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European Journal of Pharmacology Nov 2023Intestinal ischemia/reperfusion injury (IRI) is a multifactorial, complex pathophysiological process in clinical settings. In recent years, intestinal IRI has received... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Intestinal ischemia/reperfusion injury (IRI) is a multifactorial, complex pathophysiological process in clinical settings. In recent years, intestinal IRI has received increasing attention due to increased morbidity and mortality. To date, there are no effective treatments. Dexmedetomidine (DEX), a highly selective α-adrenergic receptor agonist, has been demonstrated to be effective against intestinal IRI. In this systematic review and meta-analysis, we evaluated the efficacy and potential mechanisms of DEX as a treatment for intestinal IRI in animal models.
METHODS
Five databases (PubMed, Embase, Web of Science, Cochrane Library, and Scopus) were searched until March 15, 2023. Using the SYRCLE risk bias tool, we assessed methodological quality. Statistical analysis was conducted using STATA 12 and R 4.2.2. We analyzed the related outcomes (mucosa damage-related indicators; inflammation-relevant markers, oxidative stress markers) relied on the fixed or random-effects models.
RESULTS
There were 15 articles including 18 studies included, and 309 animals were involved in the studies. Compared to the model groups, DEX improved intestinal IRI. DEX decreased Chiu's score and serum diamine oxidase (DAO) level. DEX reduced the level of inflammation-relevant markers (interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α). DEX also improved oxidative stress (decreased malondialdehyde (MDA), increased superoxide dismutase (SOD)).
CONCLUSIONS
DEX's effectiveness in ameliorating intestinal IRI has been demonstrated in animal models. Antioxidation, anti-inflammation, anti-apoptotic, anti-pyroptosis, anti-ferroptosis, enhancing mitophagy, reshaping the gut microbiota, and gut barrier protection are possible mechanisms. However, in light of the heterogeneity and methodological quality of these studies, further well-designed preclinical studies are warranted before clinical implication.
Topics: Rats; Animals; Dexmedetomidine; Rats, Sprague-Dawley; Adrenergic alpha-2 Receptor Agonists; Reperfusion Injury; Inflammation; Ischemia
PubMed: 37778612
DOI: 10.1016/j.ejphar.2023.176090 -
Lancet (London, England) Sep 2023Intravenous thrombolysis is recommended before endovascular treatment, but its value has been questioned in patients who are admitted directly to centres capable of... (Meta-Analysis)
Meta-Analysis
Value of intravenous thrombolysis in endovascular treatment for large-vessel anterior circulation stroke: individual participant data meta-analysis of six randomised trials.
BACKGROUND
Intravenous thrombolysis is recommended before endovascular treatment, but its value has been questioned in patients who are admitted directly to centres capable of endovascular treatment. Existing randomised controlled trials have indicated non-inferiority of endovascular treatment alone or have been statistically inconclusive. We formed the Improving Reperfusion Strategies in Acute Ischaemic Stroke collaboration to assess non-inferiority of endovascular treatment alone versus intravenous thrombolysis plus endovascular treatment.
METHODS
We conducted a systematic review and individual participant data meta-analysis to establish non-inferiority of endovascular treatment alone versus intravenous thrombolysis plus endovascular treatment. We searched PubMed and MEDLINE with the terms "stroke", "endovascular treatment", "intravenous thrombolysis", and synonyms for articles published from database inception to March 9, 2023. We included randomised controlled trials on the topic of interest, without language restrictions. Authors of the identified trials agreed to take part, and individual participant data were provided by the principal investigators of the respective trials and collated centrally by the collaborators. Our primary outcome was the 90-day modified Rankin Scale (mRS) score. Non-inferiority of endovascular treatment alone was assessed using a lower boundary of 0·82 for the 95% CI around the adjusted common odds ratio (acOR) for shift towards improved outcome (analogous to 5% absolute difference in functional independence) with ordinal regression. We used mixed-effects models for all analyses. This study is registered with PROSPERO, CRD42023411986.
