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.

Add-On Prostaglandin E1 in Venovenous Extracorporeal Membrane Oxygenation: A Randomized, Double-Blind, Placebo-controlled Pilot Trial.

Rationale: Prostaglandin E1 (alprostadil; PGE1), in addition to low-dose unfractionated heparin, increases the biocompatibility of extracorporeal systems and enhances the efficacy of artificial organs without increasing bleeding risk. Objectives: We investigated the safety and efficacy of PGE1 in adults receiving venovenous extracorporeal membrane oxygenation (ECMO). Methods: This study was a randomized, double-blind, placebo-controlled phase II pilot trial at two medical intensive care units at the Medical University of Vienna, Austria. Adults with venovenous ECMO were randomly assigned to receive an intravenous infusion of 5 ng/kg/min PGE1 or placebo (0.9% saline) in addition to standard anticoagulation with unfractionated heparin. Measurements and Main Results: The primary outcome was the rate of transfused packed red blood cells per ECMO day. Secondary outcomes were the incidence of and time to clinically overt bleeding and thromboembolic events. A post hoc subgroup analysis included only patients with coronavirus disease (COVID-19). Between September 2016 and April 2021, of 133 screened patients, 50 patients were randomized, of whom 48 received the assigned study medication (24 per group). The transfusion rate was similar between groups (0.41 vs. 0.39; P = 0.733). PGE1 was associated with fewer thromboembolic events (7 vs. 16; P = 0.020) and longer thromboembolism-free time (hazard ratio [HR], 0.302; P = 0.01), fewer clinically overt bleeding events (2 vs. 11; P = 0.017), and longer bleeding-free time (HR, 0.213; P = 0.047). In patients with COVID-19 (n = 25), the HRs for clinically overt bleeding and thromboembolism were 0.276 (95% confidence interval, 0.035-2.186) and 0.521 (95% confidence interval, 0.149-1.825), respectively. Conclusions: Add-on treatment with PGE1 was safe but did not meet the primary endpoint of reducing the rate of red blood cell transfusions in patients receiving venovenous ECMO. Larger studies need to evaluate the safety and efficacy of additional PGE1 in ECMO. Clinical trial registered with EudraCT (2015-005014-30) and www.clinicaltrials.gov (NCT02895373).

A MicroRNA Next-Generation-Sequencing Discovery Assay (miND) for Genome-Scale Analysis and Absolute Quantitation of Circulating MicroRNA Biomarkers.

The plasma levels of tissue-specific microRNAs can be used as diagnostic, disease severity and prognostic biomarkers for chronic and acute diseases and drug-induced injury. Thereby, the combination of diverse microRNAs into biomarker signatures using multivariate statistics seems especially powerful from the perspective of tissue and condition specific microRNA shedding into the plasma. Although next-generation sequencing (NGS) technology enables one to analyse circulating microRNAs on a genome-scale level, it suffers from potential biases (e.g., adapter ligation bias) and lacks absolute transcript quantitation as well as tailor-made quality controls. In order to develop a robust NGS discovery assay for genome-scale quantitation of circulating microRNAs, we first evaluated the sensitivity, repeatability and ligation bias of four commercially available small RNA library preparation protocols. The protocol from RealSeq Biosciences was selected based on its performance and usability and coupled with a novel panel of exogenous small RNA spike-in controls to enable quality control and absolute quantitation, thus ensuring comparability of data across independent NGS experiments. The established microRNA Next-Generation-Sequencing Discovery Assay (miND) was validated for its relative accuracy, precision, analytical measurement range and sequencing bias and was considered fit-for-purpose for microRNA biomarker discovery. Summarized, all these criteria were met, and thus, our analytical platform is considered fit-for-purpose for microRNA biomarker discovery from biofluids in the setting of any diagnostic, prognostic or patient stratification need. The established miND assay was tested on serum, cerebrospinal fluid (CSF), synovial fluid (SF) and extracellular vesicles (EV) extracted from cell culture medium of primary cells and proved its potential to be used across different sample types.

