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2.
Trials ; 25(1): 282, 2024 Apr 26.
Article in English | MEDLINE | ID: mdl-38671523

ABSTRACT

BACKGROUND: In patients requiring general anesthesia, lung-protective ventilation can prevent postoperative pulmonary complications, which are associated with higher morbidity, mortality, and prolonged hospital stay. Application of positive end-expiratory pressure (PEEP) is one component of lung-protective ventilation. The correct strategy for setting adequate PEEP, however, remains controversial. PEEP settings that lead to a lower pressure difference between end-inspiratory plateau pressure and end-expiratory pressure ("driving pressure," ΔP) may reduce the risk of postoperative pulmonary complications. Preliminary data suggests that the PEEP required to prevent both end-inspiratory overdistension and end-expiratory alveolar collapse, thereby reducing ΔP, correlates positively with the body mass index (BMI) of patients, with PEEP values corresponding to approximately 1/3 of patient's respective BMI. Thus, we hypothesize that adjusting PEEP according to patient BMI reduces ΔP and may result in less postoperative pulmonary complications. METHODS: Patients undergoing general anesthesia and endotracheal intubation with volume-controlled ventilation with a tidal volume of 7 ml per kg predicted body weight will be randomized and assigned to either an intervention group with PEEP adjusted according to BMI or a control group with a standardized PEEP of 5 mbar. Pre- and postoperatively, lung ultrasound will be performed to determine the lung aeration score, and hemodynamic and respiratory vital signs will be recorded for subsequent evaluation. The primary outcome is the difference in ΔP as a surrogate parameter for lung-protective ventilation. Secondary outcomes include change in lung aeration score, intraoperative occurrence of hemodynamic and respiratory events, oxygen requirements and postoperative pulmonary complications. DISCUSSION: The study results will show whether an intraoperative ventilation strategy with PEEP adjustment based on BMI has the potential of reducing the risk for postoperative pulmonary complications as an easy-to-implement intervention that does not require lengthy ventilator maneuvers nor additional equipment. TRIAL REGISTRATION: German Clinical Trials Register (DRKS), DRKS00031336. Registered 21st February 2023. TRIAL STATUS: The study protocol was approved by the ethics committee of the Christian-Albrechts-Universität Kiel, Germany, on 1st February 2023. Recruitment began in March 2023 and is expected to end in September 2023.


Subject(s)
Anesthesia, General , Body Mass Index , Positive-Pressure Respiration , Randomized Controlled Trials as Topic , Humans , Positive-Pressure Respiration/methods , Positive-Pressure Respiration/adverse effects , Anesthesia, General/adverse effects , Postoperative Complications/prevention & control , Postoperative Complications/etiology , Tidal Volume , Lung/physiopathology , Treatment Outcome
3.
Perioper Med (Lond) ; 13(1): 14, 2024 Mar 05.
Article in English | MEDLINE | ID: mdl-38444023

ABSTRACT

BACKGROUND: Postoperative respiratory failure is the most frequent complication in postsurgical patients. The purpose of this study is to assess whether pulmonary function testing in high-risk patients during preoperative assessment detects previously unknown respiratory impairments which may influence patient outcomes. METHODS: A targeted patient screening by spirometry and the measurement of the diffusing capacity of the lung for carbon monoxide (DLCO) was implemented in the anesthesia department of a tertiary university hospital. Patients of all surgical disciplines who were at least 75 years old or exhibited reduced exercise tolerance with the metabolic equivalent of task less than four (MET < 4) were examined. Clinical characteristics, history of lung diseases, and smoking status were also recorded. The statistical analysis entailed t-tests, one-way ANOVA, and multiple linear regression with backward elimination for group comparisons. RESULTS: Among 256 included patients, 230 fulfilled the test quality criteria. Eighty-one (35.2%) patients presented obstructive ventilatory disorders, out of which 65 were previously unknown. 38 of the newly diagnosed obstructive disorders were mild, 18 moderate, and 9 severe. One hundred forty-five DLCO measurements revealed 40 (27.6%) previously unknown gas exchange impairments; 21 were mild, 17 moderate, and 2 severe. The pulmonary function parameters of forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and DLCO were significantly lower than the international reference values of a healthy population. Patients with a lower ASA class and no history of smoking exhibited higher FVC, FEV1, and DLCO values. Reduced exercise tolerance with MET < 4 was strongly associated with lower spirometry values. CONCLUSIONS: Our screening program detected a relevant number of patients with previously unknown obstructive ventilatory disorders and impaired pulmonary gas exchange. This newly discovered sickness is associated with low metabolic equivalents and may influence perioperative outcomes. Whether optimized management of patients with previously unknown impaired lung function leads to a better outcome should be evaluated in multicenter studies. TRIAL REGISTRATION: German Registry of Clinical Studies (DRKS00029337), registered on: June 22nd, 2022.

