Intensive Care Medicine Experimental最新文献

Background: Severe hypercapnia, especially when associated with acidosis, should be avoided or actively managed, as it is an independent risk factor in critically ill patients. The ADVOS multi hemodialysis system offers the potential to correct acidosis and hypercapnia through customizable pH and bicarbonate content within the dialysate fluid. The aim of this work is to analyze the exact timing for pH correction and the main factors leading to it in patients with multiple organ failure (MOF) and hypercapnic acidosis treated with ADVOS.

Methods: Patients with MOF and metabolic or hypercapnic acidosis (pH < 7.35) were included over a study period of 13 months. All patients received at least one treatment with ADVOS hemodialysis system for at least 24 h. The primary outcome was the time to blood pH ≥ 7.35.

Results: 24 patients with a median age of 61 years and a median SOFA score of 15 points were included. The results of 134 ADVOS sessions, with a median of 5 sessions per patient, were analyzed. Median time to blood pH ≥ 7.35 was 4 h; a significant blood pH increase within 24 h was reached in all patients (7.21 before vs. 7.39 after, p < 0.01).

Conclusions: A single session of ADVOS corrected blood pH and supported the reduction of pCO₂ with a median CO₂ removal of 55 mL/min in patients with multiple organ failure and hypercapnic acidosis.

Background: Transesophageal lung ultrasound (TELUS) has emerged as a novel modality that utilizes the esophageal acoustic window to obtain high-resolution images of posterior lung regions. However, its quantitative assessment and clinical relevance remain poorly explored. This study aimed to evaluate the feasibility and prognostic value of TELUS in critically ill patients, focusing on its association with arterial oxygenation and 28-day mortality.

Methods: In this prospective observational study, TELUS was performed in 69 mechanically ventilated ICU patients. TELUS imaging was acquired at three esophageal levels corresponding to posterior apical, mid, and basal lung regions. A semi-quantitative TELUS score was derived and its correlation with clinical variables was analyzed. Univariate and multivariate logistic regression analyses were employed to identify predictors of 28-day mortality. Receiver operating characteristic (ROC) analysis was used to assess the predictive performance of TELUS for mortality and severe hypoxemia (PaO₂/FiO₂ ≤ 100).

Results: Non-survivors had significantly higher TELUS scores compared to survivors (median 5 [IQR 4-6] vs. 4 [3-5], P = 0.001). Regional TELUS scores at the upper-aortic arch level and mid-esophageal level were elevated in non-survivors (P = 0.018 and P = 0.004, respectively). TELUS scores showed a significantly negative correlation with the PaO₂/FiO₂ ratio (r = -0.51, P < 0.0001), and positive correlations with PEEP (r = 0.32, P = 0.007) and SOFA scores (r = 0.26, P = 0.032). Multivariate analysis identified both SOFA (OR 1.31, 95% CI 1.08-1.63, P = 0.009) and TELUS scores (OR 1.72, 95% CI 1.08-2.96, P = 0.030) as independent predictors of 28-day mortality. ROC analysis showed that a TELUS score ≥ 4 predicted 28-day mortality and severe hypoxemia (PaO₂/FiO₂ ≤ 100), yielding areas under the ROC (AUCs) of 0.74 and 0.72, with high sensitivity (89% and 100%, respectively) and negative predictive values (92% and 100%, respectively.) CONCLUSION: TELUS is a feasible novel technique that provides a reliable assessment of posterior lung aeration in critically ill patients. TELUS scoring correlates with impaired oxygenation and is independently associated with 28-day mortality. These findings highlight the prognostic value of TELUS and support its potential integration into transesophageal cardiopulmonary ultrasound protocols.

Background: Early identification of acute kidney injury (AKI) in the intensive care unit (ICU) remains challenging. We aimed to identify key predictors of new-onset AKI within 48 h after ICU admission and renal replacement therapy (RRT) need within 7 days, using explainable artificial intelligence (XAI) with eXtreme Gradient Boosting (XGBoost). We also assessed whether XGBoost improved predictive performance.

Methods: A retrospective cohort study across four ICUs was conducted as part of the SWECRIT biobank project. Blood samples were prospectively obtained at ICU admission and retrospectively analysed. AKI was defined by the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. XAI models were compared with logistic regression models, incorporating emerging biomarkers and routine clinical data at ICU admission. SHapley Additive exPlanations (SHAP) were used to identify key predictors. Discrimination was assessed using the mean area under the receiver operating characteristic curve (AUC).

Results: The study included 4732 admissions, with 2603 analysed for new-onset AKI and 4716 for RRT. Top predictors of new-onset AKI were urine output, endostatin, baseline creatinine, lactate, and albumin. Top predictors of RRT were creatinine, urine output, endostatin, neutrophil gelatinase-associated lipocalin (NGAL), and the Simplified Acute Physiology Score (SAPS) 3. Several clinically relevant non-linear relationships were revealed. XGBoost outperformed logistic regression for both new-onset AKI (mean AUC 0.76, 95% CI 0.70-0.81 vs. 0.74, 95% CI 0.68-0.81; p < 0.001) and RRT (mean AUC 0.92, 95% CI 0.89-0.95 vs. 0.90, 95% CI 0.87-0.94; p < 0.001).