FINDINGS
We identified 1081 studies, and six studies (n=2313; 1153 participants randomly assigned to receive endovascular treatment alone and 1160 randomly assigned to receive intravenous thrombolysis and endovascular treatment) were eligible for analysis. The risk of bias of the included studies was low to moderate. Variability between studies was small, and mainly related to the choice and dose of the thrombolytic drug and country of execution. The median mRS score at 90 days was 3 (IQR 1-5) for participants who received endovascular treatment alone and 2 (1-4) for participants who received intravenous thrombolysis plus endovascular treatment (acOR 0·89, 95% CI 0·76-1·04). Any intracranial haemorrhage (0·82, 0·68-0·99) occurred less frequently with endovascular treatment alone than with intravenous thrombolysis plus endovascular treatment. Symptomatic intracranial haemorrhage and mortality rates did not differ significantly.
INTERPRETATION
We did not establish non-inferiority of endovascular treatment alone compared with intravenous thrombolysis plus endovascular treatment in patients presenting directly at endovascular treatment centres. Further research could focus on cost-effectiveness analysis and on individualised decisions when patient characteristics, medication shortages, or delays are expected to offset a potential benefit of administering intravenous thrombolysis before endovascular treatment.
FUNDING
Stryker and Amsterdam University Medical Centers, University of Amsterdam.
Topics: Humans; Stroke; Brain Ischemia; Intracranial Hemorrhages; Ischemic Stroke; Thrombolytic Therapy; Randomized Controlled Trials as Topic
PubMed: 37640037
DOI: 10.1016/S0140-6736(23)01142-X -
Neurology International Aug 2023Atrial fibrillation (AF) significantly contributes to acute ischaemic stroke (AIS), yet its precise influence on clinical outcomes post-intravenous thrombolysis (IVT)...
Atrial fibrillation (AF) significantly contributes to acute ischaemic stroke (AIS), yet its precise influence on clinical outcomes post-intravenous thrombolysis (IVT) and post-endovascular thrombectomy (EVT) has remained elusive. Furthermore, the overall prevalence of AF in AIS patients undergoing reperfusion therapy has not been clearly determined. Employing random-effects meta-analyses, this research aimed to estimate the pooled prevalence of AF among AIS patients undergoing reperfusion therapy, while also examining the association between AF and clinical outcomes such as functional outcomes, symptomatic intracerebral haemorrhage (sICH) and mortality. Studies comparing AF and non-AF patient groups undergoing reperfusion therapy were identified and included following an extensive database search. Forty-nine studies (n = 66,887) were included. Among IVT patients, the prevalence of AF was 31% (Effect Size [ES] 0.31 [95%CI 0.28-0.35], < 0.01), while in EVT patients, it reached 42% (ES 0.42 [95%CI 0.38-0.46], < 0.01), and in bridging therapy (BT) patients, it stood at 36% (ES 0.36 [95%CI 0.28-0.43], < 0.01). AF was associated with significantly lower odds of favourable 90-day functional outcomes post IVT (Odds Ratio [OR] 0.512 [95%CI 0.376-0.696], < 0.001), but not post EVT (OR 0.826 [95%CI 0.651-1.049], = 0.117). Our comprehensive meta-analysis highlights the varying prevalence of AF among different reperfusion therapies and its differential impact on patient outcomes. The highest pooled prevalence of AF was observed in EVT patients, followed by BT and IVT patients. Interestingly, our analysis revealed that AF was significantly associated with poorer clinical outcomes following IVT. Such an association was not observed following EVT.
PubMed: 37755356
DOI: 10.3390/neurolint15030065 -
International Journal of Cardiology.... Jun 2023Despite the success of interventional coronary reperfusion strategies, morbidity and mortality from acute myocardial infarction are still substantial. Physical exercise... (Review)
Review
BACKGROUND
Despite the success of interventional coronary reperfusion strategies, morbidity and mortality from acute myocardial infarction are still substantial. Physical exercise is a well-recognized effective non-pharmacological therapy for cardiovascular diseases. Therefore, the objective of this systematic review was to analyze studies in animal models of ischemia-reperfusion in association with physical exercise protocols.
SEARCH STRATEGY
Articles published on the topic over a 13-year period (2010-2022) were searched in two databases (PubMed and Google Scholar) using the keywords exercise training, ischemia/reperfusion or ischemia reperfusion injury. Meta-analysis and quality assessment of the studies were performed using the Review Manager 5.3 program.
