Intensive Care Medicine Experimental最新文献

Background: Diabetic ketoacidosis (DKA) is a potentially life-threatening disorder associated with severe alterations in metabolism and acid-base status. Mitochondrial dysfunction is associated with diabetes and its complications. Thiamine and coenzyme Q10 (CoQ10) are important factors in aerobic metabolism. In this study, we measured cellular oxygen consumption rates (OCRs) and the effects of in vitro administration of thiamine and CoQ10 on OCRs in patients with DKA versus healthy controls.

Methods: Blood samples were collected from a prospective cohort of patients with DKA and from controls. Cellular OCRs were measured in peripheral blood mononuclear cells (PBMC) without treatment and after treatment with thiamine, CoQ10, or both. The mitochondrial profile was measured using an XFe96 Extracellular Flux Analyzer and XF Cell Mito Stress Test Kit (Seahorse Bioscience). A linear quantile mixed model was used to compare OCRs and estimate treatment effects.

Results: A total of 62 patients with DKA and 48 controls were included in the study. The median basal and maximal OCRs were lower in the DKA group than in the control group (basal: 4.7 [IQR: 3.3, 7.9] vs. 7.9 [5.0, 9.5], p = 0.036; maximal: 16.4 [9.5, 28.1] vs. 31.5 [20.6, 46.0] pmol/min/µg protein, p < 0.001). In DKA samples, basal and maximal OCRs were significantly increased when treated with thiamine, CoQ10, or both. In controls, basal and maximal OCR were significantly increased only with thiamine treatment.

Conclusion: Mitochondrial metabolic profiles of patients with DKA demonstrated lower cellular oxygen consumption when compared to healthy controls. Oxygen consumption increased significantly in cells of patients with DKA treated with thiamine or CoQ10. These results suggest that thiamine and CoQ10 could potentially have therapeutic benefits in DKA via their metabolic effects on mitochondrial cellular respiration.

Background: Quantification of pulmonary edema in patients with acute respiratory distress syndrome (ARDS) by chest computed tomography (CT) scan has not been validated in routine diagnostics due to its complexity and time-consuming nature. Therefore, the single-indicator transpulmonary thermodilution (TPTD) technique to measure extravascular lung water (EVLW) has been used in the clinical setting. Advances in artificial intelligence (AI) have now enabled CT images of inhomogeneous lungs to be segmented automatically by an intensive care physician with no prior radiology training within a relatively short time. Nevertheless, there is a paucity of data validating the quantification of pulmonary edema using automated lung segmentation on CT compared with TPTD.

Methods: A retrospective study (January 2016 to December 2021) analyzed patients with ARDS, admitted to the intensive care unit of the Department of Anesthesiology and Critical Care Medicine, University Hospital Mannheim, who underwent a chest CT scan and hemodynamic monitoring using TPTD at the same time. Pulmonary edema was estimated using manually and automated lung segmentation on CT and then compared to the pulmonary edema calculated from EVLW determined using TPTD.

Results: 145 comparative measurements of pulmonary edema with TPTD and CT were included in the study. Estimating pulmonary edema using either automated lung segmentation on CT or TPTD showed a low bias overall (- 104 ml) but wide levels of agreement (upper: 936 ml, lower: - 1144 ml). In 13% of the analyzed CT scans, the agreement between the segmentation of the AI algorithm and a dedicated investigator was poor. Manual segmentation and automated segmentation adjusted for contrast agent did not improve the agreement levels.

Conclusions: Automated lung segmentation on CT can be considered an unbiased but imprecise measurement of pulmonary edema in mechanically ventilated patients with ARDS.

Background: Escherichia coli is the most common cause of human bloodstream infections and bacterial sepsis/septic shock. However, translation of preclinical septic shock resuscitative therapies remains limited mainly due to low-fidelity of available models in mimicking clinical illness. To overcome the translational barrier, we sought to replicate sepsis complexity by creating an acutely critically-ill preclinical bacterial septic shock model undergoing active 48-h intensive care management.

