Incidence of heparin resistance and heparin failure in patients receiving extracorporeal membrane oxygenation: an exploratory retrospective analysis.

BACKGROUND: Unfractionated heparin (UFH) is used in most centers for extracorporeal membrane oxygenation (ECMO) anticoagulation. When standard doses do not achieve desired target values, heparin resistance is reported, most commonly defined as doses of UFH > 35 000 IU/d. OBJECTIVES: To study the incidence of heparin resistance and its association with thromboembolic complications in patients requiring ECMO support. METHODS: In this observational cohort study, we included adults who received venovenous, venoarterial ECMO and extracorporeal carbon dioxide removal between January 2010 and May 2022. Main risk factor was heparin resistance (UFH, > 35 000 IU/d or > 20 IU/kg/h); the outcome was thromboembolism. Multivariable Poisson regression was used to estimate the effects of heparin resistance, adjusted for several clinical variables on the thromboembolism rate per 100 ECMO patient-days. RESULTS: Of the 197 patients included, 33 (16.8%) required UFH > 35 000 IU/d and 14 (7.1%) required UFH > 20 IU/kg/h. Thromboembolic complications occurred at a rate of 5.89/100 ECMO d. Heparin resistance was not associated with thromboembolic events (incidence rate ratio [IRR], 0.93; 95% CI, 0.14-5.82), whereas COVID-19 (IRR, 2.33; 95% CI, 1.4-3.96; P < .001) and ECMO type (venoarterial ECMO: IRR, 2.29; 95% CI, 1.34-3.92; P = .002; extracorporeal carbon dioxide removal: IRR, 2.89; 95% CI, 1.46-5.59; P = .002; reference venovenous ECMO) were significantly associated with the risk of thromboembolic events. CONCLUSION: A significant proportion of patients fulfilled the common definition of heparin resistance. However, this did not influence the occurrence of thromboembolic events.

Comparison of Weaning Strategies in Patients Receiving Venovenous Extracorporeal Membrane Oxygenation: An Exploratory Retrospective Study.

Venovenous extracorporeal membrane oxygenation (VV ECMO) facilitates the reduction of mechanical ventilation (MV) support in acute respiratory failure. Contrary to increasing evidence regarding its initiation, the optimal timing of VV ECMO weaning in interaction with MV weaning is undetermined. In this retrospective study, 47 patients who received VV ECMO between 2013 and 2021 and survived ≥1 day after ECMO cessation were divided according to their MV status before ECMO removal: 28 patients were classified into an "ECMO weaning during assisted MV/spontaneous breathing" group and 19 into an "ECMO weaning during controlled MV" group. Extracorporeal membrane oxygenation duration was longer in the "assisted MV/spontaneous breathing" group (17 [Interquartile range (IQR) = 11-35] vs. 6 [5-11] days, p < 0.001). These patients had a longer intensive care unit (ICU) stay after ECMO start (48 [29-66] vs. 31 [15-40] days, p = 0.01). No significant differences were found for MV duration after ECMO start (30 [19-45] vs. 19 [12-30] days, p = 0.06) and further ICU survival (86% vs. 89%, p ≥ 0.9). There was a trend toward more patients with mechanical ECMO complications in the "assisted MV/spontaneous breathing" group (57% vs. 32%, p = 0.08). Thus, our results suggest a possible benefit of early ECMO weaning during controlled MV.

Alternative venous access sites for dual-lumen extracorporeal membrane oxygenation cannulation.

