Intensive Care Medicine Experimental最新文献

Background: The differential effects of the two most commonly investigated recruitment maneuvers (RMs), i.e., sigh recruitment and sustained inflation, have not been fully investigated yet. This study aimed to compare the effects of these two RMs on respiratory mechanics, gas exchange, and electrical impedance tomography (EIT)-derived lung volumes on mechanically ventilated ARDS patients.

Results: This is a two-period two-sequence randomized crossover study. Two RMs were tested in randomized sequence: a sigh recruitment (one minute with a PEEP of 5 cmH₂O, a driving pressure of 40 cmH₂O at a respiratory rate of 10 bpm) and a sustained inflation maneuver (constant airway pressure of 40 cmH₂O for 30 s). Following the application of the first RM, respiratory mechanics, hemodynamics and EIT-derived lung volumes were measured every 5 min for the following 30 min, while gas exchange was monitored every 15 min. After a 30-min washout period, intended to allow the lung to return to pre-recruitment steady-state conditions, the second RM was applied, and the same measurements were obtained. Twenty-three ARDS patients were enrolled; 13 patients underwent sigh recruitment as first RM and sustained inflation as the second RM, 10 patients underwent the opposite sequence. Patients who underwent both sigh recruitment or sustained inflation as first maneuver showed similar respiratory mechanics, hemodynamics, gas exchange and EIT-derived lung volumes before the RMs compared to patients who underwent sigh recruitment or sustained inflation as the second maneuver after the 30-min washout period. Independently from the order, after the application of each RMs, respiratory system, lung and chest wall mechanics, arterial oxygenation and EIT-derived lung volumes remained similar to baseline at all measurement timepoints from 5 to 30 min. Nine and 13% of patients increased PaO₂/FiO₂ over 20% from baseline 5 min after sigh recruitment and sustained inflation, respectively; a similar percentage was found after 30 min.

Conclusion: Neither a sigh recruitment nor a sustained inflation maneuvers had clinically significant effect on respiratory mechanics, gas exchange, hemodynamics or EIT-derived lung volume distribution within the first 30 min after their application.

Background: Administration of ketone bodies attenuated the severity of sepsis-induced muscle weakness in preclinical studies. Whether lipid-rich emulsions may likewise mitigate such muscle weakness by stimulating the endogenous ketogenic capacity remains uncertain, especially in relation to glucose, a critical suppressor of ketogenesis. This study investigated the ketogenic potential of parenteral nutrition rich in long- and/or medium-chain triglycerides with differing glucose content on sepsis-induced muscle weakness.

Methods: We used a parenterally fed murine model of prolonged sepsis-induced muscle weakness to investigate specific lipid mixtures in two consecutive studies. Septic mice receiving standard total parenteral nutrition (TPN) and healthy control (HC) animals were included as references in both studies. In a first study, septic mice received pure long-chain triglycerides (LCT) or long-chain triglycerides supplemented with glucose (gLCT). The second study compared a gLCT mixture to a mixed medium- and long-chain triglyceride emulsion supplemented with glucose (gMCT). After 5 days of sepsis, markers of ketone body metabolism, muscle function, and muscle and liver metabolomics were measured.

Results: In study one, ketosis was undetectable with TPN-treatment, but substantially increased with pure LCT (median 1.39 mmol/L, p < 0.001). Supplemental glucose suppressed ketosis sixfold (median 0.24 mmol/L, p < 0.001). The sepsis-induced muscle weakness was exacerbated in LCT mice, while muscle force was comparable between TPN-treated and gLCT mice (TPN 60.9%; gLCT 60.9%; LCT 33.1% of HC 128.7 mN/mm², p < 0.001). The decrease in muscle glycolytic metabolites in LCT mice relative to TPN-treated mice was attenuated by supplemental glucose. In study 2, unexpectedly, ketosis was similarly low in gLCT and gMCT mice (p = 0.1), and muscle force was equally reduced in all septic groups (TPN 68.1%; gLCT 74.0%; gMCT 65.9% of HC 105.9 mN/mm², p = 0.5) as compared to HC mice. Protein expression of the rate-limiting enzyme of ketogenesis, Hmgcs2, was suppressed in gMCT as compared to gLCT mice (p = 0.04).