Prevalence and Clinical Impact of Reduced Coagulation Factor XII Activity in Patients Receiving Extracorporeal Membrane Oxygenation.

OBJECTIVES: Extracorporeal membrane oxygenation provides large surface exposure to human blood leading to coagulation activation. Only limited clinical data are available on contact activation and coagulation factor XII activity in extracorporeal membrane oxygenation patients. DESIGN: Prospective cohort study. SETTING: Three medical ICUs at the Medical University of Vienna. PATIENTS: Adult patients receiving venovenous or venoarterial extracorporeal membrane oxygenation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the change in coagulation factor XII activity in response to extracorporeal membrane oxygenation. Secondary outcomes included the prevalence of reduced coagulation factor XII activity (< 60%) among patients receiving extracorporeal membrane oxygenation and association of coagulation factor XII activity with thromboembolic and bleeding complications. An exploratory endpoint was the association of coagulation factor XII activity and activated partial thromboplastin time in heparinase-treated samples in vitro. Fifty-one patients with a total of 117 samples were included in the study between July 2018 and February 2020. Fifty patients (98%) had reduced coagulation factor XII activity at any timepoint during extracorporeal membrane oxygenation. Median coagulation factor XII activity during extracorporeal membrane oxygenation treatment was 30% (interquartile range, 21.5-41%) and increased after discontinuation (p = 0.047). Patients with thromboembolic complications had higher median coagulation factor XII activity during extracorporeal membrane oxygenation (34% vs 23%; p = 0.023). The odds of a thromboembolic event increased by 200% per tertile of median coagulation factor XII activity (crude odds ratio, 3.034; 95% CI, 1.21-7.63). No association with bleeding was observed. In heparinase-treated samples, coagulation factor XII activity correlated well with activated partial thromboplastin time (r = -0.789; p = 0.007). CONCLUSIONS: We observed a high prevalence of reduced coagulation factor XII activity in adult patients on extracorporeal membrane oxygenation, which may confound activated partial thromboplastin time measurements and limit its clinical usefulness for monitoring and titrating anticoagulation with unfractionated heparin. Lower coagulation factor XII activity was associated with less thromboembolic complications, which may highlight the potential of coagulation factor XII to serve as a target for anticoagulation in extracorporeal membrane oxygenation.

A bi-centric experience of extracorporeal carbon dioxide removal (ECCO2 R) for acute hypercapnic respiratory failure following allogeneic hematopoietic stem cell transplantation.

Acute respiratory failure (ARF) is the main reason for ICU admission following allogeneic hematopoietic stem cell transplantation (HSCT). Extracorporeal CO2 removal (ECCO2 R) can be used as an adjunct to mechanical ventilation in patients with severe hypercapnia but has not been assessed in HSCT recipients. Retrospective analysis of all allogeneic HSCT recipients ≥18 years treated with ECCO2 R at two HSCT centers. 11 patients (m:f = 4:7, median age: 45 [IQR: 32-58] years) were analyzed. Acute leukemia was the underlying hematologic malignancy in all patients. The time from HSCT to ICU admission was 37 [8-79] months, and 9/11 (82%) suffered from chronic graft-versus-host disease (GVHD) with lung involvement. Pneumonia was the most frequent reason for ventilatory decompensation (n = 9). ECCO2 R was initiated for severe hypercapnia (Pa CO2 : 96 [84-115] mm Hg; pH: 7.13 [7.09-7.27]) despite aggressive mechanical ventilation (invasive, n = 9; non-invasive, n = 2). ECCO2 R effectively resolved blood gas disturbances in all patients, but only 2/11 (18%) could be weaned off ventilatory support, and one (9%) patient survived hospital discharge. Progressive respiratory and multiorgan dysfunction were the main reasons for treatment failure. ECCO2 R was technically feasible but resulted in a low survival rate in our cohort. A better understanding of the prognosis of ARF in patients with chronic GVHD and lung involvement is necessary before its use can be reconsidered in this setting.