OBJECTIVES: Dual-lumen cannulas for veno-venous (VV) extracorporeal membrane oxygenation (ECMO) support are typically inserted in the right internal jugular vein (RIJV); however, some scenarios can make this venous route inaccessible. This multicentre case series aims to evaluate if single-site cannulation using an alternative venous access is safe and feasible in patients with an inaccessible RIJV. METHODS: We performed a multi-institutional retrospective analysis including high-volume ECMO centres with substantial experience in dual-lumen cannulation (DLC) (defined as >10 DLC per year). Three centres [Freiburg (Germany), Toronto (Canada) and Vienna (Austria)] agreed to share their data, including baseline characteristics, technical ECMO and cannulation data as well as complications related to ECMO cannulation and outcome. RESULTS: A total of 20 patients received alternative DLC for respiratory failure. Cannula insertion sites included the left internal jugular vein (n = 5), the right (n = 7) or left (n = 3) subclavian vein and the right (n = 4) or left (n = 1) femoral vein. The median cannula size was 26 (19-28) French. The median initial target ECMO flow was 2.9 (1.8-3.1) l/min and corresponded with used cannula size and estimated cardiac output. No procedural complications were reported during cannulation and median ECMO runtime was 15 (9-22) days. Ten patients were successfully bridged to lung transplantation (n = 5) or lung recovery (n = 5). Ten patients died during or after ECMO support. CONCLUSIONS: Alternative venous access sites for single-site dual-lumen catheters are a safe and feasible option to provide veno-venous ECMO support to patients with inaccessible RIJV.

Anticoagulation with argatroban using hemoclot™ targets is safe and effective in CARDS patients receiving venovenous extracorporeal membrane oxygenation: An exploratory bi-centric cohort study.

Direct thrombin inhibitors, including argatroban, are increasingly used for anticoagulation during venovenous extracorporeal membrane oxygenation (VV ECMO). In many centers activated partial thromboplastin time (aPTT) is used for monitoring, but it can be affected by several confounders. The aim of this study was to evaluate the safety and efficacy of anticoagulation with argatroban titrated according to diluted thrombin time targets (hemoclot™ assay) compared to anti-Xa guided anticoagulation with unfractionated heparin (UFH). METHODS: This cohort study included adults at two tertiary care centers who required VV ECMO for severe COVID-19-related acute respiratory distress syndrome (CARDS). Patients received center-dependent argatroban or UFH for anticoagulation during ECMO. Argatroban was guided following a hemoclot™ target range of 0.4-0.6 µg/ml. UFH was guided by anti-factor Xa (antiXa) levels (0.2-0.3 IU/ml). The primary outcome was safety of argatroban compared to UFH, assessed by time to first clinically relevant bleeding event or death during ECMO. Secondary outcomes included efficacy (time to thromboembolism) and feasibility (proportion of anticoagulation targets within range). RESULTS: From 2019 to 2021 57 patients were included in the study with 27 patients (47 %) receiving argatroban and 30 patients (53 %) receiving UFH. The time to the first clinically relevant bleeding or death during ECMO was similar between groups (HR (argatroban vs. UFH): 1.012, 95 % CI 0.44-2.35, p = 0.978). Argatroban was associated with a decreased risk for thromboembolism compared to UFH (HR 0.494 (95 % CI 0.26-0.95; p = 0.034)). The overall proportion of anticoagulation within target ranges was not different between groups (46 % (23-54 %) vs. 46 % (37 %-57 %), p = 0.45). CONCLUSION: Anticoagulation with argatroban according to hemoclot™ targets (0.4-0.6 µg/ml) compared to antiXa guided UFH (0.2-0.3 IU/ml) is safe and may prolong thromboembolism-free time in patients with severe ARDS requiring VV ECMO.

Between a rock and a hard place: anticoagulation management for ECMO.

Anticoagulation is an essential component of optimal extracorporeal membrane oxygenation (ECMO) management. Unfractionated heparin is still the anticoagulant of choice in most centers due to longstanding familiarity with the agent. Disadvantages include alterations in drug responses due to its capability to bind multiple heparin-binding proteins that compete with antithrombin and the potential for heparin-induced thrombocytopenia. In such cases, direct thrombin inhibitors are the treatment of choice but pose difficulties in monitoring due to the limited experience and target ranges for non-aPTT-guided management (aPTT: activated partial thromboplastin time). The current trend toward low-dose anticoagulation, especially for venovenous ECMO, is supported by data associating bleeding complications with mortality but not thromboembolic events, which include circuit thrombosis. However, only prospective data will provide appropriate answers to how to individualize anticoagulation, transfusions, and bleeding management which is currently only supported by expert opinion. Empiric therapy for ECMO patients based on laboratory coagulation alone should always be critically questioned. In summary, only collaboration and future studies of coagulation management during ECMO will help us to make this life-saving therapy that has become part of daily life of the intensivist even safer and more effective. Until then, a fundamental understanding of coagulation and bleeding management, as well as pearls and pitfalls of monitoring, is essential to optimize anticoagulation during ECMO. This article is freely available.