4.
Int J Mol Sci ; 25(4)2024 Feb 19.
Article in English | MEDLINE | ID: mdl-38397127

ABSTRACT

Atherosclerosis, a major contributor to cardiovascular morbidity and mortality, is characterized by chronic inflammation of the arterial wall. This inflammatory process is initiated and maintained by both innate and adaptive immunity. Dendritic cells (DCs), which are antigen-presenting cells, play a crucial role in the development of atherosclerosis and consist of various subtypes with distinct functional abilities. Following the recognition and binding of antigens, DCs become potent activators of cellular responses, bridging the innate and adaptive immune systems. The modulation of specific DC subpopulations can have either pro-atherogenic or atheroprotective effects, highlighting the dual pro-inflammatory or tolerogenic roles of DCs. In this work, we provide a comprehensive overview of the evolving roles of DCs and their subtypes in the promotion or limitation of atherosclerosis development. Additionally, we explore antigen pulsing and pharmacological approaches to modulate the function of DCs in the context of atherosclerosis.


Subject(s)
Atherosclerosis , Dendritic Cells , Humans , Atherosclerosis/metabolism , Adaptive Immunity , Inflammation/metabolism
5.
Curr Opin Crit Care ; 30(1): 43-52, 2024 Feb 01.
Article in English | MEDLINE | ID: mdl-38085866

ABSTRACT

PURPOSE OF REVIEW: This review presents the principles and possibilities of setting positive end-expiratory pressure (PEEP) using electrical impedance tomography (EIT). It summarizes the major findings of recent studies where EIT was applied to monitor the effects of PEEP on regional lung function and to guide the selection of individualized PEEP setting. RECENT FINDINGS: The most frequent approach of utilizing EIT for the assessment of PEEP effects and the PEEP setting during the time period from January 2022 till June 2023 was based on the analysis of pixel tidal impedance variation, typically acquired during stepwise incremental and/or decremental PEEP variation. The most common EIT parameters were the fraction of ventilation in various regions of interest, global inhomogeneity index, center of ventilation, silent spaces, and regional compliance of the respiratory system. The studies focused mainly on the spatial and less on the temporal distribution of ventilation. Contrast-enhanced EIT was applied in a few studies for the estimation of ventilation/perfusion matching. SUMMARY: The availability of commercial EIT devices resulted in an increase in clinical studies using this bedside imaging technology in neonatal, pediatric and adult critically ill patients. The clinical interest in EIT became evident but the potential of this method in clinical decision-making still needs to be fully exploited.


Subject(s)
Positive-Pressure Respiration , Tomography, X-Ray Computed , Adult , Infant, Newborn , Humans , Child , Electric Impedance , Positive-Pressure Respiration/methods , Tomography, X-Ray Computed/methods , Lung , Perfusion
6.
Arch Dis Child Fetal Neonatal Ed ; 109(3): 322-327, 2024 Apr 18.
Article in English | MEDLINE | ID: mdl-38071525

ABSTRACT

OBJECTIVES: Newborn infants have unique respiratory physiology compared with older children and adults due to their lungs' structural and functional immaturity and highly compliant chest wall. To date, ventilation distribution has seldom been studied in this age group. This study aims to assess the effect of body position on ventilation distribution in spontaneously breathing healthy neonates. DESIGN: Prospective observational study. SETTING: Maternity wards of Oulu University Hospital. PATIENTS: 20 healthy, spontaneously breathing, newborn infants. INTERVENTIONS: Electrical impedance tomography data were recorded with a 32-electrode belt (Sentec AG, Landquart, Switzerland) in six different body positions in random order. Ventilation distribution was retrospectively assessed 10 minutes after each position change. MAIN OUTCOME MEASURES: In each position, regional tidal impedance variation (ΔZ) and ventral-to-dorsal and right-to-left centre of ventilation were measured. RESULTS: The mean global ΔZ was the largest in supine position and it was smaller in prone and lateral positions. Yet, global ΔZ did not differ in supine positions, ventilation distribution was more directed towards the non-dependent lung region in supine tilted position (p<0.001). In prone, a reduction of global ΔZ was observed (p<0.05) corresponding to an amount of 10% of global tidal variation in supine position. In both lateral positions, tidal ventilation was distributed more to the corresponding non-dependent lung region. CONCLUSIONS: Prone or lateral body positioning in healthy spontaneously breathing newborns leads to a redistribution of ventilation to the non-dependent lung regions and at the same time global tidal volume is reduced as compared with supine.

