Anticoagulation and Bleeding during Veno-Venous Extracorporeal Membrane Oxygenation: Insights from the PROTECMO Study.

Rationale: Definitive guidelines for anticoagulation management during veno-venous extracorporeal membrane oxygenation (VV ECMO) are lacking, whereas bleeding complications continue to pose major challenges. Objectives: To describe anticoagulation modalities and bleeding events in adults receiving VV ECMO. Methods: This was an international prospective observational study in 41 centers, from December 2018 to February 2021. Anticoagulation was recorded daily in terms of type, dosage, and monitoring strategy. Bleeding events were reported according to site, severity, and impact on mortality. Measurements and Main Results: The study cohort included 652 patients, and 8,471 days on ECMO were analyzed. Unfractionated heparin was the initial anticoagulant in 77% of patients, and the most frequently used anticoagulant during the ECMO course (6,221 d; 73%). Activated partial thromboplastin time (aPTT) was the most common test for monitoring coagulation (86% of days): the median value was 52 seconds (interquartile range, 39 to 61 s) but dropped by 5.3 seconds after the first bleeding event (95% confidence interval, -7.4 to -3.2; P < 0.01). Bleeding occurred on 1,202 days (16.5%). Overall, 342 patients (52.5%) experienced at least one bleeding event (one episode every 215 h on ECMO), of which 10 (1.6%) were fatal. In a multiple penalized Cox proportional hazard model, higher aPTT was a potentially modifiable risk factor for the first episode of bleeding (for 20-s increase; hazard ratio, 1.07). Conclusions: Anticoagulation during VV ECMO was a dynamic process, with frequent stopping in cases of bleeding and restart according to the clinical picture. Future studies might explore lower aPTT targets to reduce the risk of bleeding.

Antithrombin during veno-venous extracorporeal membrane oxygenation with heparin anticoagulation: A single-center cohort study.

INTRODUCTION: Antithrombin (AT) is a natural anticoagulant essential to enhancing the unfractionated heparin (UFH) anticoagulant effect. Its supplementation in the management of UFH-based anticoagulation during veno-venous extracorporeal membrane oxygenation (VV ECMO) has a strong pathophysiological rationale. METHODS: This is a single-center, retrospective cohort study of adult VV ECMO patients with anticoagulation maintained by UFH targeting an activated partial thromboplastin time (aPTT) of 40-50 s and AT activity >80%. We compare anticoagulation management and survival outcomes between AT subpopulations, defined by a threshold AT activity ≥80%. Linear and logistic regression analyses were used to evaluate the variation in AT activity and its association with ICU survival. RESULTS: In 244 patients enrolled from 2009 to 2022, anticoagulation was maintained by a median heparin dose of 11.4 IU/kg/h [IQR: 8.2-14.7] with a mean aPTT of 46.1 s (±7.3) and AT activity of 88.9% (±17.0). A lower mean aPTT, higher dose of UFH and shorter fraction of time without UFH were associated with higher AT activity (p < .01). Higher AT activity showed a consistent association with ICU survival (for 10% increase of AT, odds ratio for ICU mortality: 0.95; 95% CI 0.93-0.97; p value <.01). CONCLUSIONS: There is a positive association between AT activity and UFH requirements but no significant difference in the rate of bleeding events. A higher mean AT during VV ECMO was associated with ICU survival. Future studies are needed to differentiate between exogenously supplemented versus endogenous AT effect.

The role of inflammation and antithrombin supplementation on thromboelastographic parameters during veno-venous ECMO for respiratory failure.