Conclusions: Pure LCT infusion induced ketosis, but aggravated muscle weakness, which was attenuated by providing supplemental glucose. Combined with glucose, neither long-chain triglycerides nor mixed medium- and long-chain triglycerides were able to induce adequate ketosis or attenuate sepsis-induced muscle weakness.

Background: Critically ill patients are at increased risk for cytomegalovirus (CMV) reactivation, which is associated with poorer clinical outcomes. However, little is known about the longitudinal viremia trajectories in this population.

Methods: This retrospective single-center study was conducted in a medical ICU and included patients with CMV viremia ≥ 1000 International Units CMV-DNA per milliliter whole blood (IU/mL) treated between March 2014 and April 2021. Time-series clustering was applied to identify subgroups of patients with similar longitudinal viremia trajectories.

Results: 82 patients were included in the final analysis. Time-series clustering identified three distinct clusters: (1) patients with initial high viremia (median 46,700 IU/mL), 94% receiving treatment and showing subsequent steep reduction of viremia; (2) patients with moderate viremia (median 2720 IU/mL) and subsequent increase in viral load, treated in 52%; and (3) patients with moderate viremia (median 3120 IU/mL), 63% receiving treatment and showing stable viral load in follow-up measurements. No significant differences were identified between the clusters with respect to patient characteristics, including underlying immunosuppression. With respect to disease severity, the Acute Physiology and Chronic Health Evaluation II (APACHE-II) score was highest in cluster 3 and among patients without follow-up CMV-DNA measurements (P = 0.029), while the Sequential Organ Failure Assessment (SOFA) score demonstrated a similar directional trend without reaching statistical significance. Survival differed significantly between the clusters in the Kaplan-Meier estimate (p = 0.008); however, absolute 1-year survival was low across all clusters (cluster 1: 0%, cluster 2: 33%, cluster 3: 32%, patients without follow-up CMV measurement: 14%; p = 0.062). Probable CMV pneumonia with respiratory symptoms and CMV-DNA detection in bronchoalveolar lavage fluid was the most common disease manifestation (cluster 1: 35%; cluster 2: 28%; cluster 3: 7.5%; patients without follow-up CMV measurement: 23%; p = 0.040).

Conclusions: In this hypothesis-generating study, time-series clustering analysis identified three subgroups with distinct longitudinal viremia trajectories which significantly differed in viral load, treatment decisions and survival over time. The diagnostic and therapeutic relevance of longitudinal CMV viremia trajectories and the optimal CMV-DNA threshold for treatment initiation in ICU patients remain undefined and might differ from other cohorts.

Background: The renin-angiotensin system (RAS) plays a critical role in vascular homeostasis and inflammation, and its dysregulation has been implicated in the pathophysiology of COVID-19. We investigated the dynamics of RAS peptides and markers of endothelial dysfunction in relation to respiratory disease progression in hospitalized COVID-19 patients.

Methods: In this single-centre prospective observational study, 155 adult patients with confirmed SARS-CoV-2 infection were enrolled at hospital admission. Plasma levels of renin, angiotensin I (Ang I), angiotensin II (Ang II), angiotensin 1-7 (Ang 1-7), the Ang II/Ang I ratio (as a surrogate of ACE activity), and asymmetric dimethylarginine (ADMA)-a marker of endothelial dysfunction -were measured at baseline (D0) and day 3 (D3). Endothelial injury was further assessed using the Endothelial Activation and Stress Index (EASIX). Patients were stratified by respiratory trajectory using the WHO ordinal scale. Biomarker kinetics were analysed with baseline-adjusted regression models, and 28-day clinical status was evaluated using partial proportional-odds regression.

