Early sevoflurane sedation in severe COVID-19-related lung injury patients. A pilot randomized controlled trial.

BACKGROUND: This study aimed to assess a potential organ protective effect of volatile sedation in a scenario of severe inflammation with an early cytokine storm (in particular IL-6 elevation) in patients suffering from COVID-19-related lung injury with invasive mechanical ventilation and sedation. METHODS: This is a small-scale pilot multicenter randomized controlled trial from four tertiary hospitals in Switzerland, conducted between April 2020 and May 2021. 60 patients requiring mechanical ventilation due to severe COVID-19-related lung injury were included and randomized to 48-hour sedation with sevoflurane vs. continuous intravenous sedation (= control) within 24 h after intubation. The primary composite outcome was determined as mortality or persistent organ dysfunction (POD), defined as the need for mechanical ventilation, vasopressors, or renal replacement therapy at day 28. Secondary outcomes were the length of ICU and hospital stay, adverse events, routine laboratory parameters (creatinine, urea), and plasma inflammatory mediators. RESULTS: 28 patients were randomized to sevoflurane, 32 to the control arm. The intention-to-treat analysis revealed no difference in the primary endpoint with 11 (39%) sevoflurane and 13 (41%) control patients (p = 0.916) reaching the primary outcome. Five patients died within 28 days in each group (16% vs. 18%, p = 0.817). Of the 28-day survivors, 6 (26%) and 8 (30%) presented with POD (p = 0.781). There was a significant difference regarding the need for vasopressors (1 (4%) patient in the sevoflurane arm, 7 (26%) in the control one (p = 0.028)). Length of ICU stay, hospital stay, and registered adverse events within 28 days were comparable, except for acute kidney injury (AKI), with 11 (39%) sevoflurane vs. 2 (6%) control patients (p = 0.001). The blood levels of IL-6 in the first few days after the onset of the lung injury were less distinctly elevated than expected. CONCLUSIONS: No evident benefits were observed with short sevoflurane sedation on mortality and POD. Unexpectedly low blood levels of IL-6 might indicate a moderate injury with therefore limited improvement options of sevoflurane. Acute renal issues suggest caution in using sevoflurane for sedation in COVID-19. TRIAL REGISTRATION: The trial was registered on ClinicalTrials.gov (NCT04355962) on 2020/04/21.

Effects of enhanced adsorption haemofiltration versus haemoadsorption in severe, refractory septic shock with high levels of endotoxemia: the ENDoX bicentric, randomized, controlled trial.

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.

Dynamics of disease characteristics and clinical management of critically ill COVID-19 patients over the time course of the pandemic: an analysis of the prospective, international, multicentre RISC-19-ICU registry.

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 < 0.001) and the severity of organ dysfunction at ICU admission decreased (Sequential Organ Failure Assessment 8.2 [7.6-9.0] vs 5.8 [5.3-6.4], p < 0.001) and increased, while more female patients (26 [23-29]% vs 41 [35-48]%, p < 0.001) were admitted. The time span between symptom onset and hospitalization as well as ICU admission became longer later in the pandemic (6.7 [6.2-7.2| days vs 9.7 [8.9-10.5] days, p < 0.001). The PaO2/FiO2 at admission was lower (132 [123-141] mmHg vs 101 [91-113] mmHg, p < 0.001) but showed faster improvements over the initial 5 days of ICU stay in late 2021 compared to early 2020 (34 [20-48] mmHg vs 70 [41-100] mmHg, p = 0.05). The number of patients treated with steroids and tocilizumab increased, while the use of therapeutic anticoagulation presented an inverse U-shaped behaviour over the course of the pandemic. The proportion of patients treated with high-flow oxygen (5 [4-7]% vs 20 [14-29], p < 0.001) and non-invasive mechanical ventilation (14 [11-18]% vs 24 [17-33]%, p < 0.001) throughout the pandemic increased concomitant to a decrease in invasive mechanical ventilation (82 [76-86]% vs 74 [64-82]%, p < 0.001). The ICU mortality (23 [19-26]% vs 17 [12-25]%, p < 0.001) and length of stay (14 [13-16] days vs 11 [10-13] days, p < 0.001) decreased over 19 months of the pandemic. CONCLUSION: Characteristics and disease course of critically ill COVID-19 patients have continuously evolved, concomitant to the clinical management, throughout the pandemic leading to a younger, less severely ill ICU population with distinctly different clinical, pulmonary and inflammatory presentations than at the onset of the pandemic.

Impact of postoperative hypothermia on outcomes after off-pump coronary artery bypass grafting.

BACKGROUND: Even though the physiological derangements caused by hypothermia are well described, there is no consensus about its impact on postoperative outcomes. The aim of this study is to assess the effect of postoperative hypothermia on outcomes after off-pump coronary artery bypass surgery. METHODS: A total of 1979 patients undergoing isolated off-pump coronary artery bypass surgery in a single center in the period 2007-2018 were classified according to their axillary temperature measurement at intensive care unit admission postoperatively to either hypothermic (<36°C) or normothermic (≥36°C). Between-group differences on baseline characteristics and postoperative outcomes were assessed before and after propensity score matching. RESULTS: Data analysis showed that 582 patients (29.4%) were hypothermic (median temperature 35.5°C) and 1397 patients (70.6%) were normothermic (median temperature 36.4°C). Using propensity score matching, 567 patient pairs were created. Patients with hypothermia exhibited a higher rate of postoperative transfusion of at least three red cell concentrate units (14.3% vs 9%, p = 0.005), a longer intubation duration (median duration, 6 vs 5 h, p < 0.0001), and a longer intensive care unit stay (median stay, 1.6 vs 1.3 days, p = 0.008). There was no difference in reoperation for bleeding, renal replacement therapy, infections, and mortality between the two groups. CONCLUSIONS: Even though associated with a higher blood transfusion requirement and a slightly longer intensive care unit stay, mild postoperative hypothermia was not associated with a higher morbidity and mortality.

