Intensive Care Medicine Experimental最新文献

Background: In murine models, controversial data have been reported on the effect of hydrogen sulfide (H₂S) administration during resuscitation from trauma-and-hemorrhage. The H₂S donor sodium thiosulfate (Na₂S₂O₃) is a recognized drug devoid of major side effects, and, hence, we determined its effects in our full scale ICU-model of resuscitated murine trauma-and-hemorrhage. We hypothesized that Na₂S₂O₃ might improve energy metabolism and thereby exert organ-protective effects as previously demonstrated in animals with genetic cystathionine-γ-lyase (CSE) deletion (CSE^-/-).

Methods: 30 mice underwent combined blast wave-induced blunt chest trauma followed by 1 h of hemorrhagic shock (mean arterial pressure MAP = 35 ± 5 mmHg). Thereafter, resuscitation was initiated comprising re-transfusion of shed blood, lung-protective mechanical ventilation, fluid resuscitation and continuous i.v. noradrenaline infusion to maintain MAP > 55 mmHg over 6 h, and randomized administration of either i.v. 0.45 mg/g_bodyweight Na₂S₂O₃ or vehicle (NaCl 0.9%). Hemodynamics, lung mechanics, gas exchange, acid-base-status and organ function parameters were recorded. Metabolic pathways were quantified based on gas chromatography/mass spectrometry assessment of plasma isotope enrichment during primed-continuous infusion of stable, non-radioactive, isotope labeled substrates. Mitochondrial function was determined using high-resolution respirometry, and tissue target proteins (nitrotyrosine formation, extravascular albumin accumulation, CSE expression) were analyzed using immunohistochemistry.

Results: Data originate from 23 mice (Na₂S₂O₃ n = 12; vehicle n = 11)_. Na₂S₂O₃ affected neither survival nor noradrenaline requirements. While minute ventilation had to be increased over time in both groups to maintain arterial PCO₂ without intergroup difference, arterial PO₂ decreased over time in Na₂S₂O₃-treated mice (p = 0.006). Although arterial pH decreased in both groups (vehicle p = 0.049; Na₂S₂O₃ p < 0.001), metabolic acidosis was more pronounced in the Na₂S₂O₃ group. Neither metabolic pathways nor tissue mitochondrial respiratory activity or tissue target proteins showed any intergroup differences.

Discussion: In this model of resuscitated trauma-and-hemorrhage, Na₂S₂O₃ did not exert any beneficial metabolic or organ-protective effect and was even associated with impaired pulmonary function. These results are in contrast to our previous findings in CSE^-/- mice, but in line with more recent findings in CSE^-/-<

Background: Spontaneous breathing trials (SBT) are crucial for determining when mechanically ventilated patients are ready for extubation. While pressure support (PS) and T-piece trials are commonly used, humidified high-flow (HHF) is increasingly considered, but its physiological effects remain unclear. This bench study compares T-piece, PS, and HHF modalities, evaluating their impact on work of breathing (WOB), tidal volume (Vt), total positive end-expiratory pressure (PEEPtot) and CO₂ clearance.

Methods: A 3D-printed manikin head connected to an artificial lung was used. Four SBT modalities were tested: T-piece with and without supplemental oxygen, PS at 7 cmH₂O (PEEP 0 cmH₂O), and HHF at 50 L/min. The tests were performed under three lung conditions (normal, obstructive, restrictive) and two respiratory drive and effort settings (normal and intense), resulting in 24 scenarios. Measurements included WOB, CO₂ clearance, PEEPtot, and Vt.

Results: T-piece and HHF50 SBTs exhibited similar effects on WOB, irrespective of the effort pattern associated with the underlying respiratory mechanics. For intense effort patterns, the CO₂ concentration was lower with HHF than with PS, regardless of respiratory mechanics. The HHF50 SBT increased PEEPtot more than T-piece SBTs, but less than PS SBT, for all scenarios. HHF50 SBT generated lower tidal volume than T-piece and PS SBTs.