INTRODUCTION: Extracorporeal membrane oxygenation (ECMO) may act as a driver or propagator of systemic inflammation. In turn, cytokine release can modify thromboelastographic (TEG) tests which are commonly used for anticoagulation monitoring. In this context, antithrombin (AT) supplementation might further modify TEG. METHODS: This is a pre-specified sub-study of the "Randomized Controlled Trial of Antithrombin Supplementation During Extracorporeal Membrane Oxygenation" study (investigator-initiated, randomized, single-blind, two-arm trial) conducted in two Italian ECMO referral ICUs. Adult patients requiring vv-ECMO for respiratory failure and undergoing unfractioned heparin (UFH) administration were enrolled and randomized whether to receive AT supplementation. Plasma samples for cytokine assay (IL-8, IL-10, IL-6, IL-1ß, TNF-α and Pro-ADM) and heparinase TEG were collected from every patient before ECMO start, 24 h and 72 h after ECMO start, before ECMO removal, and 7 days after ECMO removal or upon ICU discharge whichever happened first. AT concentration, coagulation and clinical data were collected before ECMO start and at pre-fixed time points. RESULTS: Thirty-nine patients were enrolled (21 treatments, 18 controls). TEG-R had a weak-to-moderate positive correlation with IL-8, IL-6, IL-10 and TNF-α and a moderate positive correlation with Pro-ADM. TEG-ANG showed a weak negative correlation with IL-8, IL-6 and TNF-α, while TEG-MA negatively correlated with IL-8, TNF-α and Pro-ADM. AT supplementation seemed to modify the association between TEG-MA and IL-8, IL-10 and Pro-ADM; conversely, AT did not affect the relationship among TEG-R or TEG-ANG and the studied cytokines. CONCLUSIONS: High concentrations of systemic cytokines correlated with longer reaction times and decreased angle and amplitude at TEG, suggesting that an increase in inflammation is related with hypocoagulability as revealed by thromboelastography.

Extracorporeal membrane oxygenation for COVID-19 and influenza H1N1 associated acute respiratory distress syndrome: a multicenter retrospective cohort study.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) has become an established rescue therapy for severe acute respiratory distress syndrome (ARDS) in several etiologies including influenza A H1N1 pneumonia. The benefit of receiving ECMO in coronavirus disease 2019 (COVID-19) is still uncertain. The aim of this analysis was to compare the outcome of patients who received veno-venous ECMO for COVID-19 and Influenza A H1N1 associated ARDS. METHODS: This was a multicenter retrospective cohort study including adults with ARDS, receiving ECMO for COVID-19 and influenza A H1N1 pneumonia between 2009 and 2021 in seven Italian ICU. The primary outcome was any-cause mortality at 60 days after ECMO initiation. We used a multivariable Cox model to estimate the difference in mortality accounting for patients' characteristics and treatment factors before ECMO was started. Secondary outcomes were mortality at 90 days, ICU and hospital length of stay and ECMO associated complications. RESULTS: Data from 308 patients with COVID-19 (N = 146) and H1N1 (N = 162) associated ARDS who had received ECMO support were included. The estimated cumulative mortality at 60 days after initiating ECMO was higher in COVID-19 (46%) than H1N1 (27%) patients (hazard ratio 1.76, 95% CI 1.17-2.46). When adjusting for confounders, specifically age and hospital length of stay before ECMO support, the hazard ratio decreased to 1.39, 95% CI 0.78-2.47. ICU and hospital length of stay, duration of ECMO and invasive mechanical ventilation and ECMO-associated hemorrhagic complications were higher in COVID-19 than H1N1 patients. CONCLUSION: In patients with ARDS who received ECMO, the observed unadjusted 60-day mortality was higher in cases of COVID-19 than H1N1 pneumonia. This difference in mortality was not significant after multivariable adjustment; older age and longer hospital length of stay before ECMO emerged as important covariates that could explain the observed difference. TRIAL REGISTRATION NUMBER: NCT05080933 , retrospectively registered.

Nutrition during extracorporeal life support: A review of pathophysiological bases and application of guidelines.

BACKGROUND: Patients on extracorporeal life support (ECLS), either for respiratory or cardiac support, are at high risk of malnutrition; guidelines on nutrition in critical care have not incorporated solid evidence regarding these settings. The aim of this narrative review is to gather the available evidence in the existing literature and transpose general principles to the ECLS population. METHODS: A literature review of observational and interventional studies on nutrition during ECLS, and evaluation of nutrition guidelines in this perspective. RESULTS: Nutrition is paramount for improving outcomes in ECLS, as well as in critically ill patients. The caloric needs during ECLS can vary according to the severity of the clinical state, sedation, paralysis, and temperature stability. Precise evaluation of energy expenditure by indirect calorimetry is difficult because ECLS is a system dedicated to removing carbon dioxide; however, modified equations composed of carbon dioxide values taken from the membrane lung are available. Guidelines suggest starting early enteral nutrition (EN) with a hypocaloric (70%-80% of the needs) strategy, also in acute states such as septic or cardiogenic shock. Moreover, EN, despite previous concerns, is feasible in prone position, an increasingly adopted strategy during mechanical ventilation. The catabolic state is maximal in these patients, causing a protein and muscular reduction. Therefore, adequate protein delivery should be guaranteed by administering a high protein intake of up to 2 g/kg/day. CONCLUSIONS: Studies on nutrition tailored to ECLS patients are warranted. Early hypocaloric EN with high protein intake, tailored on indirect calorimetry, may be the most appropriate option.

