Intensive Care Medicine Experimental最新文献

Background: The "Personalized Mechanical Ventilation Guided by Lung UltraSound in Patients with Acute Respiratory Distress Syndrome" (PEGASUS) study aims to evaluate personalized mechanical ventilation (MV) in patients with acute respiratory distress syndrome (ARDS) compared to the standard of care. However, misclassification and misaligned MV strategies were shown to be harmful. We therefore aimed to assess the interobserver agreement of lung ultrasound (LUS) between the local investigator and an expert panel in classifying ARDS subphenotypes alongside protocol adherence and safety endpoints, as a pilot phase of the ongoing PEGASUS study.

Methods: The first 80 mechanically ventilated patients with moderate-to-severe ARDS were enrolled in the ongoing PEGASUS study, a randomized clinical trial (RCT), and were included in the pilot phase. Focal or non-focal subphenotypes were classified using a LUS. Positive end-expiratory pressures (PEEP), tidal volumes (VT), the application of recruitment manoeuvres, and proning were performed according to randomization arm and subphenotype. Safety limits for MV followed current guidelines. Agreement in subphenotype classification between local investigators and a panel of three experts was evaluated using Cohen's κ coefficient.

Results: In 68 out of 80 exams, the images were of sufficient quality for assessment. The interobserver agreement for the lung morphology had a Cohen's kappa of 0.72 (95% CI 0.53-0.9) and accuracy of 88% between local investigator and the expert panel. Misclassification occurred in 8/68 exams (11.8%). Among these 8 misclassified cases, 6 (75%) also showed disagreement between experts due to different LUS scores of the anterior regions. Tidal volume and PEEP were generally set according to the protocol. An exception was the TV in the non-focal ARDS patients randomized to personalized MV, where the median (6.2 ml/kg/PBW) was above the target range (4-6 ml/kg/PBW). Patients exceeding safety limits of MV were low.

Conclusion: In the pilot phase of an ongoing international subphenotype-targeted RCT, we found that local investigators' assessments agreed with expert panel consensus assessments in the large majority of cases, and nearly always when the expert panel assessment was unanimous. Protocol adherence was sufficient, but tidal volume in the non-focal subphenotype deserves attention during continuation of the study.

Trial registration: The study was registered on clinicaltrial.gov (ID: NCT05492344, date 2022-08-05).

Background: Sepsis-associated acute kidney injury (SA-AKI) is a common and severe complication in critically ill patients, but the association between hypoxemia and renal dysfunction remains uncertain.

Method: We retrospectively analyzed 2292 patients with SA-AKI from the MIMIC-IV database and stratified them into four groups based on their highest arterial partial pressure of oxygen (PO₂) within 24 h of admission: < 60 mmHg, ≥ 60 to < 80 mmHg, ≥ 80 to  < 100 mmHg, and ≥ 100 mmHg. Associations between PO₂ and renal injury markers (serum creatinine [SCr] and blood urea nitrogen [BUN]) were evaluated using multivariable regression analyses, and survival outcomes were compared with Kaplan-Meier methods. To explore mechanistic pathways, a murine model was established with four experimental conditions: normoxia, hypoxia (10% O₂), lipopolysaccharide (LPS)-induced sepsis, and combined sepsis plus hypoxia. Serum biochemical parameters, histological injury, and protein expression of hypoxia-inducible factor-1α (HIF-1α) were measured at 6, 24, and 48 h. Mitochondrial autophagy was assessed by LC3 and TOMM20 immunofluorescence colocalization.

