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Introduction: Nonagenarians and centenarians, compared with other age groups, often exhibit distinct physiological characteristics and a higher prevalence of comorbidities, thus further complicating their care in intensive care unit (ICU) settings. Despite the increasing number of such patients being admitted to ICUs, comprehensive research and studies on their characteristics, outcomes and complications during their ICU stays remain lacking. This scoping review will comprehensively address the following question: What are the characteristics, outcomes, complications and mortality rates among nonagenarians and centenarians admitted to ICUs, including their preadmission health status, reasons for admission, duration of hospital/ICU stays, and factors associated with adverse outcomes? The key objectives are to map the breadth and depth of the available evidence and identify key concepts, gaps and variations in research focus. Finally, we aim to highlight well-studied areas suitable for systematic synthesis, point to underexplored topics warranting further investigation and propose standardised approaches to research design and reporting in this domain., Methods and Analysis: We will conduct a systematic search of MEDLINE, Embase and the Cochrane Library in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews guidelines. All studies and publications reporting data on patients aged ≥90 years will be included, from an unlimited timeline to 31 August 2024. Studies reporting the characteristics, outcomes and complications of nonagenarians and centenarians admitted to ICUs will be included. The data will be analysed and summarised descriptively through a narrative approach. Qualitative data related to quality-of-life outcomes will be analysed thematically, as applicable., Ethics and Dissemination: Ethics approval was not required. The findings will be disseminated through professional networks, conference presentations and publications in scientific journals., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Background: The TARGET Protein trial will evaluate the effect of greater enteral protein delivery (augmented protein) on clinical outcomes of critically ill adult patients when compared to usual care., Objective: To describe the statistical analysis plan for the TARGET Protein trial., Methods: TARGET Protein is a cluster randomized, cross-sectional, double cross-over, open-label, registry-embedded, pragmatic clinical trial conducted across Australia and New Zealand. The trial randomized eight intensive care units (ICU) to receive enteral formula containing either higher dose enteral protein (augmented protein) or usual dose protein in a 1:1 ratio. Each ICU received one trial formula for a 3-month period and then switched to the alternate formulae. This sequence was repeated, for a total trial length of 12 months. The primary outcome is the number of days free of the index hospital and alive at day 90. Secondary outcomes include proportion of patients alive at day 90, survivor-only analysis of days free of the index hospital at day 90, duration of invasive ventilation, ICU and hospital length of stay, incidence of tracheostomy insertion, renal replacement therapy, and discharge destination. The statistical methods and models which will be used to estimate the effects for the primary and secondary outcomes are described. All statistical models will account for the cluster-randomized cross-over design to ensure correct estimation of the 95% confidence intervals. Trial enrolment is complete with 3412 patients enrolled. Data linkage is ongoing., Conclusion: This statistical analysis plan enables transparent reporting of the TARGET Protein trial. It will reduce the risk of potential selective reporting biases., Trial Registration: Australian New Zealand Clinical Trials Registry (ACTRN12621001484831). Registered on November 1, 2021., Competing Interests: Declarations. Ethics approval and consent to participate: Human research ethics approval was granted in Australia by the Central Adelaide Local Health Network Human Research Ethics Committee (2021/HRE00248) and in New Zealand by Northern B Health and Disability Ethics Committee (2021 FULL 11097). Consent for publication: All authors approved submission of the final version of this manuscript. Competing interests: LSC has received lecture fees from Nutricia and Fresenius Kabi. EJR has received lecture fees from Baxter Healthcare, Nestle, and Nutricia. AMD is employed by an institution that has received lecture fees from Baxter Healthcare for his time. All other investigators report no competing interests or individual financial support., (© 2025. The Author(s).)

This work evaluated red kiwifruit plants' spray treatment with cis-3-hexenyl butyrate (HB) as an inductor of some metabolic mechanisms related to fruit ripening, including an increase in anthocyanin content and the red hue color parameter. Considering their key role as ripening parameters for postharvest fruit quality and sorting assessment, the soluble solid content (SSC) and the flesh firmness penetrometer (FFP) were also measured. Treated plants received an application of 50 mM HB, administered exactly 2 and 4 weeks before the commercial harvest. At harvest time and during postharvest fruit ripening, near-infrared (NIR) spectral acquisitions were performed in order to check the feasibility of a rapid and non-destructive prediction of fruit anthocyanin content and SSC, coupled to destructive measurements and chemometric modelling. Regarding technological and chemical results, HB treatment indicates an optimum overall qualitative storage at 30 days. The fruit from treated plants is characterized by good quality parameters, including higher SSC, enhanced red hue (a* value) and increased anthocyanin content, despite similar weight loss to the untreated fruit. The obtained chemometric results underscore the promise and feasibility of NIRs in terms of detecting and estimating anthocyanin content and SSC in red kiwifruit, in order to pursue an evident perspective of improvement.