Cytomegalovirus in urinary sediment in patients with acute kidney injury.

BACKGROUND: Immunosuppression in solid organ transplantation is associated with frequent infections. Renal allograft recipients are susceptible to opportunistic infections and can acquire human cytomegalovirus (HCMV) infections even within the allograft. There, HCMV can be found in both the glomerulus and tubular cells, but is mostly restricted to specific and circumscribed sites. Therefore, not all organ infections are identifiable by immunohistology for HCMV proteins in fine needle core biopsies. Thus, we performed a urinalysis study to search for HCMV-specific RNA transcripts in the urine sediment of patients with acute kidney injury. METHODS: Urinary sediment of 90 patients with acute kidney injury (AKI), including 48 renal transplant recipients (RTX) and 42 non-transplant recipients (nRTX), was collected from morning urine for RNA extraction and reverse transcription. The copy number of HCMV transcripts was evaluated using a UL132 HCMV-specific probe set and by real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: Of the 48 RTX patients, ten showed HCMV copies in their urine sediment cells. Within this group, three recipients had negative HCMV serology and received an allograft from an HCMV-seropositive donor. In addition, all three RTX patients on a belatacept-based immunosuppressive regimen had HCMV transcripts in their urine. Of the 42 nRTX patients, only two had detectable HCMV transcripts in urine sediment cells and both were under immunosuppression. CONCLUSIONS: Ten immunosuppressed renal allograft recipients and two immunosuppressed non-transplant patients with AKI showed HCMV copies in urine sediment. Thus, HCMV positivity in urinary sediment appears to be associated with immunosuppression. This study describes a novel noninvasive method for detection of HCMV in urinary sediment. Whether all HCMV infections can be detected or only those with viral replication warrants further investigation.

Safety, tolerability, pharmacokinetics and pharmacodynamics of parenterally administered dutogliptin: A prospective dose-escalating trial.

AIMS: Animal studies suggest that inhibition of dipeptidyl peptidase 4 (DPP-IV) may improve heart function and survival after myocardial infarction by increasing cardiac myocytes' regenerative capacity. Parenterally administered dutogliptin may provide continuous strong DPP-IV inhibition to translate these results into humans. This trial investigated the safety and tolerability, as well as pharmacokinetics and pharmacodynamics, of parenterally administered dutogliptin after single and repeated doses. METHODS: In an open-label trial, volunteers received dutogliptin at increasing doses of 30-120 mg subcutaneously or 30 mg intravenously in the single-dose cohorts. Subjects in the multiple-dose cohort received 60, 90 or 120 mg dutogliptin subcutaneously once daily on 7 consecutive days. RESULTS: Forty healthy males were included in the trial. No related serious adverse events occurred. Mild local injection site reactions with no requirement for intervention comprised 147 of 153 (96%) related adverse events. Subcutaneous bioavailability was approximately 100%. Multiple injections at daily intervals did not lead to the accumulation of the study drug. The accumulation ratios based on AUC0-24h range from 0.90 to 1.03, supporting this argument. All subjects receiving ≥60 mg dutogliptin yielded a maximum DPP-IV inhibition >90%. The duration of DPP-IV inhibition over time increased in a dose-dependent manner and was highest in the 120-mg multiple-dosing cohort with a maximum AUEC0-24h of 342 h % (standard deviation: 73), translating into 86% DPP-IV inhibition 24 hours after dosing. CONCLUSION: Parenteral injection of dutogliptin was safe and subcutaneous bioavailability is excellent. DPP-IV inhibition increased dose dependently to >86% over 24 hours after multiple doses of 120 mg dutogliptin.

Generalisability of randomised trials evaluating perioperative ß-blocker therapy in noncardiac surgery.