Drug-Drug Interactions in Patients with Acute Respiratory Distress Syndrome.

Acute respiratory distress syndrome (ARDS) is a potential life-threatening, heterogenous, inflammatory lung disease. There are no data available on potential drug-drug interactions (pDDIs) in critically ill patients with ARDS. This study analyzed pDDIs in this specific cohort and aimed to investigate possible associations of coronavirus disease 2019 (COVID-19) as an underlying cause of ARDS and treatment with extracorporeal membrane oxygenation (ECMO) with the occurrence of pDDIs. This retrospective study included patients ≥18 years of age diagnosed with ARDS between January 2010 and September 2021. The Janusmed database was used for the identification of pDDIs. A total of 2694 pDDIs were identified in 189 patients with a median treatment duration of 22 days. These included 323 (12%) clinically relevant drug combinations that are best avoided, corresponding to a median rate of 0.05 per day. There was no difference in the number of pDDIs between COVID-19- and non-COVID-19-associated ARDS. In patients treated with ECMO, the rate of the most severely graded pDDIs per day was significantly higher compared with those who did not require ECMO. PDDIs occur frequently in patients with ARDS. On average, each patient may encounter at least one clinically relevant drug combination that should be avoided during their intensive care unit stay.

[Long-term consequences after intensive therapy]. / Langzeitfolgen nach Intensivtherapie.

Many intensive care patients are affected by serious persistent or new physical, cognitive, psychological, and social consequences after discharge (post-ICU syndrome). This has an impact on the rest of life as well as the prognosis. To reduce or avoid these complications and structured treatment after discharge must be essential goals of intensive care medicine. Prevention of PICS is of central importance. The knowledge that many elements of the symptoms are triggered or intensified by therapeutic treatments as part of intensive therapy offers the opportunity to modify. Therapy must be designed to reduce potential sequelae, with the avoidance of overtreatment, such as sedation. These understanding must lead to critically questioning who is admitted to an intensive care unit and for whom a realistic therapy goal in terms of functionality, quality of life and life expectancy can be achieved. Ultimately, the treatment of intensive care patients must not end when they are discharged from the intensive care unit or hospital. Patients at risk for the very different facets of a PICS must be identified and linked to appropriate care institutions. This requires the establishment of post-ICU facilities, such as consultation hours in clinics or outpatient clinics.

A randomized, double-blind study on the safety and immunogenicity of rTSST-1 variant vaccine: phase 2 results.

Background: Toxic shock syndrome toxin-1 (TSST-1) is a superantigen produced by Staphylococcus aureus that causes the life-threatening toxic shock syndrome. The development of a safe and immunogenic vaccine against TSST-1 remains an unmet medical need. We investigated the safety, tolerability and immunogenicity of a recombinant TSST-1 variant vaccine (rTSST-1v) after 1-3 injections in healthy volunteers. Methods: In this randomised, double-blind, adjuvant-controlled, parallel-group, phase 2 trial, healthy adults aged 18-64 were randomly allocated to undergo 1-3 injections of either 10 or 100 µg rTSST-1v or Al(OH)3. The primary endpoint was safety and tolerability of rTSST-1v in the intention-to-treat population. The per-protocol population was used for the immunogenicity analysis. The trial is registered with EudraCT#: 2015-003714-24; ClinicalTrials.gov#: NCT02814708. Findings: Between April and November 2017,140 subjects were enrolled and 126 completed the trial. rTSST-1v showed a good safety and tolerability profile. A total of 855 systemic adverse events occurred, 280 of which were suspected related adverse events, without dose dependency. Two participants were discontinued early because of allergic reactions. Seroconversion occurred in >81% of subjects within 3 months of the first immunisation which was sustained until 18 months after the third immunisation in over 70% of subjects in the pooled low-dose group and in over 85% in the pooled high-dose group. Interpretation: rTSST-1v in cumulative doses of up to 300 µg was safe, well-tolerated and highly immunogenic. Two immunisations with 100 µg rTSST-1v provided the most persistent immune response and may be evaluated in future trials. Funding: Biomedizinische Forschung & Bio-Produkte AG funded this study.

