Effects of extracorporeal CO2 removal on gas exchange and ventilator settings: a systematic review and meta-analysis.

PURPOSE: A systematic review and meta-analysis to evaluate the impact of extracorporeal carbon dioxide removal (ECCO2R) on gas exchange and respiratory settings in critically ill adults with respiratory failure. METHODS: We conducted a comprehensive database search, including observational studies and randomized controlled trials (RCTs) from January 2000 to March 2022, targeting adult ICU patients undergoing ECCO2R. Primary outcomes were changes in gas exchange and ventilator settings 24 h after ECCO2R initiation, estimated as mean of differences, or proportions for adverse events (AEs); with subgroup analyses for disease indication and technology. Across RCTs, we assessed mortality, length of stay, ventilation days, and AEs as mean differences or odds ratios. RESULTS: A total of 49 studies encompassing 1672 patients were included. ECCO2R was associated with a significant decrease in PaCO2, plateau pressure, and tidal volume and an increase in pH across all patient groups, at an overall 19% adverse event rate. In ARDS and lung transplant patients, the PaO2/FiO2 ratio increased significantly while ventilator settings were variable. "Higher extraction" systems reduced PaCO2 and respiratory rate more efficiently. The three available RCTs did not demonstrate an effect on mortality, but a significantly longer ICU and hospital stay associated with ECCO2R. CONCLUSIONS: ECCO2R effectively reduces PaCO2 and acidosis allowing for less invasive ventilation. "Higher extraction" systems may be more efficient to achieve this goal. However, as RCTs have not shown a mortality benefit but increase AEs, ECCO2R's effects on clinical outcome remain unclear. Future studies should target patient groups that may benefit from ECCO2R. PROSPERO Registration No: CRD 42020154110 (on January 24, 2021).

Computed Tomography to Exclude Cardiac Thrombus in Atrial Fibrillation-An 11-Year Experience from an Academic Emergency Department.

BACKGROUND: Computed tomography (CT) could be a suitable method for acute exclusion of left atrial appendage thrombus (LAAT) prior to cardioversion of atrial fibrillation (AF) and atrial flutter (AFL) at the emergency department. Our aim was to present our experiences with this modality in recent years. METHODS: This registry-based observational study was performed at the Department of Emergency Medicine at the Medical University of Vienna, Austria. We studied all consecutive patients with AF and AFL who underwent CT between January 2012 and January 2023 to rule out LAAT before cardioversion to sinus rhythm was attempted. Follow-ups were conducted by telephone and electronic medical records. The main variables of interest were the rate of LAAT and ischemic stroke at follow-up. RESULTS: A total of 234 patients (143 [61%] men; median age 68 years [IQR 57-76], median CHA2DS2-VASc 2 [IQR 1-4]) were analyzed. Follow-up was completed in 216 (92%) patients after a median of 506 (IQR 159-1391) days. LAAT was detected in eight patients (3%). A total of 163 patients (72%) in whom LAAT was excluded by CT were eventually successfully cardioverted to sinus rhythm. No adverse events occurred during their ED stay. All patients received anticoagulation according to the CHA2DS2-VASc risk stratification, and no patient had suffered an ischemic stroke at follow-up, resulting in an incidence risk of ischemic strokes of 0% (95% CI 0.0-1.2%). CONCLUSION: LAAT was rare in patients admitted to the ED with AF and AFL who underwent cardiac CT prior to attempted cardioversion. At follow-up, no patient had suffered an ischemic stroke. Prospective studies need to show whether this strategy is suitable for the acute treatment of symptomatic AF in the emergency setting.

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.

Automated titanium fastener vs. hand-tied knots for prosthesis fixation in infective endocarditis.