BACKGROUND: The limited applicability of evidence from RCTs in real-word practice is considered a potential bottleneck for evidence-based practice but rarely systematically assessed. Using our failure to recruit patients into a perioperative beta-blocker trial, we set out to analyse the restrictiveness and generalisability of trial eligibility criteria in a real-world cohort. METHODS: We prospectively included adult patients (≥18 yr) scheduled for elective noncardiac surgery at an academic tertiary care facility who were screened for inclusion in a planned perioperative beta-blocker RCT, which was terminated owing to recruitment failure. The primary outcome was the proportion of screened patients who matched the eligibility criteria of 36 published RCTs included in a large Cochrane meta-analysis on perioperative beta-blocker therapy. The pragmatic/explanatory level of each RCT was assessed using the PRagmatic-Explanatory Continuum Indicator Summary 2 (PRECIS-2) score, which ranges from 9 points (indicating a very explanatory study) to 45 points (indicating a very pragmatic study). RESULTS: A total of 2241 patients (54% female, n=1215; 52 [standard deviation, 20] yr) were included for the assessment of trial eligibility between October 2015 and January 2016. Only a small proportion of patients matched the inclusion and exclusion criteria for each of the 36 RCTs, ranging from 53% to 0%. The average proportion of patients who did match the eligibility criteria of all 36 RCTs was 6.5% (n=145; 95% confidence interval, 6.3-6.6). A higher PRECIS-2 score was associated with a higher proportion of matching patients (P<0.001). CONCLUSIONS: Trial eligibility criteria in perioperative beta-blocker therapy trials are overly restrictive and not generalisable to a real-world surgical population. CLINICAL TRIAL REGISTRATION: EudraCT#: 2015-002366-23.

Diagnosis and outcome of acute respiratory failure in immunocompromised patients after bronchoscopy.

OBJECTIVE: We wished to explore the use, diagnostic capability and outcomes of bronchoscopy added to noninvasive testing in immunocompromised patients. In this setting, an inability to identify the cause of acute hypoxaemic respiratory failure is associated with worse outcome. Every effort should be made to obtain a diagnosis, either with noninvasive testing alone or combined with bronchoscopy. However, our understanding of the risks and benefits of bronchoscopy remains uncertain. PATIENTS AND METHODS: This was a pre-planned secondary analysis of Efraim, a prospective, multinational, observational study of 1611 immunocompromised patients with acute respiratory failure admitted to the intensive care unit (ICU). We compared patients with noninvasive testing only to those who had also received bronchoscopy by bivariate analysis and after propensity score matching. RESULTS: Bronchoscopy was performed in 618 (39%) patients who were more likely to have haematological malignancy and a higher severity of illness score. Bronchoscopy alone achieved a diagnosis in 165 patients (27% adjusted diagnostic yield). Bronchoscopy resulted in a management change in 236 patients (38% therapeutic yield). Bronchoscopy was associated with worsening of respiratory status in 69 (11%) patients. Bronchoscopy was associated with higher ICU (40% versus 28%; p<0.0001) and hospital mortality (49% versus 41%; p=0.003). The overall rate of undiagnosed causes was 13%. After propensity score matching, bronchoscopy remained associated with increased risk of hospital mortality (OR 1.41, 95% CI 1.08-1.81). CONCLUSIONS: Bronchoscopy was associated with improved diagnosis and changes in management, but also increased hospital mortality. Balancing risk and benefit in individualised cases should be investigated further.

ECMO without anticoagulation in patients with disease-related severe thrombocytopenia: Feasible but futile?

