Cerebral oedema after reperfusion therapy in patients with ischaemic stroke : predictors, outcomes and treatment

Introduction: Reperfusion therapy by intravenous thrombolysis (IVT) and/or endovascular thrombectomy (EVT) are established treatments in ischaemic stroke. Cerebral oedema (COED), caused by dysfunction the blood brain barrier (BBB), is common early after acute ischaemic stroke (AIS), can aggravate the symptoms and worsen the prognosis. Data on predictors and the effect of recanalization on early COED is limited. A large infarction with COED involving the middle cerebral artery (MCA) can be life-threatening. Decompressive hemicraniectomy (DHC) reduces mortality and may have a positive effect on functional outcome in younger patients. Animal data suggest that imatinib, a tyrosine kinase inhibitor, may restore BBB integrity, thereby reducing haemorrhagic transformation (HT) and COED. The aim of this doctoral thesis was to contribute to the understanding of clinical aspects of COED in patients with AIS of the anterior circulation. Methods: Paper I, II and IV reported retrospective, observational studies using data from the Safe Implementations of Treatments in Stroke (SITS) International Stroke Registry, a prospective, multinational registry. These studies included patient data recorded using the SITS Registry data collection protocols for IVT and EVT, and to some extent general stroke, in time periods between 2002 and 2019. All patients had presumed ischaemic stroke. Paper III reported a phase 2, randomized, open-label, pilot study of imatinib in patients who received IVT after ischaemic stroke at 5 hospitals in Stockholm 2011-2014. All papers evaluated COED using the SITS COED scale (no, mild, moderate or severe COED). Outcomes at 3 months were functional outcome using the modified Rankin scale (mRS) score and death of any cause. Results: In paper I, the most important predictors of COED after AIS were assessed. Among 42 187 patients (median age 70 years), 12.5% had mild COED on follow-up imaging (22-36 hours or any extra investigation) and 10.2% had moderate or severe COED. Baseline National Institutes of Health Stroke Scale (NIHSS) score, followed by hyperdense artery sign (HAS), were the strongest predictors for COED. Additionally, higher blood glucose, impaired level of consciousness and imaging signs of early infarction at baseline were predictors for COED. Increasing degree of COED at 22-36 hours was associated with increasing mortality and worse functional outcome at 3 months. In paper II, the effect of recanalization on COED was assessed. Reperfusion therapy was administered to the 22 184 patients (median age 71 years and NIHSS score 16): only IVT (82.6%), IVT and EVT (13.8%) or only EVT (3.6%). Overall, recanalization was associated with a 10.6% (p<0.001) absolute risk reduction of moderate to severe COED at 22-36 hours, relative risk (RR) 0.55 (95% CI 0.52-0.58). Two models with high predictive ability provided the following estimates: adjusted OR 0.52 (95% CI, 0.46-0.59) and, with additional adjustment for parenchymal haemorrhage (PH), OR 0.46 (95% CI, 0.41-0.52). Moreover, recanalization was associated with a 13.6% (p<0.001) absolute reduction of mortality at 3 months, RR 0.58 (95% CI 0.55-0.61), adjusted OR 0.48 (95% CI 0.45-0.53). In paper III, 60 patients were randomized (15 patients in low-dose, 14 patients in medium and high-dose and 17 patients in control). Four serious adverse events (2 in control and 2 in low-dose group) resulted in the death of 3 patients. Of the dead patients 2 were allocated to low-dose group but of these, 1 did not receive imatinib and 1 patient had received only 2 doses. In the per protocol analysis, there were 21 haemorrhagic infarctions (6 in control), 3 PH (1 in control) and 4 remote parenchymal haemorrhages (0 in control). There were 33 cases of COED with moderate to severe COED being less frequent with higher doses, and no cases of moderate to severe COED in the high-dose group. After adjustment for EVT, the mean improvement in the NIHSS score compared to controls was 2 points (p=0.259) for the low-dose group, 3 points (p=0.106) for the medium-dose groups and 5 points (p=0.012) for the high-dose group. Functional independence (mRS 0-2) at 3 months was observed in 61% of the control group and 72% of all imatinib-treated patients; OR, adjusted for EVT, was 2.33 (95% CI 0.48-11.44). Paper IV reported anterior circulation AIS patients that underwent DHC. In 684 patients from 35 countries median age was 56 years and NIHSS score at baseline 18 and 98.1% received reperfusion therapy. Moderate to severe COED was detected in in 76.0% and PH in 25.8% at 22-36 hours follow-up imaging scans. Surgery-related details, for example timing of DHC, were not registered. Mortality at 3 months was 32.7% (159/486). Among baseline variables, only increasing age was independently associated with death (OR 1.06, 95% CI 1.03-1.08). Good outcome (mRS 0-3) at 3 months was observed in 13.9% (66/475) and mRS 0-4 was observed in 39.4% (187/475). Outcomes differed between patients aged ≤60 years ≥61 years (25.2% versus 47.8% for mortality and 16.6% versus 8.4% for good outcome). Right-sided involvement of vascular territory was more common than left-sided. Conclusions: The most important baseline predictors for early COED are NIHSS score, HAS, higher blood glucose, decreased level of consciousness, and signs of acute infarction at baseline. This finding can be used to improve selection and monitoring of patients for drug or surgical treatment. In patients with AIS, recanalization was associated with a lower risk for early COED even after adjustment for higher rate of PH in recanalized patients. Imatinib is safe and tolerable and may reduce neurological disability in patients treated with IVT after AIS. A confirmatory randomized trial is ongoing. DHC in routine clinical practice may have worse outcomes than randomized trials, although there are caveats due to short follow-up of the patients in this study. Right-sided arterial occlusions were more common than left-sided, which indicates a tendency to perform DHC in infarctions of the right hemisphere. In general, this doctoral thesis added new knowledge about several aspects of COED in AIS and a potential new pharmacological therapy for acute ischaemic stroke. Further research is required to confirm these results which are based on 3 retrospective observational studies and one phase 2 pilot study. In fact, an efficacy trial of imatinib is now ongoing