Inferior vena cava surgical cannulation for infants needing veno-venous extracorporeal membrane oxygenation.

INTRODUCTION: Femoral cannulation for veno-venous extracorporeal membrane oxygenation is challenging in infants because of the diameter of the vein. CASE REPORT: Prolonged ECMO support (67 days) was necessary for an 8-month-old (8 kg) girl with acute respiratory distress syndrome that was caused by H1N1 influenza. After 30 days on ECMO support and using a single 16 Fr double-lumen cannula (internal jugular vein), a second cannula was necessary to ensure adequate flow. This second 12 Fr single-lumen cannula was surgically placed through the right common iliac vein. An excellent flow profile was then achieved and ECMO continued successfully for 37 more days. DISCUSSION: As a lifesaving option, this double caval configuration successfully optimized the flow profile and oxygenation, outweighing the related risks. CONCLUSION: In small children, a surgical approach to the inferior vena cava can be considered safe, especially in those cases where there is a shortage of adequate cannulas, or when central venous access is difficult.

Tracheostomy management in patients with severe acute respiratory distress syndrome receiving extracorporeal membrane oxygenation: an International Multicenter Retrospective Study.

BACKGROUND: Current practices regarding tracheostomy in patients treated with extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome are unknown. Our objectives were to assess the prevalence and the association between the timing of tracheostomy (during or after ECMO weaning) and related complications, sedative, and analgesic use. METHODS: International, multicenter, retrospective study in four large volume ECMO centers during a 9-year period. RESULTS: Of the 1,168 patients treated with ECMO for severe ARDS (age 48 ± 16 years, 76% male, SAPS II score 51 ± 18) during the enrollment period, 353 (30%) and 177 (15%) underwent tracheostomy placement during or after ECMO, respectively. Severe complications were uncommon in both groups. Local bleeding within 24 h of tracheostomy was four times more frequent during ECMO (25 vs 7% after ECMO, p < 0.01). Cumulative sedative consumption decreased more rapidly after the procedure with sedative doses almost negligible 48-72 h later, when tracheostomy was performed after ECMO decannulation (p < 0.01). A significantly increased level of consciousness was observed within 72 h after tracheostomy in the "after ECMO" group, whereas it was unchanged in the "during-ECMO" group. CONCLUSION: In contrast to patients undergoing tracheostomy after ECMO decannulation, tracheostomy during ECMO was neither associated with a decrease in sedation and analgesia levels nor with an increase in the level of consciousness. This finding together with a higher risk of local bleeding in the days following the procedure reinforces the need for a case-by-case discussion on the balance between risks and benefits of tracheotomy when performed during ECMO.

Hemoperfusion and blood purification strategies in patients with COVID-19: A systematic review.

BACKGROUND: Coronavirus disease-19 (COVID-19) ranges from asymptomatic infection to severe cases requiring admission to the intensive care unit. Together with supportive therapies (ventilation in particular), the suppression of the pro-inflammatory state has been a hypothesized target. Pharmacological therapies with corticosteroids and interleukin-6 (IL-6) receptor antagonists have reduced mortality. The use of extracorporeal cytokine removal, also known as hemoperfusion (HP), could be a promising non-pharmacological approach to decrease the pro-inflammatory state in COVID-19. METHODS: We conducted a systematic review of PubMed and EMBASE databases in order to summarize the evidence regarding HP therapy in COVID-19. We included original studies and case series enrolling at least five patients. RESULTS: We included 11 articles and describe the characteristics of the populations studied from both clinical and biological perspectives. The methodological quality of the included studies was generally low. Only two studies had a control group, one of which included 101 patients in total. The remaining studies had a range between 10 and 50 patients included. There was large variability in the HP techniques implemented and in clinical and biological outcomes reported. Most studies described decreasing levels of IL-6 after HP treatment. CONCLUSION: Our review does not support strong conclusions regarding the role of HP in COVID-19. Considering the very low level of clinical evidence detected, starting HP therapies in COVID-19 patients does not seem supported outside of clinical trials. Prospective randomized data are needed.