Results: Of 155 patients, 89 (57%) experienced worsening respiratory status. These patients exhibited progressive RAS activation with higher renin and Ang I at D3 (p < 0.001), a decline in the Ang II/Ang I ratio (p < 0.001), and a rise in Ang 1-7 (p < 0.001). ADMA and EASIX levels increased in parallel, with significantly higher ADMA in worsening vs. non-worsening patients at D3 (0.72 [0.62-0.87] vs. 0.61 [0.50-0.70] µM/L; p < 0.001). Biomarker trajectories differed according to disease course, with significant interaction terms between baseline values and respiratory deterioration. At 28 days, outcomes were associated with renin, Ang I, Ang 1-7, and the Ang II/Ang I ratio, but not with Ang II. Elevated baseline ADMA also independently predicted worse prognosis.

Conclusions: Worsening respiratory status in COVID-19 is associated with delayed activation of the RAS, a shift toward the alternative Ang 1-7 pathway, and parallel increases in endothelial dysfunction markers. These findings suggest that serial measurements of RAS peptides and ADMA may aid in identifying high-risk phenotypes and inform personalized therapeutic strategies in COVID-19.

Objective: Immune dysregulation plays a pivotal role in the pathophysiology of sepsis and COVID-19, with lymphopenia emerging as a consistent marker of severity and poor prognosis. However, most existing studies have assessed lymphocyte counts at isolated time points, limiting insights into their temporal behavior and prognostic value. The dynamics of lymphocyte recovery or persistence of lymphopenia remain largely unexplored in large populations, as well as the impact of adjunctive therapies such as corticosteroids. We hypothesized that the persistence or recovery of lymphopenia may be key to understanding disease progression and predicting outcomes. Using the multinational ISARIC cohort, we investigated longitudinal lymphocyte trajectories in hospitalized patients and the clinical determinants associated with their evolution over time.

Methods: We conducted a multinational prospective observational cohort study using data from the ISARIC-WHO Clinical Characterization Protocol. Patients with confirmed SARS-CoV-2 infection and at least four lymphocyte measurements during the first 28 days of hospitalization were included. We analyzed lymphocyte trajectories, Cox regression survival analyses and multivariable linear regression modelling. We also applied multistate models and joint modeling to assess the association between lymphocyte trajectories and 28-day mortality, incorporating corticosteroid use as a time-varying covariate.

Results: Of 945,317 screened patients, 231,933 hospitalized adults with confirmed COVID-19 and sufficient lymphocyte data were included, with 56.6% classified as lymphopenic. Lymphopenia was independently associated with higher rates of ICU admission, organ support, and in-hospital mortality (OR = 1.52, 95% CI 1.48-1.55), and lower absolute lymphocyte counts were strongly linked to worse survival in adjusted Cox models (HR = 1.33 per 1 × 10⁹ cells/L decrease, 95% CI 1.28-1.38). Multistate modeling revealed that lymphopenic patients had a significantly higher daily transition rate to death and a shorter duration in that immune state, while corticosteroid exposure was associated with an increased likelihood of entering and remaining in lymphopenia. Joint modeling identified age, sex, and corticosteroid use as significant predictors of lower lymphocyte trajectories over time, with distinct dynamics between survivors and non-survivors.

Conclusion: Lymphopenia was common and strongly associated with worse outcomes in hospitalized COVID-19 patients, with impaired recovery particularly evident in those receiving corticosteroids. These findings highlight the value of lymphocyte monitoring to inform tailored immunomodulatory strategies in sepsis and severe viral infections.

Background: The rationale of albumin use lies in its potential to increase oncotic pressure and optimize tissue perfusion. Randomized trials have not demonstrated a survival benefit, and the effects of albumin on volemia remain unclear. This study investigates, in healthy pigs, the effects of a 48-h albumin infusion on intravascular fluid volume, albumin kinetics, and its impact on respiratory function.

Methods: Thirty-nine healthy female pigs ventilated for 48 h were grouped according to mechanical power (high ~ 18 J/min vs. low ~ 6 J/min) and type of fluid (5% albumin solution vs. crystalloid), generating four experimental groups: MP_LOW-Crystalloid; MP_LOW-Albumin; MP_HIGH-Crystalloid; and MP_HIGH-Albumin.