7.
Int J Numer Method Biomed Eng ; 40(2): e3787, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38037251

ABSTRACT

We present a novel computational model for the dynamics of alveolar recruitment/derecruitment (RD), which reproduces the underlying characteristics typically observed in injured lungs. The basic idea is a pressure- and time-dependent variation of the stress-free reference volume in reduced dimensional viscoelastic elements representing the acinar tissue. We choose a variable reference volume triggered by critical opening and closing pressures in a time-dependent manner from a straightforward mechanical point of view. In the case of (partially and progressively) collapsing alveolar structures, the volume available for expansion during breathing reduces and vice versa, eventually enabling consideration of alveolar collapse and reopening in our model. We further introduce a method for patient-specific determination of the underlying critical parameters of the new alveolar RD dynamics when integrated into the tissue elements, referred to as terminal units, of a spatially resolved physics-based lung model that simulates the human respiratory system in an anatomically correct manner. Relevant patient-specific parameters of the terminal units are herein determined based on medical image data and the macromechanical behavior of the lung during artificial ventilation. We test the whole modeling approach for a real-life scenario by applying it to the clinical data of a mechanically ventilated patient. The generated lung model is capable of reproducing clinical measurements such as tidal volume and pleural pressure during various ventilation maneuvers. We conclude that this new model is an important step toward personalized treatment of ARDS patients by considering potentially harmful mechanisms-such as cyclic RD and overdistension-and might help in the development of relevant protective ventilation strategies to reduce ventilator-induced lung injury (VILI).


Subject(s)
Pulmonary Alveoli , Respiratory Distress Syndrome , Humans , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/therapy , Lung , Respiration, Artificial/adverse effects , Respiration
8.
Sci Rep ; 13(1): 20842, 2023 11 27.
Article in English | MEDLINE | ID: mdl-38012186

ABSTRACT

Endotracheal suctioning is a widely used procedure to remove secretions from the airways of ventilated patients. Despite its prevalence, regional effects of this maneuver have seldom been studied. In this study, we explore its effects on regional lung aeration in neonates and young infants using electrical impedance tomography (EIT) as part of the large EU-funded multicenter observational study CRADL. 200 neonates and young infants in intensive care units were monitored with EIT for up to 72 h. EIT parameters were calculated to detect changes in ventilation distribution, ventilation inhomogeneity and ventilation quantity on a breath-by-breath level 5-10 min before and after suctioning. The intratidal change in aeration over time was investigated by means of regional expiratory time constants calculated from all respiratory cycles using an innovative procedure and visualized by 2D maps of the thoracic cross-section. 344 tracheal suctioning events from 51 patients could be analyzed. They showed no or very small changes of EIT parameters, with a dorsal shift of the center of ventilation by 0.5% of the chest diameter and a 7% decrease of tidal impedance variation after suctioning. Regional time constants did not change significantly. Routine suctioning led to EIT-detectable but merely small changes of the ventilation distribution in this study population. While still a measure requiring further study, the time constant maps may help clinicians interpret ventilation mechanics in specific cases.


Subject(s)
Critical Illness , Tomography , Infant, Newborn , Humans , Infant , Electric Impedance , Suction , Tomography/methods , Lung/diagnostic imaging
9.
Tomography ; 9(5): 1903-1932, 2023 10 18.
Article in English | MEDLINE | ID: mdl-37888742

ABSTRACT

Electrical Impedance Tomography (EIT) is a non-invasive bedside imaging technique that provides real-time lung ventilation information on critically ill patients. EIT can potentially become a valuable tool for optimising mechanical ventilation, especially in patients with acute respiratory distress syndrome (ARDS). In addition, EIT has been shown to improve the understanding of ventilation distribution and lung aeration, which can help tailor ventilatory strategies according to patient needs. Evidence from critically ill patients shows that EIT can reduce the duration of mechanical ventilation and prevent lung injury due to overdistension or collapse. EIT can also identify the presence of lung collapse or recruitment during a recruitment manoeuvre, which may guide further therapy. Despite its potential benefits, EIT has not yet been widely used in clinical practice. This may, in part, be due to the challenges associated with its implementation, including the need for specialised equipment and trained personnel and further validation of its usefulness in clinical settings. Nevertheless, ongoing research focuses on improving mechanical ventilation and clinical outcomes in critically ill patients.


