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Abstract Background Endotoxin adsorption is a promising but controversial therapy in severe, refractory septic shock and conflicting results exist on the effective capacity of available devices to reduce circulating endotoxin and inflammatory cytokine levels. Methods Multiarm, randomized, controlled trial in two Swiss intensive care units, with a 1:1:1 randomization of patients suffering severe, refractory septic shock with high levels of endotoxemia, defined as an endotoxin activity ≥ 0.6, a vasopressor dependency index ≥ 3, volume resuscitation of at least 30 ml/kg/24 h and at least single organ failure, to a haemoadsorption (Toraymyxin), an enhanced adsorption haemofiltration (oXiris) or a control intervention. Primary endpoint was the difference in endotoxin activity at 72-h post-intervention to baseline. In addition, inflammatory cytokine, vasopressor dependency index and SOFA-Score dynamics over the initial 72 h were assessed inter alia. Results In the 30, out of 437 screened, randomized patients (10 Standard of care, 10 oXiris, 10 Toraymyxin), endotoxin reduction at 72-h post-intervention-start did not differ among interventions (Standard of Care: 12 [1–42]%, oXiris: 21 [10–51]%, Toraymyxin: 23 [10–36]%, p = 0.82). Furthermore, no difference between groups could be observed neither for reduction of inflammatory cytokine levels (p = 0.58), nor for vasopressor weaning (p = 0.95) or reversal of organ injury (p = 0.22). Conclusions In a highly endotoxemic, severe, refractory septic shock population neither the Toraymyxin adsorber nor the oXiris membrane could show a reduction in circulating endotoxin or cytokine levels over standard of care. Trial registration ClinicalTrials.gov. NCT01948778. Registered August 30, 2013. https://clinicaltrials.gov/study/NCT01948778

Abstract Background Optimal oxygen targets in patients resuscitated after cardiac arrest are uncertain. The primary aim of this study was to describe the values of partial pressure of oxygen values (PaO2) and the episodes of hypoxemia and hyperoxemia occurring within the first 72 h of mechanical ventilation in out of hospital cardiac arrest (OHCA) patients. The secondary aim was to evaluate the association of PaO2 with patients’ outcome. Methods Preplanned secondary analysis of the targeted hypothermia versus targeted normothermia after OHCA (TTM2) trial. Arterial blood gases values were collected from randomization every 4 h for the first 32 h, and then, every 8 h until day 3. Hypoxemia was defined as PaO2 300 mmHg. Mortality and poor neurological outcome (defined according to modified Rankin scale) were collected at 6 months. Results 1418 patients were included in the analysis. The mean age was 64 ± 14 years, and 292 patients (20.6%) were female. 24.9% of patients had at least one episode of hypoxemia, and 7.6% of patients had at least one episode of severe hyperoxemia. Both hypoxemia and hyperoxemia were independently associated with 6-month mortality, but not with poor neurological outcome. The best cutoff point associated with 6-month mortality for hypoxemia was 69 mmHg (Risk Ratio, RR = 1.009, 95% CI 0.93–1.09), and for hyperoxemia was 195 mmHg (RR = 1.006, 95% CI 0.95–1.06). The time exposure, i.e., the area under the curve (PaO2-AUC), for hyperoxemia was significantly associated with mortality (p = 0.003). Conclusions In OHCA patients, both hypoxemia and hyperoxemia are associated with 6-months mortality, with an effect mediated by the timing exposure to high values of oxygen. Precise titration of oxygen levels should be considered in this group of patients. Trial registration: clinicaltrials.gov NCT02908308 , Registered September 20, 2016.