Objectives: To date, there is no evidence regarding the safety of automated titanium fastener compared with hand-tied knots for prosthesis fixation in infective endocarditis. Methods: Between January 2016 and December 2022, a total of 220 patients requiring surgery for infective endocarditis were included in this retrospective analysis. The primary study endpoint was re-endocarditis during follow-up. The secondary study endpoints included stroke onset, all-cause mortality, and a composite outcome of either re-endocarditis, stroke, or all-cause mortality during follow-up. Results: Suture-securing with an automated titanium fastener was performed in 114 (51.8%) patients, whereas the conventional technique of hand knot-tying was used in 106 (48.2%) patients. The risk of re-endocarditis was significantly lower in the automated titanium fastener group, as shown in a multivariable proportional competing risk regression model (adjusted sub-hazard ratio 0.33, 95% confidence interval 0.11-0.99, p = 0.048). The multivariable Cox proportional hazards regression analysis showed that the automated titanium fastener group was not associated with an increased risk of stroke-onset or attaining the composite outcome, respectively, (adjusted hazard ratio 0.54, 95% confidence interval 0.27-1.08, p = 0.082), (adjusted hazard ratio 0.65, 95% confidence interval 0.42-1.02, p = 0.061). Also, this group was not associated with an increased risk of all-cause mortality, as demonstrated in the multivariable Poisson regression analysis (adjusted incidence-rate ratio 1.42, 95% confidence interval 0.83-2.42, p = 0.202). Conclusions: The use of automated titanium fastener device seems to be safe for infective endocarditis. Analyses of larger cohorts are required.

Algorithm for Rapid Exclusion of Clinically Relevant Plasma Levels of Direct Oral Anticoagulants in Patients Using the DOAC Dipstick: An Expert Consensus Paper.

BACKGROUND: With the widespread use of direct oral anticoagulants (DOACs), there is an urgent need for a rapid assay to exclude clinically relevant plasma levels. Accurate and rapid determination of DOAC levels would guide medical decision-making to (1) determine the potential contribution of the DOAC to spontaneous or trauma-induced hemorrhage; (2) identify appropriate candidates for reversal, or (3) optimize the timing of urgent surgery or intervention. METHODS AND RESULTS: The DOAC Dipstick test uses a disposable strip to identify factor Xa- or thrombin inhibitors in a urine sample. Based on the results of a systematic literature search followed by an analysis of a simple pooling of five retrieved clinical studies, the test strip has a high sensitivity and an acceptably high negative predictive value when compared with levels measured with liquid chromatography tandem mass spectrometry or calibrated chromogenic assays to reliably exclude plasma DOAC concentrations ≥30 ng/mL. CONCLUSION: Based on these data, a simple algorithm is proposed to enhance medical decision-making in acute care indications useful primarily in hospitals not having readily available quantitative tests and 24/7. This algorithm not only determines DOAC exposure but also differentiates between factor Xa and thrombin inhibitors to better guide clinical management.

Risk factors for pediatric intoxications in the prehospital setting. A geospatial survey.

Background: Socioeconomic factors and the COVID-19 pandemic influence children's physical and mental health. We aimed to investigate the association between a census tract's median household income [MHI in United States Dollars ($)] and pediatric intoxications in Rhode Island, the smallest state in the United States of America. Geographical hotspots, as well as interactions with the COVID-19 pandemic, should be identified. Methods: This study is a retrospective analysis of ambulance calls for pediatric (<18 years) intoxication in Rhode Island between March 1st, 2018, and February 28th, 2022. March 1st, 2020 was considered the beginning of the COVID-19 pandemic. Prehospital data were joined with information from the United States Census Bureau. The census tracts' case counts and MHI were examined using Poisson regression. Geographical clusters were identified with the Global Moran's I and local indicators of spatial association tests in ArcGIS Pro (Esri Corporation, Redlands, CA). Results: Inclusion criteria were met by 208 incidents (48% female, median age 16 (IQR 15 to 17) years). The regression model showed a 0.6% increase (IRR 1.006, 95% CI [1.002, 1.01], p = 0.003) in pediatric intoxications for every $ 1,000 increase in MHI. Interaction analysis showed that the effect of MHI was less pronounced during the pandemic (IRR 0.98, 95% CI [0.964, 0.997], p = 0.02). Thirty-four (14%) of the 244 census tracts contributed to geographical clusters, which changed after the onset of the pandemic. Conclusion: Higher median household income could be a risk factor for pediatric intoxications. Geographical hotspots changed with the pandemic.