Result: Patients with lower PO₂ had higher illness severity and unadjusted BUN and SCr levels, multivariable analyses revealed no independent association between PO₂ and renal injury markers. Survival differed significantly across groups, with the ≥ 100 mmHg group showing the best outcomes (log-rank P < 0.001). In animal experiments, sepsis groups developed increased SCr and BUN at 24 and 48 h, but combined hypoxia did not exacerbate these parameters compared to sepsis alone. Histological analysis revealed severe tubular injury with no significant aggravation in the sepsis-plus hypoxia group. HIF-1α expression was lowest in sepsis-only kidneys but markedly upregulated in the sepsis-plus-hypoxia group at 6 h. Immunofluorescence demonstrated less colocalization of LC3 and TOMM20 in the sepsis-only group than in sepsis-plus-hypoxia mice, suggesting more efficient mitophagy with hypoxemia.

Conclusions: These clinical and experimental findings indicate that hypoxemia was not independently associated with aggravated renal injury in SA-AKI and may activate HIF-1α and promote adaptive mitophagy. This challenges the conventionally held belief that hypoxemia is uniformly detrimental to renal function during sepsis.

Background: Acute pulmonary embolism (PE) is a leading cause of cardiovascular death, primarily due to abrupt increased pulmonary vascular resistance (PVR) leading to acute right ventricular (RV) failure. Ketone bodies, especially 3-hydroxybutyrate (3-OHB), have shown potential to increase cardiac output (CO) and reduce PVR in pulmonary hypertension, suggesting possible benefits in PE. We hypothesized that 3-OHB would induce pulmonary vasorelaxation and increase CO in a porcine model of acute PE.

Methods: We conducted a randomized, controlled, assessor-blinded study in a porcine model of acute PE. Acute PE was induced, followed by a 3-h infusion of 3-OHB (0.22 g/kg/h, n = 8) or control (isovolumic saline of equimolar tonicity) (n = 8). Hemodynamic parameters were monitored hourly including right heart catheterization and RV pressure-volume loop acquisition. Primary outcome was the difference in CO during 3 h. Ex vivo effects on isolated pulmonary arteries were tested using wire myography.

Results: Compared with control infusion, 3-OHB did not increase CO significantly (between-group difference: 0.7 [-0.2 to 1.6] L/min, p = 0.131). However, 3-OHB treatment lowered the PVR/systemic vascular resistance (SVR) ratio (-0.05 [-0.09; -0.01], p = 0.046) and increased pulmonary artery pulsatility index (5 [2-8], p = 0.006). Ex vivo, 3-OHB caused vasorelaxation in pre-contracted pulmonary arteries (p < 0.0001).

Conclusions: 3-OHB reduced PVR/SVR ratio, while CO was not significantly increased in a porcine model of acute PE. The present findings demonstrated potential hemodynamic effects in PE. Further studies are needed to explore the translational potential of ketone body therapy in humans with PE.

Background: Uncontrolled hemorrhagic shock (UHS) is prevalent in military operations, disaster relief, and traffic accidents at high altitudes. Due to reduced tolerance to resuscitation fluids and prolonged evacuation times, its management poses substantial challenges. Whether 4-phenylbutyric acid (PBA) can protect vital organ function and extend the golden period for UHS at high altitudes remains unclear.

Methods: Rats airlifted from Chongqing to Lhasa were used to establish a UHS model. The experiment consisted of three parts: Part 1 investigated PBA's effect on extending the golden period (prehospital treatment window). Specifically, using a high-altitude rat model of UHS, we observe the duration that PBA + LR maintains mean arterial pressure (MAP) at 50-60 mmHg without definitive hemostasis; Parts 2 and 3 involve hypotensive maintenance of MAP at 50-60 mmHg for 1 and 2 h, respectively, prior to definitive hemostasis, simulating 1-h and 2-h prehospital phases. After hypotensive maintenance, definitive hemostasis is performed. Parameters including vital organ injury markers, blood gas profiles, and survival rates were assessed.