Abstract Background The sublingual microcirculation presumably exhibits disease-specific changes in function and morphology. Algorithm-based quantification of functional microcirculatory hemodynamic variables in handheld vital microscopy (HVM) has recently allowed identification of hemodynamic alterations in the microcirculation associated with COVID-19. In the present study we hypothesized that supervised deep machine learning could be used to identify previously unknown microcirculatory alterations, and combination with algorithmically quantified functional variables increases the model’s performance to differentiate critically ill COVID-19 patients from healthy volunteers. Methods Four international, multi-central cohorts of critically ill COVID-19 patients and healthy volunteers (n = 59/n = 40) were used for neuronal network training and internal validation, alongside quantification of functional microcirculatory hemodynamic variables. Independent verification of the models was performed in a second cohort (n = 25/n = 33). Results Six thousand ninety-two image sequences in 157 individuals were included. Bootstrapped internal validation yielded AUROC(CI) for detection of COVID-19 status of 0.75 (0.69–0.79), 0.74 (0.69–0.79) and 0.84 (0.80–0.89) for the algorithm-based, deep learning-based and combined models. Individual model performance in external validation was 0.73 (0.71–0.76) and 0.61 (0.58–0.63). Combined neuronal network and algorithm-based identification yielded the highest externally validated AUROC of 0.75 (0.73–0.78) (P

Abstract Background It remains elusive how the characteristics, the course of disease, the clinical management and the outcomes of critically ill COVID-19 patients admitted to intensive care units (ICU) worldwide have changed over the course of the pandemic. Methods Prospective, observational registry constituted by 90 ICUs across 22 countries worldwide including patients with a laboratory-confirmed, critical presentation of COVID-19 requiring advanced organ support. Hierarchical, generalized linear mixed-effect models accounting for hospital and country variability were employed to analyse the continuous evolution of the studied variables over the pandemic. Results Four thousand forty-one patients were included from March 2020 to September 2021. Over this period, the age of the admitted patients (62 [95% CI 60–63] years vs 64 [62–66] years, p

Abstract Background Recently, a randomized controlled trial (RCT) demonstrated rapid but individually variable hemodynamic improvement with therapeutic plasma exchange (TPE) in patients with septic shock. Prediction of clinical efficacy in specific sepsis treatments is fundamental for individualized sepsis therapy. Methods In the original RCT, patients with septic shock of

Abstract Background Patients undergoing extracorporeal membrane oxygenation (ECMO) are critically ill and show high mortality. Inter-hospital transfer of these patients has to be safe, with high survival rates during transport without potentially serious and life-threatening adverse events. The Swiss Air-Rescue provides 24-h/7-days per week inter-hospital helicopter transfers that include on-site ECMO cannulation if needed. This retrospective observational study describes adverse events of patients on ECMO transported by helicopter, and their associated survival. Methods All patients on ECMO with inter-hospital transfer by helicopter from start of service in February 2009 until May 2021 were included. Patients not transported by helicopter or with missing medical records were excluded. Patient demographics (age, sex) and medical history (type of and reason for ECMO), mission details (flight distance, times, primary or secondary transport), adverse events during the inter-hospital transfer, and survival of transferred patients were recorded. The primary endpoint was patient survival during transfer. Secondary endpoints were adverse events during transfer and 28-day survival. Results We screened 214 ECMO-related missions and included 191 in this analysis. Median age was 54.6 [IQR 46.1–62.0] years, 70.7% were male, and most patients had veno-arterial ECMO (56.5%). The main reasons for ECMO were pulmonary (46.1%) or cardiac (44.0%) failure. Most were daytime (69.8%) and primary missions (n = 100), median total mission time was 182.0 [143.0–254.0] min, and median transfer distance was 52.7 [33.2–71.1] km. All patients survived the transfer. Forty-four adverse events were recorded during 37 missions (19.4%), where 31 (70.5%) were medical and none resulted in patient harm. Adverse events occurred more frequently during night-time missions (59.9%, p = 0.047). Data for 28-day survival were available for 157 patients, of which 86 (54.8%) were alive. Conclusion All patients under ECMO survived the helicopter transport. Adverse events were observed for about 20% of the flight missions, with a tendency during the night-time flights, none harmed the patients. Inter-hospital transfer for patients undergoing ECMO provided by 24-h/7-d per week helicopter emergency medical service teams can be considered as feasible and safe. The majority of the patients (54.8%) were still alive after 28 days.