Conclusions: Humidified high-flow at 50 L/min, while preserving WOB and not increasing tidal volume, may offer specific advantages, such as improved CO₂ clearance and PEEP effect, and could be considered as a trade-off for T-piece or PS SBTs.

Background: Despite advanced and early treatment in the intensive care unit (ICU), mortality in patients with sepsis remains high. Sepsis is often associated with hemolysis. In the clinical routine, hemolysis is often overlooked, as markers of hemolysis are often not routinely measured. Aim of this scoping literature review is to quantify the incidence and extent of hemolysis in patients with sepsis and the association with mortality.

Methods: Systematic literature search in bibliographic databases MEDLINE, EMBASE and Web of Science for sepsis and hemolysis.

Results: A total of 3382 studies underwent title-abstract screening and 169 studies were reviewed in full. There were 34 studies with a total of 27,702 patients with sepsis and reported hemolysis or hemolytic markers and clinical outcomes included in the final analyses. Mortality ranged from 5.4 to 78.6% with a mean mortality of 20.1% across all studies. A significant association between hemolysis or hemolytic markers with increased mortality was observed in nine studies.

Conclusions: Although significant associations between hemolysis and outcome in patients with sepsis were observed, hemolytic markers are not yet routinely and regularly monitored in clinical routine on the ICU. Hemolytic markers can provide information about disease severity and outcome on ICU admission and during the course of the disease. Future work should focus on identification of reliable markers of hemolysis with a potential for easy and timely measurements ideally at the patients' bedside. With an additional definition of monitoring standards, the potential of hemolysis monitoring for prognostication and therapeutic approaches will emerge.

Background: In congenital heart disease (CHD), the evaluation of pulmonary perfusion remains challenging, particularly in pediatric critically ill patients, where anatomical anomalies significantly impact pulmonary blood flow. We aim at demonstrating the reliability and the accuracy to investigate pulmonary perfusion in the presence of CHD by using electrical impedance tomography (EIT), a non-invasive, bedside, real-time, radiation-free imaging technique that assesses lung ventilation and perfusion.

Results: This methodologies series explores the application of EIT in three pediatric critically ill patients with CHD admitted to the Pediatric Intensive Care Unit at Papa Giovanni XXIII Hospital, Bergamo, Italy: (1) a newborn post-corrective surgery for transposition of the great arteries; (2) an infant post-repair of tetralogy of Fallot with bilateral pulmonary branch stenosis; and (3) an infant with severe hypoxemia following Stage I Norwood-Sano repair. EIT perfusion was performed by injecting a bolus of 0.5 ml/kg of 5% saline through a central venous catheter during an inspiratory hold and was compared to standard imaging techniques that assess pulmonary perfusion. EIT findings were consistent with conventional imaging modalities that are not available at bedside (i.e., computed tomography, magnetic resonance imaging, angiography) or that do not allow regional assessment of lung perfusion and are operator dependent (i.e., ultrasound), demonstrating the reliability and the accuracy of EIT assessment. EIT provided critical insights into ventilation-perfusion dynamics, allowing to identify perfusion defects and guiding clinical decisions.

Conclusions: This clinical investigation highlights the potential of EIT to improve pulmonary perfusion monitoring and clinical management of complex CHD cases in pediatric critically ill patients. Further research is needed to establish standardized protocols and validate the EIT clinical utility in larger cohorts.

Background: Controlled clinical trials investigating ongoing questions about extracorporeal membrane oxygenation (ECMO) for patients with the acute respiratory distress syndrome (ARDS), including what the optimal mechanical ventilation (MV) tidal volume (TV) strategies are and whether ECMO potentiates injurious host responses, are difficult. We therefore conducted a systematic literature search and review to characterize studies investigating ECMO in adult animal lung injury models and to determine whether they inform these questions.

Methods: A systematic literature search with relevant search terms was conducted of four data bases through 2/2/24.