A Randomized Controlled Trial of Antithrombin Supplementation During Extracorporeal Membrane Oxygenation.

OBJECTIVES: Supplementation of antithrombin might decrease the amount of heparin needed to achieve a given anticoagulation target during extracorporeal membrane oxygenation. However, exogenous antithrombin itself may increase the risk of bleeding. We conceived a study to evaluate the effect of antithrombin supplementation in adult patients requiring venovenous extracorporeal membrane oxygenation for respiratory failure on heparin dose, adequacy of anticoagulation, and safety. DESIGN: Prospective randomized controlled trial. SETTING: ICUs of two Italian referral extracorporeal membrane oxygenation centers. PATIENTS: Adult patients requiring venovenous extracorporeal membrane oxygenation for severe respiratory failure and unfractionated heparin for systemic anticoagulation. INTERVENTIONS: Before extracorporeal membrane oxygenation start, patients were randomized to either receive antithrombin concentrate to maintain a plasmatic level 80-120% (treatment) or not (control) during the extracorporeal membrane oxygenation course. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the total amount of heparin required to maintain activated partial thromboplastin time ratio 1.5-2. Secondary outcomes were anti-factor Xa, the incidence of hemorrhagic and thrombotic events, and the amount of blood products transfused. Twenty-four patients in the treatment group and 24 in the control group were included in the intention-to-treat analysis. Antithrombin was 109.5% (93.0-123.0%) in the treatment group and 84.0% (68.5-98.0%) in the control group (p = 0.001). Supplementation of antithrombin did not decrease heparin dose (13.5 international units/kg/hr [9.6-17.9 international units/kg/hr] vs 15.1 international units/kg/hr [10.7-18.3 international units/kg/hr] in the treatment and control group, respectively; p = 0.33) and anti-Factor Xa levels (0.4 international units/mL [0.3-0.5 international units/mL] vs 0.3 international units/mL [0.2-0.5 international units/mL] in the treatment group and control group respectively; p = 0.65). Bleeding, blood product transfusions, and thrombosis were not different in the two groups. CONCLUSIONS: Antithrombin supplementation may not decrease heparin requirement nor diminish the incidence of bleeding and/or thrombosis in adult patients on venovenous extracorporeal membrane oxygenation.

Mechanical Ventilation Management during Extracorporeal Membrane Oxygenation for Acute Respiratory Distress Syndrome. An International Multicenter Prospective Cohort.

Rationale: Current practices regarding mechanical ventilation in patients treated with extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome are unknown.Objectives: To report current practices regarding mechanical ventilation in patients treated with ECMO for severe acute respiratory distress syndrome (ARDS) and their association with 6-month outcomes.Methods: This was an international, multicenter, prospective cohort study of patients undergoing ECMO for ARDS during a 1-year period in 23 international ICUs.Measurements and Main Results: We collected demographics, daily pre- and per-ECMO mechanical ventilation settings and use of adjunctive therapies, ICU, and 6-month outcome data for 350 patients (mean ± SD pre-ECMO PaO2/FiO2 71 ± 34 mm Hg). Pre-ECMO use of prone positioning and neuromuscular blockers were 26% and 62%, respectively. Vt (6.4 ± 2.0 vs. 3.7 ± 2.0 ml/kg), plateau pressure (32 ± 7 vs. 24 ± 7 cm H2O), driving pressure (20 ± 7 vs. 14 ± 4 cm H2O), respiratory rate (26 ± 8 vs. 14 ± 6 breaths/min), and mechanical power (26.1 ± 12.7 vs. 6.6 ± 4.8 J/min) were markedly reduced after ECMO initiation. Six-month survival was 61%. No association was found between ventilator settings during the first 2 days of ECMO and survival in multivariable analysis. A time-varying Cox model retained older age, higher fluid balance, higher lactate, and more need for renal-replacement therapy along the ECMO course as being independently associated with 6-month mortality. A higher Vt and lower driving pressure (likely markers of static compliance improvement) across the ECMO course were also associated with better outcomes.Conclusions: Ultraprotective lung ventilation on ECMO was largely adopted across medium- to high-case volume ECMO centers. In contrast with previous observations, mechanical ventilation settings during ECMO did not impact patients' prognosis in this context.