Severe thrombocytopenia poses a high risk for bleeding thus representing a relative contraindication for anticoagulation and therefore extracorporeal membrane oxygenation (ECMO). We herein report on a series of immunocompromised patients with severe thrombocytopenia undergoing long-term ECMO without systemic anticoagulation. We retrospectively identified seven adult patients with anticoagulation withdrawal for ≥3 days (range 5-317) during venovenous ECMO therapy due to thrombocytopenia < 50 G/L treated in a university-affiliated hospital from January 2013 to April 2017. All ECMO systems used were heparin coated. Overall, 530 ECMO days were observed, 404 (76%) of them without systemic anticoagulation. Platelet count during ECMO treatment was 24 G/L (median, range 1-138), ECMO duration was 35 days (5-317), and ECMO was run without any anticoagulation for 20 days (5-317). Altogether, five clotting events were seen leading to oxygenator exchanges. Bleeding was common including one fatal intracerebral hemorrhage. Altogether, 29 platelet concentrates per patient (7-207) were administered, which correspond to 0.8 per day (0.6-1.3). One patient survived ICU and hospital. In patients with thrombocytopenia, ECMO can be run without anticoagulation even for considerably long periods of time. Bleeding remains common, while clotting events seem to be rare. However, prognosis of this patient population undergoing ECMO support seems grim.

Increased Fibrinolysis as a Specific Marker of Poor Outcome After Cardiac Arrest.

OBJECTIVES: Recent data suggest that early increased fibrinolysis may be associated with unfavorable prognosis in cardiac arrest. The current study aimed to assess whether there is an optimal fibrinolysis cutoff value as determined by thrombelastometry at hospital admission to predict poor outcome in a cohort of adult patients with out-of-hospital cardiac arrest. DESIGN: Prospective observational cohort study. SETTING: Emergency department of a 2.100-bed tertiary care facility in Vienna, Austria, Europe. PATIENTS: Patients with out-of-hospital cardiac arrest of presumed cardiac origin, subjected to targeted temperature management, who had achieved return of spontaneous circulation at admission were analyzed. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Fibrinolysis was assessed by thrombelastometry at the bedside immediately after hospital admission and is given as maximum lysis (%). The outcome measure was the optimal cutoff for maximum lysis at hospital admission to predict poor outcome (a composite of Cerebral Performance Category 3-5 or death) at day 30, assessed by receiver operating characteristic curve analysis. Seventy-eight patients (61% male, median 59 yr) were included in the study from March 2014 to March 2017. Forty-two patients (54%) had a poor 30-day outcome including 23 nonsurvivors (30%). The maximum lysis cutoff at admission predicting poor 30-day outcome with 100% specificity (95% CI, 90-100%) was greater than or equal to 20%. Tissue-type plasminogen activator antigen levels were likewise elevated in patients with poor neurologic outcome or death 52 ng/mL (interquartile range, 26-79 ng/mL) versus 29 ng/mL (interquartile range, 17-49 ng/mL; p = 0.036). CONCLUSIONS: Increased fibrinolysis at admission assessed by thrombelastometry specifically predicts poor outcome in cardiac arrest with presumed cardiac etiology.

[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.

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.

[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.

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.

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.

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 centres 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/day. 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 (VV), venoarterial (VA) ECMO, and extracorporeal CO2-removal (ECCO2R) between January 2010 and May 2022. Main risk factor was heparin resistance (UFH >35,000 IU/day 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/day, and 14 (7.1%) required >20 IU/kg/h. Thromboembolic complications occurred at a rate of 5.89/100 ECMO days. Heparin resistance was not associated with thromboembolic events (incidence rate ratio (IRR) 0.93, 95% confidence interval (CI) 0.14 to 5.82), whereas COVID-19 (IRR 2.33, CI 1.4 to 3.96, p<0.001) and ECMO type (VA ECMO: IRR 2.29, CI 1.34 to 3.92, p=0.002; ECCO2R: IRR 2.89, CI 1.46 to 5.59, p=0.002; reference VV ECMO) were significantly associated with the risk of thromboembolic events. CONCLUSIONS: A significant proportion of patients fulfilled the common definition of heparin resistance. However, this did not influence the occurrence of thromboembolic events.

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.