A Randomised Controlled Trial of SFX-01 After Subarachnoid Haemorrhage - The SAS Study.

SFX-01 is a novel drug for clinical delivery of sulforaphane (SFN). SFN is a potent nuclear factor erythroid 2-related factor 2 activator that reduces inflammation and oxidation, improving outcomes after subarachnoid haemorrhage (SAH) in animal models. This was a multi-centre, double-blind, placebo-controlled, parallel-group randomised clinical trial to evaluate the safety, pharmacokinetics and efficacy of 28 days of SFX-01 300 mg BD in patients aged 18-80 with spontaneous SAH and high blood load on CT. Primary outcomes were (1) safety, (2) plasma and CSF SFN and metabolite levels and (3) vasospasm on transcranial doppler ultrasound. Secondary outcomes included CSF haptoglobin and malondialdehyde and clinical outcome on the modified Rankin Scale (mRS) and SAH outcome tool (SAHOT). A total of 105 patients were randomised (54 SFX-01, 51 placebo). There were no differences in adverse events other than nausea (9 SFX-01 (16.7%), 1 placebo (2.0%)). SFN, SFN-glutathione and SFN-N-acetyl-cysteine AUClast were 16.2, 277 and 415 h × ng/ml. Plasma SFN was higher in GSTT1 null individuals (t = 2.40, p = 0.023). CSF levels were low with many samples below the lower limit of quantification and predicted by the CSF/serum albumin ratio (R2 = 0.182, p = 0.039). There was no difference in CSF haptoglobin (1.981 95%CI 0.992-3.786, p = 0.052) or malondialdehyde (1.12 95%CI 0.7477-1.687, p = 0.572) or middle cerebral artery flow velocity (1.04 95%CI 0.903-1.211, p = 0.545) or functional outcome (mRS 1.647 95%CI 0.721-3.821, p = 0.237, SAHOT 1.082 95%CI 0.464-2.525, p = 0.855). SFX-01 is safe and effective for the delivery of SFN in acutely unwell patients. SFN penetrated CSF less than expected and did not reduce large vessel vasospasm or improve outcome. Trial registration: NCT02614742 clinicaltrials.gov.

Cost-effectiveness of craniotomy versus decompressive craniectomy for UK patients with traumatic acute subdural haematoma.

OBJECTIVE: To estimate the cost-effectiveness of craniotomy, compared with decompressive craniectomy (DC) in UK patients undergoing evacuation of acute subdural haematoma (ASDH). DESIGN: Economic evaluation undertaken using health resource use and outcome data from the 12-month multicentre, pragmatic, parallel-group, randomised, Randomised Evaluation of Surgery with Craniectomy for Patients Undergoing Evacuation-ASDH trial. SETTING: UK secondary care. PARTICIPANTS: 248 UK patients undergoing surgery for traumatic ASDH were randomised to craniotomy (N=126) or DC (N=122). INTERVENTIONS: Surgical evacuation via craniotomy (bone flap replaced) or DC (bone flap left out with a view to replace later: cranioplasty surgery). MAIN OUTCOME MEASURES: In the base-case analysis, costs were estimated from a National Health Service and Personal Social Services perspective. Outcomes were assessed via the quality-adjusted life-years (QALY) derived from the EuroQoL 5-Dimension 5-Level questionnaire (cost-utility analysis) and the Extended Glasgow Outcome Scale (GOSE) (cost-effectiveness analysis). Multiple imputation and regression analyses were conducted to estimate the mean incremental cost and effect of craniotomy compared with DC. The most cost-effective option was selected, irrespective of the level of statistical significance as is argued by economists. RESULTS: In the cost-utility analysis, the mean incremental cost of craniotomy compared with DC was estimated to be -£5520 (95% CI -£18 060 to £7020) with a mean QALY gain of 0.093 (95% CI 0.029 to 0.156). In the cost-effectiveness analysis, the mean incremental cost was estimated to be -£4536 (95% CI -£17 374 to £8301) with an OR of 1.682 (95% CI 0.995 to 2.842) for a favourable outcome on the GOSE. CONCLUSIONS: In a UK population with traumatic ASDH, craniotomy was estimated to be cost-effective compared with DC: craniotomy was estimated to have a lower mean cost, higher mean QALY gain and higher probability of a more favourable outcome on the GOSE (though not all estimated differences between the two approaches were statistically significant). ETHICS: Ethical approval for the trial was obtained from the North West-Haydock Research Ethics Committee in the UK on 17 July 2014 (14/NW/1076). TRIAL REGISTRATION NUMBER: ISRCTN87370545.

A pilot clinical study to estimate intracranial pressure utilising cerebral photoplethysmograms in traumatic brain injury patients.

PURPOSE: In this research, a non-invasive intracranial pressure (nICP) optical sensor was developed and evaluated in a clinical pilot study. The technology relied on infrared light to probe brain tissue, using photodetectors to capture backscattered light modulated by vascular pulsations within the brain's vascular tissue. The underlying hypothesis was that changes in extramural arterial pressure could affect the morphology of recorded optical signals (photoplethysmograms, or PPGs), and analysing these signals with a custom algorithm could enable the non-invasive calculation of intracranial pressure (nICP). METHODS: This pilot study was the first to evaluate the nICP probe alongside invasive ICP monitoring as a gold standard. nICP monitoring occurred in 40 patients undergoing invasive ICP monitoring, with data randomly split for machine learning. Quality PPG signals were extracted and analysed for time-based features. The study employed Bland-Altman analysis and ROC curve calculations to assess nICP accuracy compared to invasive ICP data. RESULTS: Successful acquisition of cerebral PPG signals from traumatic brain injury (TBI) patients allowed for the development of a bagging tree model to estimate nICP non-invasively. The nICP estimation exhibited 95% limits of agreement of 3.8 mmHg with minimal bias and a correlation of 0.8254 with invasive ICP monitoring. ROC curve analysis showed strong diagnostic capability with 80% sensitivity and 89% specificity. CONCLUSION: The clinical evaluation of this innovative optical nICP sensor revealed its ability to estimate ICP non-invasively with acceptable and clinically useful accuracy. This breakthrough opens the door to further technological refinement and larger-scale clinical studies in the future. TRIAL REGISTRATION: NCT05632302, 11th November 2022, retrospectively registered.