent is often considered problematic. We investigated the opinions of patients, proxies, and physicians about deferred consent in an acute stroke trial to gain insight into its acceptability and effects. METHODS: Paper-based surveys were sent to patients who were randomly assigned in the Ultra-early Tranexamic Acid After Subarachnoid Hemorrhage (ULTRA) trial between 2015 and 2018 in two tertiary referral centers and to physicians of centers who agreed or declined to participate. The primary outcome measure was the proportion of respondents who agreed with deferral of consent in the ULTRA trial. Secondary outcomes included respondents' preferred consent procedure for the ULTRA trial, the effect of deferred consent on trust in physicians and scientific research, and the willingness to participate in future research. RESULTS: Eighty-nine of 135 (66%) patients or proxies and 20 of 30 (67%) physicians completed the survey. Of these, 82 of 89 (92%) patients or proxies and 14 of 20 (70%) physicians agreed with deferral of consent in the ULTRA trial. When asked for their preferred consent procedure for the ULTRA trial, 31 of 89 (35%) patients or proxies indicated deferred consent, 15 of 89 (17%) preferred immediate informed consent, and 32 of 89 (36%) had no preference. None of the patients' or proxies' trust in physicians or scientific research had decreased because of the deferred consent procedure. Willingness to participate in future studies remained the same or increased in 84 of 89 (94%) patients or proxies. CONCLUSIONS: A large majority of the surveyed patients and proxies and a somewhat smaller majority of the surveyed physicians agreed with deferred consent in the ULTRA trial. Deferred consent may enable acute care trials in an acceptable manner without decreasing trust in medicine. Future research should investigate factors facilitating the responsible use of deferred consent, such as in-depth interviews, to study the minority of participants who agreed with deferred consent but still preferred immediate informed consent.

Risk, Clinical Course, and Outcome of Ischemic Stroke in Patients Hospitalized With COVID-19: A Multicenter Cohort Study.

BACKGROUND AND PURPOSE: The frequency of ischemic stroke in patients with coronavirus disease 2019 (COVID-19) varies in the current literature, and risk factors are unknown. We assessed the incidence, risk factors, and outcomes of acute ischemic stroke in hospitalized patients with COVID-19. METHODS: We included patients with a laboratory-confirmed SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) infection admitted in 16 Dutch hospitals participating in the international CAPACITY-COVID registry between March 1 and August 1, 2020. Patients were screened for the occurrence of acute ischemic stroke. We calculated the cumulative incidence of ischemic stroke and compared risk factors, cardiovascular complications, and in-hospital mortality in patients with and without ischemic stroke. RESULTS: We included 2147 patients with COVID-19, of whom 586 (27.3%) needed treatment at an intensive care unit. Thirty-eight patients (1.8%) had an ischemic stroke. Patients with stroke were older but did not differ in sex or cardiovascular risk factors. Median time between the onset of COVID-19 symptoms and diagnosis of stroke was 2 weeks. The incidence of ischemic stroke was higher among patients who were treated at an intensive care unit (16/586; 2.7% versus nonintensive care unit, 22/1561; 1.4%; P=0.039). Pulmonary embolism was more common in patients with (8/38; 21.1%) than in those without stroke (160/2109; 7.6%; adjusted risk ratio, 2.08 [95% CI, 1.52-2.84]). Twenty-seven patients with ischemic stroke (71.1%) died during admission or were functionally dependent at discharge. Patients with ischemic stroke were at a higher risk of in-hospital mortality (adjusted risk ratio, 1.56 [95% CI, 1.13-2.15]) than patients without stroke. CONCLUSIONS: In this multicenter cohort study, the cumulative incidence of acute ischemic stroke in hospitalized patients with COVID-19 was ≈2%, with a higher risk in patients treated at an intensive care unit. The majority of stroke patients had a poor outcome. The association between ischemic stroke and pulmonary embolism warrants further investigation.

White matter integrity in hospitalized COVID-19 patients is not associated with short- and long-term clinical outcomes.