Purpose: Clinical trials focusing on critically ill patients with metabolic acidosis, a common exclusion criterion is the presence of a PaCO 2  > 45 mmHg. The aim of this study was to assess the impact of mild hypercapnia on patient characteristics, severity, and clinical outcomes in critically ill patients with metabolic acidosis., Material and Methods: Multicentre, retrospective, observational study conducted in 12 intensive care units (ICUs) in Queensland, Australia. Patients with metabolic acidosis and concurrent vasopressor requirement were included and the exposure of interest was the PaCO 2 level at the time of meeting the eligibility criteria divided in two groups: PaCO 2  ≤ 45 mmHg and PaCO 2 46-50 mmHg. Primary clinical outcome was major adverse kidney events within 30 days (MAKE30)., Results: We studied 5601 patients, with 3605 (64.4 %) in the PaCO 2  ≤ 45 mmHg group and 1996 (35.6 %) in the PaCO 2 46-50 mmHg group. The incidence of MAKE30 was lower in the PaCO 2 46-50 mmHg group (29 % vs. 34 %; OR, 0.79 [95 %CI, 0.69 to 0.90]; p < 0.001) as was the use of renal replacement therapy, and the incidence of acute kidney injury. After adjustment for confounders, no outcome was different between the groups. The maximum fall of pH associated with an increase of 1 mmHg of PaCO 2 in the PaCO 2 46-50 mmHg group was 0.006., Conclusion: In patients with metabolic acidosis, after adjustment for potential confounders, mild hypercapnia does not increase the MAKE-30 rate and does not have a major impact on pH., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The impact of noninvasive ventilation (NIV) managed outside the intensive care unit in patients with early acute respiratory failure remains unclear. We aimed to determine whether adding early NIV prevents the progression to severe respiratory failure., Methods: In this multinational, randomised, open-label controlled trial, adults with mild acute respiratory failure (arterial oxygen partial pressure/fraction of inspiratory oxygen [Pao 2 /FiO 2 ] ratio ≥200) were enrolled across 11 hospitals in Italy, Greece, and Kazakhstan. Patients were randomised to receive early NIV or usual care. Patients in the early NIV group received 2-h cycles of NIV applied every 8 h for up to 12 days. The primary outcome was the progression to severe acute respiratory failure, defined by severe hypoxaemia, severe respiratory distress, or hypercapnic acidaemia during hospitalisation., Results: Between May 6, 2012, and July 18, 2023, we randomised 524 patients (44.8% female; median age 73 yr, interquartile range [IQR] 63-83 yr). One patient withdrew consent. Progression to severe acute respiratory failure occurred in 49/265 (18.5%) patients randomised to early NIV, compared with 73/258 (28.3%) patients receiving usual care (relative risk 0.65, 95% confidence interval 0.48-0.90, P=0.0080). Median length of hospital stay was 10 (IQR 6-16) days in the early NIV group and 9 (IQR 5-16) days in the usual care group (P=0.30). Respiratory complications, 28-day mortality, and adverse events were not different between early NIV and usual care., Conclusions: In patients with mild acute respiratory failure treated in nonintensive care wards, early NIV reduced the progression to severe acute respiratory failure., Clinical Trial Registration: NCT01572337., Competing Interests: Declaration of interest All authors have no conflict of interest to declare., (Copyright © 2024 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Purpose: To use natural language processing (NLP) to study the incidence, characteristics, trajectory, associations, and outcomes of hallucinations and disturbed behaviour in intensive care unit (ICU) patients., Methods: We used NLP to scan clinical progress notes of a large cohort of ICU patients to detect words indicating that a patient had experienced hallucinations. We also used NLP to detected disturbed behaviour during ICU stay. Moreover, we studied the use of antipsychotic medications in a nested cohort. Finally, we obtained the demographics, trajectory, associations, and outcome of these patients., Results: We conducted a non-interventional, observational study of 7525 patients. We found that 625 (8.31%) had experienced hallucinations. Among these, 623 (99.7%) also had NLP-diagnosed behavioural disturbance (NLP-Dx-BD). In contrast, in patients without hallucinations, only 3274 (47.4%) were NLP-Dx-BD positive. Among the 2904 nested cohort patients with electronic medications data, 252 (8.7%) experienced hallucinations. Of these, 60 (23.8%) received medications compared with 147 (5.5%) (p < 0.001) patients without hallucinations. There was no difference on outcomes in patients with or without hallucination., Conclusions: Hallucinations affect one in 12 ICU patients and are strongly associated with disturbed behaviour, and the use of antipsychotic medications. Hallucinations may represent another phenotype of critical illness associated neurocognitive dysfunction and require a dedicated research program., Competing Interests: Declarations. Ethical approval and consent to participate: This study was approved by the Austin Hospital Human Research Ethics Committee (LNR/19/Austin/38), which waived the requirement for informed consent. Consent for publication: The authors hereby provide consent for this manuscript titled "Hallucinations and Disturbed Behaviour in the Critically Ill: Incidence, Patient Characteristics, Associations, Trajectory, and Outcomes" to be published. The authors confirm that they have read and approved the final version of the manuscript. They further affirm that the work described in the manuscript is original and has not been published elsewhere. Competing interest: The authors declare no competing interests., (© 2025. The Author(s).)