RESULTS
From the 238 articles retrieved from PubMed and 200 from Google Scholar, after screening and eligibility assessment, 26 articles were included in the systematic review and meta-analysis. For meta-analysis comparing the group of previously exercised animals with the non-exercised animals and then submitted to ischemia-reperfusion, the infarct size was significantly decreased by exercise (p < 0.00001). In addition, the group exercised had increased heart-to-body weight ratio (p < 0.00001) and improved ejection fraction as measured by echocardiography (p < 0.0004) in comparison to non-exercised animals.
CONCLUSION
We concluded that the animal models of ischemia-reperfusion indicates that exercise reduce infarct size and preserve ejection fraction, associated with beneficial myocardial remodeling.
PubMed: 37181278
DOI: 10.1016/j.ijcha.2023.101214 -
Journal of Central Nervous System... 2022Inflammation may mediate response to acute reperfusion therapy (RT) in acute cerebral ischaemia. Neutrophil-lymphocyte ratio (NLR), an inflammatory biomarker, may play...
BACKGROUND
Inflammation may mediate response to acute reperfusion therapy (RT) in acute cerebral ischaemia. Neutrophil-lymphocyte ratio (NLR), an inflammatory biomarker, may play an important role in acute ischaemic stroke (AIS) prognostication.
OBJECTIVE
This meta-analysis sought to examine the effect of NLR on functional outcomes, mortality and adverse outcomes in AIS patients receiving RT.
METHODS
Individual studies were retrieved from PubMed/Medline, EMBASE and Cochrane databases. Data were extracted using a standardised data sheet and meta-analysis on association of admission (pre-RT) or delayed (post-RT) NLR with clinical/safety outcomes after RT was conducted.
RESULTS
Thirty-five studies (n = 10 308) were identified for the systematic review with 27 (n = 8537) included in the meta-analyses. Lower admission NLR was associated with good functional outcomes (GFOs), defined as 3-month modified Rankin scale (mRS) 0-2 (SMD = -.46; 95% CI = -.62 to -.29; P < .0001), mRS 0-1 (SMD = -.44; 95% CI = -.66 to -.22; P < .0001) and early neurological improvement (ENI) (SMD = -.55; 95 %CI = -.84 to -.25; P < .0001). Lower delayed admission NLR was also associated with GFOs (SMD = -.80; 95%CI = -.91 to -.68; P < .0001). Higher admission NLR was significantly associated with mortality (SMD = .49; 95%CI = .12 to .85; P = .009), intracerebral haemorrhage (ICH) (SMD = .34; 95% CI = .09 to .59; P = .007), symptomatic ICH (sICH) (SMD = .48; 95% CI = .07 to .90; P = .022) and stroke-associated infection or pneumonia (SMD = .85; 95% CI = .50, 1.19; P < .0001). Higher delayed NLR was significantly associated with sICH (SMD = 1.40; 95% CI = .60 to 2.19; P = .001), ICH (SMD = .94; 95% CI = .41 to 1.46; P < .0001) and mortality (SMD = 1.12; 95% CI = .57 to 1.67; P < .0001). There were variations in outcomes across RT groups.
CONCLUSION
Higher admission or delayed NLR is significantly associated with worse morbidity, mortality and safety outcomes in AIS patients receiving RT.
PubMed: 35492740
DOI: 10.1177/11795735221092518 -
Acta Neurologica Belgica Apr 2022Pre-intervention CT imaging-based biomarkers, such as hyperdense middle cerebral artery sign (HMCAS) may have a role in acute ischaemic stroke prognostication. However,... (Meta-Analysis)
Meta-Analysis
Prognostic capacity of hyperdense middle cerebral artery sign in anterior circulation acute ischaemic stroke patients receiving reperfusion therapy: a systematic review and meta-analysis.