Aim: To develop a clinically relevant large-animal (ovine) live-bacterial infusion model for septic shock.

Methods: Septic shock was induced by intravenous infusion of the live antibiotic resistant extra-intestinal pathogenic E. coli sequence type 131 strain EC958 in eight anesthetised and mechanically ventilated sheep. A bacterial dose range of 2 × 10⁵-2 × 10⁹ cfu/mL was used for the dose optimisation phase (n = 4) and upon dose confirmation the model was developed (n = 5). Post-shock the animals underwent an early-vasopressor and volume-restriction resuscitation strategy with active haemodynamic management and monitoring over 48 h. Serial blood samples were collected for testing of pro-inflammatory (IL-6, IL-8, VEGFA) and anti-inflammatory (IL-10) cytokines and hyaluronan assay to assess endothelial integrity. Tissue samples were collected for histopathology and transmission electron microscopy.

Results: The 2 × 10⁷ cfu/mL bacterial dose led to a reproducible distributive shock within a pre-determined 12-h period. Five sheep were used to demonstrate consistency of the model. Bacterial infusion led to development of septic shock in all animals. The baseline mean arterial blood pressure reduced from a median of 91 mmHg (71, 102) to 50 mmHg (48, 57) (p = 0.004) and lactate levels increased from a median of 0.5 mM (0.3, 0.8) to 2.1 mM (2.0, 2.3) (p = 0.02) post-shock. The baseline median hyaluronan levels increased significantly from 25 ng/mL (18, 86) to 168 ng/mL (86, 569), p = 0.05 but not the median vasopressor dependency index which increased within 1 h of resuscitation from zero to 0.39 mmHg^-1 (0.06, 5.13), p = 0.065, and. Over the 48 h, there was a significant decrease in the systemic vascular resistance index (F = 7.46, p = 0.01) and increase in the pro-inflammatory cytokines [IL-6 (F = 8.90, p = 0.02), IL-8 (F = 5.28, p = 0.03), and VEGFA (F = 6.47, p = 0.02)].

Conclusions: This critically ill large-animal model was consistent in reproducing septic shock and will be applied in investigating advanced resuscitation and therapeutic interventions.

Background: Popularity of electrical impedance tomography (EIT) and esophageal pressure (Pes) monitoring in the ICU is increasing, but there is uncertainty regarding their bedside use within a personalized ventilation strategy. We aimed to gather insights about the current experiences and perceived role of these physiological monitoring techniques, and to identify barriers and facilitators/solutions for EIT and Pes implementation.

Methods: Qualitative study involving (1) a survey targeted at ICU clinicians with interest in advanced respiratory monitoring and (2) an expert focus group discussion. The survey was shared via international networks and personal communication. An in-person discussion session on barriers, facilitators/solutions for EIT implementation was organized with an international panel of EIT experts as part of a multi-day EIT meeting. Pes was not discussed in-person, but we found the focus group results relevant to Pes as well. This was confirmed by the survey results and four additional Pes experts that were consulted.

Results: We received 138 survey responses, and 26 experts participated in the in-person discussion. Survey participants had diverse background [physicians (54%), respiratory therapists (19%), clinical researchers (15%), and nurses (6%)] with mostly > 10 year ICU experience. 84% of Pes users and 74% of EIT users rated themselves as competent to expert users. Techniques are currently primarily used during controlled ventilation for individualization of PEEP (EIT and Pes), and for monitoring lung mechanics and lung stress (Pes). EIT and Pes are considered relevant techniques to guide ventilation management and is helpful for educating clinicians; however, 57% of EIT users and 37% of Pes users agreed that further validation is needed. Lack of equipment/materials, evidence-based guidelines, clinical protocols, and/or the time-consuming nature of the measurements are main reasons hampering Pes and EIT application. Identified facilitators/solutions to improve implementation include international guidelines and collaborations between clinicians/researcher and manufacturers, structured courses for training and use, easy and user-friendly devices and standardized analysis pipelines.