A narrative review of antithrombin use during veno-venous extracorporeal membrane oxygenation in adults: rationale, current use, effects on anticoagulation, and outcomes.

BACKGROUND: During extracorporeal membrane oxygenation, the large contact surface between the blood and the extracorporeal circuit causes a continuous activation of coagulation and inflammation. Unfractionated heparin, a glycosaminoglycan that must bind to antithrombin as a cofactor, is currently the standard anticoagulant adopted during extracorporeal membrane oxygenation. Antithrombin, beyond being a potent natural anticoagulant, acts in the cross-talk between coagulation and inflammatory system through anticoagulation and coagulation-independent effects. OBJECTIVES: In this review, we describe, in the adult setting of veno-venous extracorporeal membrane oxygenation, the pathophysiological rationale for antithrombin use, the current practice of administration, and the effects of antithrombin on anticoagulation, bleeding, and outcomes. DATA SOURCES: Studies on adults (18 years or older) on veno-venous extracorporeal membrane oxygenation published from 1995 to 2018 in order to evaluate the use of antithrombin. RESULTS: In adults on veno-venous extracorporeal membrane oxygenation, antithrombin supplementation has a highly pathophysiological rationale since coagulation factor consumption, systemic inflammatory response syndrome, and endothelial activation are triggered by extracorporeal membrane oxygenation. Eleven articles are focused on the topic but among the authors there is no consensus on the threshold for supplementation (ranging from 70% to 80%) as well as on the dose (rarely standardized) and time of administration (bolus vs continuous infusion). Consistently, antithrombin is considered able to achieve better anticoagulation targets in or not in the presence of heparin resistance. The impact of antithrombin administration on bleeding still shows contrasting results. CONCLUSION: Antithrombin use in veno-venous extracorporeal membrane oxygenation should be investigated on the threshold for supplementation, dose, and time of administration.

The role of endoscopy as non-invasive procedure to manage gastrointestinal complications during extracorporeal membrane oxygenation.

INTRODUCTION: Gastrointestinal bleeding is a life-threatening complication in patients undergoing extracorporeal membrane oxygenation support. Despite data on increased mortality due to gastrointestinal bleeding, there is little data on the treatment of such conditions under extracorporeal membrane oxygenation, and on the possibilities of advanced endoscopic therapy to non-invasively solve these bleeding complications. No clear treatment in the case of extracorporeal membrane oxygenation support is recommended in the guidelines. METHODS: Retrospective observational cohort study including 134 veno-venous extracorporeal membrane oxygenation patients for acute respiratory failure from 2009 to 2018 at IRCCS-ISMETT (Italy). Patients were divided into two groups according to gastrointestinal bleeding episodes and reviewed for type of endoscopic therapy. Gastrointestinal bleeding group was characterized for pre-extracorporeal membrane oxygenation characteristics, management variables-including amount of transfusions and clinical outcomes. RESULTS: Fourteen (14) patients (10.4%) experienced upper (n = 13) or lower (n = 1) gastrointestinal bleeding. Gastrointestinal bleeding and no-gastrointestinal bleeding group had similar characteristics apart from higher creatinine in the gastrointestinal bleeding group (1.9 mg/dL (1.3-4.9) vs 1.2 mg/dL (0.7-1.8), p = 0.03). In 3 of the 14 patients (21%), endoscopy showed no signs of active bleeding (nasogastric or feeding tube decubitus), and no specific intervention was performed. Active bleeding was recognized in 11 of the 14 patients (79 %). No patients died of fatal bleeding in the gastrointestinal bleeding group. Endoscopic therapy was feasible, with a complete bleeding control in all the cases: five Hemospray®, two fibrin glue, two metallic clips, one combined approach metallic clips with epinephrine, and one cyanoacrylate. The extracorporeal membrane oxygenation course was significantly longer in the gastrointestinal bleeding group: 19.5 (15-36) days vs 13.5 (8-25) days, p = 0.01. No significant differences in mortality were found between the two groups (all p values > 0.05). CONCLUSION: Advanced endoscopic therapy during veno-venous extracorporeal membrane oxygenation may contribute to reducing the negative effects on mortality for gastrointestinal bleeding episodes.