Pre-intervention CT imaging-based biomarkers, such as hyperdense middle cerebral artery sign (HMCAS) may have a role in acute ischaemic stroke prognostication. However, the clinical utility of HMCAS in settings of reperfusion therapy and the level of prognostic association is still unclear. This systematic review and meta-analysis investigated the association of HMCAS sign with clinical outcomes and its prognostic capacity in acute ischaemic stroke patients treated with reperfusion therapy. Prospective and retrospective studies from the following databases were retrieved from EMBASE, MEDLINE and Cochrane. Association of HMCAS with functional outcome, symptomatic intracerebral haemorrhage (sICH) and mortality were investigated. The random effect model was used to calculate the risk ratio (RR). Subgroup analyses were performed for subgroups of patients receiving thrombolysis (tPA), mechanical thrombectomy (EVT) and/or combined therapy (tPA + EVT). HMCAS significantly increased the rate of poor functional outcome by 1.43-fold in patients (RR 1.43; 95% CI 1.30-1.57; p < 0.0001) without any significant differences in sICH rates (RR 0.91; 95% CI 0.68-1.23; p = 0.546) and mortality (RR 1.34; 95% CI 0.72-2.51; p = 354) in patients with positive HMCAS as compared to negative HMCAS. In subgroup analyses, significant association between HMCAS and 90 days functional outcome was observed in patients receiving tPA (RR 1.53; 95% CI 1.40-1.67; p < 0.0001) or both therapies (RR 1.40; 95% CI 1.08-1.80; p = 0.010). This meta-analysis demonstrated that pre-treatment HMCAS increases risk of poor functional outcomes. However, its prognostic sensitivity and specificity in predicting long-term functional outcome, mortality and sICH after reperfusion therapy is poor.
Topics: Brain Ischemia; Cerebral Hemorrhage; Fibrinolytic Agents; Humans; Ischemic Stroke; Middle Cerebral Artery; Prognosis; Prospective Studies; Reperfusion; Retrospective Studies; Stroke; Thrombolytic Therapy; Tomography, X-Ray Computed; Treatment Outcome
PubMed: 34095978
DOI: 10.1007/s13760-021-01720-3 -
Acta Radiologica (Stockholm, Sweden :... Sep 2022Computed tomography perfusion (CTP) imaging has emerged as an important adjunct to the current armamentarium of acute ischemic stroke (AIS) workflow. However, its...
Value of pre-intervention computed tomography perfusion imaging in the assessment of tissue outcome and long-term clinical prognosis in patients with anterior circulation acute ischemic stroke receiving reperfusion therapy: a systematic review.
BACKGROUND
Computed tomography perfusion (CTP) imaging has emerged as an important adjunct to the current armamentarium of acute ischemic stroke (AIS) workflow. However, its adoption in routine clinical practice is far from optimal.
PURPOSE
To investigate the putative association of CTP imaging biomarkers in the assessment of prognosis in acute ischemic stroke.
MATERIAL AND METHODS
We performed a systematic review of the literature using MEDLINE, EMBASE, and Cochrane Central Register of Clinical Trials focusing on CTP biomarkers, tissue-based and clinical-based patient outcomes. We included randomized controlled trials, prospective cohort studies, and case-controlled studies published from January 2005 to 28 August 2020. Two independent reviewers conducted the study appraisal, data extraction, and quality assessment of the studies.
RESULTS
A total of 60 full-text studies were included in the final systematic review analysis. Increasing infarct core volume is associated with reduced odds of achieving functional independence (modified Rankin score 0-2) at 90 days and is correlated with the final infarct volume when reperfusion is achieved.
CONCLUSION
CTP has value in assessing tissue perfusion status in the hyperacute stroke setting and the long-term clinical prognosis of patients with AIS receiving reperfusion therapy. However, the prognostic use of CTP requires optimization and further validation.
Topics: Humans; Brain Ischemia; Infarction; Ischemic Stroke; Perfusion Imaging; Prognosis; Prospective Studies; Reperfusion; Stroke; Tomography, X-Ray Computed
PubMed: 34342497
DOI: 10.1177/02841851211035892 -
Biomedicines Oct 2023Cerebral microbleeds (CMBs), a notable neuroimaging finding often associated with cerebral microangiopathy, demonstrate a heightened prevalence in patients diagnosed...
Prevalence and Impact of Cerebral Microbleeds on Clinical and Safety Outcomes in Acute Ischaemic Stroke Patients Receiving Reperfusion Therapy: A Systematic Review and Meta-Analysis.