Abstract Background A higher-than-usual resistance to standard sedation regimens in COVID-19 patients suffering from acute respiratory distress syndrome (ARDS) has led to the frequent use of the second-line anaesthetic agent ketamine. Simultaneously, an increased incidence of cholangiopathies in mechanically ventilated patients receiving prolonged infusion of high-dose ketamine has been noted. Therefore, the objective of this study was to investigate a potential dose–response relationship between ketamine and bilirubin levels. Methods Post hoc analysis of a prospective observational cohort of patients suffering from COVID-19-associated ARDS between March 2020 and August 2021. A time-varying, multivariable adjusted, cumulative weighted exposure mixed-effects model was employed to analyse the exposure–effect relationship between ketamine infusion and total bilirubin levels. Results Two-hundred forty-three critically ill patients were included into the analysis. Ketamine was infused to 170 (70%) patients at a rate of 1.4 [0.9–2.0] mg/kg/h for 9 [4–18] days. The mixed-effects model revealed a positively correlated infusion duration–effect as well as dose–effect relationship between ketamine infusion and rising bilirubin levels (p

Objectives: To assess the risk of venous thromboembolic events (VTEs) and bleeding with or without thromboprophylaxis during neoadjuvant chemotherapy in bladder cancer patients scheduled for radical cystectomy. Materials and Methods: We conducted a retrospective cohort study in 4886 patients with non‐metastatic bladder cancer undergoing cystectomy across 28 centres in 13 countries between 1990 and 2021. Inverse probability weighting analyses were performed to estimate the effect of thromboprophylaxis on VTE and bleeding. Results: In 147 patients (3%) VTEs were recorded within the first year. These occurred a median (interquartile range [IQR]) of 127 (82–198) days after bladder cancer diagnosis. Bleeding events occurred in 131 patients (3%) within the first year. These occurred a median (IQR) of 101 (83–171) days after cancer diagnosis. In inverse probability weighting analyses, compared to patients without thromboprophylaxis during chemotherapy, patients with thromboprophylaxis had not only a lower risk of VTE (hazard ratio [HR] 0.32, 95% confidence interval [CI] 0.12–0.81; P = 0.016) but also a lower bleeding risk (HR 0.03, 95% CI 0.09–0.12; P <0.0001). The retrospective nature of the study was its main limitation. Conclusions: In this retrospective analysis, the benefit of thromboprophylaxis during neoadjuvant chemotherapy before cystectomy is in line with data from randomised trials in other malignancies. Our data suggest thromboprophylaxis is protective against VTEs and should be the standard of care during neoadjuvant chemotherapy. [ABSTRACT FROM AUTHOR]

Abstract Background Non-invasive oxygenation strategies have a prominent role in the treatment of acute hypoxemic respiratory failure during the coronavirus disease 2019 (COVID-19). While the efficacy of these therapies has been studied in hospitalized patients with COVID-19, the clinical outcomes associated with oxygen masks, high-flow oxygen therapy by nasal cannula and non-invasive mechanical ventilation in critically ill intensive care unit (ICU) patients remain unclear. Methods In this retrospective study, we used the best of nine covariate balancing algorithms on all baseline covariates in critically ill COVID-19 patients supported with > 10 L of supplemental oxygen at one of the 26 participating ICUs in Catalonia, Spain, between March 14 and April 15, 2020. Results Of the 1093 non-invasively oxygenated patients at ICU admission treated with one of the three stand-alone non-invasive oxygenation strategies, 897 (82%) required endotracheal intubation and 310 (28%) died during the ICU stay. High-flow oxygen therapy by nasal cannula (n = 439) and non-invasive mechanical ventilation (n = 101) were associated with a lower rate of endotracheal intubation (70% and 88%, respectively) than oxygen masks (n = 553 and 91% intubated), p