Background: In critically ill patients with acute kidney injury (AKI), a fluid balance (FB) > 2 L at 72 h after AKI diagnosis is associated with adverse outcomes. Identification of patients at high-risk for such fluid accumulation may help prevent it., Methods: We used Australian electronic medical record (EMR)-based clinical data to develop the "AKI-FB risk score", validated it in a British cohort and used it to predict a positive FB >2 L at 72 h after AKI diagnosis., Results: We developed the AKI-FB score in 32,030 patients with a median age of 63 years and a median APACHE 2 score of 16. We validated it in 4465 patients, with significant differences in admission diagnoses and interventions. The key score variables were admission after trauma, sepsis or septic shock, and, on the day of AKI diagnosis, highest creatinine, daily cumulative FB, mechanical ventilation, noradrenaline use, noradrenaline equivalent dose >0.07 μg/kg/min, lactate ≥2 mmol/L, transfusion, and nutritional support. A score threshold of 32 had a sensitivity of 75 % and a specificity of 72 % for predicting a > 2 L positive FB with an AUC-ROC of 0.805; 95 % CI 0.799 to 0.810. External validation demonstrated an AUC of 0.761 (95 % CI 0.746 to 0.775)., Conclusion: We developed and validated the "AKI-FB risk score" to predict patients who developed a positive FB >2 L within 72 h of AKI diagnosis. This prediction score was robust and facilitated the identification of high-risk AKI patients who could be the tarted for preventive measures and be included in future clinical trials of FB management., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The centralization of childbirth and newborn care in large maternity units has become increasingly prevalent in Europe. While this trend offers potential benefits such as specialized care and improved outcomes, it can also lead to longer travel and waiting times, especially for women in rural areas., Objective: This study aimed to evaluate the association between hospital maternity unit (HMU) volumes, road travel distance (RTD) to the hospital, and other neonatal outcomes., Methods: We conducted a population-based cohort study including all live births in hospitals without intensive care units between 2016 and 2019 in the Lombardy region, Italy. Given the hierarchical structure of our data (births nested within hospitals), we employed log-binomial regression models with random intercepts to estimate relative risks and 95% CIs for evaluating the association between HMU volumes (≥1500 births/year) and RTD (<5 km) with the risk of being transferred and/or death after birth (primary outcome). Secondary outcomes included a low Apgar score at 5 minutes and low adherence to antenatal care (ANC). We controlled for several potential confounders including adherence to the ANC pathway for the primary and low Apgar outcomes. To explore the influence of HMU volumes on the primary outcome, we identified the fractional polynomial model that best described this relationship., Results: Of 65,083 live births, 71% (n=45,955) occurred in low-volume hospitals (<1000 births/year), 21% (n=13,560) involved long-distance travel (>15 km), 1% (n=735) were transferred and/or died after birth, 0.5% (n=305) had a low Apgar score at 5 minutes, and 64% (n=41,317) completely adhered to ANC. The risk of transfer and/or death increased as HMU volume decreased, ranging from 1% for hospitals with 1000-1500 births/year to a 3.6-fold high risk for hospitals with <500 births/year (compared to high-volume hospitals). Travel distance did not affect the primary outcome. Neither HMU volume nor RTD were associated with low Apgar scores. Conversely, the risk of complete adherence to ANC decreased with lower HMU volumes but increased with shorter RTD. Additionally, high-volume hospitals demonstrated a decreasing trend in the frequency of the primary outcome, with transfer and/or death rates ranging from 2% to 0.5% and flattening to 0.5% in hospitals, with activity volume ≥1000 mean births/year., Conclusions: Our findings showed an excess risk of neonatal transfer and/or death for live births in HMUs with low activity volumes without an intensive care unit. In contrast, RTD primarily affected adherence to ANC. Moreover, data suggest that 1000 births/year could be an optimal cutoff for maternity hospitals to ensure an appropriate standard of care at delivery., (© Anna Cantarutti, Riccardo Boracchini, Roberto Bellù, Raffaella Ronco, Federico Rea, Anna Locatelli, Rinaldo Zanini, Giovanni Corrao. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org).)

The development of surgical techniques, chemotherapy, biological agents, and multidisciplinary approaches have made patients with unresectable colorectal liver metastases eligible for surgery. Many strategies have been developed to allow patients for surgical resection (percutaneous portal vein embolization, liver venous deprivation, parenchyma-sparing liver surgery, reverse strategy, associating liver partition and portal vein ligation for staged hepatectomy, and liver transplantation), the only form of disease control and curative treatment.

