Anti-Xa-guided Anticoagulation With Unfractionated Heparin and Thrombosis During Extracorporeal Membrane Oxygenation Support: A Systematic Review and Meta-analysis.

OBJECTIVE: The initiation of extracorporeal membrane oxygenation (ECMO) triggers complex coagulation processes necessitating systemic anticoagulation. Therefore, anticoagulation monitoring is crucial to avoid adverse events such as thrombosis and hemorrhage. The main aim of this work was to analyze the association between anti-Xa levels and thrombosis occurrence during ECMO support. DESIGN: Systematic literature review and meta-analysis (Scopus and PubMed, up to July 29, 2023). SETTING: All retrospective and prospective studies. PARTICIPANTS: Patients receiving ECMO support. INTERVENTION: Anticoagulation monitoring during ECMO support. MEASUREMENTS AND MAIN RESULTS: A total of 16 articles with 1,968 patients were included in the review and 7 studies in the meta-analysis (n = 374). Patients with thrombosis had significantly lower mean anti-Xa values (standardized mean difference -0.36, 95% confidence interval [CI] -0.62 to -0.11, p < 0.01). Furthermore, a positive correlation was observed between unfractionated heparin infusion and anti-Xa levels (pooled estimate of correlation coefficients 0.31, 95% CI 0.19 to 0.43, p < 0.001). The most common adverse events were major bleeding (42%) and any kind of hemorrhage (36%), followed by thromboembolic events (30%) and circuit or oxygenator membrane thrombosis (19%). More than half of the patients did not survive to discharge (52%). CONCLUSIONS: This work revealed significantly lower levels of anti-Xa in patients experiencing thromboembolic events and a positive correlation between anti-Xa and unfractionated heparin infusion. Considering the contemplative limitations of conventional monitoring tools, further research on the role of anti-Xa is warranted. New trials should be encouraged to confirm these findings and determine the most suitable monitoring strategy for patients receiving ECMO support.

Association of anti-factor Xa-guided anticoagulation with hemorrhage during ECMO support: A systematic review and meta-analysis.

BACKGROUND: The use of extracorporeal membrane oxygenation (ECMO) is associated with complex hemostatic changes. Systemic anticoagulation is initiated to prevent clotting in the ECMO system, but this comes with an increased risk of bleeding. Evidence on the use of anti-Xa-guided monitoring to prevent bleeding during ECMO support is limited. Therefore, we aimed to analyze the association between anti-factor Xa-guided anticoagulation and hemorrhage during ECMO. METHODS: A systematic review and meta-analysis was performed (up to August 2023). PROSPERO: CRD42023448888. RESULTS: Twenty-six studies comprising 2293 patients were included in the analysis, with six works being part of the meta-analysis. The mean anti-Xa values did not show a significant difference between patients with and without hemorrhage (standardized mean difference -0.05; 95% confidence interval [CI]: -0.19; 0.28, p = .69). We found a positive correlation between anti-Xa levels and unfractionated heparin dose (UFH; pooled estimate of correlation coefficients 0.44; 95% CI: 0.33; 0.55, p < .001). The most frequent complications were any type of hemorrhage (pooled 36%) and thrombosis (33%). Nearly half of the critically ill patients did not survive to hospital discharge (47%). CONCLUSIONS: The most appropriate tool for anticoagulation monitoring in ECMO patients is uncertain. Our analysis did not reveal a significant difference in anti-Xa levels in patients with and without hemorrhagic events. However, we found a moderate correlation between anti-Xa and the UFH dose, supporting its utilization in monitoring UFH anticoagulation. Given the limitations of time-guided monitoring methods, the role of anti-Xa is promising and further research is warranted.

aPTT-guided anticoagulation monitoring during ECMO support: A systematic review and meta-analysis.

INTRODUCTION: The initiation of the extracorporeal membrane oxygenation (ECMO) is associated with complex coagulatory and inflammatory processes and consequently needed anticoagulation. Systemic anticoagulation bears an additional risk of serious bleeding, and its monitoring is of immense importance. Therefore, our work aims to analyze the association of anticoagulation monitoring with bleeding during ECMO support. MATERIAL AND METHODS: Systematic literature review and meta-analysis, complying with the PRISMA guidelines (PROSPERO-CRD42022359465). RESULTS: Seventeen studies comprising 3249 patients were included in the final analysis. Patients experiencing hemorrhage had a longer activated partial thromboplastin time (aPTT), a longer ECMO duration, and higher mortality. We could not find strong evidence of any aPTT threshold association with the bleeding occurrence, as less than half of authors reported a potential relationship. Finally, we identified the acute kidney injury (66%, 233/356) and hemorrhage (46%, 469/1046) to be the most frequent adverse events, while almost one-half of patients did not survive to discharge (47%, 1192/2490). CONCLUSION: The aPTT-guided anticoagulation is still the standard of care in ECMO patients. We did not find strong evidence supporting the aPTT-guided monitoring during ECMO. Based on the weight of the available evidence, further randomized trials are crucial to clarify the best monitoring strategy.