Subject(s)
Critical Illness , Tomography , Humans , Electric Impedance , Tomography/methods , Lung/diagnostic imaging , Tomography, X-Ray Computed/methods
10.
Int J Numer Method Biomed Eng ; 39(9): e3745, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37403527

ABSTRACT

We present a new approach for physics-based computational modeling of diseased human lungs. Our main object is the development of a model that takes the novel step of incorporating the dynamics of airway recruitment/derecruitment into an anatomically accurate, spatially resolved model of respiratory system mechanics, and the relation of these dynamics to airway dimensions and the biophysical properties of the lining fluid. The importance of our approach is that it potentially allows for more accurate predictions of where mechanical stress foci arise in the lungs, since it is at these locations that injury is thought to arise and propagate from. We match the model to data from a patient with acute respiratory distress syndrome (ARDS) to demonstrate the potential of the model for revealing the underlying derangements in ARDS in a patient-specific manner. To achieve this, the specific geometry of the lung and its heterogeneous pattern of injury are extracted from medical CT images. The mechanical behavior of the model is tailored to the patient's respiratory mechanics using measured ventilation data. In retrospective simulations of various clinically performed, pressure-driven ventilation profiles, the model adequately reproduces clinical quantities measured in the patient such as tidal volume and change in pleural pressure. The model also exhibits physiologically reasonable lung recruitment dynamics and has the spatial resolution to allow the study of local mechanical quantities such as alveolar strains. This modeling approach advances our ability to perform patient-specific studies in silico, opening the way to personalized therapies that will optimize patient outcomes.

11.
J Crit Care ; 78: 154350, 2023 12.
Article in English | MEDLINE | ID: mdl-37327507

ABSTRACT

PURPOSE: To compare ICU-free (ICU-FD) and ventilator-free days (VFD) in the 30 days after randomization in patients that received isoflurane or propofol without receiving the other sedative. MATERIALS AND METHODS: A recent randomized controlled trial (RCT) compared inhaled isoflurane via the Sedaconda® anaesthetic conserving device (ACD) with intravenous propofol for up to 54 h (Meiser et al. 2021). After end of study treatment, continued sedation was locally determined. Patients were eligible for this post-hoc analysis only if they had available 30-day follow-up data and never converted to the other drug in the 30 days from randomization. Data on ventilator use, ICU stay, concomitant sedative use, renal replacement therapy (RRT) and mortality were collected. RESULTS: Sixty-nine of 150 patients randomized to isoflurane and 109 of 151 patients randomized to propofol were eligible. After adjusting for potential confounders, the isoflurane group had more ICU-FD than the propofol group (17.3 vs 13.8 days, p = 0.028). VFD for the isoflurane and propofol groups were 19.8 and 18.5 respectively (p = 0.454). Other sedatives were used more frequently (p < 0.0001) and RRT started in a greater proportion of patients in the propofol group (p = 0.011). CONCLUSIONS: Isoflurane via the ACD was not associated with more VFD but with more ICU-FD and less concomitant sedative use.


Subject(s)
Isoflurane , Propofol , Humans , Hypnotics and Sedatives , Intensive Care Units , Respiration, Artificial
12.
J Clin Med ; 12(9)2023 May 06.
Article in English | MEDLINE | ID: mdl-37176754