Abstract Background Necrotizing soft-tissue infections are infections with high mortality. The use of immunoglobulins within a combination therapy including broad-spectrum antibiotics has been debated. We assessed potential benefits of immunoglobulins and hypothesized that they were associated with a treatment benefit in a high-resource setting. Methods Patients with necrotizing soft-tissue infection hospitalized in the tertiary intensive care unit of the University Hospital of Zurich, Switzerland, between 2008 and 2020 were included retrospectively. The association between immunoglobulin administration and in-hospital survival, intensive care unit length of stay, the incidences of acute renal failure, acute respiratory distress syndrome and septic shock were analyzed. Results After adjustment for confounders, no difference for in-hospital survival (hazard ratio 2.20, 95% confidence interval [CI] 0.24–20.20, p = 0.5), intensive care unit length of stay (subhazard ratio [SHR] 0.90, CI 0.41–1.98, p = 0.8) and the development of acute respiratory distress syndrome (SHR 1.2, CI 0.36–4.03, p = 0.77) was observed in patients with or without immunoglobulin treatment. The Simplified Acute Physiology Score II, the risk of developing acute renal failure (SHR 2.86, CI 1.33–6.15, p = 0.01) and septic shock (SHR 1.86, CI 1.02–3.40, p = 0.04) was higher in patients treated with immunoglobulins, possibly reflecting a higher disease severity beyond measured confounders. Conclusions No clear evidence for a benefit of immunoglobulins in our cohort with consistent antibiotic use was found. Patients receiving immunoglobulins appeared more severely ill. Complementary to high treatment standards and appropriate antibiotics including beta lactams and protein synthesis inhibitors, immunoglobulins should be administered on a case-to-case basis, at least while more evidence from larger randomized controlled trials is missing.

Abstract Background The use of awake prone position concomitant to non-invasive mechanical ventilation in acute respiratory distress syndrome (ARDS) secondary to COVID-19 has shown to improve gas exchange, whereas its effect on the work of breathing remain unclear. The objective of this study was to evaluate the effects of awake prone position during helmet continuous positive airway pressure (CPAP) ventilation on inspiratory effort, gas exchange and comfort of breathing. Methods Forty consecutive patients presenting with ARDS due to COVID-19 were prospectively enrolled. Gas exchange, esophageal pressure swing (ΔPes), dynamic transpulmonary pressure (dTPP), modified pressure time product (mPTP), work of breathing (WOB) and comfort of breathing, were recorded on supine position and after 3 h on prone position. Results The median applied PEEP with helmet CPAP was 10 [8–10] cmH2O. The PaO2/FiO2 was higher in prone compared to supine position (Supine: 166 [136–224] mmHg, Prone: 314 [232–398] mmHg, p