Association of aPTT-Guided Anticoagulation Monitoring with Thromboembolic Events in Patients Receiving V-A ECMO Support: A Systematic Review and Meta-Analysis.

BACKGROUND: The initiation of extracorporeal membrane oxygenation (ECMO) is associated with complex inflammatory and coagulatory processes, raising the need for systemic anticoagulation. The balance of anticoagulatory and procoagulant factors is essential, as therapeutic anticoagulation confers a further risk of potentially life-threatening bleeding. Therefore, our study aims to systematize and analyze the most recent evidence regarding anticoagulation monitoring and the thromboembolic events in patients receiving veno-arterial ECMO support. METHODS: Using the PRISMA guidelines, we systematically searched the Scopus and PubMed databases up to October 2022. A weighted effects model was employed for the meta-analytic portion of the study. RESULTS: Six studies comprising 1728 patients were included in the final analysis. Unfractionated heparin was used for anticoagulation, with an activated partial thromboplastin time (aPTT) monitoring goal set between 45 and 80 s. The majority of studies aimed to investigate the incidence of adverse events and potential risk factors for thromboembolic and bleeding events. None of the authors found any association of aPTT levels with the occurrence of thromboembolic events. Finally, the most frequent adverse events were hemorrhage (pooled 43%, 95% CI 28.4; 59.5) and any kind of thrombosis (pooled 36%, 95% CI 21.7; 53.7), and more than one-half of patients did not survive to discharge (pooled 54%). CONCLUSIONS: Despite the tremendous development of critical care, aPTT-guided systemic anticoagulation is still the standard monitoring tool. We did not find any association of aPTT levels with thrombosis. Further evidence and new trials should clarify the true incidence of thromboembolic events, along with the best anticoagulation and monitoring strategy in veno-arterial ECMO patients.

Extracorporeal membrane oxygenation for cardiogenic shock: a meta-analysis of mortality and complications.

BACKGROUND: Venoarterial extracorporeal membrane oxygenation (va-ECMO) is an advanced life support for critically ill patients with refractory cardiogenic shock. This temporary support bridges time for recovery, permanent assist, or transplantation in patients with high risk of mortality. However, the benefit of this modality is still subject of discussion and despite the continuous development of critical care medicine, severe cardiogenic shock remains associated with high mortality. Therefore, this work aims to analyze the current literature regarding in-hospital mortality and complication rates of va-ECMO in patients with cardiogenic shock. METHODS: We conducted a systematic review and meta-analysis of the most recent literature to analyze the outcomes of va-ECMO support. Using the PRISMA guidelines, Medline (PubMed) and Scopus (Elsevier) databases were systematically searched up to May 2022. Meta-analytic pooled estimation of publications variables was performed using a weighted random effects model for study size. RESULTS: Thirty-two studies comprising 12756 patients were included in the final analysis. Between 1994 and 2019, 62% (pooled estimate, 8493/12756) of patients died in the hospital. More than one-third of patients died during ECMO support. The most frequent complications were renal failure (51%, 693/1351) with the need for renal replacement therapy (44%, 4879/11186) and bleeding (49%, 1971/4523), bearing the potential for permanent injury or death. Univariate meta-regression analyses identified age over 60 years, shorter ECMO duration and presence of infection as variables associated with in-hospital mortality, while the studies reporting a higher incidence of cannulation site bleeding were unexpectedly associated with a reduced in-hospital mortality. CONCLUSIONS: Extracorporeal membrane oxygenation is an invasive life support with a high risk of complications. We identified a pooled in-hospital mortality of 62% with patient age, infection and ECMO support duration being associated with a higher mortality. Protocols and techniques must be developed to reduce the rate of adverse events. Finally, randomized trials are necessary to demonstrate the effectiveness of va-ECMO in cardiogenic shock.

Anticoagulation Strategies during Extracorporeal Membrane Oxygenation: A Narrative Review.