Conclusion: XGBoost identified key predictors of early new-onset AKI and RRT need in the ICU, highlighting both emerging (endostatin, NGAL) and established biomarkers (lactate, albumin), alongside known clinical predictors. It also improved predictive accuracy for both outcomes. Further clinical evaluation of these biomarkers and XAI models is warranted.

Background: Induced hypothermia after cardiac arrest is neuroprotective in several animal models of cardiac arrest, but few high-quality studies have been conducted in larger animals. Recent clinical trials have questioned the beneficial effects of post-ischemic hypothermia. This study investigated whether immediate cooling or a 2-h delay in cooling to 33 °C after cardiac arrest was neuroprotective compared to controlled normothermia in large animals.

Methods: Young adult female swine were anesthetized and kept at normothermia (38 °C). All animals were subject to 10 min of cardiac arrest by ventricular fibrillation, followed by 4 min of cardiopulmonary resuscitation, before the first countershock. At 10 min of return of spontaneous circulation (ROSC), animals were included and randomized to receive immediate hypothermia (33 °C), 2-h delayed hypothermia (33 °C), or normothermia for 30 h, including both cooling and rewarming time. Animals were extubated and assessed for 7 days. The primary outcome was brain histopathology using a modified Histology Damage Score. Secondary outcomes were neurocognitive testing, neurologic deficit score, and biomarkers of brain injury.

Results: Among 42 animals, 33 were included; 11 in each arm, 23 survived until day 7. The modified Histology Damage Score was not significantly different between groups (p = 0.29). Neither neurocognitive testing nor neurologic deficit scores showed significant differences between the groups (p = 0.11 and p = 0.67, respectively). Neurofilament light chain (NfL) levels were significantly lower in the immediate hypothermia group at 48 h and on day 7 compared to the normothermia group (p = 0.0087, p = 0.012), but not in the delayed hypothermia group (p = 0.075, p = 0.33).

Conclusion: Our experimental model in large swine showed no neuropathological or functional protective effect of induced hypothermia after cardiac arrest, but NfL levels were lower in animals receiving immediately induced hypothermia, suggesting mitigation of neuronal injury.

Trial registry: Preclinicaltrials.eu (PCTE0000272), published 2021-11-03.

Background: Translational failure remains a major barrier in critical illness research, with preclinical findings from animal models often failing to replicate in human trials.

Hypothesis: we hypothesize that the integration of advanced in vitro models derived from human cells-particularly those from ICU patients-prior to animal studies will enhance clinical translation in critical care research.

Main text: These emerging human-relevant platforms-such as organ-on-chip microfluidic systems-recapitulate key aspects of human physiology and pathology that animal models often cannot, thereby avoiding interspecies differences, capturing patient-specific variability, and enabling the study of disease phenotypes and endotypes. We propose that advanced in vitro models should be used first to gain mechanistic insights and assess efficacy in a human-relevant setting, while subsequent animal studies would then serve to evaluate systemic effects and safety before translation to patients. By leveraging such complementary strengths, an integrated in vitro-in vivo pipeline could better bridge the bench-to-bedside gap. This approach aligns with 3Rs principles by refining and reducing animal use (screening therapeutics in human models to focus subsequent animal experiments), and potentially replacing certain animal tests pending rigorous validation and regulatory acceptance. Implementation will require regulatory support, as well as training and funding to overcome technical barriers. This hypothesis is testable through analyses of past translational failures to determine whether human in vitro models could have predicted outcomes, and through prospective studies comparing drug development pipelines with and without an in vitro prescreening step to assess improvements in clinical success rates.

Conclusions: By harnessing the strengths of both model systems, this two-step strategy could help bridge the translational gap in critical care, improve therapeutic development, and accelerate precision medicine in sepsis and other critical illnesses.

Background: Autonomic nervous system (ANS) dysfunction contributes to the pathophysiology of sepsis. However, studies using reliable methods for ANS activity monitoring and evaluating its association with outcomes in sepsis patients are scarce. The Sudoscan^® device offers a non-invasive method to evaluate sympathetic function by measuring electrochemical skin conductance (ESC), but its clinical relevance in sepsis remains unclear. This study aimed to assess autonomic sympathetic activity in septic patients using the Sudoscan^® technology and explore its relationship with peripheral perfusion and outcomes.

Methods: This prospective, observational, single-center study included 97 consecutive adult ICU septic patients without or with shock. Sudoscan^® measurements were performed at admission and serially for 72 h, alongside standard hemodynamic and peripheral perfusion assessments (e.g., knee capillary refill time [CRT], mottling, cardiac output). Associations between ESC ("sudoscore"), clinical parameters, and mortality at day-28 were analyzed.