BACKGROUND
Cerebral microbleeds (CMBs), a notable neuroimaging finding often associated with cerebral microangiopathy, demonstrate a heightened prevalence in patients diagnosed with acute ischemic stroke (AIS), which is in turn linked to less favourable clinical prognoses. Nevertheless, the exact prevalence of CMBs and their influence on post-reperfusion therapy outcomes remain inadequately elucidated.
MATERIALS AND METHODS
Through systematic searches of PubMed, Embase and Cochrane databases, studies were identified adhering to specific inclusion criteria: (a) AIS patients, (b) age ≥ 18 years, (c) CMBs at baseline, (d) availability of comparative data between CMB-positive and CMB-negative groups, along with relevant post-reperfusion therapy outcomes. The data extracted were analysed using forest plots of odds ratios, and random-effects modelling was applied to investigate the association between CMBs and symptomatic intracerebral haemorrhage (sICH), haemorrhagic transformation (HT), 90-day functional outcomes, and 90-day mortality post-reperfusion therapy.
RESULTS
In a total cohort of 9776 AIS patients who underwent reperfusion therapy, 1709 had CMBs, with a pooled prevalence of 19% (ES 0.19; 95% CI: 0.16, 0.23, < 0.001). CMBs significantly increased the odds of sICH (OR 2.57; 95% CI: 1.72; 3.83; < 0.0001), HT (OR 1.53; 95% CI: 1.25; 1.88; < 0.0001), as well as poor functional outcomes at 90 days (OR 1.59; 95% CI: 1.34; 1.89; < 0.0001) and 90-day mortality (OR 1.65; 95% CI: 1.27; 2.16; < 0.0001), relative to those without CMBs, in AIS patients undergoing reperfusion therapy (encompassing intravenous thrombolysis [IVT], endovascular thrombectomy [EVT], either IVT or EVT, and bridging therapy). Variations in the level of association can be observed among different subgroups of reperfusion therapy.
CONCLUSIONS
This meta-analysis underscores a significant association between CMBs and adverse postprocedural safety outcomes encompassing sICH, HT, poor functional outcome, and increased mortality in AIS patients undergoing reperfusion therapy. The notable prevalence of CMBs in both the overall AIS population and those undergoing reperfusion therapy emphasizes their importance in post-stroke prognostication.
PubMed: 37893237
DOI: 10.3390/biomedicines11102865 -
Pharmacological Reviews Apr 2021The complement system was discovered at the end of the 19th century as a heat-labile plasma component that "complemented" the antibodies in killing microbes, hence the...
The complement system was discovered at the end of the 19th century as a heat-labile plasma component that "complemented" the antibodies in killing microbes, hence the name "complement." Complement is also part of the innate immune system, protecting the host by recognition of pathogen-associated molecular patterns. However, complement is multifunctional far beyond infectious defense. It contributes to organ development, such as sculpting neuron synapses, promoting tissue regeneration and repair, and rapidly engaging and synergizing with a number of processes, including hemostasis leading to thromboinflammation. Complement is a double-edged sword. Although it usually protects the host, it may cause tissue damage when dysregulated or overactivated, such as in the systemic inflammatory reaction seen in trauma and sepsis and severe coronavirus disease 2019 (COVID-19). Damage-associated molecular patterns generated during ischemia-reperfusion injuries (myocardial infarction, stroke, and transplant dysfunction) and in chronic neurologic and rheumatic disease activate complement, thereby increasing damaging inflammation. Despite the long list of diseases with potential for ameliorating complement modulation, only a few rare diseases are approved for clinical treatment targeting complement. Those currently being efficiently treated include paroxysmal nocturnal hemoglobinuria, atypical hemolytic-uremic syndrome, myasthenia gravis, and neuromyelitis optica spectrum disorders. Rare diseases, unfortunately, preclude robust clinical trials. The increasing evidence for complement as a pathogenetic driver in many more common diseases suggests an opportunity for future complement therapy, which, however, requires robust clinical trials; one ongoing example is COVID-19 disease. The current review aims to discuss complement in disease pathogenesis and discuss future pharmacological strategies to treat these diseases with complement-targeted therapies. SIGNIFICANCE STATEMENT: The complement system is the host's defense friend by protecting it from invading pathogens, promoting tissue repair, and maintaining homeostasis. Complement is a double-edged sword, since when dysregulated or overactivated it becomes the host's enemy, leading to tissue damage, organ failure, and, in worst case, death. A number of acute and chronic diseases are candidates for pharmacological treatment to avoid complement-dependent damage, ranging from the well established treatment for rare diseases to possible future treatment of large patient groups like the pandemic coronavirus disease 2019.