ABSTRACT

Devices used to deliver inhaled sedation increase dead space ventilation. We therefore compared ventilatory effects among isoflurane sedation via the Sedaconda ACD-S (internal volume: 50 mL), isoflurane sedation via the Sedaconda ACD-L (100 mL), and propofol sedation with standard mechanical ventilation with heat and moisture exchangers (HME). This is a substudy of a randomized trial that compared inhaled isoflurane sedation via the ACD-S or ACD-L to intravenous propofol sedation in 301 intensive care patients. Data from the first 24 h after study inclusion were analyzed using linear mixed models. Primary outcome was minute ventilation. Secondary outcomes were tidal volume, respiratory rate, arterial carbon dioxide pressure, and isoflurane consumption. In total, 151 patients were randomized to propofol and 150 to isoflurane sedation; 64 patients received isoflurane via the ACD-S and 86 patients via the ACD-L. While use of the ACD-L was associated with higher minute ventilation (average difference (95% confidence interval): 1.3 (0.7, 1.8) L/min, p < 0.001), higher tidal volumes (44 (16, 72) mL, p = 0.002), higher respiratory rates (1.2 (0.1, 2.2) breaths/min, p = 0.025), and higher arterial carbon dioxide pressures (3.4 (1.2, 5.6) mmHg, p = 0.002), use of the ACD-S did not significantly affect ventilation compared to standard mechanical ventilation and sedation. Isoflurane consumption was slightly less with the ACD-L compared to the ACD-S (-0.7 (-1.3, 0.1) mL/h, p = 0.022). The Sedaconda ACD-S compared to the ACD-L is associated with reduced minute ventilation and does not significantly affect ventilation compared to a standard mechanical ventilation and sedation setting. The smaller ACD-S is therefore the device of choice to minimize impact on ventilation, especially in patients with a limited ability to compensate (e.g., COPD patients). Volatile anesthetic consumption is slightly higher with the ACD-S compared to the ACD-L.

13.
Intensive Care Med Exp ; 11(1): 28, 2023 May 22.
Article in English | MEDLINE | ID: mdl-37211573

ABSTRACT

BACKGROUND: Mechanical power is a major contributor to lung injury and mortality in adults receiving mechanical ventilation. Recent advances in our understanding of mechanical power have allowed the different mechanical components to be isolated. The preterm lung shares many of the same similarities that would indicate mechanical power may be relevant in this group. To date, the role of mechanical power in neonatal lung injury is unknown. We hypothesise that mechanical power maybe useful in expanding our understanding of preterm lung disease. Specifically, that mechanical power measures may account for gaps in knowledge in how lung injury is initiated. HYPOTHESIS-GENERATING DATA SET: To provide a justification for our hypothesis, data in a repository at the Murdoch Children's Research Institute, Melbourne (Australia) were re-analysed. 16 preterm lambs 124-127d gestation (term 145d) who received 90 min of standardised positive pressure ventilation from birth via a cuffed endotracheal tube were chosen as each was exposed to three distinct and clinically relevant respiratory states with unique mechanics. These were (1) the respiratory transition to air-breathing from an entirely fluid-filled lung (rapid aeration and fall in resistance); (2) commencement of tidal ventilation in an acutely surfactant-deficient state (low compliance) and (3) exogenous surfactant therapy (improved aeration and compliance). Total, tidal, resistive and elastic-dynamic mechanical power were calculated from the flow, pressure and volume signals (200 Hz) for each inflation. RESULTS: All components of mechanical power behaved as expected for each state. Mechanical power increased during lung aeration from birth to 5 min, before again falling immediately after surfactant therapy. Before surfactant therapy tidal power contributed 70% of total mechanical power, and 53.7% after. The contribution of resistive power was greatest at birth, demonstrating the initial high respiratory system resistance at birth. CONCLUSIONS: In our hypothesis-generating dataset, changes in mechanical power were evident during clinically important states for the preterm lung, specifically transition to air-breathing, changes in aeration and surfactant administration. Future preclinical studies using ventilation strategies designed to highlight different types of lung injury, including volu-, baro- and ergotrauma, are needed to test our hypothesis.

14.
PLoS One ; 18(4): e0285110, 2023.
Article in English | MEDLINE | ID: mdl-37104369

ABSTRACT

PURPOSE: The role of positive endexpiratory pressure (PEEP) for successful cannulation of the subclavian vein (SCV) remains inconclusive. The aim of our study was to assess the effect of different levels of PEEP on distance from SCV to parietal pleura (DVP) and on the cross-sectional area (CSA) of the SCV. METHODS: Invasive mechanically ventilated adult patients with a clinical indication for a stepwise PEEP-trial (0, 5, 10, and 15 cm H2O) were included in this prospective observational single-center study. Ultrasound examinations of SCV were performed with a linear ultrasound probe using the infraclavicular view. DVP and CSA were measured on the right and left bodyside. Examinations were repeated at each PEEP step. RESULTS: 27 patients were enrolled (12 female; 60±21 years; BMI 24.6±4.9 kg/m2; 20 patients on controlled, 7 on assisted ventilation). A statistically significant increase of DVP in the in-plane view was found on the left side which was not clinically relevant. No significant differences of DVP were observed in all other views. PEEP induced changes in CSAs were statistically significant but clinically not relevant on both sides. The largest change in CSA (2mm2) was observed when comparing PEEP 10 with PEEP 0 cm H2O. CONCLUSION: A stepwise PEEP increase was not associated with clinically relevant changes of the DVP and CSA. Thus, a PEEP-optimization for the cannulation of the subclavian vein is not indicated.