Transcription factors (TFs) bind combinatorially to cis-regulatory elements, orchestrating transcriptional programs. Although studies of chromatin state and chromosomal interactions have demonstrated dynamic neurodevelopmental cis-regulatory landscapes, parallel understanding of TF interactions lags. To elucidate combinatorial TF binding driving mouse basal ganglia development, we integrated chromatin immunoprecipitation sequencing (ChIP-seq) for twelve TFs, H3K4me3-associated enhancer-promoter interactions, chromatin and gene expression data, and functional enhancer assays. We identified sets of putative regulatory elements with shared TF binding (TF-pRE modules) that orchestrate distinct processes of GABAergic neurogenesis and suppress other cell fates. The majority of pREs were bound by one or two TFs; however, a small proportion were extensively bound. These sequences had exceptional evolutionary conservation and motif density, complex chromosomal interactions, and activity as in vivo enhancers. Our results provide insights into the combinatorial TF-pRE interactions that activate and repress expression programs during telencephalon neurogenesis and demonstrate the value of TF binding toward modeling developmental transcriptional wiring., Competing Interests: Declaration of interests J.L.R.R. is a co-founder, a stockholder, and currently on the scientific board of Neurona, a company studying the therapeutic use of interneuron transplantation., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The Treatment of Mechanically Ventilated Adults with Early Activity and Mobilisation (TEAM) trial reported a higher occurrence of adverse events with greater mobilisation. However, their timing and nature remained unexplored. We conducted an in-depth exploration of such events., Objective: The purpose of this paper is to thoroughly examine the timing and characteristics of adverse events reported within the TEAM trial., Methods: Adverse event data were collected daily in real time. Categorical data were compared using the Fisher's exact test. The relationship between adverse events and patient survival was analysed using a Cox-regression frailty model., Results: Overall, 37 out of 371 patients (10.0%) in the early mobilisation group and 16 out of 370 patients (4.3%) in the usual care group experienced adverse events, with 71 events in the early mobilisation group compared to 24 events in the usual care group. The most common adverse events were altered blood pressure in 21 out of 53 patients (39.6%), arrhythmia in 17 out of 53 patients (32.1%), and oxygen desaturation in nine of 53 patients (17.0%). Patients with an adverse event were more likely to have congestive heart failure (absolute percentage difference: 16.1, 95% confidence interval [CI]: 6.1 to 26.1), peripheral vascular disease (absolute percentage difference: 6.4, 95% CI: 1.3 to 11.5), heart attack (absolute percentage difference: 13.5, 95% CI: 5.9 to 21.1), or stroke (absolute percentage difference: 9.3, 95% CI: 3.5 to 15.1). Adverse events occurred at a median of 4 days with early mobilisation and 7 days with usual care. There was no significant difference in survival for patients who experienced an adverse event compared to those without an adverse event., Conclusion: Adverse events were more common in patients randomised to early active mobilisation, were cardiovascular and respiratory in nature, tended to occur earlier with active mobilisation, and cardiovascular comorbidities were more common in such patients. This information can help guide future studies in this field., Trial Registration: TEAM ClinicalTrials.gov number, NCT03133377, registered 28 April 2017., Competing Interests: Conflict of interest The authors declare that they have no competing interests., (Copyright © 2024 Australian College of Critical Care Nurses Ltd. Published by Elsevier Ltd. All rights reserved.)

Introduction: Angiotensin II may reduce muscle ischemia during intermittent hemodialysis (IHD) and thereby decrease the incidence and/or intensity of intradialytic muscle cramps. We aimed to test whether angiotensin II infusion during IHD is safe, feasible, and effective in the attenuation of muscle cramps., Methods: We performed a pilot, single-blinded, randomized crossover trial of patients receiving IHD who frequently experience intradialytic muscle cramps. Patients were randomly allocated to receive either intravenous angiotensin II or placebo for the duration of their first dialysis session of the week. They crossed over to the alternate arm each week for 4 weeks. The primary outcome was safety. Secondary outcomes included cramp-related symptoms, hemodynamic parameters, dialysis prescription alterations, and biomarkers., Results: We studied 24 sessions in 6 patients. Intradialytic hypertension (systolic blood pressure >180 mm Hg) occurred more often with angiotensin II than with placebo (4/12 sessions, 33% vs. 2/12 sessions, 17% sessions, p = 0.64). There were no other adverse events. Compared with placebo, muscle cramps were less frequent (4/12 sessions, 33% vs. 11/12 sessions, 92% sessions, p = 0.009) and of lower intensity with angiotensin II (median Brief Pain Inventory score 1.4 vs. 5.3; p < 0.001; maximal Brief Pain Inventory score 1.2 vs. 6.0; p < 0.001). Fluid bolus administration for cramps was less common during angiotensin II infusion than placebo (0/12 sessions, 0% vs. 5/12 sessions, 42% sessions, p = 0.037)., Conclusion: Angiotensin II increased blood pressure and heart rate but not cardiac output or levels of troponin, creatine kinase, or renin. Angiotensin II infusion during IHD appears safe and effective at reducing intradialytic muscle cramps. These observations justify further investigation in larger controlled studies., (© 2025 The Author(s). Published by S. Karger AG, Basel.)