Results: In Part 1, PBA (20 mg/kg) reduced blood loss by 13.3% (from 53.6 ± 2.4% to 45.28 ± 3.4%) and resuscitation fluid volume by 28% compared to LR alone. PBA (20 mg/kg) prolonged the duration of sustained hypotensive resuscitation by 243% (from 39 ± 4.6 min to 134 ± 10.6 min) compared to LR, stabilized hemodynamics, and improved 2-h survival from 12.5% to 62.5%. In Part 2, 20 mg/kg PBA attenuated vital organ damage, increased 72-h survival from 18.7% (LR group) to 50% (20 mg/kg PBA group), and meanwhile reduced blood loss by 7.7% and resuscitation fluid volume by 16.3% compared to LR alone. In Part 3, despite extending hypotensive resuscitation to 2 h, PBA still significantly ameliorated organ function, reduced blood loss, decreased fluid administration, and enhanced 72-h survival in rats from 0% (LR group) to 31.25% (20 mg/kg PBA group).

Conclusion: PBA administration during hypotensive resuscitation protects vital organs (heart, liver, kidney), reduces pulmonary and cerebral edema incidence, and significantly extends the golden period for UHS at high altitudes.

Background: Patients with severe acute pancreatitis (SAP) frequently develop hypoxic acute respiratory failure (AHRF), with a mortality rate as high as 37%. However, the optimal partial pressure of oxygen (PaO₂) for SAP patients remains unclear to date. This study aims to investigate whether partial pressure of oxygen is associated with mortality in SAP patients.

Methods: A retrospective cohort study was conducted on patients with severe acute pancreatitis (SAP) admitted to the First Affiliated Hospital of Nanchang University from 2015 to 2024. Propensity score matching (based on whether arterial oxygen partial pressure PaO₂ ≥ 80 mmHg during the first 3 days after ICU admission, assigning patients to the liberal PaO₂ group or conservative PaO₂ group), univariate logistic regression analysis, Cox regression analysis, subgroup analysis, Kaplan-Meier (K-M curve) survival analysis, and sensitivity analysis were employed to thoroughly evaluate the association between PaO₂ and mortality in SAP patients. The primary outcome was 28-day mortality.

Results: The study included 1585 patients. We found that higher PaO₂ was associated with lower 28-day mortality rates. In logistic regression analysis after propensity score matching, the incidence rates of adverse outcomes such as persistent circulatory failure (OR 0.50; 95% CI 0.35-0.69; P < 0.001) and persistent multiple organ failure (OR 0.60; 95% CI 0.47-0.78; P < 0.001) significantly decreased. The K-M curve demonstrated significant reductions in 28-day mortality (P = 0.02), 90-day mortality (P = 0.0079), and overall mortality (P = 0.008) in the liberal PaO₂ group, with all P values showing statistical significance. Subgroup analysis revealed that the association between higher PaO₂ and mortality in SAP patients varied across different age groups, BMI values, SIRS and APACHE II scores, and smoking status. Sensitivity analysis demonstrated stable results after excluding specific populations. On the third day of ICU admission (P = 0.016), higher PaO₂ correlated with improved outcomes compared to the conservative group, particularly when PaO₂ stabilized around 100 mmHg.

Conclusions: Early maintenance of higher PaO₂ (≥80 mmHg) during the initial ICU period was associated with lower mortality.

Background: Bronchoscopy in ventilated patients narrows the endotracheal tube lumen and increases resistance, which can lead to hypoventilation and intrinsic PEEP build-up. These ventilation impairments depend on the geometry of the tube-bronchoscope combination, ventilator settings, and patient mechanics. Currently, no predictive method exists to quantify these impairments or guide compensatory strategies.

Methods: We measured pressure-flow relationships across multiple tube-bronchoscope configurations in a bench setup and derived a scaling law describing the nonlinear, flow-dependent resistance as a function of the effective tube diameter, defined as the diameter of a circular tube with the same open cross-sectional area as the remaining lumen. We then assessed the ventilatory consequences of bronchoscopy using an intensive care ventilator connected to an active lung simulator under both volume- and pressure-controlled modes.