Results: Intravascular fluid volume was similar across groups (MP_LOW-Crystalloid: 1.92 (± 0.38)L; MP_HIGH-Crystalloid: 1.72 (± 0.40)L; MP_LOW-Albumin: 1.86 (± 0.37)L; MP_HIGH-Albumin: 2.10 (± 0.58)L; p 0.389). For the same mechanical power, the fraction of albumin lost from the plasma was higher in the albumin compared to the crystalloid groups (MP_LOW-Albumin: 62 (± 13)% vs. MP_LOW-Crystalloid: - 16 (± 66)%; and MP_HIGH-Albumin: 58 (± 24)% vs. MP_HIGH-Crystalloid: 29 (± 14)%; p < 0.001). Albumin groups showed greater ascites (MP_LOW-Crystalloid: 261 (± 380)mL; MP_HIGH-Crystalloid: 144 (± 148)mL; MP_LOW-Albumin: 710 (± 664)mL; MP_HIGH-Albumin: 685 (± 651)mL; p 0.034), and worse end-expiratory lung gas volume and elastance, despite comparable histological damage.

Conclusions: In our cohort, prolonged albumin infusion did not lead to a difference in intravascular fluid volume, but it resulted in the loss of ~ 60% of the infused albumin and ascites development. Ascites was associated with lower end-expiratory lung gas volume and higher elastance, despite similar histological lung damage across the groups.

Inhaled nitric oxide (iNO), long used as a selective pulmonary vasodilator, has demonstrated potential antimicrobial and antiviral properties when administered at high concentrations (> 20 parts per million, ppm). While definitive evidence is still lacking, this narrative review synthesizes the emerging clinical and mechanistic properties supporting high-dose iNO as a potential therapeutic strategy for lower respiratory tract infections, including drug-resistant bacterial pneumonias, COVID-19, nontuberculous mycobacteria, and bronchiolitis. We summarize safety data from laboratory studies, Phase I trials, clinical findings from 27 predominantly early-phase studies, and highlight its as both hospital-based and home-based therapy. High-dose iNO acts through multiple pathways, including direct microbial killing, biofilm disruption, immune modulation, and mucociliary enhancement, and holds promise in addressing unmet needs in respiratory infection management. We also propose a roadmap for future research to optimize dosing, delivery, and efficacy endpoints in well-defined patient populations.

Background: Sepsis-induced immunosuppression impairs bacterial clearance and increases mortality. Liver and spleen macrophages are an essential part of the mononuclear phagocyte system and crucial for bacterial elimination. Systemic inflammation hampers bacterial clearance in the liver. We hypothesized that immunosuppression due to systemic inflammation might lead to decreased bacterial clearance by the spleen.

Methods: Anesthetized pigs were subjected to an E. coli infusion for three hours in an intensive care setting. The Naive group only received the bacterial infusion (n = 10). The ETX group (n = 10) received an endotoxin infusion for 24 h, inducing systemic inflammation before the E. coli infusion. The Control group (n = 3) received saline instead of endotoxin for 24 h to study the effects of anesthesia alone. Bacterial counts and endotoxin levels were analyzed during the E. coli infusion. The levels of IL-6 and TNF were analyzed, and the piglets' physiological response was evaluated.

Results: There was no difference in the bacterial counts in the artery, splenic vein or hepatic vein. However, the splenic venous to arterial bacterial counts ratio at 1-3 h was lower in Naive compared to ETX group (0.54 (0.34-1.07), 0.54 (0.20-0.85), 0.52 (0.21-0.64) vs. 0.77 (0.61-1.06), 0.85 (0.63-0.89), 0.74 (0.53-0.88); p < 0.01), but there was no difference in the animals' blood ex vivo bactericidal capacity. There was no difference in endotoxin clearance in the spleen between the groups. The peak log IL-6 and TNF levels in response to the E. coli infusion were higher in the Naive compared to the ETX group (3.40 ± 0.41 vs. 2.94 ± 0.43 pg × mL^-1 and 3.78 ± 0.68 vs. 2.23 ± 0.36 pg × mL^-1; p < 0.05 and p < 0.001, respectively). The respiratory, circulatory and metabolic response to the E. coli infusion was dampened in the animals pre-exposed to endotoxin.

