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.

Temporal Profile of Pneumonia After Stroke.

BACKGROUND AND PURPOSE: The occurrence of pneumonia after stroke is associated with a higher risk of poor outcome or death. We assessed the temporal profile of pneumonia after stroke and its association with poor outcome at several time points to identify the most optimal period for testing pneumonia prevention strategies. METHODS: We analyzed individual patient data stored in the VISTA (Virtual International Stroke Trials Archive) from randomized acute stroke trials with an inclusion window up to 24 hours after stroke onset and assessed the occurrence of pneumonia in the first 90 days after stroke. Adjusted odds ratios and hazard ratios were calculated for the association between pneumonia and poor outcome and death by means of logistic and Cox proportional hazard regression, respectively, at different times of follow-up. RESULTS: Of 10 821 patients, 1017 (9.4%) had a total of 1076 pneumonias. Six hundred eighty-nine (64.0%) pneumonias occurred in the first week after stroke. The peak incidence was on the third day and the median time of onset was 4.0 days after stroke (interquartile range, 2-12). The presence of a pneumonia was associated with an increased risk of poor outcome (adjusted odds ratio, 4.8 [95% CI, 3.8-6.1]) or death (adjusted hazard ratio, 4.1 [95% CI, 3.7-4.6]). These associations were present throughout the 90 days of follow-up. CONCLUSIONS: Two out of 3 pneumonias in the first 3 months after stroke occur in the first week, with a peak incidence on the third day. The most optimal period to assess pneumonia prevention strategies is the first 4 days after stroke. However, pneumonia occurring later was also associated with poor functional outcome or death.

Regulatory delays in a multinational clinical stroke trial.

INTRODUCTION: The initiation and conduct of randomised clinical trials are complicated by multiple barriers, including delays in obtaining regulatory approvals. Quantitative data on the extent of the delays due to national or local review in randomised clinical trials is scarce. MATERIALS AND METHODS: We assessed the times needed to obtain regulatory approval and to initiate a trial site for an academic, EU-funded, phase III, randomised clinical trial of pharmacological prevention of complications in patients with acute stroke in over 80 sites in nine European countries. The primary outcome was the time from the first submission to a regulatory authority to initiation of a trial site. Secondary outcomes included time needed to complete each individual preparatory requirement and the number of patients recruited by each site in the first 6 and 12 months. RESULTS: The median time from the first submission to a regulatory authority to initiation of a trial site was 784 days (IQR: 586-1102). The single most time-consuming step was the conclusion of a clinical trial agreement between the national coordinator and the trial site, which took a median of 194 days (IQR: 93-293). A longer time to site initiation was associated with a lower patient recruitment rate in the first six months after initiation (B = -0.002; p = 0.02). CONCLUSION: In this EU-funded clinical trial, approximately 26 months were needed to initiate a trial site for patient recruitment. The conclusion of a contract with a trial site was the most time-consuming activity. To simplify and speed up the process, we suggest that the level of detail of contracts for academic trials should be proportional to the risks and commercial interests of these trials.

PRECIOUS: PREvention of Complications to Improve OUtcome in elderly patients with acute Stroke-statistical analysis plan of a randomised, open, phase III, clinical trial with blinded outcome assessment.

RATIONALE: Aspiration, infections, and fever are common in the first days after stroke, especially in older patients. The occurrence of these complications has been associated with an increased risk of death or dependency. AIMS AND DESIGN: PREvention of Complications to Improve OUtcome in elderly patients with acute Stroke (PRECIOUS) is an international, multi-centre, 3 × 2 factorial, randomised, controlled, open-label clinical trial with blinded outcome assessment, which will assess whether prevention of aspiration, infections, or fever with metoclopramide, ceftriaxone, paracetamol, respectively, or any combination of these in the first 4 days after stroke onset improves functional outcome at 90 days in elderly patients with acute stroke. DISCUSSION: This statistical analysis plan provides a technical description of the statistical methodology and unpopulated tables and figures. The paper is written prior to data lock and unblinding of treatment allocation. TRIAL REGISTRATION: ISRCTN registry ISRCTN82217627 . Registered on 22 September 2015. The trial was prospectively registered.

Signs of Pulmonary Infection on Admission Chest Computed Tomography Are Associated With Pneumonia or Death in Patients With Acute Stroke.