Objectives: SARS-CoV-2 infection is associated with a decline in functional outcomes; many patients experience persistent symptoms, while the underlying pathophysiology remains unclear. This study investigated white matter (WM) integrity on brain MRI in hospitalized COVID-19 patients and its associations with clinical outcomes, including long COVID. Materials and methods: We included hospitalized COVID-19 patients and controls from CORONavirus and Ischemic Stroke (CORONIS), an observational cohort study, who underwent MRI-DWI imaging at baseline shortly after discharge (<3 months after positive PCR) and 3 months after baseline scanning. We assessed WM integrity using diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) and performed comparisons between groups and within patients. Clinical assessment was conducted at 3 and 12 months with functional outcomes such as modified Rankin Scale (mRS), Post-COVID-19 Functional Status scale (PCFS), Visual Analogue Scale (VAS), and long COVID, cognitive assessment was conducted by the Modified Telephone Interview for Cognitive Status (TICS-M), and the Hospital Anxiety and Depression Scale (HADS) was used to assess mood disorder. Associations between WM integrity and clinical outcomes were evaluated using logistic regression and linear regression. Results: A total of 49 patients (mean age 59.5 years) showed higher overall peak width of skeletonized mean diffusivity (PSMD) (p = 0.030) and lower neurite density index (NDI) in several WM regions compared with 25 controls at the baseline (p < 0.05; FWE-corrected) but did not remain statistically significant after adjusting for WM hyperintensities. Orientation dispersion index (ODI) increased after 3-month follow-up in several WM regions within patients (p < 0.05), which remained significant after correction for changes in WMH volume. Patients exhibited worse clinical outcomes compared with controls. Low NDI at baseline was associated with worse performance on the Post-COVID-19 Functional Status scale after 12 months (p = 0.018). Conclusion: After adjusting for WMH, hospitalized COVID-19 patients no longer exhibited lower WM integrity compared with controls. WM integrity was generally not associated with clinical assessments as measured shortly after discharge, suggesting that factors other than underlying WM integrity play a role in worse clinical outcomes or long COVID.

Prevention of infections and fever to improve outcome in older patients with acute stroke (PRECIOUS): a randomised, open, phase III, multifactorial, clinical trial with blinded outcome assessment.

Background: Infections and fever after stroke are associated with poor functional outcome or death. We assessed whether prophylactic treatment with anti-emetic, antibiotic, or antipyretic medication would improve functional outcome in older patients with acute stroke. Methods: We conducted an international, 2∗2∗2-factorial, randomised, controlled, open-label trial with blinded outcome assessment in patients aged 66 years or older with acute ischaemic stroke or intracerebral haemorrhage and a score on the National Institutes of Health Stroke Scale ≥ 6. Patients were randomly allocated (1:1) to metoclopramide (oral, rectal, or intravenous; 10 mg thrice daily) vs. no metoclopramide, ceftriaxone (intravenous; 2000 mg once daily) vs. no ceftriaxone, and paracetamol (oral, rectal, or intravenous; 1000 mg four times daily) vs. no paracetamol, started within 24 h after symptom onset and continued for four days. All participants received standard of care. The target sample size was 3800 patients. The primary outcome was the score on the modified Rankin Scale (mRS) at 90 days analysed with ordinal logistic regression and reported as an adjusted common odds ratio (an acOR < 1 suggests benefit and an acOR > 1 harm). This trial is registered (ISRCTN82217627). Findings: From April 2016 through June 2022, 1493 patients from 67 European sites were randomised to metoclopramide (n = 704) or no metoclopramide (n = 709), ceftriaxone (n = 594) or no ceftriaxone (n = 482), and paracetamol (n = 706) or no paracetamol (n = 739), of whom 1471 were included in the intention-to-treat analysis. Prophylactic use of study medication did not significantly alter the primary outcome at 90 days: metoclopramide vs. no metoclopramide (adjusted common odds ratio [acOR], 1.01; 95% CI 0.81-1.25), ceftriaxone vs. no ceftriaxone (acOR 0.99; 95% CI 0.77-1.27), paracetamol vs. no paracetamol (acOR 1.19; 95% CI 0.96-1.47). The study drugs were safe and not associated with an increased incidence of serious adverse events. Interpretation: We observed no sign of benefit of prophylactic use of metoclopramide, ceftriaxone, or paracetamol during four days in older patients with a moderately severe to severe acute stroke. Funding: This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No: 634809.