Predictors for cerebral edema in acute ischemic stroke treated with intravenous thrombolysis

Cerebral edema (CED) is a severe complication of acute ischemic stroke. There is uncertainty regarding the predictors for the development of CED after cerebral infarction. We aimed to determine which baseline clinical and radiological parameters predict development of CED in patients treated with intravenous thrombolysis. We used an image-based classification of CED with 3 degrees of severity (less severe CED 1 and most severe CED 3) on postintravenous thrombolysis imaging scans. We extracted data from 42 187 patients recorded in the SITS International Register (Safe Implementation of Treatments in Stroke) during 2002 to 2011. We did univariate comparisons of baseline data between patients with or without CED. We used backward logistic regression to select a set of predictors for each CED severity. CED was detected in 9579/42 187 patients (22.7%: 12.5% CED 1, 4.9% CED 2, 5.3% CED 3). In patients with CED versus no CED, the baseline National Institutes of Health Stroke Scale score was higher (17 versus 10; P&#60;0.001), signs of acute infarct was more common (27.9% versus 19.2%; P&#60;0.001), hyperdense artery sign was more common (37.6% versus 14.6%; P&#60;0.001), and blood glucose was higher (6.8 versus 6.4 mmol/L; P&#60;0.001). Baseline National Institutes of Health Stroke Scale, hyperdense artery sign, blood glucose, impaired consciousness, and signs of acute infarct on imaging were independent predictors for all edema types. The most important baseline predictors for early CED are National Institutes of Health Stroke Scale, hyperdense artery sign, higher blood glucose, decreased level of consciousness, and signs of infarct at baseline. The findings can be used to improve selection and monitoring of patients for drug or surgical treatment

Association of cholesterol levels with hemorrhagic transformation and cerebral edema after reperfusion therapies