Conclusions: This study revealed insights on the role and implementation of advanced respiratory monitoring with EIT and Pes. The identified barriers, facilitators and strategies can serve as input for further discussions to promote the development of EIT-guided or Pes-guided personalized ventilation strategies.

Introduction: Unregulated expiratory flow may contribute to ventilator-induced lung injury. The amount of energy dissipated into the lungs with tidal mechanical ventilation may be used to quantify potentially injurious ventilation. Previously reported devices for variable expiratory flow regulation (FLEX) require, either computer-controlled feedback, or an initial expiratory flow trigger. In this bench study we present a novel passive expiratory flow regulation device.

Methods: The device was tested using a commercially available mechanical ventilator with a range of settings (tidal volume 420 ml and 630 ml, max. inspiratory flow rate 30 L/min and 50 L/min, respiratory rate 10 min^-1, positive end-expiratory pressure 5 cmH₂O), and a test lung with six different combinations of compliance and resistance settings. The effectiveness of the device was evaluated for reduction in peak expiratory flow, expiratory time, mean airway pressure, and the reduction of tidal dissipated energy (measured as the area within the airway pressure-volume loop).

Results: Maximal and minimal reduction in peak expiratory flow was from 97.18 ± 0.41 L/min to 25.82 ± 0.07 L/min (p < 0.001), and from 44.11 ± 0.42 L/min to 26.30 ± 0.06 L/min, respectively. Maximal prolongation in expiratory time was recorded from 1.53 ± 0.06 s to 3.64 ± 0.21 s (p < 0.001). As a result of the extended expiration, the maximal decrease in I:E ratio was from 1:1.15 ± 0.03 to 1:2.45 ± 0.01 (p < 0.001). The greatest increase in mean airway pressure was from 10.04 ± 0.03 cmH₂O to 17.33 ± 0.03 cmH₂O. Dissipated energy was significantly reduced with the device under all test conditions (p < 0.001). The greatest reduction in dissipated energy was from 1.74 ± 0.00 J to 0.84 ± 0.00 J per breath. The least reduction in dissipated energy was from 0.30 ± 0.00 J to 0.16 ± 0.00 J per breath. The greatest and least percentage reduction in dissipated energy was 68% and 33%, respectively.

Conclusions: The device bench tested in this study demonstrated a significant reduction in peak expiratory flow rate and dissipated energy, compared to ventilation with unregulated expiratory flow. Application of the device warrants further experimental and clinical evaluation.

Background: Cardiopulmonary resuscitation-associated lung edema (CRALE) is a phenomenon that has been recently reported in both experimental and out-of-hospital cardiac arrest patients. We aimed to explore the respiratory and cardiovascular pathophysiology of CRALE in an experimental model of cardiac arrest undergoing prolonged manual and mechanical chest compression (CC). Oxygen delivery achieved during mechanical or manual CC were also investigated as a secondary aim, to describe CRALE evolution under different hemodynamic supports generated during CPR.

Methods: Ventricular fibrillation (VF) was induced and left untreated for 5 min prior to begin cardiopulmonary resuscitation (CPR), including CC, ventilation with oxygen, epinephrine administration and defibrillation. Continuous mechanical and manual CC was performed alternating one of the two strategies every 5 min for a total of 25 min. Unsynchronized mechanical ventilation was resumed simultaneously to CC. A lung computed tomography (CT) was performed at baseline and 1 h after return of spontaneous circulation (ROSC) in surviving animals. Partitioned respiratory mechanics, gas exchange, hemodynamics, and oxygen delivery were evaluated during the experimental study at different timepoints. Lung histopathology was performed.

Results: After 25 min of CPR, a marked decrease of the respiratory system compliance with reduced oxygenation and CO₂ elimination were observed in all animals. The worsening of the respiratory system compliance was driven by a significant decrease in lung compliance. The presence of CRALE was confirmed by an increased lung weight and a reduced lung aeration at the lung CT, together with a high lung wet-to-dry ratio and reduced airspace at histology. The average change in esophageal pressure during the 25-min CPR highly correlated with the severity of CRALE, i.e., lung weight increase.