Prevalence of FXII-Deficiency and Its Relevance to Monitoring Anticoagulation in Adults Receiving Extracorporeal Membrane Oxygenation.

During extracorporeal membrane oxygenation (ECMO) blood is exposed to artificial surfaces, resulting in contact activation of the intrinsic coagulation pathway initiated by coagulation factor XII (FXII). Little is known about the prevalence of acquired FXII-deficiency, especially during ECMO. The primary outcome was the prevalence of acquired FXII-deficiency (FXII activity <60%) during ECMO. Secondary outcomes included differences in hemorrhagic/thromboembolic complications, doses of unfractionated heparin administered, and time points of anticoagulation within target ranges between patients with and without FXII-deficiency. Of 193 adults receiving ECMO therapy between 2013 and 2021, FXII testing was performed in 64 (33%) patients. Of these, 89% ( n = 57) had an acquired FXII-deficiency. Median complication-free intervals were not different between patients with and without acquired FXII-deficiency (bleeding: 28 days [6-145] vs. 12 days [11-not available], p = 0.85; thromboembolism: 16 days [8-54] vs. 13 days [3-15], p = 0.053). Patients with acquired FXII-deficiency received less heparin (16,554 IU/day vs. 25,839 IU/day; p = 0.009) and were less likely to be within aPTT-target ranges (23.1% [14.3%-36.4%] vs. 37.8% [33.7%-58.3%], p = 0.005). Acquired FXII-deficiency is common during ECMO and may affect monitoring of anticoagulation. The impact of FXII-activity on complications needs to be determined in future studies.

[Side effects of immune checkpoint inhibitor therapy : What intensive care specialists need to know]. / Nebenwirkungen nach Immuncheckpointinhibitortherapie : Wissenswertes für Intensivmediziner:innen.

Immunotherapies, and in particular checkpoint inhibitors, have revolutionized the treatment of cancer. However, due to their mechanism of action, the activation of the body's own T cells, side effects are frequently associated with these therapies. So-called immune-related adverse events (irAEs) manifest as autoimmunological phenomena, can occur in any organ system, and even lead to severe organ failure. Due to the time latency of up to months after administration of a checkpoint inhibitor until the first manifestation of an irAE, it is essential to consider a therapy-specific adverse event at any time during therapy. In case of incipient organ failure, discontinuation of the checkpoint inhibitor and rapid initiation of high-dose corticosteroid therapy is essential, which, in the absence of response, should be extended by further immunosuppressive or anti-inflammatory therapies. In general, the response to corticosteroids and extended therapy options is good, and in this sense organ failure is often reversible. Nevertheless, intensive medical care with the possible need for organ-supporting therapies should only be provided strictly according to the patient's wishes and in close consultation with the hematologist/oncologist in charge. Because of the great therapeutic benefit of immunotherapies, their frequent use, and potential to be used in curative lines of therapy in the future, intensive care physicians will also be confronted more frequently with irAEs after checkpoint inhibition. Accordingly, understanding, recognizing, and treating side effects after immunotherapies is increasingly essential for intensivists.

Disseminated Intravascular Coagulation in Anaphylaxis.