Background: Connecting an infusion line to a closed stopcock results in pressurization of fluid within the syringe infusion pump assembly leading to flow irregularities when opening the stopcock and activating the pump. Aims: It was the purpose of this study to assess the extent of pressurization under different conditions and its impact on start‐up fluid delivery. Methods: Intraluminal pressures and start‐up fluid delivery at 1 mL/h flow rate were assessed with connection of the infusion line 1 min (delayed connection) or immediately after purging (immediate connection) using two different infusion lines made from polyvinylchloride (PVC) or polyethylene (PE). Results: Delayed connection resulted in an increase of intraluminal pressures from zero to 5.1 [4.5 to 5.7] mmHg with the PVC line and from zero to 47.1 [44.8 to 49.3] mmHg with the PE line (mean difference 42.0 [95% CI 39.3–44.7] mmHg; p <.0001). Immediate connection resulted in an increase of intraluminal pressures from zero to 44.3 [41.8–46.8] mmHg with the PVC line and from zero to 61.3 [57.2–65.4] mmHg with the PE line (mean difference 17.0 [95% CI 11.8–22.2] mmHg; p <.0001). The increase in intraluminal pressures was significantly higher with PE lines for both delayed and immediate connection when compared to the PVC lines (mean difference 29.5 [95% CI 19.3–39.7] mmHg; p <.0001). Related fluid volumes delivered at 10 s and 360 s after starting the pump ranged from −252% to 1321% (10 s) of expected infusion volumes and from 59% to 129% (360 s), respectively. Conclusions: Both, timing of infusion line connection after purging and infusion line characteristics considerably affect intraluminal pressures and start‐up fluid delivery when connecting a new syringe infusion pump assembly to a closed stopcock. Consecutive alterations in drug administration can have considerable hemodynamic consequences when dealing with catecholamine infusions in critically ill patients. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with significant mortality and morbidity. Approval of antifibrotic therapy has ameliorated disease progression, but therapy response is heterogeneous and to date, adequate biomarkers predicting therapy response are lacking. In recent years metabolomic technology has improved and is broadly applied in cancer research thus enabling its use in other fields. Recently both aberrant metabolic and lipidomic pathways have been described to influence profibrotic responses. We thus aimed to characterize the metabolomic and lipidomic changes between IPF and healthy volunteers (HV) and analyze metabolomic changes following treatment with nintedanib and pirfenidone. We collected serial serum samples from two IPF cohorts from Germany (n = 122) and Spain (n = 21) and additionally age-matched healthy volunteers (n = 16). Metabolomic analysis of 630 metabolites covering 14 small molecule and 12 different lipid classes was carried out using flow injection analysis tandem mass spectrometry for lipids and liquid chromatography tandem mass spectrometry for small molecules. Levels were correlated with survival and disease severity. We identified 109 deregulated analytes in IPF compared to HV in cohort 1 and 112 deregulated analytes in cohort 2. Metabolites which were up-regulated in both cohorts were mainly triglycerides while the main class of down-regulated metabolites were phosphatidylcholines. Only a minority of de-regulated analytes were small molecules. Triglyceride subclasses were inversely correlated with baseline disease severity (GAP-score) and a clinical compound endpoint of lung function decline or death. No changes in the metabolic profiles were observed following treatment with pirfenidone. Nintedanib treatment induced up-regulation of triglycerides and phosphatidylcholines. Patients in whom an increase in these metabolites was observed showed a trend towards better survival using the 2-years composite endpoint (HR 2.46, p = 0.06). In conclusion, we report major changes in metabolites in two independent cohorts testing a large number of patients. Specific lipidic metabolite signatures may serve as biomarkers for disease progression or favorable treatment response to nintedanib.

Abstract Background In intensive care units (ICUs) treating patients with Coronavirus disease 2019 (COVID-19) invasive ventilation poses a high risk for aerosol and droplet formation. Surface contamination of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) or bacteria can result in nosocomial transmission. Methods Two tertiary care COVID-19 intensive care units treating 53 patients for 870 patient days were sampled after terminal cleaning and preparation for regular use to treat non-COVID-19 patients. Results A total of 176 swabs were sampled of defined locations covering both ICUs. No SARS-CoV-2 ribonucleic acid (RNA) was detected. Gram-negative bacterial contamination was mainly linked to sinks and siphons. Skin flora was isolated from most swabbed areas and Enterococcus faecium was detected on two keyboards. Conclusions After basic cleaning with standard disinfection measures no remaining SARS-CoV-2 RNA was detected. Bacterial contamination was low and mainly localised in sinks and siphons.

Introduction Mechanical ventilation is a fundamental component in the management of patients post cardiac arrest. However, the ventilator settings and the gas-exchange targets used after cardiac arrest may not be optimal to minimise post-anoxic secondary brain injury. Therefore, questions remain regarding the best ventilator management in such patients.Methods and analysis This is a preplanned analysis of the international randomised controlled trial, targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest (OHCA)–target temperature management 2 (TTM2). The primary objective is to describe ventilatory settings and gas exchange in patients who required invasive mechanical ventilation and included in the TTM2 trial. Secondary objectives include evaluating the association of ventilator settings and gas-exchange values with 6 months mortality and neurological outcome. Adult patients after an OHCA who were included in the TTM2 trial and who received invasive mechanical ventilation will be eligible for this analysis. Data collected in the TTM2 trial that will be analysed include patients’ prehospital characteristics, clinical examination, ventilator settings and arterial blood gases recorded at hospital and intensive care unit (ICU) admission and daily during ICU stay.Ethics and dissemination The TTM2 study has been approved by the regional ethics committee at Lund University and by all relevant ethics boards in participating countries. No further ethical committee approval is required for this secondary analysis. Data will be disseminated to the scientific community by abstracts and by original articles submitted to peer-reviewed journals.Trial registration number NCT02908308.