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.

The return of a former foe: syphilis with antiphospholipid syndrome as a cause of acute stroke.

This article highlights a rare complication of syphilis infection and the importance of including syphilis and antiphospholipid antibody testing in the acute stroke screen..

Clinical and laboratory predictors of deep vein thrombosis after acute stroke.

BACKGROUND: Deep vein thrombosis (DVT) is a common complication of acute stroke, but the new incidence in the era of improved specialist input in stroke care is yet unknown. The models for VTE diagnosis is well established, but prediction models to target at-risk patients for pharmacological prophylaxis is lacking and requires further research, particularly in the aftermath of acute stroke. OBJECTIVES: To predict DVT after acute stroke using markers of haemostatic activation and stroke severity scores. METHODS: We examined the clinical utility of laboratory factors such as thrombin generation, D-dimer, fibrinogen alongside clinical factors (National Institute of Health Stroke Scale and Barthel Index) in the prediction of asymptomatic DVT, among 92 consecutively admitted patients. RESULTS: One in five patients (19.6%) had objectively confirmed DVT (6 proximal, 12 distal). Thrombolytic therapy did not protect against DVT, with 21% (6/29) of patients treated with r-tPA went on to develop DVT. Thrombin generation and fibrinogen had no clinical utility, but D-dimer at baseline and week 2 had high clinical potential in the prediction of asymptomatic DVT (2425ng/mL versus 1010ng/mL; p=0.001) and (2240 Vs 970ng/mL; p<0.001) respectively. Patients with DVT had worse stroke severity, and are functionally less able, with lower Barthel index (p=0.05), and high National Institute of Health Stroke Score (p=0.07). CONCLUSION: Thrombolytic therapy and specialist stroke intervention does not protect against DVT risk. D-dimer concentration within 48h of acute stroke is independently associated with development of DVT. This observation would require confirmation in a large study.

Thrombin Generation in Acute Ischaemic Stroke.

Introduction. Stroke remains a global leading cause of death and disability. Traditional description of plasma biology in the aftermath of acute ischaemic stroke favours development of hypercoagulability, resulting from complex interplay between plasma and endothelial factors. However, no single assay measures the overall global coagulation process. We postulate that thrombin generation would assist in identifying coagulation abnormalities after acute stroke. Aim. To investigate the coagulation abnormalities after acute ischaemic stroke using thrombin generation. Methods. We evaluated thrombin generation, measured with calibrated automated thrombography in stroke of different aetiological types (n = 170) within 48 hours of symptoms onset (baseline) and in the second week (time 2) and in normal healthy volunteers (n = 71). Results. Two-point thrombin generation assays showed prolonged lag time and time to peak at baseline (3.3 (2.9, 4.0) versus 3.6 (3.2, 4.7); p = 0.005) and (3.3 (2.9, 4.0) versus 3.6 (3.2, 4.7); p = 0.002), respectively, and at time 2 (3.5 (2.9, 4.2) versus 4.0 (3.1, 4.9); p = 0.004) and (5.9 (5.3, 6.6) versus 6.8 (5.8, 7.7) p = 0.05), respectively, in cardioembolic stroke (n = 39), when compared to noncardioembolic stroke (n = 117). The result was reproduced in multiple comparisons between acute ischaemic stroke subgroups and normal healthy volunteers. Endogenous thrombin potential and peak thrombin did not indicate hypercoagulability after acute ischaemic stroke, and thrombolytic therapy did not affect thrombin generation assays. Conclusion. Our findings suggest that thrombin generation in platelet poor plasma is not useful in defining hypercoagulability in acute ischaemic stroke. This is similar to observed trend in coronary artery disease and contrary to other hypercoagulable states.

The evaluation of delirium post-stroke.