The development of extracorporeal life support technology has added a new dimension to the care of critically ill patients who fail conventional treatment options. Extracorporeal membrane oxygenation (ECMO)-specialized temporary life support for patients with severe cardiac or pulmonary failure-plays a role in bridging the time for organ recovery, transplant, or permanent assistance. The overall patient outcome is dependent on the underlying disease, comorbidities, patient reaction to critical illness, and potential adverse events during ECMO. Moreover, the contact of the blood with the large artificial surface of an extracorporeal system circuit triggers complex inflammatory and coagulation responses. These processes may further lead to endothelial injury and disrupted microcirculation with consequent end-organ dysfunction and the development of adverse events like thromboembolism. Therefore, systemic anticoagulation is considered crucial to alleviate the risk of thrombosis and failure of ECMO circuit components. The gold standard and most used anticoagulant during extracorporeal life support is unfractionated heparin, with all its benefits and disadvantages. However, therapeutic anticoagulation of a critically ill patient carries the risk of clinically relevant bleeding with the potential for permanent injury or death. Similarly, thrombotic events may occur. Therefore, different anticoagulation strategies are employed, while the monitoring and the balance of procoagulant and anticoagulatory factors is of immense importance. This narrative review summarizes the most recent considerations on anticoagulation during ECMO support, with a special focus on anticoagulation monitoring and future directions.

Nicotine, cocaine, amphetamine, morphine, and ethanol increase norepinephrine output in the bed nucleus of stria terminalis of freely moving rats.

The bed nucleus of stria terminalis (BNST) is a complex limbic area involved in neuroendocrine and behavioural responses and, in particular, in the modulation of the stress response. BNST is innervated by dopamine and norepinephrine, which are known to be involved in drug addiction. It is also known that several drugs of abuse increase dopamine transmission in the BNST, but there has been less research regarding the effect on norepinephrine transmission. Here, we have used the microdialysis technique to investigate the effect of several drugs of abuse on norepinephrine transmission in the BNST of freely moving rats. We observed that nicotine (0.2-0.4 mg/kg), cocaine (2.5-5 mg/kg), amphetamine (0.25-0.5 mg/kg), and ethanol (0.5-1.0 g/kg), dose-dependently increased norepinephrine output while the effect of morphine at 3.0 was lower than that of 1.0 mg/kg. These results suggest that many drugs of abuse, though possessing diverse mechanisms of action, share the property of increasing norepinephrine transmission in the BNST. Furthermore, we suggest that the recurring activation of NE transmission in the BNST, due to drug administration, contributes to the alteration of the function that BNST assumes in how the behavioural response to stress manifests, favouring the establishment of the stress-induced drug seeking.

Neurosteroid dehydroepiandrosterone improves active avoidance retrieval and induces antidepressant-like behavior in rats.

Various studies reported beneficial effects of dehydroepiandrosterone (DHEA) and its sulphate (DHEAS), the neurosteroids involved in various brain functions, on synaptic plasticity, neuronal survival, memory, learning and behavior. This study aimed to investigate the behavioral profile of acute DHEA treatment by using active avoidance (AA) task, primarily predictive of the effects on the retrieval-based learning, and by applying forced swim test (FST), for assessment of antidepressant-like potential. Adult male Wistar rats received intraperitoneal injections of either DHEA (2, 10, 20mg/kg) or solvent, 30min prior to testing. DHEA, in a manner resembling an inverted U shape, influenced the retrieval imposed to rats in AA paradigm. The significant improvement of the performance in the retention session was observed following 10mg/kg DHEA treatment and it was not due to the changes in the motor activity, as indicated by unaltered locomotor parameters (inter-trial crossing). Moreover, 10mg/kg of DHEA significantly decreased the duration of immobility in FST, demonstrating antidepressant-like effects. The capability of bicuculline (2mg/kg) to antagonize the effects of DHEA has been evaluated simultaneously. The retrieval-facilitating as well as antidepressant-like effects of 10mg/kg DHEA were counteracted by bicuculline, a competitive antagonist of GABAA receptors, suggesting involvement of GABAergic system. These results support administration of DHEA as potential therapeutic strategy for treating depression and related cognitive impairments, but emphasized the importance of adequate dosing, as DHEA levels that are too high or too low may not be beneficial.

Differential induction of dyskinesia and neuroinflammation by pulsatile versus continuous l-DOPA delivery in the 6-OHDA model of Parkinson's disease.