[Hypothermic temperature control after successful resuscitation of out-of-hospital cardiac arrest in adults : Statement from the resuscitation and postresuscitation treatment working groups of the German Society of Medical Intensive Care and Emergency Medicine (DGIIN) and the German Interdisciplinary Association for Intensive Care and Emergency Medicine (DIVI), the German Society for Interdisciplinary Emergency and Acute Medicine (DGINA) and the Austrian Association of Emergency Medicine (AAEM)]. / Hypotherme Temperaturkontrolle nach erfolgreicher Wiederbelebung eines außerklinischen Herz-Kreislauf-Stillstands beim Erwachsenen : Statement der Arbeitsgruppen Reanimation und Post-Reanimationsbehandlung in der Deutschen Gesellschaft für Internistische Intensiv- und Notfallmedizin (DGIIN) und Deutschen Interdisziplinären Vereinigung für Intensiv- und Notfallmedizin (DIVI), der Deutschen Gesellschaft Interdisziplinäre Notfall- und Akutmedizin (DGINA) und der Österreichischen Gesellschaft für Notfallmedizin (AAEM).

In Germany per year approximately 60,000 and in Austria 5,000 adult patients suffer from out-of-hospital cardiac arrest. Only 10-15% of these patients survive without neurological damage. For decades hypothermic temperature control has been a central component of post-resuscitation treatment, but is controversial due to recently published studies.

Urinary Collectrin as Promising Biomarker for Acute Kidney Injury in Patients Undergoing Cardiac Surgery.

BACKGROUND: Early detection of acute kidney injury (AKI) is crucial for timely intervention and improved patient outcomes after cardiac surgery. This study aimed to evaluate the potential of urinary collectrin as a novel biomarker for AKI in this patient population. METHODS: In this prospective, observational cohort study, 63 patients undergoing elective cardiac surgery with cardiopulmonary bypass (CPB) were studied at the Medical University of Vienna between 2016 and 2018. We collected urine samples prospectively at four perioperative time points, and urinary collectrin was measured using an enzyme-linked immunosorbent assay. Patients were divided into two groups, AKI and non-AKI, defined by Kidney Disease: Improving Global Outcomes Guidelines, and differences between groups were analyzed. RESULTS: Postoperative AKI was found in 19 (30%) patients. Urine sample analysis revealed an inverse correlation between urinary collectrin and creatinine and AKI stages, as well as significant changes in collectrin levels during the perioperative course. Baseline collectrin levels were 5050 ± 3294 pg/mL, decreased after the start of CPB, reached their nadir at the end of surgery, and began to recover slightly on postoperative day (POD) 1. The most effective timepoint for distinguishing between AKI and non-AKI patients based on collectrin levels was POD 1, with collectrin levels of 2190 ± 3728 pg/mL in AKI patients and 3768 ± 3435 pg/mL in non-AKI patients (p = 0.01). CONCLUSIONS: Urinary collectrin shows promise as a novel biomarker for the early detection of AKI in patients undergoing cardiac surgery on CPB. Its dynamic changes throughout the perioperative period, especially on POD 1, provide valuable insights for timely diagnosis and intervention. Further research and validation studies are needed to confirm its clinical usefulness and potential impact on patient outcomes.

Population-based incidence of all-cause anaphylaxis and its development over time: a systematic review and meta-analysis.