Anaphylaxis is a life-threatening condition that involves severe cutaneous, respiratory, and cardiovascular symptoms. Disseminated intravascular coagulation (DIC) is an acquired, widespread activation of coagulation that can be caused by infectious conditions (e.g., sepsis) and noninfectious conditions. The onset of DIC following anaphylaxis is not commonly known, and information regarding the pathomechanism linking anaphylaxis to DIC is scarce. Further, demographic and clinical data in anaphylaxis-induced DIC are still missing to this day. Triggered by a case of anaphylaxis-induced DIC that seamlessly transitioned to lethal sepsis-induced DIC, we aimed to characterize the patient population affected by anaphylaxis-induced DIC by performing a review of existing literature and expand the discussion to underlying mechanisms. The overall mortality of the patient cohort (n = 30) identified by the literature review was 50%. All patients that died either suffered a bleeding event or a thrombotic event. The majority of patients (n = 25/30; 83%) had bleeding events; thrombotic events were only reported in nonsurvivors (n = 9/15 or 60% of nonsurvivors; vs. n = 0/15 in survivors; p < 0.001). Nonsurvivors of anaphylaxis-induced DIC were on average 25 years older than survivors (p = 0.068). In conclusion, DIC can complicate anaphylaxis and is expected to contribute to poor microvascular perfusion after anaphylaxis. Particularly, elderly patients with known cardiovascular disease and patients who develop thrombotic events are susceptible to lethal outcomes. As a rare and largely uncharacterized disease entity, further research is needed to investigate the link between DIC and anaphylaxis and to potentially identify better treatment strategies.

Prevalence and Impact of Lupus Anticoagulant in Patients Receiving Extracorporeal Membrane Oxygenation.

BACKGROUND: Monitoring of blood coagulation is essential in ECMO patients. We investigated the prevalence of lupus anticoagulant (LA) and its association with coagulation testing and hemostaseologic complications in patients treated with ECMO. METHODS: This is a retrospective analysis including adult patients who received ECMO at a medical intensive care unit at the Medical University of Vienna. The primary outcome was the prevalence of LA. Secondary outcomes included conditions associated with LA positivity, rates of bleeding and thromboembolic events, as well as the proportions of aPTT and antiXa measurements within the target range. RESULTS: Between 2013 and 2021 193 patients received ECMO, in 62 (32%) of whom LA diagnostics were performed. Twenty-two (35%) patients tested positive. LA positive patients had more frequently received VV ECMO (77.3% vs 34.3%; p = 0.002), were more frequently diagnosed with viral respiratory infections (SARS-CoV2: 45.5% vs 20%; p = 0.041, influenza virus: 22.7% vs 0%; p = 0.003), had a longer ECMO treatment duration (25 vs 10 days; p = 0.011) and a longer ICU stay (48 vs 25 days; p = 0.022), but similar rates of bleeding and thromboembolic events.

Inadequate Energy Delivery Is Frequent among COVID-19 Patients Requiring ECMO Support and Associated with Increased ICU Mortality.

BACKGROUND: Patients receiving extracorporeal membrane oxygenation (ECMO) support are at high risk for malnutrition. There are currently no general nutrition guidelines for coronavirus disease 2019 (COVID-19) patients during ECMO therapy. METHODS: We conducted a retrospective analysis of COVID-19 patients requiring venovenous ECMO support at a large tertiary hospital center. Nutrition goals were calculated using 25 kcal/kg body weight (BW)/day. Associations between nutrition support and outcome were evaluated using Kaplan-Meier and multivariable Cox regression analyses. RESULTS: Overall, 102 patients accounted for a total of 2344 nutrition support days during ECMO therapy. On 40.6% of these days, nutrition goals were met. Undernutrition was found in 40.8%. Mean daily calorie delivery was 73.7% of calculated requirements, mean daily protein delivery was 0.7 g/kg BW/d. Mean energy intake of ≥70% of calculated targets was associated with significantly lower ICU mortality independently of age, disease severity at ECMO start and body mass index (adjusted hazard ratio: 0.372, p = 0.007). CONCLUSIONS: Patients with a mean energy delivery of ≥70% of calculated targets during ECMO therapy had a better ICU survival compared to patients with unmet energy goals. These results indicate that adequate nutritional support needs to be a major priority in the treatment of COVID-19 patients requiring ECMO support.