OBJECTIVE: The aim of this study was to assess and compare the Confusion Assessment Method (CAM) and the Delirium Rating Scale (DRS) in the detection of delirium in the acute stroke setting, when used by a non-psychiatrist doctor. METHODS: Consecutive participants within 4 days of an acute stroke were screened for delirium using the CAM and the DRS. Patients also had a Mini-Mental State Examination at each assessment. Patients were screened weekly for a maximum of 4 weeks. The CAM and DRS were compared against each other with respect to agreement and applicability. RESULTS: Of 110 eligible patients, 82 were recruited over a 7 month period. Delirium developed in 23 patients (28%), 21 of whom developed delirium during week 1. We found high agreement between the CAM and the DRS in the detection of stroke in the acute stroke setting (kappa values 0.97, 0.86, 0.79 and 1 at weeks 1, 2, 3 and 4, respectively). In addition, there was strong correlation between low MMSE scores (MMSE less that 10) and delirium (kappa scores 1.0, 0.82, 0.83 and 1.0 at weeks 1, 2, 3 and 4, respectively). CONCLUSIONS: Delirium is a common complication post-stroke. The CAM is equivalent to the DRS in the acute stroke setting when used by a trained non-psychiatrist. A low MMSE score may have a small benefit in identifying patients that are at risk of having delirium.

The course of delirium in acute stroke.

BACKGROUND AND PURPOSE: several studies have assessed delirium post-stroke but conflicting results have been obtained. Also, the natural history and outcome of delirium post-stroke need to be fully elucidated. METHODOLOGY: eligible stroke patients were assessed for delirium on admission and for four consecutive weeks using the Confusion Assessment Method (CAM). Risk factors for delirium were recorded. Our outcome measures were length of stay, inpatient mortality and discharge destination. RESULTS: of 110 eligible patients, 82 were recruited over 7 months. Delirium was detected in 23 patients (28%); 21 of these were delirious on their first assessment. Sixty-nine per cent of patients who had four weekly assessments were delirious at 4 weeks. Multivariate logistic regression analysis was performed, and two models were identified. With unsafe swallow in the analysis, delirium was associated with an unsafe swallow on admission (OR 28.4, P<0.001), Barthel score < 10 (OR 32.1, P = 0.004) and poor vision pre-stroke (OR 110.8, P = 0.01). With unsafe swallow removed from the analysis, delirium was associated with an admission C-reactive protein (CRP) > 5 mg/l (OR 10.2, P = 0.009), Barthel score < 10 (OR 46.5, P = 0.001) and poor vision pre-stroke (OR 85.2, P = 0.01). Delirious patients had a higher mortality (30.4% vs. 1.7%, P<0.001), longer length of stay (62.2 vs. 28.9 days, P<0.001) and increased risk of institutionalisation (43.7 vs. 5.2%, OR 14, P<0.001). CONCLUSIONS: delirium is common post-stroke. Most cases develop at stroke onset and remain delirious for an appreciable period. Delirium onset is associated with stroke severity (low admission Barthel), unsafe swallow on admission, poor vision pre-stroke and a raised admission CRP. Delirium is a marker of poor prognosis.

New onset diabetes complicated by haemolysis and rhabdomyolysis: a case report and review of the literature.

INTRODUCTION: Previously undiagnosed glucose-6-phosphate dehydrogenase (G6PD) deficiency can be unmasked by a diabetic crisis and both can be associated with rhabdomyolysis. The relationship between diabetes and G6PD deficiency is discussed and the possible triggers for haemolysis as outlined in this case report. The incidence of G6PD deficiency is 10% in African-American males and up to 35% in parts of Africa so an increased awareness of G6PD deficiency is important when treating diabetes in these populations. CASE PRESENTATION: A 54-year-old Kenyan man presented with a 3-day history of reduced appetite, weakness and reduced level of consciousness as a result of a hyperglycaemic diabetic crisis with both hyperosmolarity and ketoacidosis. The patient then developed haemolysis and a raised creatine kinase level. A diagnosis of G6PD deficiency and rhabdomyolysis was made. CONCLUSION: This case highlights the importance of simple laboratory investigations in the early identification of the rarer complications of diabetic crisis such as haemolysis secondary to G6PD deficiency and rhabdomyolysis.

Delirium post-stroke.