Background and Purpose- In patients with acute stroke, the occurrence of pneumonia has been associated with poor functional outcomes and an increased risk of death. We assessed the presence and consequences of signs of pulmonary infection on chest computed tomography (CT) before the development of clinically overt pneumonia. Methods- In 200 consecutive patients with acute ischemic stroke who had CT angiography from skull to diaphragm (including CT of the chest) within 24 hours of symptom onset, we assessed the presence of consolidation, ground-glass-opacity and the tree-in-bud sign as CT signs of pulmonary infection and assessed the association with the development of clinically overt pneumonia and death in the first 7 days and functional outcome after 90 days with logistic regression. Results- The median time from stroke onset to CT was 151 minutes (interquartile range, 84-372). Thirty patients (15%) had radiological signs of infection on admission, and 22 (11.0%) had a clinical diagnosis of pneumonia in the first 7 days. Patients with radiological signs of infection had a higher risk of developing clinically overt pneumonia (30% versus 7.6%; adjusted odds ratios, 4.2 [95% CI, 1.5-11.7]; P=0.006) and had a higher risk of death at 7 days (adjusted odds ratios, 3.7 [95% CI, 1.2-11.6]; P=0.02), but not at 90 days. Conclusions- About 1 in 7 patients with acute ischemic stroke had radiological signs of pulmonary infection within hours of stroke onset. These patients had a higher risk of clinically overt pneumonia or death. Early administration of antibiotics in these patients may lead to better outcomes.

Fever worsens outcomes in animal models of ischaemic stroke: A systematic review and meta-analysis.

BACKGROUND: Subfebrile temperatures and fever in the first days after stroke are associated with a greater risk of a poor outcome. If this relation is causal, prevention of hyperthermia may improve outcome. Causality can be tested in animal models. We therefore assessed the effects of hyperthermia on outcomes in animal models of ischaemic stroke and explored under which conditions prevention of hyperthermia could be most effective. METHODS: We performed a systematic review and meta-analysis of data from animal experiments testing the effect of spontaneous or induced hyperthermia on outcome after focal cerebral ischaemia. Our primary outcome measure was infarct size. Normalised mean differences were combined using the random effects model and stratified meta-analysis was used to explore the impact of study characteristics. RESULTS: We included 19 publications, reporting on 49 comparisons involving 603 animals. Overall, hyperthermia increased infarct size by 43.4% (95% confidence interval, 29.8-56.9%) and worsened neurobehavioral outcomes by 48.5% (17.2-79.8%). The increase in infarct size was larger with higher temperatures. Hyperthermia was most harmful if present for more than 2 h and when started at the time of artery occlusion rather than later. CONCLUSION: Hyperthermia substantially increased infarct size in animal models of ischaemic stroke, suggesting that the relation between fever and poor outcome observed in patients is at least in part causal. These data provide support to trials testing the effect of the prevention of fever with antipyretic drugs in patients with acute stroke.

[Broader indications for treatment of ischaemic stroke]. / Ruimere behandelindicaties voor herseninfarct.

Broader indications for treatment of ischaemic stroke Current guidelines suggest that selected patients with ischaemic stroke can be treated with intravenous thrombolysis or mechanical thrombectomy within 4.5 or 6 hours, respectively, after onset of the stroke. Recent developments in imaging have made it possible to distinguish permanently damaged brain tissue from brain tissue that is potentially salvageable after reperfusion, and recent trials have demonstrated that the window of time for intravenous thrombolysis and mechanical thrombectomy can be extended by selecting patients on the basis of the amount of potentially salvageable brain tissue. Patients with symptoms of acute stroke must be referred to a specialist stroke centre as soon as possible, even if more than 6 hours have passed since the onset of clinical symptoms.

PRECIOUS: PREvention of Complications to Improve OUtcome in elderly patients with acute Stroke. Rationale and design of a randomised, open, phase III, clinical trial with blinded outcome assessment.

BACKGROUND: Elderly patients are at high risk of complications after stroke, such as infections and fever. The occurrence of these complications has been associated with an increased risk of death or dependency.Hypothesis: Prevention of aspiration, infections, or fever with metoclopramide, ceftriaxone, paracetamol, or any combination of these in the first four days after stroke onset will improve functional outcome at 90 days in elderly patients with acute stroke. DESIGN: International, 3 × 2-factorial, randomised-controlled, open-label clinical trial with blinded outcome assessment (PROBE) in 3800 patients aged 66 years or older with acute ischaemic stroke or intracerebral haemorrhage and an NIHSS score ≥ 6. Patients will be randomly allocated to any combination of oral, rectal, or intravenous metoclopramide (10 mg thrice daily); intravenous ceftriaxone (2000 mg once daily); oral, rectal, or intravenous paracetamol (1000 mg four times daily); or usual care, started within 24 h after symptom onset and continued for four days or until complete recovery or discharge from hospital, if earlier.Outcome: The primary outcome measure is the score on the modified Rankin Scale at 90 days (± 14 days), as analysed with multiple regression.Summary: This trial will provide evidence for a simple, safe and generally available treatment strategy that may reduce the burden of death or disability in patients with stroke at very low costs.Planning: First patient included in May 2016; final follow-up of the last patient by April 2020.Registration: ISRCTN, ISRCTN82217627, https://doi.org/10.1186/ISRCTN82217627.