Timing and causes of death after endovascular thrombectomy in patients with acute ischemic stroke.

Introduction: Endovascular thrombectomy (EVT) increases the chance of good functional outcome after ischemic stroke caused by a large vessel occlusion, but the risk of death in the first 90 days is still considerable. We assessed the causes, timing and risk factors of death after EVT to aid future studies aiming to reduce mortality. Patients and methods: We used data from the MR CLEAN Registry, a prospective, multicenter, observational cohort study of patients treated with EVT in the Netherlands between March 2014, and November 2017. We assessed causes and timing of death and risk factors for death in the first 90 days after treatment. Causes and timing of death were determined by reviewing serious adverse event forms, discharge letters, or other written clinical information. Risk factors for death were determined with multivariable logistic regression. Results: Of 3180 patients treated with EVT, 863 (27.1%) died in the first 90 days. The most common causes of death were pneumonia (215 patients, 26.2%), intracranial hemorrhage (142 patients, 17.3%), withdrawal of life-sustaining treatment because of the initial stroke (110 patients, 13.4%) and space-occupying edema (101 patients, 12.3%). In total, 448 patients (52% of all deaths) died in the first week, with intracranial hemorrhage as most frequent cause. The strongest risk factors for death were hyperglycemia and functional dependency before the stroke and severe neurological deficit at 24-48 h after treatment. Discussion and conclusion: When EVT fails to decrease the initial neurological deficit, strategies to prevent complications like pneumonia and intracranial hemorrhage after EVT could improve survival, as these are often the cause of death.

Preventive ceftriaxone in patients at high risk of stroke-associated pneumonia. A post-hoc analysis of the PASS trial.

BACKGROUND: Infections complicate the acute phase of stroke in one third of patients and especially pneumonia is associated with increased risk of death or dependency. In randomized trials of stroke patients, preventive antibiotics reduced overall infections, but did not reduce pneumonia or improve outcome. This may be explained by broad selection criteria, including many patients with a low risk of pneumonia. To assess the potential of selection of patients at high risk of pneumonia, we performed a post-hoc analysis in the Preventive Antibiotics in Stroke Study (PASS). METHODS: PASS was a multicentre phase 3 trial in acute stroke patients who were randomized to preventive ceftriaxone for four days within 24 hours or standard care. For this analysis patients were divided based on the ISAN risk score for pneumonia as follows: low (0-6), medium (7-14) and high (15-21). Primary outcomes were pneumonia rate during admission as judged by the treating physician, and by an independent committee; secondary outcomes were overall infections and unfavorable outcome (modified Rankin Scale ≥3). We adjusted with multivariable regression for possible confounders: age, stroke subtype and severity, pre-stroke dependency and diabetes. RESULTS: Pneumonia occurred more frequently in higher risk groups (25.7% (high), 9.0% (medium) 1.5%, (low)). The absolute difference in pneumonia rate between patients treated with ceftriaxone or standard care increased with the ISAN score (low: 0.5%, medium: 1.2%, high: 10.1%). After adjustment ceftriaxone reduced overall infections in the low and medium groups, not in the high-risk group. There was a trend towards reduction of pneumonia as judged by the committee (3.7% vs 13.6%, aOR = 0.164, p = 0.063) in the high-risk group. CONCLUSIONS: This post-hoc analysis of PASS confirmed higher rates of pneumonia with higher ISAN scores, and suggests that in acute stroke patients with an ISAN score of ≥15, preventive ceftriaxone for four days may reduce pneumonia rate.