[Background] The association between cholesterol levels and cerebral edema (CED) or hemorrhagic transformation (HT) as an expressions of blood-brain barrier (BBB) dysfunction after ischemic stroke is not well established. The aim of this study is to determine the association of total cholesterol (TC) levels with the incidence of HT and CED after reperfusion therapies.[Methods] We analyzed SITS Thrombolysis and Thrombectomy Registry data from January 2011 to December 2017. We identified patients with data on TC levels at baseline. TC values were categorized in three groups (reference group ⩾200 mg/dl). The two primary outcomes were any parenchymal hemorrhage (PH) and moderate to severe CED on follow up imaging. Secondary outcomes included death and functional independence (mRS 0–2) at 3 months. Multivariable logistic regression analysis adjusted for baseline factors including statin pretreatment was used to assess the association between TC levels and outcomes.[Results] Of 35,314 patients with available information on TC levels at baseline, 3372 (9.5%) presented with TC levels ⩽130 mg/dl, 8203 (23.2%) with TC 130–200 mg/dl and 23,739 (67.3%) with TC ⩾ 200 mg/dl. In the adjusted analyses, TC level as continuous variable was inversely associated with moderate to severe CED (OR 0.99, 95% CI 0.99–1.00, p = 0.025) and as categorical variable lower TC levels were associated with a higher risk of moderate to severe CED (aOR 1.24, 95% CI 1.10–1.40, p = 0.003). TC levels were not associated with any PH, functional independence, and mortality at 3 months.[Conclusions] Our findings indicate an independent association between low levels of TC and higher odds of moderate/severe CED. Further studies are needed to confirm these findings.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The SITS registry is financed directly and indirectly by grants from Karolinska Institutet, Stockholm County Council, the Swedish Heart-Lung Foundation, as well as from an unrestricted sponsorship from Boehringer-Ingelheim. SITS has previously received grants from the European Union Framework 7, the European Union Public Health Authority, and conducted studies supported by EVER Pharma and Ferrer Internacional, as well as in collaboration with Karolinska Institutet, supported by Stryker, Covidien, and Phenox. SITS is currently conducting studies supported by Boehringer-Ingelheim and Biogen. N Ahmed is supported by Stockholm County Council and Swedish Heart-lung Foundation. Irene Escudero-Martínez has received a grant from “Fundación Progreso y Salud, Junta de Andalucía” (grant EF-0437-2018).Peer reviewe

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Resource economy of carnivorous plants: Interactions between prey capture and plant performance in three subarctic Pinguicula species

In this thesis, I have studied in situ the resource economy of the three carnivorous plant species Pinguicula alpina, P. villosa and P. vulgaris in a subarctic environment. The prey capture varied among individual plants, years and species. It was higher in young leaves then in old ones. P. vulgaris captured more prey that the other species and reproductive individuals of P. vulgaris captured more than non-reproductive ones. There was no response to increased fertiliser to the soil. When these plants were supplied with supplementary prey they responded by increased growth, reproduction and survival. All species experienced a cost of reproduction in terms of decreased growth. For all species the reproductive effort was larger than the cost of reproduction. High altitude plants were less affected by supplementary feeding and previous reproduction. P. alpina was less affected by defoliation and previous reproduction and responded less to supplementary feeding than P. vulgaris and P. villosa. P. alpina showed characteristics typical of capital breeder whereas P. vulgaris and P. villosa behaved like income-breeders

Hur påverkar ägarbilden hos svenska företag den rörliga ersättningen till den verkställande direktören?

Bakgrund Det diskuteras mycket idag om ersättningar till verkställande direktörer (Vd) och storleken på dessa. Många har synpunkter på den enligt dem väldigt höga ersättningen och framförallt är många kritiska till de stora bonusar som tilldelas till företagsledare. Samtidigt är det ägarna som genom representation i styrelse och på bolagstämma bestämmer ersättningen. Syfte Syftet med studien är att undersöka om det föreligger ett samband mellan ägarbilden och andel rörlig lön till den verkställande direktören. Metod I studien tillämpas en deduktiv forskningsansats där vi utgått från existerande teorier och tidigare empirisk forskning för att skapa en hypotes som sedan kan bekräftas eller förkastas. Hypotesen testas genom en kvantitativ metod där data samlats in över 56 stycken svenska bolag för att sedan testas med statistisk regressionsanalys. Slutsats Undersökningen visar att det finns ett negativt samband mellan ett större ägande och andel rörlig ersättning till verkställande direktör