Results: Bronchoscope insertion sharply increases resistance, which scales with the inverse fifth power of the effective diameter. A simulation tool based on this scaling law accurately predicts the experimentally observed dynamic hyperinflation and intrinsic PEEP build-up in volume-controlled modes, as well as the reduced tidal volumes in pressure-controlled modes. Ventilation with automatic tube compensation during pressure control fully prevents both impairments.

Conclusions: The commonly cited recommendation of a ≥ 2 mm difference between endotracheal tube and bronchoscope diameters does not reliably prevent ventilation impairments during bronchoscopy. Our findings suggest that a quantitative framework, which accounts for ventilator settings, patient mechanics, and the effective tube diameter, can provide additional guidance for tube selection and help anticipate impairments. We demonstrate proof of principle that pressure-controlled ventilation with automatic tube compensation is a feasible strategy to mitigate bronchoscopy-induced ventilation impairments.

Background: Cardiopulmonary bypass (CPB) is integral to the conduct of cardiac surgery but is associated with postoperative acute kidney injury (AKI). Dexmedetomidine, an α₂-adrenoceptor agonist with anti-inflammatory and sympatholytic properties, has putative renoprotective effects. In a recent meta-analysis, dexmedetomidine during CPB reduced AKI; conversely, a large, randomised trial reported an increase in postoperative AKI. Further, we found increased renal tubular injury in sheep receiving dexmedetomidine during CPB. Here, we aimed to determine whether dexmedetomidine during CPB induces changes in renal vascular reactivity or endothelial integrity that could explain focal renal tubular injury.

Methods: Fourteen instrumented Merino ewes underwent 2 h of non-pulsatile CPB (flow 70 mL/kg/min; MAP 65-75 mmHg; cooled by 3 °C) under standardised propofol-fentanyl-sevoflurane anaesthesia. Animals were randomly allocated to dexmedetomidine (0.4-0.8 µg/kg/h, n = 7) or fluid-matched saline (n = 7) from induction of anesthesia to end-CPB. Arterial pressure, renal blood flow, cortical and medullary perfusion and PO₂ were measured in vivo (n = 7/group). Post-CPB, renal interlobar arteries were isolated for wire myography. Due to standardisation failures, in vitro analyses of dose-response curves for phenylephrine were performed in n = 6 per group, while endothelial-dependent and independent relaxation responses were performed in n = 7 per group. Endothelial histology of CPB arteries was compared with arteries from a separate cohort of healthy Merino ewes (n = 7).

Results: In vitro functional investigations demonstrated that interlobar arteries from dexmedetomidine-treated sheep exhibited a 2.3-fold increase in phenylephrine sensitivity (pEC₅₀ 5.82 ± 0.27 vs. 5.45 ± 0.23; p = 0.034), with unchanged maximal contraction. Endothelium-dependent and independent relaxations were similar between groups, though inhibitor studies indicated a shift towards cyclooxygenase-mediated dilation under dexmedetomidine. Histology revealed intact endothelial architecture and no damage to endothelial integrity in all groups.

Conclusions: Perioperative dexmedetomidine during CPB enhanced α₁-adrenergic vasoconstrictor sensitivity in renal interlobar arteries without disrupting endothelial integrity or compromising renal blood flow or intrarenal perfusion. The enhanced vasoreactivity may contribute to focal renal ischaemia and tubular injury during CPB, which cannot be detected by in vivo measurements of global and regional kidney perfusion and oxygenation. Further investigation is warranted to elucidate the pathways through which dexmedetomidine contributes to renal tubular injury during CPB.

Background: Cardiac arrest (CA) remains a leading cause of mortality and long-term neurological disability. In cases of refractory CA, extracorporeal cardiopulmonary resuscitation (ECPR) may be implemented as a salvage therapy to mitigate hypoxic-ischemic brain injury and improve outcomes. However, the optimal target temperature in the specific context of ECPR remains uncertain. The objective of this study was to evaluate the impact of hypothermia on brain function using a controlled experimental model of ECPR.

