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.

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.

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.

[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.