Impact of chronic graft-versus-host-disease on intensive care outcome in allogeneic hematopoietic stem cell recipients.

Chronic graft-vs-host-disease (cGvHD) is the most relevant long-term complication after allogeneic stem cell transplantation (HSCT) with major impact on non-relapse mortality, but data on intensive care unit (ICU) outcome are missing. In this retrospective, multicenter study we analyzed 174 adult HSCT recipients with cGvHD requiring intensive care treatment. Skin, pulmonary, liver, and intestinal involvement were present in 76.7%, 47.1%, 38.1% and 24.1%, respectively, and a total of 63.2% had severe cGvHD. Main reasons for ICU admission were respiratory failure (69.7%) and sepsis (34.3%). Hospital- and 3-year OS rates were 51.7% and 28.6%, respectively. Global severity of cGvHD did not impact short- and long-term survival. However, patients with severe liver cGvHD or the overlap subtype had a reduced hospital survival, while severe pulmonary cGvHD was associated with worse long-term survival. In multivariate analysis need for invasive ventilation (HR 1.08 (95% CI 1.02-1.14)) or hemodialysis (HR 1.73 (95% CI 1.14-2.62)) and <1 year since HSCT (HR 1.56 (95% CI 1.03-2.39)) were independently associated with a poorer survival. While the global severity of cGvHD does not per se affect patients' survival after intensive care treatment, pre-existing severe hepatic, intestinal or pulmonary cGvHD is associated with worse outcomes.

Association of Intravenous Potassium and Magnesium Administration With Spontaneous Conversion of Atrial Fibrillation and Atrial Flutter in the Emergency Department.

Importance: Whether the simultaneous intravenous administration of potassium and magnesium is associated with the probability of spontaneous conversion to sinus rhythm (SCV) in the acute treatment of atrial fibrillation (AF) and atrial flutter (AFL) is unknown. Objective: To assess potassium and magnesium administration and SCV probability in AF and AFL in the emergency department. Design, Setting, and Participants: A registry-based cohort study was conducted in the Department of Emergency Medicine of the Medical University of Vienna, Austria. All consecutive patients with AF or AFL were screened between February 6, 2009, and February 16, 2020. Interventions: Intravenous administration of potassium, 24 mEq, and magnesium, 145.8 mg. Main Outcomes and Measures: The primary outcome was the probability of SCV during the patient's stay in the emergency department. Multivariable cluster-adjusted logistic regression was used to estimate the association between potassium and magnesium administration and the probability of SCV. Results: A total of 2546 episodes of nonpermanent AF (median patient age, 68 [IQR, 58-75] years, 1411 [55.4%] men) and 573 episodes of nonpermanent AFL (median patient age, 68 [IQR, 58-75] years; 332 [57.9%] men) were observed. In AF episodes, intravenous potassium and magnesium administration vs no administration was associated with increased odds of SCV (19.2% vs 10.4%; odds ratio [OR], 1.98; 95% CI, 1.53-2.57). In AFL episodes, in contrast, no association was noted for the probability of SCV with potassium and magnesium vs no administration (13.0% vs 12.5%; OR, 1.05; 95% CI, 0.65-1.69). Conclusions and Relevance: The findings of this registry-based cohort study on intravenous administration of potassium and magnesium suggest an increased probability of SCV in nonpermanent AF, but not AFL, during a patients' stay in the emergency department.

Applicability of Vasopressor Trials in Adult Critical Care: A Prospective Multicentre Meta-Epidemiologic Cohort Study.