Acute Kidney Injury (AKI) is a common complication after cardiac surgery affecting up to 40% leading to increased morbidity and mortality. To date, there is no specific treatment for AKI, thus, clinical research efforts are focused on preventive measures. The only pharmacological preventive intervention that has demonstrated a beneficial effect on AKI in a high-quality, double-blind, randomized controlled trial is a short perioperative infusion of a balanced mixture of amino acid solution. Amino acid infusion reduced the incidence of AKI by recruiting renal functional reserve and, therefore, increasing the glomerular filtration rate. The beneficial effect of amino acids was further confirmed for severe AKI and applied to patients with chronic kidney disease. Among non-pharmacological interventions, international guidelines on AKI suggest the implementation of a bundle of good clinical practice measures to reduce the incidence of perioperative AKI or to improve renal function whenever AKI occurs. The Kidney Disease Improving Global Outcomes (KDIGO) bundle includes the discontinuation of nephrotoxic agents, volume status and perfusion pressure assessment, renal functional hemodynamic monitoring, serum creatine, and urine output monitoring, and the avoidance of hyperglycemia and radiocontrast procedures. However, pooled data from a meta-analysis did not find a significant reduction in AKI. The aim of this review is to delineate the most appropriate evidence-based approach to prevent AKI in cardiac surgery patients., Competing Interests: Declaration of competing interest The authors have disclosed that they do not have any conflicts of interest. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Purpose: To evaluate whether the effectiveness of topical antiseptic solutions in restoring skin continuity solutions is related to their antimicrobial action or to their action in maintaining moisture, in dogs undergoing elective surgeries., Methods: Forty dogs, 20 males and 20 females, underwent orchiectomy and oophorectomy, respectively. Thereafter, the animals were allocated into four groups (n = 5) and treated with different topical solutions: polyhexanide 0.1% (G1), chlorhexidine digluconate 0.05% (G2), povidone-iodine 0.1% (G3), and sodium chloride 0.9% (control). Macroscopically evaluation of wounds on days 1, 5, and 10 after procedures, and hematological parameters were performed. Data were subjected to statistical analysis (p 0.05)., Results: No significant differences in the macroscopic evaluation of the wounds and hematological parameters were observed among groups, in the healing of clean elective surgical wounds. However, applying a topical solution dressing to maintain a moist wound promoted adequate tissue healing., Conclusion: In our experimental conditions, moisture provided by topical antiseptic solutions is an important factor compared to the antiseptic activity of these solutions, for skin wound healing in post-surgical dressings resulting from clean, short-term elective surgeries in male and female dogs. Moreover, the type of topical antiseptic solution used does not influence the development of post-surgical infection.

Background: Hypernatremia is relatively common in acutely ill patients and associated with mortality. Guidelines recommend a slow rate of correction (≤ 0.5 mmol/L per hour). However, a faster correction rate may be safe and improve outcomes., Objectives: To evaluate the impact of sodium correction rates on mortality and hospital length of stay and to assess types of hypernatremia treatment and treatment side effects., Methods: We conducted a systematic review and meta-analysis according to PRISMA guidelines, searching Ovid MEDLINE, Embase, and CENTRAL databases from inception to August 2024. Studies reporting sodium correction rates and clinical outcomes in hospitalized adults were included. A random-effects meta-analysis assessed mortality and hospital length of stay, with subgroup analyses exploring correction timing and severity. Treatment method and side effects were analyzed qualitatively., Results: We reviewed 4445 articles and included 12 studies. Faster correction rates (> 0.5 mmol/L/h) overall showed no significant change in mortality and a high level of heterogeneity (OR 0.68, 95 % CI: 0.38-1.24, I 2  = 95 %). However, subgroup analyses found significantly lower mortality with faster correction of hypernatremia at the time of hospital admission (OR 0.48, 95 % CI: 0.35-0.68, I 2  = 2 %), with fast correction within the first 24 h of diagnosis (OR 0.48, 95 % CI: 0.31-0.73, I 2  = 65 %), and for severe hypernatremia (OR 0.55, 95 % CI: 0.33-0.92, I 2  = 79 %). There was no significant different in hospital length of stay by correction rate. No major neurological complications were reported when the correction rate was < 1 mmol/L/h., Conclusion: Faster sodium correction appears safe and may benefit patients with severe admission-related hypernatremia, particularly within the first 24 h. Further studies are needed to refine correction protocols., Competing Interests: Declaration of competing interest I have nothing to declare., (Copyright © 2024. Published by Elsevier Inc.)