Topics: COVID-19; Collectins; Complement Activating Enzymes; Complement C3; Complement Inactivating Agents; Complement System Proteins; Genetic Therapy; Humans; Inflammation Mediators; Lectins; Mannose-Binding Protein-Associated Serine Proteases; Pandemics; Rare Diseases; SARS-CoV-2; Synapses; Ficolins
PubMed: 33687995
DOI: 10.1124/pharmrev.120.000072 -
Lancet (London, England) Aug 2017Fibrinolytic therapy offers an alternative to mechanical reperfusion for ST-segment elevation myocardial infarction (STEMI) in settings where health-care resources are... (Meta-Analysis)
Meta-Analysis Review
Comparative efficacy and safety of reperfusion therapy with fibrinolytic agents in patients with ST-segment elevation myocardial infarction: a systematic review and network meta-analysis.
BACKGROUND
Fibrinolytic therapy offers an alternative to mechanical reperfusion for ST-segment elevation myocardial infarction (STEMI) in settings where health-care resources are scarce. Comprehensive evidence comparing different agents is still unavailable. In this study, we examined the effects of various fibrinolytic drugs on clinical outcomes.
METHODS
We did a network meta-analysis based on a systematic review of randomised controlled trials comparing fibrinolytic drugs in patients with STEMI. Several databases were searched from inception up to Feb 28, 2017. We included only randomised controlled trials that compared fibrinolytic agents as a reperfusion therapy in adult patients with STEMI, whether given alone or in combination with adjunctive antithrombotic therapy, against other fibrinolytic agents, a placebo, or no treatment. Only trials investigating agents with an approved indication of reperfusion therapy in STEMI (streptokinase, tenecteplase, alteplase, and reteplase) were included. The primary efficacy outcome was all-cause mortality within 30-35 days and the primary safety outcome was major bleeding. This study is registered with PROSPERO (CRD42016042131).
FINDINGS
A total of 40 eligible studies involving 128 071 patients treated with 12 different fibrinolytic regimens were assessed. Compared with accelerated infusion of alteplase with parenteral anticoagulants as background therapy, streptokinase and non-accelerated infusion of alteplase were significantly associated with an increased risk of all-cause mortality (risk ratio [RR] 1·14 [95% CI 1·05-1·24] for streptokinase plus parenteral anticoagulants; RR 1·26 [1·10-1·45] for non-accelerated alteplase plus parenteral anticoagulants). No significant difference in mortality risk was recorded between accelerated infusion of alteplase, tenecteplase, and reteplase with parenteral anticoagulants as background therapy. For major bleeding, a tenecteplase-based regimen tended to be associated with lower risk of bleeding compared with other regimens (RR 0·79 [95% CI 0·63-1·00]). The addition of glycoprotein IIb or IIIa inhibitors to fibrinolytic therapy increased the risk of major bleeding by 1·27-8·82-times compared with accelerated infusion alteplase plus parenteral anticoagulants (RR 1·47 [95% CI 1·10-1·98] for tenecteplase plus parenteral anticoagulants plus glycoprotein inhibitors; RR 1·88 [1·24-2·86] for reteplase plus parenteral anticoagulants plus glycoprotein inhibitors).
INTERPRETATION
Significant differences exist among various fibrinolytic regimens as reperfusion therapy in STEMI and alteplase (accelerated infusion), tenecteplase, and reteplase should be considered over streptokinase and non-accelerated infusion of alteplase. The addition of glycoprotein IIb or IIIa inhibitors to fibrinolytic therapy should be discouraged.
FUNDING
None.
Topics: Female; Fibrinolytic Agents; Hemorrhage; Humans; Male; Middle Aged; Myocardial Reperfusion; Network Meta-Analysis; Patient Safety; Risk Factors; ST Elevation Myocardial Infarction; Stroke; Treatment Outcome
PubMed: 28831992
DOI: 10.1016/S0140-6736(17)31441-1