Introduction: It is extremely difficult to compare studies investigating the frequency of anaphylaxis making it challenging to satisfactorily assess the worldwide incidence rate. Using a systematic review and meta-analysis, this publication aims to determine the current incidence of all-cause anaphylaxis worldwide. Additionally, we investigated whether the incidence of anaphylaxis has changed over time and which factors influence the rates determined by individual studies. Methods: A literature search was performed in four databases. All articles that reported relevant information on population-based incidence rates of all-cause anaphylaxis were included. The protocol was published on INPLASY, the International Platform of Registered Systematic Review and Meta-analysis Protocols. Results: The database query and screening process resulted in 46 eligible articles on anaphylaxis. The current incidence worldwide was found to be approximately 46 cases per 100,000 population per year (95% CI 21-103). Evaluating confounding factors showed that studies using allergy clinics and hospitalizations as data source result in comparably low rates. Moreover, children are less prone to develop anaphylaxis compared to the general population. Using a random effects Poisson model we calculated a yearly increase of anaphylaxis incidence by 7.4% (95% CI 7.3-7.6, p < 0.05). Discussion: This seems to be the first approach to analyze every reported all-cause anaphylaxis incidence rate until 2017 for an at most accurate determination of its epidemiology. Based on these results, future research could investigate the underlying causes for the rising incidence in order find ways to decrease the condition's frequency. Systematic Review Registration: inplasy.com, identifier [INPLASY202330047].

Lower serum cholesterol levels as a risk factor for critical illness polyneuropathy: a matched case-control study.

Critical illness polyneuropathy (CIP) is a frequent and underdiagnosed phenomenon among intensive care unit patients. The lipophilic nature of neuronal synapses may result in the association of low serum cholesterol levels with a higher rate of CIP development. We aimed to investigate this issue in critically ill patients. All cases diagnosed with CIP in our tertiary care hospital between 2013 and 2017 were 1:1 matched with controls without the condition by age, sex, and ICD diagnoses. The main risk factors examined were the differences in change between initial and minimum serum total cholesterol levels, and minimum serum total cholesterol levels between matched pairs. Other predictors were serum markers of acute inflammation. We included 67 cases and 67 controls (134 critically ill patients, 49% female, 46% medical). Serum total cholesterol levels decreased more profoundly in cases than controls (median: -74 (IQR -115 to -24) vs. -39 (IQR -82 to -4), median difference: -28, 95% CI [-51, -5]), mg/dl). Minimum serum total cholesterol levels were lower in the cases (median difference: -24, 95% CI [-39, -9], mg/dl). We found significant median differences across matched pairs in maximum serum C-reactive protein (8.9, 95% CI [4.6, 13.2], mg/dl), minimum albumin (-4.2, 95% CI [-6.7, -1.7], g/l), decrease in albumin (-3.9, 95% CI [-7.6, -0.2], g/l), and lowest cholinesterase levels (-0.72, 95% CI [-1.05, -0.39], U/l). Subsequently, more pronounced decreases in serum total cholesterol levels and lower minimum total cholesterol levels during critical care unit hospitalizations may be a risk factor for CIP.

Serum neurofilament light chain as an early diagnostic biomarker for critical illness polyneuropathy.

BACKGROUND: Critical illness polyneuropathy (CIP) commonly occurs in critical care unit (CCU) patients, but timely diagnosis can be challenging. Therefore, new biomarkers, such as serum neurofilament light chain (sNfL), could help to improve early identification of patients with this condition. METHODS: CIP was diagnosed or excluded with neurological assessment and nerve conduction measurement in a prospective study of CCU patients. sNfL and secondary predictors for neuropathy (neuron-specific enolase (NSE), S100, folic acid, and vitamin B12) were measured at admission. Cases and controls were compared regarding the predictors. RESULTS: Nineteen patients met the inclusion criteria. CIP was considered definitely or most likely present in seven (37%, cases) and definitely or most likely absent in 12 individuals (63%, controls). At admission, sNfL levels were significantly higher in the cases than in the controls: 405 (IQR 77 to 835) vs. 27 (IQR 12 to 90) pg/mL; difference of medians 375, 95% confidence interval [14, 736], pg/mL; P=0.04. We found no significant differences regarding the secondary predictors at baseline. Cases had longer durations of CCU stay (median 19 (IQR 11 to 44) vs. 8 (IQR five to ten) and increased mortality (57% vs. 33% deceased) compared to controls. CONCLUSIONS: Levels of serum neurofilament light chain are higher in patients who develop CIP soon after CCU admission and might be helpful in identifying those individuals early.