Objective: To compare the effects of fluid bolus therapy (FBT) with 20% albumin to crystalloid FBT on the incidence of cardiac surgery-associated acute kidney injury (CSA-AKI) and its severity and duration., Design: Secondary analysis of the multicenter, parallel-group, open-label, randomized HAS FLAIR-II trial., Setting: Six intensive care units., Participants: Patients who required clinician-determined FBT after cardiac surgery requiring cardiopulmonary bypass., Interventions: Patients were randomized to receive FBT with 20% albumin (up to 400 mL/day) or crystalloid fluid for all FBTs in the intensive care unit., Measurements and Main Results: A total of 452 patients were included in the modified intention-to-treat population (224 in the 20% albumin group and 228 in the crystalloid group). AKI occurred in 54 (24%) patients in the 20% albumin group and 50 (22%) in the crystalloid group (odds ratio: 1.13, 95% confidence interval [CI]: 0.73 to 1.76). However, in patients who developed stages 2 and 3 AKI, those allocated to 20% albumin had a significantly lower median time-weighted average (TWA) creatinine: 144 µmol/L (interquartile range [IQR]: 109 to 162) versus 254 µmol/L (IQR: 182 to 294) than the crystalloid group (difference -105 µmol/L, [95% CI -170 to -41], p = 0.003) and a lower peak serum creatinine (-110 µmol/L [-189 to -32], p = 0.01). The reduced TWA creatinine in the 20% albumin group was seen in patients with both a low (p = 0.04) and normal preoperative serum albumin concentration (p < 0.001)., Conclusions: FBT with 20% albumin compared with crystalloid-based regimen did not reduce the occurrence of AKI in patients after cardiac surgery. However, it reduced the severity and duration of stages 2 and 3 AKI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To compare the effect of balanced multielectrolyte solutions (BMESs) versus normal saline (NS) for intravenous fluid on chloride levels and clinical outcomes in patients with predicted severe acute pancreatitis (pSAP)., Background: Isotonic crystalloids are recommended for initial fluid therapy in acute pancreatitis, but whether the use of BMES in preference to NS confers clinical benefits is unknown., Methods: In this multicenter, stepped-wedge, cluster-randomized trial, we enrolled patients with pSAP (acute physiology and chronic health evaluation II score ≥8 and C-reactive protein >150 mg/L) admitted within 72 hours of the advent of symptoms. The study sites were randomly assigned to staggered start dates for a one-way crossover from the NS phase (NS for intravenous fluid) to the BMES phase (sterofudin for intravenous fluid). The primary endpoint was the serum chloride concentration on trial day 3. Secondary endpoints included a composite of clinical and laboratory measures., Results: Overall, 259 patients were enrolled from 11 sites to receive NS (n = 147) or BMES (n = 112). On trial day 3, the mean chloride level was significantly lower in patients who received BMES [101.8 mmol/L (SD: 4.8) vs 105.8 mmol/L (SD: 5.9), difference -4.3 mmol/L (95% CI: -5.6 to -3.0 mmol/L) ; P < 0.001]. For secondary endpoints, patients who received BMES had less systemic inflammatory response syndrome (19/112, 17.0% vs 43/147, 29.3%, P = 0.024) and increased organ failure-free days [3.9 days (SD: 2.7) vs 3.5 days (SD: 2.7), P < 0.001] by trial day 7. They also spent more time alive and out of the intensive care unit [26.4 days (SD: 5.2) vs 25.0 days (SD: 6.4), P = 0.009] and hospital [19.8 days (SD: 6.1) vs 16.3 days (SD: 7.2), P < 0.001] by trial day 30., Conclusions: Among patients with pSAP, using BMES in preference to NS resulted in a significantly more physiological serum chloride level, which was associated with multiple clinical benefits (Trial registration number: ChiCTR2100044432)., Competing Interests: W.L. reports consultancy fees and grants from Jiangsu Nhwa Pharmaceuticals. L.K. reports speaker fees from Nhwa Pharmaceuticals. S.J. reports receiving consulting fees from Drager, Medtronic, Mindray, Fresenius, Baxter, and Fisher & Paykel. J.W. reports consulting fees and grants from Fisher and Paykel Healthcare and Viatris Ltd. R.B. received grants and consultancy fees from Baxter Health Care. The remaining authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Objective: The combination of catecholamine-resistant vasodilatory shock and acute kidney injury (AKI) is associated with high morbidity and mortality. The role of angiotensin II (ANGII) in this setting is unclear. Methods: We conducted a post hoc analysis of the Angiotensin II for the Treatment of High-Output Shock (ATHOS) 3 trial which assessed the effect of Intravenous ANG II or placebo in patients with refractory vasodilatory shock in 75 intensive care units across nine countries in North America, Australasia, and Europe. We included patients with all stages AKI at initiation of ANG II or placebo and assessed 28-day mortality as primary outcome. We studied mean arterial pressure (MAP) response and days alive and free from renal replacement therapy (RRT) up to day 7 as secondary outcome. Results: Of 321 ATHOS-3 patients, 203 (63%) had AKI at randomization, with stage 3 AKI being dominant (67%). Median age was 63 years and median APACHE II score was 30. By day 28, overall, 118 (58%) of patients had died (53% with ANGII vs. 63% with placebo, hazard ratio = 0.75, 95% CI [0.52-1.08], P = 0.121). Among AKI stage 3 patients, however, ANGII was associated with significantly lower mortality (48% vs. 67%, hazard ratio = 0.57, 95% CI [0.36-0.91], P = 0.024). Additionally, in this subgroup, compared with placebo, patients receiving ANGII were more likely to achieve a MAP response (P < 0.001) and had more days alive and free from RRT (P < 0.001). Conclusions: Compared with placebo, in patients with catecholamine-resistant vasodilatory shock and stage 3 AKI, ANGII is associated with lower 28-day, greater likelihood of MAP response, and more days alive and free from RRT. These findings support the conduct of future ANGII trials in patients with stage 3 AKI., Competing Interests: Conflict of interest statement: R.B. reports receiving research grants, speaking engagement fees and advisory board fees from Paion, Viatris, La Jolla, Baxter Healthcare, and Jafron Healthcare. A.Z. reports receiving advisory board fees from Paion and VIATRIS. A.C. reports no conflict of interest. L.F. reports advisory board fees and lecture fees from Paion. J.H. reports receiving advisory board fees from Paion. E.K. reports working for Paion. G.L. reports receiving advisory board fees from VIATRIS. P.P. reports receiving advisory board fees from Paion., (Copyright © 2024 by the Shock Society.)