Delirium is not only one of the most common complications that older patients develop after admission to hospital but it is also one of the most serious. Although stroke is a known predisposing factor for delirium, few studies have investigated this association and results from existing studies give conflicting results with prevalence estimates ranging from 13 to 48%. The aetiology of delirium post-stroke is poorly understood. There is no consensus on the best screening tool to use to detect delirium in the post-stroke setting. Specific stroke types may be more likely to precipitate delirium than others, for example, delirium is more frequent after intracerebral haemorrhage and total anterior circulation infarction (TACI). In addition, case reports have suggested that delirium may be associated with specific lesions, for example, in the thalamus and caudate nucleus. There is a lack of intervention data in both the prevention and treatment of delirium post-stroke. However, it is known that the development of delirium post-stroke has grave prognostic implications. It is associated with longer stay in hospital, increased mortality and increased risk of institutionalisation post discharge. In this article, we review the literature to date on delirium in the acute stroke setting.

Effects of folic acid supplementation on psychomotor performance and hemorheology in healthy elderly subjects.

Cognitive impairment is associated with increased blood concentrations of homocysteine and high blood viscosity. Previous studies have shown that vitamin B supplementation reduces homocysteine and enhances cognitive function in patients with mild dementia and low serum folic acid. However, whether folic acid enhances cognitive function in elderly subjects without dementia and normal serum folic acid is unknown. Twenty-four healthy elderly subjects (age 73.0+/-5.6 years, mean+/-S.D.) with normal serum folic acid (6.3+/-2.4 microg/l) and Mini Mental State Examination (MMSE) >27/30 were randomized to 4-week treatment with folic acid 5mg/day or placebo in a randomized, placebo-controlled, parallel-group study. Continuous Attention Test (CAT), Four-Choice Reaction Time (FCRT), Digit-Symbol Substitution (DSS), Scanning Memory Sets (SMS), and blood viscosity for different shear rates were measured before and after treatment. Folic acid supplementation induced a significant increase in serum folic acid levels (+13.8 versus +1.6 microg/l, p<0.001) and fall in homocysteine levels (-1.91 versus -0.41 micromol/l, p=0.05) compared to placebo. However, there was no significant change in CAT, FCRT, DSS, SMS, and blood viscosity between the two groups. Short-term folic acid supplementation does not enhance psychomotor performance or reduce blood viscosity in healthy elderly subjects with normal serum folic acid levels and preserved cognitive function.

Altered megakaryocyte-platelet-haemostatic axis in patients with acute stroke.

Platelet function is accentuated in acute ischaemic stroke (IS) and may also be altered in haemorrhagic stroke. Whether these changes are a direct reaction to the stroke or are secondary to changes in megakaryocytes (MKs) is unknown. To determine whether MKs are altered in acute stroke we studied 24 patients (18 with ischaemic stroke, six with haemorrhagic stroke) within 3 days of symptom onset, and 14 matched controls. MK ploidy (DNA content, N), size (forward scatter, FSC, arbitrary units), granularity (side scatter, SSC, arbitrary units) and glycoprotein (GP) IIIa expression (arbitrary units) were assessed by flow cytometry. Platelet size (MPV, fl), platelet count (PC, x109/l), circulating reticulated platelets (%), and cutaneous bleeding time (s) were also measured. MK ploidy 22.5 (2.7) vs. 20.6 (1.7) (2p = 0.014); FSC 629 (51) vs. 594 (41) (2p = 0.025); and SSC 843 (88) vs. 776 (76) (2p = 0.020) were each increased, whereas bleeding time 318 (102) vs. 401 (94) (2p = 0.050) was decreased in patients with acute stroke as compared with controls. Trends to increased MK GP IIIa expression and reticulated platelets were also apparent. In a post hoc analysis, the increase in MK ploidy was most prominent in patients with a prior history of hypertension. Ischaemic stroke was associated with non-significant increases in MK ploidy, size, and granularity. However, MK parameters were different in acute haemorrhagic stroke as compared with controls: MK ploidy 23.0 (1.8) vs. 20.6 (1.7) (2p = 0.018); MK FSC 637 (21) vs. 594 (41) (2p = 0.050); MK SSC 872 (41) vs. 776 (76) (2p = 0.020), changes which could be related to the high prevalence of hypertension (83%) in this group. These results demonstrate that pro-thrombotic changes in the megakaryocyte-platelet-haemostatic axis (MPHA) are present in acute stroke. Although megakaryocyte changes are likely, in part, to be secondary to the stroke, they could also precede the stroke and therefore explain some of the increased platelet function observed in acute stroke.