Subject(s)
Catheterization, Central Venous , Subclavian Vein , Adult , Humans , Female , Subclavian Vein/diagnostic imaging , Respiration, Artificial , Positive-Pressure Respiration , Pleura
16.
Am J Physiol Endocrinol Metab ; 324(2): E144-E153, 2023 02 01.
Article in English | MEDLINE | ID: mdl-36576355

ABSTRACT

Although brown fat is strongly associated with a constellation of cardiometabolic benefits in animal models and humans, it has also been tied to cancer cachexia. In humans, cancer-associated cachexia increases mortality, raising the possibility that brown fat in this context may be associated with increased cancer death. However, the effect of brown fat on cancer-associated cachexia and survival in humans remains unclear. Here, we retrospectively identify patients with and without brown fat on fluorodeoxyglucose (18F-FDG) positron-emission tomography (PET) scans obtained as part of routine cancer care and assemble a cohort to address these questions. We did not find an association between brown fat status and cachexia. Furthermore, we did not observe an association between brown fat and increased mortality in patients with cachexia. Our analyses controlled for confounding factors including age at cancer diagnosis, sex, body mass index, cancer site, cancer stage, outdoor temperature, comorbid conditions (heart failure, type 2 diabetes mellitus, coronary artery disease, hypertension, dyslipidemia, cerebrovascular disease), and ß-blocker use. Taken together, our results suggest that brown fat is not linked to cancer-associated cachexia and does not worsen overall survival in patients with cachexia.NEW & NOTEWORTHY This study finds that brown fat is not linked to cancer-associated cachexia. Moreover, this work shows that brown fat does not worsen overall survival in patients with cachexia.


Subject(s)
Diabetes Mellitus, Type 2 , Neoplasms , Animals , Humans , Adipose Tissue, Brown/diagnostic imaging , Retrospective Studies , Cachexia , Diabetes Mellitus, Type 2/complications , Fluorodeoxyglucose F18 , Positron-Emission Tomography/methods , Neoplasms/complications
18.
Ann Intensive Care ; 12(1): 116, 2022 Dec 20.
Article in English | MEDLINE | ID: mdl-36538243

ABSTRACT

BACKGROUND: Acute hypoxemic respiratory failure (AHRF) is a leading concern in critically ill patients. Experimental and clinical data suggest that early sedation with volatile anesthestics may improve arterial oxygenation and reduce the plasma and alveolar levels of markers of alveolar epithelial injury and of proinflammatory cytokines. METHODS: An a priori hypothesis substudy of a multicenter randomized controlled trial (The Sedaconda trial, EUDRA CT Number 2016-004551-67). In the Sedaconda trial, 301 patients on invasive mechanical ventilation were randomized to 48 h of sedation with isoflurane or propofol in a 1:1 ratio. For the present substudy, patients with a ratio of arterial pressure of oxygen (PaO2) to inspired fraction of oxygen (FiO2), PaO2/FiO2, of ≤ 300 mmHg at baseline were included (n = 162). The primary endpoint was the change in PaO2/FiO2 between baseline and the end of study sedation. A subgroup analysis in patients with PaO2/FiO2 ≤ 200 mmHg was performed (n = 82). RESULTS: Between baseline and the end of study sedation (48 h), oxygenation improved to a similar extent in the isoflurane vs. the propofol group (isoflurane: 199 ± 58 to 219 ± 76 mmHg (n = 70), propofol: 202 ± 62 to 236 ± 77 mmHg (n = 89); p = 0.185). On day seven after randomization, PaO2/FiO2 was 210 ± 79 mmHg in the isoflurane group (n = 41) and 185 ± 87 mmHg in the propofol group (n = 44; p = 0.411). In the subgroup of patients with PaO2/FiO2 ≤ 200 mmHg, PaO2/FiO2 increase between baseline and end of study sedation was 152 ± 33 to 186 ± 54 mmHg for isoflurane (n = 37), and 150 ± 38 to 214 ± 85 mmHg for propofol (n = 45; p = 0.029). On day seven, PaO2/FiO2 was 198 ± 69 mmHg in patients randomized to isoflurane (n = 20) and 174 ± 106 mmHg in patients randomized to propofol (n = 20; p = 0.933). Both for the whole study population and for the subgroup with PaO2/FiO2 ≤ 200 mmHg, no significant between-group differences were observed for PaCO2, pH and tidal volume as well as 30-day mortality and ventilator-free days alive. CONCLUSIONS: In patients with AHRF, inhaled sedation with isoflurane for a duration of up to 48 h did not lead to improved oxygenation in comparison to intravenous sedation with propofol. Trial registration The main study was registered in the European Medicines Agency's EU Clinical Trial register (EudraCT), 2016-004551-67, before including the first patient. The present substudy was registered at German Clinical Trials Register (DRKS, ID: DRKS00018959) on January 7th, 2020, before opening the main study data base and obtaining access to study results.