Influence of high altitude after a prior ascent on physical exhaustion during cardiopulmonary resuscitation: a randomised crossover alpine field experiment.

BACKGROUND: Performing cardiopulmonary resuscitation (CPR) inevitably causes significant physical, as well as psychological stress for rescuers. Physical activity at high altitude, a hypobaric and hypoxic environment, similarly adds to the level of stress and causes multiple physiological changes. Continuous measurement of pulse rate serves as an objective measure of fatigue during CPR. We therefore aimed to investigate rescuers' heart rates as a measure of physical strain during CPR in a high-altitude alpine environment to provide a better understanding of the physiological changes under these very special conditions. METHODS: Twenty experienced mountaineers performed basic life support (BLS) on a manikin for 16 min, both at baseline altitude and at high altitude (3454 m) following a quick and exhausting ascent over 1200 m. Sequence of scenarios was randomised for analysis. Heart rate was continuously measured and compared between baseline and high altitude by absolute differences and robust confidence intervals. RESULTS: During CPR at baseline, the average heart rate increased from 87 bpm (SD 16 bpm) to 104 bpm [increase 17 bpm (95% CI 8.24-24.76)], compared to an increase from 119 bpm (SD 12 bpm) to 124 bpm [increase 5 bpm (95% CI - 1.59 to 12.19)] at high altitude [difference between two groups 32 bpm (95% CI 25-39)]. Differences between periods of chest compressions and ventilations were very similar at baseline [19 bpm (95%CI 16.98-20.27)] and at high altitude [20 bpm 95% CI 18.56-21.44)], despite starting from a much higher level at high altitude. The average heart rates of rescuers at high altitude at any point were higher than those at baseline at any other point. CONCLUSION: Performing BLS CPR causes exhaustion both at base level and at a high altitude. A further increase during CPR might imply a physiological reserve for adapting to additional physical exertion at high altitude. Phases of ventilation are much needed recovery-periods, but heart rates remain very high. Subjective measures of exhaustion, such as the BORG-scale, might lead to rescuers' overestimation of their own performance.

Socioeconomic Risk Factors for Pediatric Out-of-hospital Cardiac Arrest: A Statewide Analysis.

INTRODUCTION: Economic hardship is a major threat to children's health, implying that pediatric out-of-hospital cardiac arrest (pOHCA) might be promoted by lower incomes and child poverty. To target resources, it is helpful to identify geographical hotspots. Rhode Island is the smallest state by area in the United States of America. It has one million inhabitants and is comparable to many larger cities worldwide. We aimed to investigate the possible associations of pOHCA with economic factors and the coronavirus 2019 (COVID-19) pandemic. Our goal was to identify high-risk areas and evaluate whether the COVID-19 pandemic had an influence on delays in prehospital care. METHODS: We analyzed all pOHCA cases (patients <18 years of age) in Rhode Island between March 1, 2018-February 28, 2022. We performed Poisson regression with pOHCA as dependent and economic risk factors (median household income [MHI] and child poverty rate from the US Census Bureau) as well as the COVID-19 pandemic as independent variables. Hotspots were identified using local indicators of spatial association (LISA) statistics. We used linear regression to assess the association of emergency nedical services-related times with economic risk factors and COVID-19. RESULTS: A total of 51 cases met our inclusion criteria. Lower MHIs (incidence-rate ratio [IRR]) 0.99 per $1,000 MHI; P=0.01) and higher child poverty rates (IRR 1.02 per percent; P=0.02) were significantly associated with higher numbers of ambulance calls due to pOHCA. The pandemic did not have a significant influence (IRR 1.1; P=0.7). LISA identified 12 census tracts as hotspots (P<0.01). The pandemic was not associated with delays in prehospital care. CONCLUSION: Lower median household income and higher child poverty rate are associated with higher numbers of pediatric out-of-hospital cardiac arrest.

Hypothermia for neuroprotection in adults after cardiac arrest.