Results: Of the 97 septic patients included, 37% had shock. Mottling was frequent (53%), and mean knee CRT was 3.3 ± 2.5 s. The mean admission Sudoscore was 31.2 ± 21 µS and was significantly higher in patients with peripheral perfusion abnormalities, such as mottling compared to no mottling (35.7 ± 21 vs 28.5 ± 19.5 µS, P = 0.04) and prolonged knee CRT > 5 s compared to CRT < 5 s (44.2 ± 25 vs 29.6 ± 18.6 µS, P = 0.03). Additionally, Sudoscore positively correlated with CRT (P = 0.01, R = 0.27). There was no difference in Sudoscore between patients receiving vasopressors or not, and between patients receiving sedative drugs or not. Longitudinally, the Sudoscore course was significantly lower over the first 72 h in survivors compared to non-survivors (P = 0.04, two-way ANOVA mixed model effect).

Conclusion: Electrochemical skin conductance measured via Sudoscan^® may serve as a surrogate marker of autonomic sympathetic hyperactivation during sepsis and is associated with peripheral circulatory impairment. Although admission values were not independently predictive of mortality, elevated and persistently high Sudoscores are associated with death at day 28. Sudoscan^® may offer a non-invasive window into sympathetic activity during septic shock and warrants further investigations.

Background: Percutaneous ventricular assist devices (pVADs) support patients in circulatory failure and increasingly concomitant respiratory failure. The presence of co-existent lung disease creates a management challenge due to cardiopulmonary interactions, especially when there is simultaneous mechanical ventilation and mechanical circulatory support. Enhanced understanding of the combined effects of these devices is necessary to better inform care for circulatory failure patients.

Methods: A porcine model of titratable acute cardiogenic shock was used to quantify the effect of pVAD support on cardiac loading states in five intubated animals with positive pressure ventilation and varied intrathoracic pressure. Cardiovascular hemodynamics were assessed across positive end-expiratory pressure (PEEP) ramps in animals in health, health with pVAD, and pVAD-supported cardiogenic shock induced via coronary microembolization.

Results: This study employed invasive physiological metrics and assessment of right and left ventricular press-volume loops to recreate classic Frank-Starling curves. Increased intrathoracic pressure altered transmural pressure in the ventricles and the pulmonary vasculature and resulted in decreased venous return and stroke volume while increasing end-diastolic pressure consistent with decreased ventricular compliance. In pVAD-supported cardiogenic shock, elevated PEEP enhanced left ventricular output and increased pulmonary vascular compliance in several animals, contrary to traditional decrements observed with elevated PEEP. The right ventricular functional response aligned with these varied responses in pulmonary vascular state.

Conclusions: These results demonstrate that combined used of cardiopulmonary support devices in cardiogenic shock can create variable responses compared to classic physiological understanding. In pVAD-supported cardiogenic shock, an increase in ventilatory PEEP increased unloading from the heart and improved right ventricular function, counter to traditional findings. This demonstrates that combined use of these technologies could be leveraged to optimize a patient's volume status in complex shock and provides promise for management of patients with cardiopulmonary failure requiring simultaneous use of mechanical circulatory support and mechanical ventilation.

Background: The reach of dialysis in toxicology is limited by two factors, high toxicant volume of distribution and low dialytic extraction of protein bound toxicants in blood. Therapeutic actions for lipid emulsion as antidote are thought involve a "lipid shuttle", whereby lipid droplets in the circulation "shuttle" lipophilic toxicants with "boarding" in well perfused heart and brain tissue with high toxicant concentrations and "exit" to biologically inert slower equilibrating sites such as muscle or adipose where toxicant concentrations are lower. Such a mechanism raises the conceptual possibility of an extracorporeal "exit" potentially mitigating toxicity through increased drug clearance. In experimental models drug binding nanoparticles in dialysate have been shown to mitigate the problem of blood proteins binding toxicant. We investigated whether the addition of intravenous lipid emulsion would increase extraction of amitriptyline into nanoparticle augmented peritoneal dialysate in rats orally dosed with amitriptyline for 1 week.

Methods: Rats were dosed with amitriptyline in drinking water for a week. On the day of the experiment, anaesthetised rats received either an initial bolus then infusion of lipid emulsion for one hour, or a bolus of saline at the initiation of the experiment equal to the total volume of lipid emulsion given. After a 50 min equilibration period, a 10 min pH gradient nanoparticle augmented peritoneal dialysis dwell was undertaken. Animals were humanely euthanised at the end of the experiment. Blood was sampled 0, 10, 45 and 60 min and peritoneal dialysate was analysed for amitriptyline concentration.

Results: There were no significant differences in baseline physiology, initial amitriptyline blood concentration, nor pulse and blood pressure at any time between groups. Time weighted individual subject mean blood amitriptyline concentrations (median (IQR)); control 104 (87-125) nmol/l, lipid 219 (148-357) nmol/L, p = 0.03 and dialysate amitriptyline concentration; control 31(14-52) nmol/L, lipid 105 (62-185) nmol/L, p = 0.03 were greater in animals given intravenous lipid emulsion.

Conclusion: These are the first data to our knowledge showing experimental support for the approach of simultaneously decreasing volume of distribution with an intravascular nanoparticle in conjunction with a drug binding particle in dialysate. Further work in this area is warranted.