19.
Cell ; 185(24): 4654-4673.e28, 2022 11 23.
Article in English | MEDLINE | ID: mdl-36334589

ABSTRACT

Brown adipose tissue (BAT) regulates metabolic physiology. However, nearly all mechanistic studies of BAT protein function occur in a single inbred mouse strain, which has limited the understanding of generalizable mechanisms of BAT regulation over physiology. Here, we perform deep quantitative proteomics of BAT across a cohort of 163 genetically defined diversity outbred mice, a model that parallels the genetic and phenotypic variation found in humans. We leverage this diversity to define the functional architecture of the outbred BAT proteome, comprising 10,479 proteins. We assign co-operative functions to 2,578 proteins, enabling systematic discovery of regulators of BAT. We also identify 638 proteins that correlate with protection from, or sensitivity to, at least one parameter of metabolic disease. We use these findings to uncover SFXN5, LETMD1, and ATP1A2 as modulators of BAT thermogenesis or adiposity, and provide OPABAT as a resource for understanding the conserved mechanisms of BAT regulation over metabolic physiology.


Subject(s)
Adipose Tissue, Brown , Proteome , Humans , Mice , Animals , Adipose Tissue, Brown/metabolism , Proteome/metabolism , Thermogenesis/physiology , Adiposity , Obesity/metabolism , Mice, Inbred C57BL , Proto-Oncogene Proteins/metabolism
20.
Physiol Meas ; 43(10)2022 10 18.
Article in English | MEDLINE | ID: mdl-36137548

ABSTRACT

Objective.Viral lower respiratory tract infections (LRTI) are the leading cause for acute admission to the intensive care unit in infants and young children. Nebulized bronchodilators are often used when treating the most severe cases. The aim of this study was to investigate the bronchodilator effect on respiratory mechanics during intensive care with electrical impedance tomography (EIT) and to assess the feasibility of EIT in this context.Approach.We continuously monitored the children with chest EIT for up to 72 h in an observational study design. The treatment decisions were done by clinical assessment, as the clinicians were blinded to the EIT information during data collection. In a retrospective analysis, clinical parameters and regional expiratory time constants determined by EIT were used to assess the effects of bronchodilator administration, especially regarding airway resistance.Main results.We included six children from 11 to 27 months of age requiring intensive care due to viral LRTI and receiving bronchodilator agents. Altogether 131 bronchodilator administrations were identified during EIT monitoring. After validation of the exact timing of events and EIT data quality, 77 administrations were included in the final analysis. Fifty-five bronchodilator events occurred during invasive ventilation and 22 during high-flow nasal cannulae treatment. Only 17% of the bronchodilator administrations resulted in a relevant decrease in calculated expiratory time constants.Significance.Continuous monitoring with EIT might help to optimize the treatment of LRTI in pediatric intensive care units. In particular, EIT-based regional expiratory time constants would allow objective assessment of the effects of bronchodilators and other respiratory therapies.


Subject(s)
Bronchodilator Agents , Respiratory Tract Infections , Infant , Humans , Child , Child, Preschool , Bronchodilator Agents/pharmacology , Bronchodilator Agents/therapeutic use , Tomography/methods , Electric Impedance , Retrospective Studies , Lung , Respiratory Tract Infections/drug therapy
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