Objectives: The optimal approach for resuscitation in septic shock remains unclear despite multiple randomized controlled trials (RCTs). Our objective was to investigate whether previously uncharacterized variation across individuals in their response to resuscitation strategies may contribute to conflicting average treatment effects in prior RCTs., Design: We randomly split study sites from the Australian Resuscitation of Sepsis Evaluation (ARISE) and Protocolized Care for Early Septic Shock (ProCESS) trials into derivation and validation cohorts. We trained machine learning models to predict individual absolute risk differences (iARDs) in 90-day mortality in derivation cohorts and tested for heterogeneity of treatment effect (HTE) in validation cohorts and swapped these cohorts in sensitivity analyses. We fit the best-performing model in a combined dataset to explore roles of patient characteristics and individual components of early goal-directed therapy (EGDT) to determine treatment responses., Setting: Eighty-one sites in Australia, New Zealand, Hong Kong, Finland, Republic of Ireland, and the United States., Patients: Adult patients presenting to the emergency department with severe sepsis or septic shock., Interventions: EGDT vs. usual care., Measurements and Main Results: A local-linear random forest model performed best in predicting iARDs. In the validation cohort, HTE was confirmed, evidenced by an interaction between iARD prediction and treatment ( p < 0.001). When patients were grouped based on predicted iARDs, treatment response increased from the lowest to the highest quintiles (absolute risk difference [95% CI], -8% [-19% to 4%] and relative risk reduction, 1.34 [0.89-2.01] in quintile 1 suggesting harm from EGDT, and 12% [1-23%] and 0.64 [0.42-0.96] in quintile 5 suggesting benefit). Sensitivity analyses showed similar findings. Pre-intervention albumin contributed the most to HTE. Analyses of individual EGDT components were inconclusive., Conclusions: Treatment response to EGDT varied across patients in two multicenter RCTs with large benefits for some patients while others were harmed. Patient characteristics, including albumin, were most important in identifying HTE., Competing Interests: Drs. Shah’s, Talisa’s, Chang’s, Tang’s, Cooper’s, Angus’s, and Yende’s institutions received funding from the National Institutes of Health (NIH; GM141081). Dr. Shah’s institution received funding from the NIH (K23GM122069, R21HL168070). Dr. Shah, Dr. Talisa, Dr. Chang, Dr. Triantafyllou, Dr. Tang, Mr. Kennedy, Dr. Cooper, Dr. Yealy, Dr. Seymour, Dr. Angus, and Dr. Yende received support for article research from the NIH. Dr. Talisa disclosed the study was supported by the NIH (UL1TR001857; S10OD028483). Dr. Triantafyllou, Mr. Kennedy, Dr. Cooper, and Dr. Seymour’s institutions received funding from the NIH (R01HL164835). Dr. Mayr’s institution received funding from the NIH (K23GM132688); he disclosed government work; and he received personal fees from Baxter for serving on a racial disparities advisory board outside the submitted work. Dr. Higgins’ institution received funding from the National Health and Medical Research Council (NHMRC) (GNT2008447); she received support for article research from the NHMRC. Mr. Mouncey’s institution received funding from the National Institute for Health and Care Research Health Technology Assessment program; he received support for article research from the National Institute for Health and Care Research. Mr. Kennedy’s and Dr. Seymour’s institutions received funding from the NIH (R21GM144851). Mr. Kennedy’s, Dr. Cooper’s, and Dr. Seymour’s institution received funding from the National Institute for General Medical Sciences (R35GM119519). Dr. Yealy’s institution received funding from the NIH. Dr. Seymour received funding from Beckman Coulter and Octapharma. Dr. Angus received funding from AM-Pharma and Abionyx. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: Estrogen deficiency and Diabetes mellitus (DM) cause joint tissue deterioration, although the mechanisms are uncertain. This study evaluated the immunoexpression of autophagy and NLRP3-inflammasome markers, in rat articular cartilage with estrogen deficiency and DM., Methods: Twenty rats were sham-operated (SHAM) or ovariectomized (OVX) and equally allocated into four groups: SHAM and OVX groups administered with vehicle solution; SHAM and OVX groups treated with 60 mg/kg/body weight of streptozotocin, intraperitoneally, to induce DM (SHAM-DM and OVX-DM groups). After seven weeks, the rats were euthanized, and their joint knees were processed for paraffin embedding. Sections were stained with haematoxylin-eosin, toluidine blue, safranin-O/fast-green or subjected to picrosirius-red-polarisation method; immunohistochemistry to detect beclin-1 and microtubule-associated protein 1B-light chain 3 (autophagy markers), NLRP3 and interleukin-1β (IL-1β) (inflammasome activation markers), along with matrix metalloproteinase-9 (MMP-9), Nuclear factor-kappa B (NFκB), and