Active clearance of chest tubes after cardiac surgery: a propensity score matched analysis.

AIMS OF THE STUDY: Chest tubes inserted to drain shed mediastinal blood after cardiac surgery often become clogged, limiting their capacity to evacuate blood, and leading to blood retention and retained blood syndrome. The aim of this study was the assessment of the efficacy of an active tube clearance (ATC) system in the reduction of retained blood syndrome after cardiac surgery. METHODS: This study included 2461 adult patients undergoing major cardiac surgery. Patients receiving conventional chest tubes only (n = 1980) were compared with patients receiving an ATC tube in the retrosternal position (n = 481) for interventions caused by retained blood syndrome (re-exploration for bleeding or tamponade and interventions for pleural effusion or pneumothorax), kidney replacement therapy, postoperative atrial fibrillation, sternal infection and chest tube output before and after propensity score matching. RESULTS: Propensity score matching generated 471 patient-pairs balanced for their baseline characteristics. Matched patients with an ATC tube in the retrosternal position had no statistically significant difference in the rate of intervention for retained blood syndrome (33% vs 31%, p = 1), re-exploration because of bleeding or tamponade (2.5% vs 4%, p = 1), intervention for pneumothorax (4.7% vs 4.9%, p = 1) and intervention for pleural effusion (28% vs 28%, p = 1), but had statistically significantly less chest tube output on the first postoperative day (median 480, IQR 316–700 ml vs median 590, IQR 380–905 ml; p <0.0001) and second postoperative day (median 505, IQR 342–800 ml vs median 597, IQR 383–962 ml; p = 0.0012)  in comparison with patients with conventional chest tubes only. CONCLUSION: An ATC tube in the retrosternal position reduced chest tube output but showed no reduction in the rate of intervention for retained blood syndrome. Further research should be performed to test the combination of ATC in the retrosternal and the inferior pericardial space.

Human F(ab')2-containing immune complexes together with anti-hinge natural antibodies stimulate complement amplification in vitro and in vivo.

The systemic inflammatory response syndrome (SIRS) is triggered by C5a generation following an excessive complement amplification, but it has remained unclear how complement amplification is stimulated. It is known that neutrophilic elastase can cleave IgG to F(ab')(2) and that F(ab')(2)-containing immune complexes (F(ab')(2)-IC) stimulate complement amplification together with an unidentified plasma factor. We show that absorption of plasma on F(ab')(2) from human IgG removed this factor and prevented F(ab')(2)-IC from stimulating complement amplification. The required factor was purified from pooled whole human IgG (IVIG) as those naturally occurring antibodies (NAbs) that bind to F(ab')(2), but not to intact IgG. These "anti-hinge NAbs" restored complement amplification by F(ab')(2)-IC in absorbed plasma. Anti-hinge NAbs must have formed secondary, rigidified IC from F(ab')(2)-IC, because the F(ab')(2) fragments evidently captured dimeric C3b, known as a potent C3 convertase precursor. This process may also stimulate complement amplification in vivo, because plasma from septic patients at the onset of SIRS indeed contained F(ab')(2) fragments. The concentrations of F(ab')(2) and that of factor Bb, an unbiased measure of complement amplification, correlated linearly with that of released elastase. Moreover, the F(ab')(2) fragments migrated on gelfiltration columns together with anti-hinge NAbs as ICs with MW of up to approximately 750kDa, as verified on plasma of each of the nine patients studied. These findings provide for the first time a plausible mechanism of how F(ab')(2)-containing immune complexes stimulate complement amplification together with anti-hinge NAbs. The same mechanism may contribute to complement overreaction at the onset of SIRS.

Measurement of cardiac output after cardiac surgery by a new transesophageal Doppler device.

OBJECTIVES: Assessment of hemodynamics by transesophageal Doppler devices (TDD) may be a less invasive alternative to the pulmonary artery catheter. In contrast to the TDD evaluated so far, a new monitor (HemoSonic100) measures both blood flow velocity and the diameter of the descending aorta. The aim of this study was to assess the accuracy of the cardiac output/index (CO/CI) measured by this device compared with the CO/CI measured by thermodilution. DESIGN: Prospective nonrandomized study. SETTING: Community hospital; university-based statistician. PARTICIPANTS: Twenty-two patients. INTERVENTIONS: Elective coronary artery bypass grafting and/or valve replacement/repair. MEASUREMENTS AND MAIN RESULTS: After routine cardiac surgery, CO/CI was determined in the intensive care unit by iced-water bolus (IWB), continuous cardiac index (CCI) assessment, and the TDD. Matched measurements were made with each patient at intervals of 30 minutes. Six percent of sets were incomplete because of failed signal detection by the TDD. Bland-Altman analysis revealed a mean bias of 0.23 L/min/m(2) for TDD and IWB. Mean bias for CCI and IWB was 0.11 L/min/m(2). The correlation between TDD and IWB (r(2) = 0.09) for cardiac index was found to be inferior to the correlation between CCI and IWB (r(2) = 0.65). Trend analysis between sequential measurements (T1-4: dTDD, dCCI, dIWB) showed a lower correlation between dTDD and dIWB (r(2) = 0.1) compared with the correlation between dCCI and dIWB (r(2) = 0.44). CONCLUSION: The transesophageal Doppler device (HemoSonic100) cannot be recommended as a sole method for monitoring cardiac output in patients after cardiac surgery.