GABAergic Mechanisms in Schizophrenia: Linking Postmortem and In Vivo Studies.

Schizophrenia is a psychiatric disorder characterized by hallucinations, delusions, disorganized thinking, and impairments in cognitive functioning. Evidence from postmortem studies suggests that alterations in cortical γ-aminobutyric acid (GABAergic) neurons contribute to the clinical features of schizophrenia. In vivo measurement of brain GABA levels using magnetic resonance spectroscopy (MRS) offers the possibility to provide more insight into the relationship between problems in GABAergic neurotransmission and clinical symptoms of schizophrenia patients. This study reviews and links alterations in the GABA system in postmortem studies, animal models, and human studies in schizophrenia. Converging evidence implicates alterations in both presynaptic and postsynaptic components of GABAergic neurotransmission in schizophrenia, and GABA may thus play an important role in the pathophysiology of schizophrenia. MRS studies can provide direct insight into the GABAergic mechanisms underlying the development of schizophrenia as well as changes during its course.

Through-Plane Movement at Multiple Aortic Levels on Dynamic Computed Tomography Angiography Is Limited in Patients With an Abdominal Aortic Aneurysm.

PURPOSE: To analyze the movement of the aorta in the craniocaudal direction (through-plane movement) during the cardiac cycle at several levels to determine any potential impact on endovascular aneurysm repair (EVAR) of abdominal aortic aneurysm (AAA). METHODS: For this study, 30 patients (median age 73.0 years; 27 men) with an infrarenal AAA were randomly selected from a prospectively maintained EVAR database. All patients had undergone preoperative electrocardiogram-gated computed tomography angiography consisting of 8 phases. After semiautomatic segmentation, a 3-dimensional location probe was placed in the center of the aorta (center point) on the orthogonal slices at 12 different levels along the aorta and iliac arteries for all 8 phases. Movement of the center point during the cardiac cycle was analyzed for each level. Values are given as the median and interquartile range (IQR). RESULTS: The median through-plane movement of all levels was 3.0 mm (IQR 2.8-3.2) and appeared to be lower in the region of the celiac and renal arteries: 2.6 mm (IQR 1.7-3.1) at 3 cm proximal to the most distal renal artery and 2.4 mm (IQR 1.9-2.9) at 1 cm distal to the most distal renal artery, respectively. The thoracic part of the aorta showed the largest through-plane motion: 4.1 mm (IQR 2.7-4.6). CONCLUSION: This study quantifies aortic through-plane motion in the craniocaudal direction. Since through-plane movement appears to be limited, findings of previous studies investigating pulsatile in-plane distension seem to be representative for aortic distension.

Safety of a dedicated brain MRI protocol in patients with a vagus nerve stimulator.

Although implanted metallic devices constitute a relative contraindication to magnetic resonance imaging (MRI) scanning, the safety of brain imaging in a patient with a vagus nerve stimulator (VNS) is classified as "conditional," provided that specific manufacturer guidelines are followed when a transmit and receive head coil is used at 1.5 or 3.0 Tesla. The aim of this study was to evaluate the safety of performing brain MRI scans in patients with the VNS. From September 2009 until November 2011, 101 scans were requested in 73 patients with the VNS in The Netherlands. Patients were scanned according to the manufacturer's guidelines. No patient reported any side effect, discomfort, or pain during or after the MRI scan. In one patient, a lead break was detected based on device diagnostics after the MRI-scan. However, because no system diagnostics had been performed prior to MR scanning in this patient, it is unclear whether MR scanning was responsible for the lead break. The indication for most scans was epilepsy related. Twenty-six scans (26%) were part of a (new) presurgical evaluation and could probably better have been performed prior to VNS implantation. Performing brain MRI scans in patients with an implanted VNS is safe when a modified MRI protocol is followed.