Vascular endothelial growth factor A (VEGF-A) were performed., Results: Deterioration of articular cartilage and subchondral bone were greater in SHAM-DM and OVX-DM groups. Higher percentages of immunolabeled chondrocytes to NLRP3, IL-1β, MMP-9, NFκB, and VEGF-A, as well as lower percentages of chondrocytes immunolabeled to autophagy markers, were noticed in estrogen-deficient and diabetic groups. These differences were greater in the OVX-DM group. Percentages of immunolabeled chondrocytes showed negative correlation between autophagy markers v.s IL-1β, NLRP-3, MMP-9, NFκB, and VEGF-A, along with positive correlation between VEGF-A vs. MMP-9, NFκB, IL-1β, and NLRP3, and MMP-9 vs. NFκB., Conclusions: In conclusion, autophagy reduction and NLRP3 inflammasome activation in chondrocytes may be implicated in articular cartilage degradation, under estrogen-deficient and DM conditions. Moreover, the combination of estrogen deficiency and DM may potentiate those effects., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background: Normothermic machine perfusion (NMP) aims to reduce ischemia-reperfusion injury in donor livers and its clinical manifestation, early allograft dysfunction (EAD) by maintaining perfusion and oxygenation. However, there is limited data on which NMP perfusate biomarkers might be associated with such EAD and the role of perfusate hemoglobin has not been assessed., Methods: We performed a pilot retrospective analysis of adult donor livers undergoing NMP between 2020 and 2022 at our center. NMP was commenced at the recipient hospital after initial static cold storage. All NMP circuits were primed in the same manner according to the manufacturer's instructions. Livers were stratified by initial perfusate hemoglobin below (≤5.2 mmol/L) or above (>5.2 mmol/L) the median. The association between hemoglobin levels and EAD or recipient peak transaminase levels was assessed., Results: Among 23 livers, eight were considered unsuitable for transplantation, leaving 15 livers for assessment. Higher initial hemoglobin was associated with a lower risk of EAD (0% vs. 55.6%, p = 0.04). Perfusate hemoglobin decreased after NMP initiation (p = 0.003) and negatively correlated with recipient peak transaminase levels (ALT: ρ = -0.72, p = 0.002; AST: ρ = -0.79, p < 0.001). Consistently, higher hemoglobin livers also demonstrated lower perfusate liver enzymes., Conclusions: Perfusate hemoglobin levels decreased during NMP, and lower perfusate hemoglobin levels were associated with a higher incidence of EAD and higher levels of liver injury markers. Maintaining higher hemoglobin levels during NMP may help reduce ischemia-reperfusion injury and prevent or attenuate EAD. Larger prospective studies are needed to validate the findings of this pilot study., (© 2024 The Author(s). Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Background: There are no published minute-by-minute physiological assessment data for endotracheal intubation (ETT) performed in the intensive care unit (ICU). The majority of physiological data is available from Europe and North America where etomidate is the induction agent administered most commonly., Aims: The aim of this study was to describe the feasibility of obtaining minute-by-minute physiological and medication data surrounding ETT in an Australian tertiary ICU and to assess its associated outcomes., Methods: We performed a single-centre feasibility observational study. We obtained minute-by-minute data on physiological variables and medications for 15 min before and 30 min after ETT. We assessed feasibility as enrolled to screened patient ratio and completeness of data collection in enrolled patients. Severe hypotension (systolic blood pressure < 65 mmHg) and severe hypoxaemia (pulse oximetry saturation < 80%) were the secondary clinical outcomes., Results: We screened 43 patients and studied 30 patients. The median age was 58.5 (interquartile range: 49-70) years, and 18 (60%) were male. Near-complete (97%) physiological and medication data were obtained in all patients at all times. Overall, 15 (50%) ETTs occurred after hours (17:30-08:00) and 90% were by video laryngoscopy with a 90% first-pass success rate. Prophylactic vasopressors were used in 50% of ETTs. Fentanyl was used in all except one ETT at a median dose of 2.5 mcg/kg. Propofol (63%) or midazolam (50%) were used as adjuncts at low dose. Rocuronium was used in all but one patient. There were no episodes of severe hypotension and only one episode of short-lived severe hypoxaemia., Conclusion: Minute-by-minute recording of ETT-associated physiological changes in the ICU was feasible but only fully available in two-thirds of the screened patients. ETT was based on fentanyl induction, low-dose adjunctive sedation, and frequent prophylactic vasopressor therapy and was associated with no severe hypotension and a single short-lived episode of severe hypoxaemia., (Copyright © 2024 Australian College of Critical Care Nurses Ltd. Published by Elsevier Ltd. All rights reserved.)