BACKGROUND: Good neurological outcome after cardiac arrest is difficult to achieve. Interventions during the resuscitation phase and treatment within the first hours after the event are critical for a favourable prognosis. Experimental evidence suggests that therapeutic hypothermia is beneficial, and several clinical studies on this topic have been published. This review was originally published in 2009; updated versions were published in 2012 and 2016. OBJECTIVES: To evaluate the benefits and harms of therapeutic hypothermia after cardiac arrest in adults compared to standard treatment. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 30 September 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs in adults comparing therapeutic hypothermia after cardiac arrest with standard treatment (control). We included studies with adults cooled by any method, applied within six hours of cardiac arrest, to target body temperatures of 32 °C to 34 °C. Good neurological outcome was defined as no or only minor brain damage allowing people to live an independent life. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcome was 1. neurological recovery. Our secondary outcomes were 2. survival to hospital discharge, 3. quality of life, 4. cost-effectiveness and 5. ADVERSE EVENTS: We used GRADE to assess certainty. MAIN RESULTS: We found 12 studies with 3956 participants reporting the effects of therapeutic hypothermia on neurological outcome or survival. There were some concerns about the quality of all the studies, and two studies had high risk of bias overall. When we compared conventional cooling methods versus any type of standard treatment (including a body temperature of 36 °C), we found that participants in the therapeutic hypothermia group were more likely to reach a favourable neurological outcome (risk ratio (RR) 1.41, 95% confidence interval (CI) 1.12 to 1.76; 11 studies, 3914 participants). The certainty of the evidence was low. When we compared therapeutic hypothermia with fever prevention or no cooling, we found that participants in the therapeutic hypothermia group were more likely to reach a favourable neurological outcome (RR 1.60, 95% CI 1.15 to 2.23; 8 studies, 2870 participants). The certainty of the evidence was low. When we compared therapeutic hypothermia methods with temperature management at 36 °C, there was no evidence of a difference between groups (RR 1.78, 95% CI 0.70 to 4.53; 3 studies; 1044 participants). The certainty of the evidence was low. Across all studies, the incidence of pneumonia, hypokalaemia and severe arrhythmia was increased amongst participants receiving therapeutic hypothermia (pneumonia: RR 1.09, 95% CI 1.00 to 1.18; 4 trials, 3634 participants; hypokalaemia: RR 1.38, 95% CI 1.03 to 1.84; 2 trials, 975 participants; severe arrhythmia: RR 1.40, 95% CI 1.19 to 1.64; 3 trials, 2163 participants). The certainty of the evidence was low (pneumonia, severe arrhythmia) to very low (hypokalaemia). There were no differences in other reported adverse events between groups. AUTHORS' CONCLUSIONS: Current evidence suggests that conventional cooling methods to induce therapeutic hypothermia may improve neurological outcomes after cardiac arrest. We obtained available evidence from studies in which the target temperature was 32 °C to 34 °C.

A multicentre, patient- and assessor-blinded, non-inferiority, randomised and controlled phase II trial to compare standard and torque teno virus-guided immunosuppression in kidney transplant recipients in the first year after transplantation: TTVguideIT.

BACKGROUND: Immunosuppression after kidney transplantation is mainly guided via plasma tacrolimus trough level, which cannot sufficiently predict allograft rejection and infection. The plasma load of the non-pathogenic and highly prevalent torque teno virus (TTV) is associated with the immunosuppression of its host. Non-interventional studies suggest the use of TTV load to predict allograft rejection and infection. The primary objective of the current trial is to demonstrate the safety, tolerability and preliminary efficacy of TTV-guided immunosuppression. METHODS: For this purpose, a randomised, controlled, interventional, two-arm, non-inferiority, patient- and assessor-blinded, investigator-driven phase II trial was designed. A total of 260 stable, low-immunological-risk adult recipients of a kidney graft with tacrolimus-based immunosuppression and TTV infection after month 3 post-transplantation will be recruited in 13 academic centres in six European countries. Subjects will be randomised in a 1:1 ratio (allocation concealment) to receive tacrolimus either guided by TTV load or according to the local centre standard for 9 months. The primary composite endpoint includes the occurrence of infections, biopsy-proven allograft rejection, graft loss, or death. The main secondary endpoints include estimated glomerular filtration rate, graft rejection detected by protocol biopsy at month 12 post-transplantation (including molecular microscopy), development of de novo donor-specific antibodies, health-related quality of life, and drug adherence. In parallel, a comprehensive biobank will be established including plasma, serum, urine and whole blood. The date of the first enrolment was August 2022 and the planned end is April 2025. DISCUSSION: The assessment of individual kidney transplant recipient immune function might enable clinicians to personalise immunosuppression, thereby reducing infection and rejection. Moreover, the trial might act as a proof of principle for TTV-guided immunosuppression and thus pave the way for broader clinical applications, including as guidance for immune modulators or disease-modifying agents. TRIAL REGISTRATION: EU CT-Number: 2022-500024-30-00.