Results: Forty-five studies met inclusion criteria, and most parameters examined were represented similarly in studies with (n = 24) or without (n = 21) severe ARDS PaO₂/FiO₂s levels (≤ 100 mmHg or > 100 mmHg). Overall, while only 11 studies were published from 1971 to 2005, 5, 8, and 11 were published in subsequent 5-year periods up to 2020 and then 10 through 2/2/24 (Figure 1). Most studies investigated pig or sheep models (n = 32), but since 2016, six studies employed rat models. Eighteen studies administered lung lavage alone or with another lung injury challenge (17 with PaO₂/FiO₂s ≤ 100) and 9 used oleic acid. Although seven studies administered lipopolysaccharide, very different from clinical ARDS only one used a bacterial and none a viral challenge. Thirty-two studies employed V-V ECMO. The most frequent duration of ECMO investigated was 24 h in 16 studies but only 2 studies investigated longer periods (48 and 96 h). Differences in study questions, methodologies and outcome measures precluded formal meta-analysis. However, overall in studies that compared mechanical ventilation alone (MV) to ECMO groups or that compared differing ECMO groups: in 5 studies ECMO supported tidal volume reductions that approached apneic levels in 2; all but 1 of 10 studies indicated that ECMO with or without TV reductions either did not increase or reduced lung injury measures; 2 studies did while 4 did not find that ECMO aggravated molecular or cellular markers of inflammation; and only 2 studies examined host thrombotic responses with ECMO. Fig. 1 Flow diagram for the literature search CONCLUSION: Animal models to date have addressed important questions facing ECMO use for ARDS, but ones more closely simulating ARDS in patients appear warranted.

Background: Switching from controlled to assisted ventilation is crucial in the trajectory of intensive care unit (ICU) stay, but no guidelines exist. We described current practices, analyzed patient characteristics associated with switch success or failure, and explored the feasibility to predict switch failure.

Methods: In this retrospective study, we obtained highly granular longitudinal ICU data sets from three medical centers, covering demographics, severity scores, vital signs, ventilation, and laboratory parameters. The primary endpoint was switch success, considering a switch attempt to be successful if a patient did not return to controlled ventilation for the next 72 h while alive, and to be failed otherwise. We compared the characteristics of patients with successful vs. failed first switch attempts at ICU admission, immediately before, and 3 h after the attempt. We trained LASSO logistic regression models to predict switch failure.

Results: In 4524/6715 (67%) patients attempting a switch, the first attempt failed. The first switch attempt, regardless of success or failure, was generally made at normalized PaCO₂ and pH levels, with PEEP < 10 cmH₂O and PaO₂/FiO₂ indicating mild injury. Despite very similar baseline disease severity, switch failure was associated with significantly worse outcomes, including a 28-day mortality of 27% vs. 16% and median ventilator-free days of 16 vs. 22 (p < 0.001). Failed attempts were initiated significantly earlier than successful ones (median 1.8 vs. 1.3 days, p < 0.001). Before the switch, PaO₂/FiO₂, if measured at PEEP > 10 cmH₂O, and respiratory system compliance was lower in patients with switch failure (median 185 vs. 205 mmHg, p < 0.001; 39 vs. 41 mL/cmH₂O, P = 0.001), and post-switch, patients with switch failure experienced greater deterioration in gas exchange and minimal improvement in ventilatory parameters post-switch. Contrary to our hypotheses, patient characteristics for failed vs. successful switches were surprisingly similar, resulting in prediction models with limited discriminative performance.

Conclusions: Approximately two-thirds of attempts to switch patients to assisted ventilation fail, which are associated with significantly worse clinical outcomes, despite similar baseline disease severity. Contrary to our hypotheses, patients with successful and failed attempts showed similar characteristics, making switch failure difficult to predict. These findings underscore the importance of preventing switch failures and, given the retrospective nature of this study, highlight the need for prospective studies to better understand the reasons for switch failure and when spontaneous breathing can be safely initiated.