Utredning om möjligheterna att minska utsläppen av fossil koldioxid från järn- och stålindustrin

IVL Svenska miljöinstitutet har på uppdrag av Naturvårdsverket genomfört föreliggande projekt avseende möjligheter att minska utsläppen av fossil koldioxid från järn- och stålindustrin. Projektet har upphandlats av Naturvårdsverket genom anbudsinbjudan med diarienummer 231-1773-05 Rm. Projektets omfattning och utförande är mycket väl definierat av upphandlingsunderlaget. Projektet omfattar i huvudsak tre olika delar, nämligen: 1. En beskrivning av befintliga produktionsprocesser och dess nuvarande status i Sverige. 2. Redovisning av tekniska möjligheter att reducera koldioxidemissioner inklusive redovisning av CO2-emissioner och dess utveckling i industrin. 3. Ekonomiska beräkningar av olika reduktionsmöjligheter i syfte att beräkna reduktionskostnaden i t.ex. kr/ton reducerad CO2. Tidshorisonten för analyserna är definierad som den handelsperiod som nästa fördelningsplan omfattar (2008-2012). För projektet innebär detta år 2010 som ligger mitt i nästa handelsperiod. Men det är också av intresse att få en bild av potentialen något längre fram i tiden. Därför har vi också inkluderat en bedömning för en tidshorisont som sträcker sig till år 2020.....IVL Svenska miljöinstitutet har på uppdrag av Naturvårdsverket genomfört föreliggande projekt avseende möjligheter att minska utsläppen av fossil koldioxid från järn- och stålindustrin. Projektet har upphandlats av Naturvårdsverket genom anbudsinbjudan med diarienummer 231-1773-05 Rm. Projektets omfattning och utförande är mycket väl definierat av upphandlingsunderlaget. Projektet omfattar i huvudsak tre olika delar, nämligen: 1. En beskrivning av befintliga produktionsprocesser och dess nuvarande status i Sverige. 2. Redovisning av tekniska möjligheter att reducera koldioxidemissioner inklusive redovisning av CO2-emissioner och dess utveckling i industrin. 3. Ekonomiska beräkningar av olika reduktionsmöjligheter i syfte att beräkna reduktionskostnaden i t.ex. kr/ton reducerad CO2. Tidshorisonten för analyserna är definierad som den handelsperiod som nästa fördelningsplan omfattar (2008-2012). För projektet innebär detta år 2010 som ligger mitt i nästa handelsperiod. Men det är också av intresse att få en bild av potentialen något längre fram i tiden. Därför har vi också inkluderat en bedömning för en tidshorisont som sträcker sig till år 2020....

Short time to blood culture positivity in Enterococcus faecalis infective endocarditis

Time to blood culture positivity (TTP) is an indirect measure of bacterial concentration in blood. A short TTP has been linked to the presence of infective endocarditis (IE) and to poor prognosis in Staphylococcus aureus bacteremia. We analyze factors influencing TTP in bacteremia with Enterococcus faecalis. This retrospective observational study of medical records included adults diagnosed with monomicrobial E. faecalis bacteremia between 2015 and 2018 in the Skåne region (Sweden). For each episode, the shortest TTP was recorded. Median TTP was compared between patients grouped based on age, sex, comorbidity, site of acquisition, and focus of infection. Using a dichotomized TTP (shorter or longer than 12 h), a multivariable logistic regression for factors associated to TTP was performed. The association between TTP and IE or mortality was evaluated. Three hundred sixty-seven episodes with monomicrobial E. faecalis bacteremia with the corresponding TTP were identified. Median TTP for the entire cohort was 11.6 (IQR 9.9–14.1) h and a significantly shorter TTP was noted for episodes which represented IE (n = 55, 9.4 (IQR 6.4–10.6) h). Only IE remained associated with a short TTP (≤ 12 h) in binary logistic regression analysis. Factors associated with IE were investigated and TTP was associated with IE also when adjusted for age, gender, comorbidity, and nosocomial acquisition. There was no association between TTP and mortality. A low TTP is associated with IE in E. faecalis bacteremia and could be used as a help in determining the need for echocardiography in patients with this condition