Objective: To assess the applicability of evidence from landmark randomized controlled trials (RCTs) of vasopressor treatment in critically ill adults. Study Design and Setting: This prospective, multi-center cohort study was conducted at five medical and surgical intensive care units at three tertiary care centers. Consecutive cases of newly initiated vasopressor treatment were included. The primary end point was the proportion of patients (≥18 years) who met the eligibility criteria of 25 RCTs of vasopressor therapy in critically ill adults included in the most recent Cochrane review. Multilevel Poisson regression was used to estimate the eligibility proportions with 95% confidence intervals for each trial. Secondary end points included the eligibility criteria that contributed most to trial ineligibility, and the relationship between eligibility proportions and (i) the Pragmatic-Explanatory Continuum Indicator Summary-2 (PRECIS-2) score, and (ii) the recruitment-to-screening ratio of each RCT. The PRECIS-2 score was used to assess the degree of pragmatism of each trial. Results: Between January 1, 2017, and January 1, 2019, a total of 1189 cases of newly initiated vasopressor therapy were included. The median proportion of cases meeting eligibility criteria for all 25 RCTs ranged from 1.3% to 6.0%. The eligibility criteria contributing most to trial ineligibility were the exceedance of a specific norepinephrine dose, the presence of a particular shock type, and the drop below a particular blood pressure value. Eligibility proportions increased with the PRECIS-2 score but not with the recruitment-to-screening ratio of the trials. Conclusion: The applicability of evidence from available trials on vasopressor treatment in critically ill adults to patients receiving vasopressors in daily practice is limited. Applicability increases with the degree of study pragmatism but is not reflected in a high recruitment-to-screening ratio. Our findings may help researchers design vasopressor trials and promote standardized assessment and reporting of the degree of pragmatism achieved.

Micellar Curcumin: Pharmacokinetics and Effects on Inflammation Markers and PCSK-9 Concentrations in Healthy Subjects in a Double-Blind, Randomized, Active-Controlled, Crossover Trial.

SCOPE: Preclinical models have demonstrated the anti-inflammatory and lipid-lowering effects of curcumin. Innovative formulations have been developed to overcome the poor bioavailability of native curcumin. The study hypothesizes that the bioavailability of micellar curcumin is superior to native curcumin and investigates the potential anti-inflammatory and proprotein convertase subtilisin/kexin type 9 (PCSK9) concentration lowering effects. METHODS AND RESULTS: In this double-blind, randomized, crossover trial, 15 healthy volunteers receive micellar or native curcumin (105 mg day-1 ) for 7 days with a ≥7 days washout period. Curcumin and metabolite concentrations are quantified by high-performance liquid chromatography with fluorescence detection (HPLC-FD), and pharmacokinetics are calculated. To analyze anti-inflammatory effects, blood samples (baseline, 2 h, 7 days) are stimulated with 50 ng mL-1 lipopolysaccharides (LPS). Interleukin (IL)-6, tumor-necrosis factor (TNF-α), and PCSK9 concentrations are quantified. Micellar curcumin demonstrates improved bioavailability (≈39-fold higher maximum concentrations, ≈14-fold higher area-under-the-time-concentration curve, p < 0.001) but does not reduce pro-inflammatory cytokines in the chosen model. Subjects receiving micellar curcumin have significantly lower PCSK9 concentrations (≈10% reduction) after 7 days compared to baseline (p = 0.038). CONCLUSION: Micellar curcumin demonstrates an improved oral bioavailability but does not show anti-inflammatory effects in this model. Potential effects on PCSK9 concentrations warrant further investigation.

Multi-phasic life-threatening anaphylaxis refractory to epinephrine managed by extracorporeal membrane oxygenation (ECMO): A case report.

We present a case of a 52-year-old patient suffering from multi-phasic life-threatening anaphylaxis refractory to epinephrine treatment. Extracorporeal membrane oxygenation (ECMO) therapy was initiated as the ultima ratio to stabilize the patient hemodynamically during episodic severe bronchospasm. ECMO treatment was successfully weaned after 4 days. Mastocytosis was diagnosed as the underlying condition. Although epinephrine is recommended as a first-line treatment for anaphylaxis, this impressive case provides clear evidence of its limited therapeutic success and emphasizes the need for causal therapies.