Methods: Twelve pigs were subjected to 5 min of untreated ventricular fibrillation, followed by 25 min of conventional cardiopulmonary resuscitation (CPR). At 30 min, veno-arterial extracorporeal membrane oxygenation support was initiated, and defibrillation attempts were performed until the achievement of return of spontaneous circulation (ROSC). Following ROSC, animals were randomly assigned to one of two groups: hypothermia (HT), targeting a core body temperature of 33-34 °C, or controlled normothermia (NT), targeting 37-38 °C. All animals underwent continuous multimodal neurological and cardiovascular monitoring. Blood samples were collected at predefined time points to assess circulating biomarkers of organ injury. The primary outcome was the change of brain tissue oxygen tension (PbtO₂) over time. Other neurological and hemodynamical parameters were treated as secondary analyses. At 12 h post-ROSC, animals were euthanized via intracardiac injection of potassium chloride. Brain tissues were immediately harvested and appropriately stored for molecular analyses.

Results: A total of 12 pigs were included in the study, with six animals allocated to each group. Baseline characteristics were comparable between the groups and ROSC was achieved in all animals. Throughout the experiment, PbtO₂ gradually declined and intracranial pressure (ICP) increased in both groups; however, no significant differences were observed between groups. Similarly, there were no significant differences in cerebral metabolites, cortical activity, or gene expression in either frontal or parietal brain tissues. Notably, neurofilament light chain (NfL) concentrations were significantly lower at the end of the observation period in the HT group compared to NT (p = 0.04), while neuron-specific enolase (NSE) and glial fibrillary acidic protein (GFAP) levels did not differ significantly between the two groups.

Conclusions: HT did not improve cerebral perfusion or metabolic parameters in this refractory cardiac arrest ECPR model; the early decrease in NfL levels requires cautious interpretation and further investigation.

Background: Sepsis-associated encephalopathy (SAE) is a common complication of sepsis, contributing to poor outcomes and increased mortality. Early detection remains challenging due to the absence of observable direct brain injury. Transcranial Doppler (TCD) ultrasonography provides a non-invasive, bedside tool for assessing cerebral hemodynamics and may help identify patients at risk. SAE was defined as new-onset delirium (positive CAM-ICU) or unexplained coma (GCS < 8) not attributable to structural or metabolic causes. This study aimed to evaluate the role of TCD in predicting the incidence and prognosis of SAE in septic patients admitted to the ICU.

Methods: This prospective cohort study included 93 patients with sepsis. Demographic, clinical, and laboratory data were recorded upon admission. Daily TCD was performed for seven consecutive days to measure the pulsatility index (PI) and resistive index (RI). Neurological dysfunction was assessed daily using the Confusion Assessment Method for the ICU (CAM-ICU) and the Glasgow Coma Scale (GCS).

Results: A total of 93 patients were included, of whom 44 (47.3%) developed SAE. SAE patients showed greater illness severity, with higher median SOFA (6 [5-7] vs. 5 [3-6], p < 0.001) and APACHE II (14 [12-17] vs. 11 [9-14], p < 0.001) scores, and higher 28-day mortality (61.4% vs. 22.4%, p < 0.001). The median PI and RI were consistently higher in SAE patients across all study days, while the mean flow velocity (mFV) was lower. PI on day 1 had the best accuracy for predicting SAE, with a cutoff ≥ 1.30 (AUC: 0.963, sensitivity 95.45%, specificity 100%). RI on day 3 was also highly predictive (AUC: 0.971, cutoff ≥ 0.67, sensitivity 95.45%, specificity 95.92%).

Conclusions: In this sample of septic patients, PI and RI are strong predictors of SAE, with PI serving as a reliable early indicator of both SAE and mortality. Trial Preregistration The study was registered in the Pan African Clinical Trials Registry: PACTR202410707982429, date: 7/10/2024.