Conclusions: In this porcine model of cardiac arrest followed by a 25-min interval of CPR with mechanical and manual CC, CRALE was consistently present and was characterized by lung inhomogeneity with alveolar tissue and hemorrhage replacing alveolar airspace. Despite mechanical CPR is associated with a more severe CRALE, the higher cardiac output generated by the mechanical compression ultimately accounted for a greater oxygen delivery. Whether specific ventilation strategies might prevent CRALE while preserving hemodynamics remains to be proved.

Background: We previously showed in animals that transpulmonary driving pressure (PL) can be estimated during Neurally Adjusted Ventilatory Assist (NAVA) and Neural Pressure Support (NPS) using a single lower assist maneuver (LAM). The aim of this study was to test the LAM-based estimate of PL (PL_LAM) in patients with acute respiratory failure.

Methods: This was a prospective, physiological, and interventional study in intubated patients with acute respiratory failure. During both NAVA and simulated NPS (high and low levels of assist), a LAM was performed every 3 min by manually reducing the assist to zero for one single breath (by default, ventilator still provides 2 cmH₂O). Following NAVA and NPS_SIM periods, patients were sedated and passively ventilated in volume control and pressure control ventilation, to obtain PL during controlled mechanical ventilation (PL_CMV). PL using an esophageal balloon (PL_Pes) was also compared to PL_LAM and PL_CMV. We measured diaphragm electrical activity (Edi), ventilator pressure (PVent), esophageal pressure (Pes) and tidal volume. PL_LAM and PL_Pes were compared to themselves, and to PL_CMV for matching flows and volumes.

Results: Ten patients were included in the study. For the group, PL_LAM was closely similar to PL_CMV, with a high correlation (R² = 0.88). Bland-Altman analysis revealed a low Bias of 0.28 cmH₂O, and 1.96SD of 5.26 cmH₂O. PL_LAM vs PL_Pes were also tightly related (R² = 0.77).

Conclusion: This physiological study in patients confirms our previous pre-clinical data that PL_LAM is as good an estimate as PL_Pes to determine PL, in spontaneously breathing patients on assisted mechanical ventilation. Trial registration The study was registered at clinicaltrials.gov (ID NCT05378802) on November 6, 2021.

Background: Polymyxins have been revived as a last-line therapeutic option for multi-drug resistant bacteria and continue to account for a significant proportion of global antibiotic usage. However, kidney injury is often a treatment limiting event with kidney failure rates ranging from 5 to 13%. The mechanisms underlying polymyxin-induced nephrotoxicity are currently unclear. Researches of polymyxin-associated acute kidney injury (AKI) models need to be more standardized, which is crucial for obtaining consistent and robust mechanistic results.

Methods: In this study, male C57BL/6 mice received different doses of polymyxin B (PB) and polymyxin E (PE, also known as colistin) by different routes once daily (QD), twice daily (BID), and thrice daily (TID) for 3 days. We continuously monitored the glomerular filtration rate (GFR) and the AKI biomarkers, including serum creatinine (Scr), blood urea nitrogen (BUN), neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1). We also performed histopathological examinations to assess the extent of kidney injury.

Results: Mice receiving PB (35 mg/kg/day subcutaneously) once daily exhibited a significant decrease in GFR and a notable increase in KIM-1 two hours after the first dose. Changes in GFR and KIM-1 at 24, 48 and 72 h were consistent and demonstrated the occurrence of kidney injury. Histopathological assessments showed a positive correlation between the severity of kidney injury and the changes in GFR and KIM-1 (Spearman's rho = 0.3167, P = 0.0264). The other groups of mice injected with PB and PE did not show significant changes in GFR and AKI biomarkers compared to the control group.

Conclusion: The group receiving PB (35 mg/kg/day subcutaneously) once daily consistently developed AKI at 2 h after the first dose. Establishing an early and stable AKI model facilitates researches into the mechanisms of early-stage kidney injury. In addition, our results indicated that PE had less toxicity than PB and mice receiving the same dose of PB in the QD group exhibited more severe kidney injury than the BID and TID groups.