Health-care professionals and researchers have a legal and ethical responsibility to inform patients before carrying out diagnostic tests or treatment interventions as part of a clinical study.... Show moreHealth-care professionals and researchers have a legal and ethical responsibility to inform patients before carrying out diagnostic tests or treatment interventions as part of a clinical study. Interventional research in emergency situations can involve patients with some degree of acute cognitive impairment, as is regularly the case in traumatic brain injury and ischaemic stroke. These patients or their proxies are often unable to provide informed consent within narrow therapeutic time windows. International regulations and national laws are criticised for being inconclusive or restrictive in providing solutions. Currently accepted consent alternatives are deferred consent, exception from consent, or waiver of consent. However, these alternatives appear under-utilised despite being ethically permissible, socially acceptable, and regulatorily compliant. We anticipate that, when the requirements for medical urgency are properly balanced with legal and ethical conduct, the increased use of these alternatives has the potential to improve the efficiency and quality of future emergency interventional studies in patients with an inability to provide informed consent. Show less
Background and Purpose:Optimal blood pressure (BP) targets before endovascular treatment (EVT) for acute ischemic stroke are unknown. We aimed to assess the relation between admission BP and... Show moreBackground and Purpose:Optimal blood pressure (BP) targets before endovascular treatment (EVT) for acute ischemic stroke are unknown. We aimed to assess the relation between admission BP and clinical outcomes and successful reperfusion after EVT.Methods:We used data from the MR CLEAN (Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry, an observational, prospective, nationwide cohort study of patients with ischemic stroke treated with EVT in routine clinical practice in the Netherlands. Baseline systolic BP (SBP) and diastolic BP (DBP) were recorded on admission. The primary outcome was the score on the modified Rankin Scale at 90 days. Secondary outcomes included successful reperfusion (extended Thrombolysis in Cerebral Infarction score 2B-3), symptomatic intracranial hemorrhage, and 90-day mortality. Multivariable logistic and linear regression were used to assess the associations of SBP and DBP with outcomes. The relations between BPs and outcomes were tested for nonlinearity. Parameter estimates were calculated per 10 mm Hg increase or decrease in BP.Results:We included 3180 patients treated with EVT between March 2014 and November 2017. The relations between admission SBP and DBP with 90-day modified Rankin Scale scores and mortality were J-shaped, with inflection points around 150 and 81 mm Hg, respectively. An increase in SBP above 150 mm Hg was associated with poor functional outcome (adjusted common odds ratio, 1.09 [95% CI, 1.04-1.15]) and mortality at 90 days (adjusted odds ratio, 1.09 [95% CI, 1.03-1.16]). Following linear relationships, higher SBP was associated with a lower probability of successful reperfusion (adjusted odds ratio, 0.97 [95% CI, 0.94-0.99]) and with the occurrence of symptomatic intracranial hemorrhage (adjusted odds ratio, 1.06 [95% CI, 0.99-1.13]). Results for DBP were largely similar.Conclusions:In patients with acute ischemic stroke treated with EVT, higher admission BP is associated with lower probability of successful reperfusion and with poor clinical outcomes. Further research is needed to investigate whether these patients benefit from BP reduction before EVT. Show less
BackgroundSome studies have suggested that transdermal administration of glyceryl trinitrate (GTN; nitroglycerin) in the first few hours after symptom onset increases the chance of a favourable... Show moreBackgroundSome studies have suggested that transdermal administration of glyceryl trinitrate (GTN; nitroglycerin) in the first few hours after symptom onset increases the chance of a favourable outcome after ischaemic stroke or intracerebral haemorrhage, possibly through an increase in intracranial collateral blood flow and a reduction in blood pressure. The Multicentre Randomised trial of Acute Stroke treatment in the Ambulance with a nitroglycerin Patch (MR ASAP) aims to assess the effect of transdermal GTN, started within 3 h after stroke onset in the prehospital setting, on functional outcome at 90days in patients with acute ischaemic stroke or intracerebral haemorrhage.MethodsMR ASAP is a phase III, multicentre, randomised, open-label clinical trial with a blinded outcome assessment. A total of 1400 adult patients with suspected stroke and a systolic blood pressure140mmHg will be randomised to transdermal GTN (5mg/day), administered as a transdermal patch by paramedics in the prehospital setting within 3h of stroke onset and continued for 24h or to standard care. The primary outcome is the score on the modified Rankin Scale (mRS) at 90days, analysed with ordinal logistic regression. Secondary outcomes include blood pressure and collateral circulation at hospital admission, neurological deficit measured with the National Institutes of Health Stroke Scale at 24h, and mortality and poor outcome (mRS score 3 to 6) at 90days. This trial will be conducted in the Netherlands and will use a deferred consent procedure. The trial is part of the Collaboration for New Treatments of Acute Stroke (CONTRAST) programme.DiscussionMR ASAP will assess whether very early administration of GTN improves outcome after stroke in a setting where rates of intravenous thrombolysis and endovascular treatment for acute ischaemic stroke are high. The deferred consent procedure facilitates prompt GTN treatment and will prevent delay to revascularisation therapies. If early transdermal GTN treatment proves to be effective, this low-cost treatment can be readily implemented into daily clinical practice.Trial registrationISRCTN Registry, ISRCTN99503308. Registered on 2 January 2018. Show less
Berg, S.A. van den; Boer, M. de; Meulen-de Jong, A.E. van der; Jansen, J.M.; Hoentjen, F.; Russel, M.G.V.M.; ... ; Boer, N.K.H. de 2016
High fat feeding induces a variety of obese and lean phenotypes in inbred rodents. Compared to Diet Resistant (DR) rodents, Diet Induced Obese (DIO) rodents are insulin resistant and have a reduced... Show moreHigh fat feeding induces a variety of obese and lean phenotypes in inbred rodents. Compared to Diet Resistant (DR) rodents, Diet Induced Obese (DIO) rodents are insulin resistant and have a reduced dopamine receptor D2 (DRD2) mediated tone. We hypothesized that this differing dopaminergic tone contributes to the distinct metabolic profiles of these animals. C57Bl6 mice were classified as DIO or DR based on their weight gain during 10 weeks of high fat feeding. Subsequently DIO mice were treated with the DRD2 agonist bromocriptine and DR mice with the DRD2 antagonist haloperidol for 2 weeks. Compared to DR mice, the bodyweight of DIO mice was higher and their insulin sensitivity decreased. Haloperidol treatment reduced the voluntary activity and energy expenditure of DR mice and induced insulin resistance in these mice. Conversely, bromocriptine treatment tended to reduce bodyweight and voluntary activity, and reinforce insulin action in DIO mice. These results show that DRD2 activation partly redirects high fat diet induced metabolic anomalies in obesity-prone mice. Conversely, blocking DRD2 induces an adverse metabolic profile in mice that are inherently resistant to the deleterious effects of high fat food. This suggests that dopaminergic neurotransmission is involved in the control of metabolic phenotype. Show less