Epidemiology and successful containment of a carbapenem-resistant Enterobacteriaceae outbreak in a Southern Italian Transplant Institute.

INTRODUCTION: Carbapenem-resistant enterobacteriaceae (CRE) infections are difficult to treat and pose a serious threat to solid organ transplant (SOT) recipients. At our institute we observed an infection burden in 2012. METHODS: In order to contain the spread of CRE infections, we established a taskforce to implement guidelines suggested by the Centers for Disease Control and Prevention (CDC) for this type of outbreak. Here, we describe the epidemiology of the outbreak in our SOT population, and the effectiveness of such interventions, by comparing levels of CRE hospital-acquired infection (HAI) pre- and post-task force intervention (from January 2009 to December 2012, and from September 2013 to December 2016, respectively) through a linear regression model. RESULTS: In this study, we included 933 patients who underwent a total of 1017 SOT procedures, 286 of whom had a CRE-positive culture (28.8%), of which 65 (22.7% of CRE positive) developed infection. One-year mortality post-SOT was significantly higher in patients with CRE infection. After the taskforce intervention, the CRE HAI rate in SOT showed a significant inverse trend (event rate: -1.28, CI -1.70 to 0.86; P < 0.01). CONCLUSION: In the paucity of treatment options, the application of CDC measures in our SOT institute contributed significantly to containing CRE infections.

Limb ischemia in peripheral veno-arterial extracorporeal membrane oxygenation: a narrative review of incidence, prevention, monitoring, and treatment.

Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) is an increasingly adopted life-saving mechanical circulatory support for a number of potentially reversible or treatable cardiac diseases. It is also started as a bridge-to-transplantation/ventricular assist device in the case of unrecoverable cardiac or cardio-respiratory illness. In recent years, principally for non-post-cardiotomy shock, peripheral cannulation using the femoral vessels has been the approach of choice because it does not need the chest opening, can be quickly established, can be applied percutaneously, and is less likely to cause bleeding and infections than central cannulation. Peripheral ECMO, however, is characterized by a higher rate of vascular complications. The mechanisms of such adverse events are often multifactorial, including suboptimal arterial perfusion and hemodynamic instability due to the underlying disease, peripheral vascular disease, and placement of cannulas that nearly occlude the vessel. The effect of femoral artery damage and/or significant reduced limb perfusion can be devastating because limb ischemia can lead to compartment syndrome, requiring fasciotomy and, occasionally, even limb amputation, thereby negatively impacting hospital stay, long-term functional outcomes, and survival. Data on this topic are highly fragmentary, and there are no clear-cut recommendations. Accordingly, the strategies adopted to cope with this complication vary a great deal, ranging from preventive placement of antegrade distal perfusion cannulas to rescue interventions and vascular surgery after the complication has manifested.This review aims to provide a comprehensive overview of limb ischemia during femoral cannulation for VA-ECMO in adults, focusing on incidence, tools for early diagnosis, risk factors, and preventive and treating strategies.

Trying to identify who may benefit most from future vitamin D intervention trials: a post hoc analysis from the VITDAL-ICU study excluding the early deaths.