Prevalence, risk factors, and long-term outcomes of cerebral ischemia in hospitalized COVID-19 patients - study rationale and protocol of the CORONIS study: A multicentre prospective cohort study.

Background: COVID-19 is often complicated by thrombo-embolic events including ischemic stroke. The underlying mechanisms of COVID-19-associated ischemic stroke, the incidence and risk factors of silent cerebral ischemia, and the long-term functional outcome in these patients are currently unknown. Patients and methods: CORONavirus and Ischemic Stroke (CORONIS) is a multicentre prospective cohort study investigating the prevalence, risk factors and long-term incidence of (silent) cerebral ischemia, and the long-term functional outcome among patients with COVID-19. We aim to include 200 adult patients hospitalized with COVID-19 without symptomatic ischemic stroke to investigate the prevalence of silent cerebral ischemia compared with 60 (matched) controls with MRI. In addition, we will identify potential risk factors and/or causes of cerebral ischemia in COVID-19 patients with (n = 70) or without symptomatic stroke (n = 200) by means of blood sampling, cardiac workup and brain MRI. We will measure functional outcome and cognitive function after 3 and 12 months with standardized questionnaires in all patients with COVID-19. Finally, the long-term incidence of (new) silent cerebral ischemia in patients with COVID-19 will be assessed with follow up MRI (n = 120). Summary: The CORONIS study is designed to add further insight into the prevalence, long-term incidence and risk factors of cerebral ischemia, and the long-term functional outcome in hospitalized adult patients with COVID-19.

Assessment of Recurrent Stroke Risk in Patients With a Carotid Web.

Importance: A carotid web (CW) is a shelf-like lesion along the posterior wall of the internal carotid artery bulb and an underrecognized cause of young stroke. Several studies suggest that patients with symptomatic CW have a high risk of recurrent stroke, but high-quality data are lacking. Objective: To assess the 2-year risk of recurrent stroke in patients with a symptomatic CW. Design, Setting, and Participants: A comparative cohort study used data from the MR CLEAN trial (from 2010-2014) and MR CLEAN Registry (from 2014-2017). Data were analyzed in September 2020. The MR CLEAN trial and MR CLEAN Registry were nationwide prospective multicenter studies on endovascular treatment (EVT) of large vessel occlusion (LVO) stroke in the Netherlands. Baseline data were from 3439 consecutive adult patients with anterior circulation LVO stroke and available computed tomography (CT)-angiography of the carotid bulb. Two neuroradiologists reevaluated CT-angiography images for presence or absence of CW and identified 30 patients with CW ipsilateral to the index stroke. For these 30 eligible CW participants, detailed follow-up data regarding stroke recurrence within 2 years were acquired. These 30 patients with CW ipsilateral to the index stroke were compared with 168 patients without CW who participated in the MR CLEAN extended follow-up trial and who were randomized to the EVT arm. Main Outcomes and Measures: The primary outcome was recurrent stroke occurring within 2 years after the index stroke. Cox proportional hazards regression models were used to compare recurrent stroke rates within 2 years for patients with and without CW, adjusted for age and sex. The research question was formulated prior to data collection. Results: Of 3439 patients with baseline CT-angiography assessed, the median age was 72 years (interquartile range, 61-80 years) and 1813 (53%) were men. Patients with CW were younger (median age, 57 [interquartile range, 46-66] years vs 66 [interquartile range, 56-77] years; P = .02 and more often women (22 of 30 [73%] vs 67 of 168 [40%]; P = .001) than patients without CW. Twenty-eight of 30 patients (93%) received medical management after the index stroke (23 with antiplatelet therapy and 5 with anticoagulant therapy). During 2 years of follow-up, 5 of 30 patients (17%) with CW had a recurrent stroke compared with 5 of 168 patients (3%) without CW (adjusted hazard ratio, 4.9; 95% CI, 1.4-18.1). Conclusions and Relevance: In this study, 1 of 6 patients with a symptomatic CW had a recurrent stroke within 2 years, suggesting that medical management alone may not provide sufficient protection for patients with CW.