Neuroinflammation is associated with l-DOPA treatment in Parkinson's disease (PD), suggesting a role in l-DOPA-induced dyskinesia (LID), however it is unclear whether increased inflammation is specifically related to the dyskinetic outcome of l-DOPA treatment. Diversely from oral l-DOPA, continuous intrajejunal l-DOPA infusion is associated with very low dyskinetic outcome in PD patients. We reproduced these regimens of administration in 6-OHDA-lesioned hemiparkinsonian rats, where dyskinetic responses and striatal neuroinflammation induced by chronic pulsatile (DOPAp) or continuous (DOPAc) l-DOPA were compared. Moreover, we investigated the contribution of a peripheral inflammatory challenge with lipopolysaccharide (LPS), to DOPAp-induced dyskinetic and neuroinflammatory responses. Rats 6-OHDA-infused in the medial forebrain bundle received two weeks treatment with DOPAp, DOPAc via subcutaneous osmotic minipumps, or DOPAp followed by DOPAc. l-DOPA plasma levels were measured in all experimental groups. An independent group of rats received one peripheral dose of LPS 24h before DOPAp treatment. Abnormal involuntary movements (AIMs) were evaluated as a rat model of LID. Immunoreactivity (IR) for OX-42, microglial and neuronal TNF-α, iNOS and GFAP was quantified in denervated and contralateral striatum. In addition, serum TNF-α was measured. The 6-OHDA denervation induced a mild microgliosis in the striatum two weeks after neurotoxin infusion, and increased TNF-α IR in microglia. Rats receiving the DOPAp treatment developed AIMs and displayed increased striatal OX-42, microglial TNF-α, iNOS and GFAP. Moreover, TNF-α IR was also increased in a subpopulation of striatal neurons. Conversely, DOPAc did not induce AIMs or inflammatory responses in either drug-naïve animals or rats that were previously dyskinetic when exposed to DOPAp. Serum TNF-α was not altered by any l-DOPA treatment. LPS pre-treatment increased the degree of DOPAp-induced AIMs and striatal IR for OX-42, TNF-α, iNOS and GFAP. Altogether the present findings indicate that in the 6-OHDA model, chronic l-DOPA induces striatal inflammatory responses, which however depend upon the administration regimen and the dyskinetic outcome of drug treatment. The potentiation of dyskinetic responses by LPS suggests a reciprocal causal link between neuroinflammation and LID.

Ketamine modulates catecholamine transmission in the bed nucleus of stria terminalis: The possible role of this region in the antidepressant effects of ketamine.

Since the therapeutic treatment of depression is far from being satisfactory, new therapeutic strategies ought to be pursued. In addition, further investigation on brain areas involved in the action mechanism of antidepressants can shed light on the aetiology of depression. We have previously reported that typical and atypical antidepressants strongly stimulate catecholamine transmission in the bed nucleus of stria terminalis (BNST). In this study, we have built on that work to examine the effect of ketamine, an unusual antidepressant that can produce a fast-acting and long-lasting antidepressant effect after administration of a single sub-anaesthetic dose. Ketamine is an antagonist of the ionotropic N-methyl-D-aspartate (NMDA) receptor but can also act through its metabolite (2R-6R)-hydroxynorketamine. Using the microdialysis technique in freely moving rats, we monitored the acute effect of ketamine on catecholamine release in the BNST to gain clues to its prompt antidepressant effect. Male Sprague-Dawley rats were implanted with a microdialysis probe in the BNST and 48h later, were injected with ketamine (10, 20, and 40mg/kg, i.p.). Ketamine increased norepinephrine (127%, 155%, 186%) and dopamine (114%, 156%, 176%) extracellular concentration above basal in a time and dose dependent manner, without significantly modifying motility. Since the effect of ketamine, although lower, was not substantially different from that produced by classical antidepressants, we suggest that catecholamine increase in BNST is not likely to be related to a rapid ketamine antidepressant effect, though it might be related to its performance in predictive tests of antidepressant properties.

[The effects of resveratrol on rat behaviour in the forced swim test].

INTRODUCTION: The trans-isomer of resveratrol is the active ingredient of Poligonum cuspidatum, known for its medicinal properties and traditionally used in the treatment of neuropsychiatric disorders. It is also found abundantly in the skin of red grapes and red wine. Previous studies have suggested that trans-resveratrol demonstrates a variety of pharmacological activities including antioxidant, anti-inflammatory, as well as neuroprotective properties and procognitive effects. OBJECTIVE: The goal of the present study was to examine the influence of trans-resveratrol on behavior in rats and its antidepressant properties. METHODS: Male Wistar rats were treated intraperitoneally (i.p.) with the increasing doses of trans-resveratrol (5, 10 and 20 mg/kg) or vehicle (dimethyl sulfoxide--DMSO), 30 minutes before testing of the spontaneous locomotor activity or forced swimming. For the experiments, the behavior of the animals was recorded by a digital camera, and the data were analyzed by one-way ANOVA, followed by Tukey post-hoc test. RESULTS: Testing of spontaneous locomotor activity, after the application of vehicle or increasing doses of trans-resveratrol, showed no statistically significant difference between groups (p > 0.05). In the forced swim test, one-way ANOVA indicated statistically significant effects of trans-resveratrol (p < 0.001).Tukey post-hoc test showed that resveratrol significantly decreased immobility time at the doses of 10 mg/kg and 20 mg/kg, manifesting the acute antidepressant-like effects. There were no statistically significant differences between the resveratrol treatment of 5 mg/kg and vehicle (p > 0.05). CONCLUSION: The results from our study suggest that transresveratrol produces significant effects in the central nervous system. After single application, it has acute antidepressant effects, but without influence on locomotor activity.