BACKGROUND: Vitamin D supplementation has shown promise for reducing mortality in the intensive care setting. As a steroid prohormone with pleiotropic effects, there may be a lag between administration and observing clinical benefit. This secondary analysis of the VITdAL-ICU study sought to explore whether the effect size of vitamin D on mortality was different when study participants who died or were discharged early were excluded. METHODS: The VITdAL-ICU study was a randomized, placebo-controlled trial in critically ill adults who received placebo or 540,000 IU cholecalciferol followed by monthly supplementation. The effect of vitamin D on 28-day mortality was evaluated after exclusion of participants who died or were discharged within 7 days from study drug administration, according to vitamin D concentrations on day 3, using a bivariate analysis adjusted for confounders and in a stepwise multiple analysis. RESULTS: Of 475 study participants, 65 died or were discharged within the first 7 days. In the remaining 410 patients, vitamin D supplementation was associated with a reduction in 28-day mortality [OR 0.58 (95% CI 0.35-0.97) p value = 0.035]. The effect on mortality was not significant after adjusting for age, severity scores, female gender, chronic liver and kidney disease, COPD, diagnosis of the tumor, mechanical ventilation, and vasopressors at enrollment (all p > 0.05). In a multiple model, the mortality reduction by vitamin D supplementation did not remain independently significant [OR 0.61 (95% CI 0.35-1.05) p = 0.075]. Vitamin D metabolite response, in the treatment group, demonstrated that survivors at 28 days, had higher levels of 25-hydroxyvitamin D (34.4 vs 25.4 ng/ml, p = 0.010) and 1,25-dihydroxyvitamin D (107.6 vs 70.3 pg/ml, p = 0.049) on day 3. The increase of plasma metabolites after vitamin D oral supplementation, independent of the baseline value, was associated with lower odds of death [OR 0.48 (95% CI 0.27-0.87) p value = 0.016]. CONCLUSIONS: High-dose vitamin D3 supplementation was associated with a reduction of 28-day mortality in a mixed population of critically ill adults with vitamin D deficiency when excluding patients who died or were discharged within 7 days after study inclusion. However, this survival benefit was not independently confirmed when adjusted for other factors strongly associated with mortality.

Anticoagulation and Transfusions Management in Veno-Venous Extracorporeal Membrane Oxygenation for Acute Respiratory Distress Syndrome: Assessment of Factors Associated With Transfusion Requirements and Mortality.

PURPOSE: We describe an approach for anticoagulation and transfusions in veno-venous-extracorporeal membrane oxygenation (VV-ECMO), evaluating factors associated with higher transfusion requirements, and their impact on mortality. METHODS: Observational study on consecutive adults supported with VV-ECMO for acute respiratory distress syndrome (ARDS). We targeted an activated partial thromboplastin time of 40 to 50 seconds and a hematocrit of 24% to 30%. Univariate and multiple analyses were done to evaluate factors associated with transfusion requirements and the influence of increasing transfusions on mortality during ECMO. RESULTS: In a cohort of 82 VV-ECMO patients (PRedicting dEath for SEvere ARDS on VV-ECMO [PRESERVE] score: 4, Interquartile range [IQR]: 3-5, Respiratory Extracorporeal Membrane Oxygenation Survival Prediction [RESP] score: 2, IQR: 2-4), 76 (92.7%) patients received at least 1 unit of packed red blood cells (PRBCs) during the intensive care unit stay related to ECMO (median PRBC/d 156 mL, IQR: 93-218; median ECMO duration 14 days, IQR: 8-22). A higher requirement of PRBC transfusions was associated with pre-ECMO hematocrit, and with the following conditions during ECMO: platelet nadir, antithrombin III (ATIII), and stage 3 of acute kidney injury (all P < .05). Sixty-two (75.6%) patients survived ECMO. Pre-ECMO hospital stay, PRBC transfusion, and septic shock were associated with mortality (all P < .05). The adjusted odds ratio for each 100mL/d increase in PRBC transfusion was 1.9 (95% confidence interval [CI]: 1.1-3.2, P = .01); for the development of septic shock it was 15.4 (95% CI: 1.7-136.8, P = .01), and for each day of pre-ECMO stay it was 1.1 (95% CI: 1-1.2, P = .04). CONCLUSION: Implementation of a comprehensive protocol for anticoagulation and transfusions in VV-ECMO for ARDS resulted in a low PRBC requirement, and an ECMO survival comparable to data in the literature. Lower ATIII emerged as a factor associated with increased need for transfusions. Higher PRBC transfusions were associated with ECMO mortality. Further investigations are needed to better understand the right level of anticoagulation in ECMO, and the factors to take into account in order to manage personalized transfusion practice in this select setting.