Individualization of Mycophenolic Acid Therapy through Pharmacogenetic, Pharmacokinetic and Pharmacodynamic Testing.

Mycophenolic acid (MPA) is a widely used immunosuppressive agent and exerts its effect by inhibiting inosine 5'-monophosphate dehydrogenase (IMPDH), the main regulating enzyme of purine metabolism. However, significant unexplained differences in the efficacy and tolerability of MPA therapy pose a clinical challenge. Therefore, broad pharmacogenetic, pharmacokinetic, and pharmacodynamic approaches are needed to individualize MPA therapy. In this prospective cohort study including 277 renal transplant recipients, IMPDH2 rs11706052 SNP status was assessed by genetic sequencing, and plasma MPA trough levels were determined by HPLC and IMPDH enzyme activity in peripheral blood mononuclear cells (PBMCs) by liquid chromatography-mass spectrometry. Among the 277 patients, 84 were identified with episodes of biopsy-proven rejection (BPR). No association was found between rs11706052 SNP status and graft rejection (OR 1.808, and 95% CI, 0.939 to 3.479; p = 0.076). Furthermore, there was no association between MPA plasma levels and BPR (p = 0.69). However, the patients with graft rejection had a significantly higher predose IMPDH activity in PBMCs compared to the controls without rejection at the time of biopsy (110.1 ± 50.2 vs. 95.2 ± 45.4 pmol/h; p = 0.001), and relative to the baseline IMPDH activity before transplantation (p = 0.042). Our results suggest that individualization of MPA therapy, particularly through pharmacodynamic monitoring of IMPDH activity in PBMCs, has the potential to improve the clinical outcomes of transplant patients.

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.

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.

Urinary Collectrin (TMEM27) as Novel Marker for Acute Kidney Injury.

Acute kidney injury (AKI) is a leading complication in hospitalized patients of different disciplines due to various aetiologies and is associated with the risk of chronic kidney disease, the need for dialysis and death. Since nephrons are not supplied with pain signals, kidney injury is mostly diagnosed by serum creatinine with a time delay. Recent work has shown that certain urinary biomarkers are available for early detection of AKI. In total, 155 subjects, including 102 patients with AKI at various stages and 53 subjects without AKI, were enrolled, and their course and laboratory data were recorded. Urinary collectrin (TMEM27) was measured by a commercially available ELISA assay. Changes in serum creatinine were used to determine AKI stage. Patients with AKI presented with significantly lower levels of urinary collectrin compared to patients without AKI (1597 ± 1827 pg/mL vs. 2855 ± 2073; p = 0.001). Collectrin was found to inversely correlate with serum creatinine and stages of AKI. Collectrin levels were lowest in AKI stage III (1576 ± 1686 pg/mL; p = 0.001) and also significantly lower in stage II (1616 ± 2148 pg/mL; p = 0.021) and stage I (1630 ± 1956 pg/mL; p = 0.019) compared to subjects without AKI. An optimal minimum collectrin cut-off value of 1606 [95% CI 1258 to 1954] pg/mL was determined to detect AKI. In conclusion, urinary collectrin represents an indicator of AKI that, unlike all other established AKI biomarkers, decreases with stage of AKI and thus may be associated with a novel pathogenic pathway.