Background: Injury to the vascular endothelium occurs in up to 34% of patients acutely following severe traumatic injury and can be quantified clinically by measuring the plasma concentration of syndecan-1 (SDC-1). Tranexamic acid (TXA) attenuates endothelial damage in animal and cell culture models and has been associated with lower SDC-1 levels after prehospital TXA administration. The aim of this study was to assess the association of prehospital TXA on SDC-1 levels in a more severely injured prehospital cohort.

Methods: The PATCH-Trauma trial randomised patients to receive pre-hospital TXA or placebo. In this sub-cohort, SDC-1 was measured in blood samples collected on hospital admission, at 8 and 24 h. Relationships between SDC-1 levels over time, treatment groups, and outcomes were analyzed using regression modelling controlling for potential confounding factors.

Results: There were 89 patients included, with 57 administered TXA and 32 administered placebo (per protocol). SDC-1 levels were available in 87 patients on arrival to hospital, 70 at 8 h, and 69 at 24 h. Patients had a median SDC-1 on admission of 106 ng/mL (IQR 88-137). There was no effect of TXA treatment on SDC-1 levels over the first 24 h of hospital admission, even after controlling for known confounders. There was no association between SDC-1 level at any time point and the development of deep vein thrombosis or sepsis, mortality at 28-days, or days alive and out of hospital, even after adjustment for confounding factors.

Conclusion: Administration of TXA, initiated pre-hospital, did not affect SDC-1 levels in the first 24 h of hospital admission in this severely injured cohort. Further research is required to elucidate the mechanisms of the effect of TXA on the endothelium as well as the utility of SDC-1 as an endothelial biomarker.

Background: Cardiopulmonary bypass (CPB) may decrease the renal functional reserve (RFR). However, the temporal changes in RFR after during the recovery period after CPB remains unknown. We assessed RFR before and then weekly after CPB over four weeks following CPB in non-anaesthetised sheep.

Methods: In 10 Merino ewes, amino acids were infused before CPB and weekly for four weeks to assess RFR. At each assessment, we measured renal blood flow (RBF), renal oxygen delivery (RDO₂), creatinine clearance and medullary and cortical oxygenation. Histological assessment was performed at 4 weeks.

Results: Before CPB, amino acid infusion increased RBF from (mean ± SD) 6.60 ± 1.64 to 8.56 ± 1.80 mL/kg/min, and RDO₂ from 0.80 ± 0.28 to 1.12 ± 0.37 mL O₂/kg/min. These renal macro-circulatory responses remained consistent across all weekly assessments after CPB. Amino acid infusion also increased creatinine clearance (from 62.5 ± 15.0 to 110 ± 30.6 mL/h pre-CPB) throughout the study period. RFR remained unchanged over time (P = 0.53). However, compared with pre-CPB values, medullary (33.9 ± 9.0 pre-CPB to 15.1 ± 13.2 mmHg at 4 weeks, P = 0.0068) and cortical tissue PO₂ (46.0 ± 14.2 to 17.2 ± 6.5 mmHg, P = 0.0029) decreased over time. Furthermore, the response of the medullary (but not cortical) PO₂ to amino acid infusion changed over time (P = 0.0064). While medullary PO₂ did not change in response to amino acid infusion pre-CPB and at one week after CPB, it appeared to fall from two weeks thereafter (P = 0.039 and 0.091 at weeks 2 and 3, respectively). Despite preserved RFR, sheep exposed to CPB showed greater peritubular inflammation, interstitial fibrosis and tubular casts compared with healthy controls (P = 0.007, 0.021, 0.007, respectively).

Conclusions: In this large mammalian model of CPB, weekly amino acid administration consistently recruited RFR over four weeks, despite the presence of histological injury. However, it was associated with the development of renal medullary hypoxia after two weeks. These findings highlight the complexity of the pathophysiological response of the kidney to CPB.