Hemoglobin trigger and approach to red blood cell transfusions during veno-venous extracorporeal membrane oxygenation: the international TRAIN-ECMO survey.

INTRODUCTION: Optimal red blood cell transfusion practice during veno-venous extracorporeal membrane oxygenation (VV ECMO) is still under debate. This survey aimed to assess the Hb trigger (also comparing with other critically ill patients) and major physiologic determinants considered for transfusions during veno-venous extracorporeal membrane oxygenation. METHODS: Voluntary Web-based survey, endorsed by the European Society of Intensive Care Medicine, conducted among VV ECMO pratictioners worldwide. RESULTS: A total of 447 respondents worldwide answered the questionnaire: 277 (61.9%) from Europe, 99 (22.1%) from North America, 36 (8.2%) from Asia and Oceania, and 35 (7.8%) from Central and South America. Among the respondents, 59.2% managed less than 12 venous extracorporeal membrane oxygenation runs/year, 19.4% between 12 and 24 runs/year, and 21.4% more than 24 runs/year. Of the respondents, 54.4% do not use a predefined Hb trigger in veno-venous extracorporeal membrane oxygenation, and, while the rate of adoption of a defined trigger varied worldwide, the effective value of Hb did not differ significantly among macro-regions. In patients on veno-venous extracorporeal membrane oxygenation, the Hb trigger to initiate red blood cell transfusion, was higher than in other critically ill patients: 9.1 ± 1.8 g/dL versus 8.3 ± 1.7 g/dL, p < 0.01. The Hb trigger was lower in centers with more than 24 venous extracorporeal membrane oxygenation runs/year (8.4 mg/dL (95% CI: 7.7-8.9)); (8.9 mg/dL (95% CI: 8.2-9.7)) in centers with between 12 and 24 venous extracorporeal membrane oxygenation runs/year; and (9.6 mg/dL (95% CI: 9.1-10.0)) in centers with fewer than 12 venous extracorporeal membrane oxygenation runs/year (p < 0.01). Several and variable adjunctive parameters are considered in cases of uncertainty for transfusion: the principal are hemodynamic status, SvO2, lactates, and fluid balance. CONCLUSION: Although the use of a predefined Hb trigger is still under-adopted among centers with low or median extracorporeal membrane oxygenation case volume, the majority of respondents use a higher Hb trigger for veno-venous extracorporeal membrane oxygenation patients compared with other critically ill patients. Higher volume centers tolerate lower Hb levels.

In-hospital outcomes after emergency or prophylactic veno-arterial extracorporeal membrane oxygenation during transcatheter aortic valve implantation: a comprehensive review of the literature.

Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) has been used to deal with life-threatening complications as well as back-up or active cardiovascular support during high-risk procedures in patients undergoing transcatheter aortic valve implantation (TAVI). PubMed and MEDLINE electronic databases were searched in order to identify studies with emergency or prophylactic V-A ECMO application in association with TAVI procedures. From November 2012 to November 2017, 14 relevant studies were identified that included 5,115 TAVI patients of whom 102 (2%) required V-A ECMO (22 prophylactically, 66 as an emergency and 14 without a reported indication). The reason for emergency V-A ECMO institution was detailed in 64 patients: left ventricle free wall rupture (n = 14), haemodynamic instability (n = 12), ventricular arrhythmias (n = 7), aortic annulus rupture (n = 6), coronary obstruction (n = 6), low left ventricular output (ejection fraction <35%) (n = 5), uncontrollable bleeding (n = 5), severe aortic regurgitation (n = 4), prosthesis embolisation (n = 3), aortic dissection (n = 1) and respiratory failure (n = 1). Femoral arterial and vein cannulation was the most common access technique for V-A ECMO institution. Major bleeding (n = 7) and vascular access complications (n = 7) were reported after ECMO institution. The overall in-hospital survival was 73% (61% in the emergency vs. 100% in the prophylactic group). V-A ECMO support should be available at any centre performing TAVI and provides effective mechanical circulatory support in an emergency setting. We present an algorithm to aid decisions about prophylactic circulatory assistance with V-A ECMO and it should form part of the heart team discussion before a TAVI procedure is undertaken.