Conclusion: The splenic bacterial clearance is impaired by pre-existing systemic inflammation, while differences in endotoxin elimination were not detected. The inflammatory and physiological response to bacteremia is diminished during ongoing inflammation. Since the animals' ex vivo bactericidal capacity was not affected by pre-existing inflammation, our results suggest that inherent mechanisms in the spleen were involved.

Background: Biological heterogeneity in host inflammatory responses to severe pneumonia predicts clinical outcomes and may influence the effectiveness of immunomodulatory therapy. The upstream drivers of this heterogeneity remain poorly defined. We hypothesized that microbial translocation from the lungs to the bloodstream, detectable via multi-compartment metagenomic analysis, contributes to divergent host responses in pneumonia.

Methods: In this nested case-control study of mechanically ventilated patients with severe pneumonia, we collected paired plasma and endotracheal aspirate samples at baseline. Plasma samples underwent microbial cell-free DNA (mcfDNA) sequencing, and endotracheal aspirates were analyzed by Nanopore metagenomic sequencing. Host-response biomarkers were measured in both plasma and endotracheal aspirate samples. Microbial translocation of pulmonary origin was defined by the genus-level concordance of detectable taxa between matched endotracheal aspirate and plasma samples.

Results: Among 98 patients (76 pneumonia, 22 controls), plasma mcfDNA was markedly higher in microbiologically confirmed pneumonia compared with culture-negative pneumonia (median 4015 vs. 210 molecules/μL, p = 0.0006). Pulmonary microbial translocation was identified in 31 (41%) pneumonia patients and correlated significantly with plasma soluble ST2 levels, independent of clinical severity. Patients classified into the prognostically adverse hyperinflammatory subphenotype exhibited greater translocating microbial DNA levels compared to hypoinflammatory patients (p = 0.04), further linking translocation to host-response heterogeneity.

Conclusions: Microbial lung-to-blood translocation is a measurable biological process associated with systemic inflammatory heterogeneity in severe pneumonia. This pathway may represent a novel mechanistic target for precision therapeutic strategies aimed at mitigating immune dysregulation.

Background: Critically ill patients in intensive care units (ICUs) experience high rates of hospital-acquired (nosocomial) infections, commonly caused by translocation and dissemination of pathogenic microorganisms that colonize the intestinal tract (pathobionts). Multiple immune barriers protect the host against commensal and pathogenic colonizers, including a repertoire of circulating anti-commensal antibodies. The integrity of this systemic antibody-mediated defense system, its relationship with gut microbiota dysbiosis, and its impact on nosocomial infections in the ICU have not been explored.

Results: We performed a longitudinal cohort study of 46 critically ill patients at day 1 and day 3 of their ICU admission compared to 28 healthy volunteer controls. Circulating IgM, IgG, and IgA responses against 10 common gut and extra-intestinal pathobionts were quantified by flow cytometry, together with high-dimensional analyses of circulating B cell populations, fecal microbiota composition, and clinical outcomes. We observed reduced plasma IgM and IgG reactivity against intestinal pathobionts such as Escherichia coli, Klebsiella pneumoniae, and Enterococcus faecalis in ICU patients compared to healthy volunteers. Reduced gut pathobiont antibody responses in ICU patients was associated with B cell lymphopenia, and patients with gut microbiota dysbiosis had reduced levels of natural antibody producing B1-like B cells. Reduced IgG and IgM reactivity against gut Gram-negative pathobionts was associated with an increased risk of nosocomial infection or death.

Conclusions: These findings indicate that the systemic antibody barrier against microbiota pathobionts is compromised in critical illness and associated with increased risk of nosocomial infections.