BACKGROUND: Postoperative patients have been underrepresented in randomized controlled trials of acute respiratory distress syndrome (ARDS). Whether postoperative ARDS differs from medical ARDS in its clinical trajectory...BACKGROUND: Postoperative patients have been underrepresented in randomized controlled trials of acute respiratory distress syndrome (ARDS). Whether postoperative ARDS differs from medical ARDS in its clinical trajectory, outcomes, and prognostic determinants remains unclear. We aimed to compare postoperative and medical ARDS with respect to early trajectory, mortality, and risk factors for mortality. METHODS: We conducted a retrospective analysis of prospectively collected data in a tertiary ICU from 2003 to 2023. All consecutive intubated adults fulfilling the ARDS New Global Definition were included. ARDS cases were labeled as postoperative when onset occurred within 15 days after surgery. The primary outcome was 90-day mortality, assessed with multivariable Cox analysis. Early ARDS trajectories were assessed at day 3. Multivariable Cox analyses were used to identify factors independently associated with mortality. RESULTS: Among 1,077 intubated ARDS patients, 455(42%) had postoperative ARDS. Compared with medical ARDS, postoperative ARDS showed more favorable early trajectories (p = 0.03) and lower 90-day mortality (36% vs. 49%, p < 0.001). Postoperative ARDS remained independently associated with lower 90-day mortality after adjustment (adjusted hazard ratio[aHR] = 0.68, 95%CI:0.56-0.83, p < 0.001). Prognostic determinants differed markedly. In postoperative ARDS, mortality was independently associated with extrapulmonary organ dysfunction (non-respiratory SOFA score: aHR = 1.10, 95%CI:1.05-1.15; bicarbonate: aHR = 0.81 per 5mmol/L, 95%CI:0.69-0.96) and surgical context, (esophageal surgery: aHR = 0.41, 95%CI:0.24-0.70; upper abdominal surgery: aHR = 0.64, 95%CI:0.46-0.91 versus lower abdominal surgery), while no marker of respiratory failure was independently associated with mortality. In medical ARDS, mortality was independently associated with respiratory failure, including PaO/FiO ratio (aHR = 0.88 per 50mmHg, 95%CI:0.81-0.96) and driving pressure (aHR = 1.13 per 5cmHO, 95%CI = 1.01-1.27), and extrapulmonary organ dysfunction. CONCLUSION: Postoperative ARDS differs from medical ARDS in its early clinical trajectory, outcomes, and prognostic determinants. These findings support postoperative ARDS as a distinct clinical subtype, mainly driven by extrapulmonary and surgery-related factors rather than by the lung injury itself, supporting a management approach focused on perioperative prevention and early identification of surgery-related complications.
BACKGROUND: Liberation from mechanical ventilation (MV) remains challenging, particularly in difficult-to-wean patients. Weaning failure (i.e. inability to wean or post-extubation failure) and spontaneous breathing trial...BACKGROUND: Liberation from mechanical ventilation (MV) remains challenging, particularly in difficult-to-wean patients. Weaning failure (i.e. inability to wean or post-extubation failure) and spontaneous breathing trial (SBT) failure are often grouped together despite distinct underlying mechanisms. Moreover, most studies have focused on a single physiological predictor of weaning success, although ventilator liberation is a complex, multiorgan process. We hypothesized that a multimodal, ultrasound-based assessment performed during SBT in difficult-to-wean patients would improve prediction of weaning outcomes compared with individual physiological parameters. METHODS: In this single-center prospective observational study, adult difficult-to-wean patients (≥ 48 h of mechanical ventilation and failure of the first separation attempt) underwent a standardized SBT. A comprehensive assessment of diaphragmatic function, lung aeration, cardiac function, and peripheral muscle strength was performed. In addition, dyspnea assessment and clinical variables were recorded before and at the end of the SBT. An integrated predictive model was developed using clinical selection and Least Absolute Shrinkage and Selection Operator (LASSO) regression, and it was compared with individual predictors. The primary outcome was to predict weaning failure (inability to wean or post-extubation failure). SBT failure was evaluated as a secondary outcome and defined as the inability to successfully complete the SBT due to clinical signs of intolerance. RESULTS: Weaning failure occurred in 27% of patients. Compared with successfully weaned patients, those with weaning failure had lower diaphragmatic contractile reserve (maximal diaphragm thickening fraction), reduced handgrip strength, higher prevalence of ICU-acquired weakness, greater dyspnea after SBT, and more pronounced loss of lung aeration during SBT. Cardiac parameters, including higher ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e') and ejection fraction, were associated with SBT failure, whereas neuromuscular impairment was more strongly associated with post-extubation failure. An integrated model demonstrated good predictive performance (AUROC 0.88; 95% CI 0.78-0.95), outperforming individual predictors in predicting weaning failure. CONCLUSIONS: In difficult-to-wean patients, SBT failure and weaning failure are driven by several interacting physiological mechanisms. A multimodal, ultrasound-based approach integrating cardiac, pulmonary, diaphragmatic, and neuromuscular domains improves prediction of weaning outcomes and may enable more individualized ventilator liberation strategies. TRIAL REGISTRATION: This study was prospectively registered in clinicaltrial.gov (NCT05539599; First Posted 2022-09-14).
Bouras M, Pageau M, Gagnon MA
… +14 more, Costerousse O, Demers K, Grenier-Gagnon A, Isaac CJ, Torkomyan TH, Lauzier F, Zarychanski R, Francoeur CL, Gerges P, Abiala G, Moore L, English SW, Turgeon AF, Canadian Traumatic Brain Injury Research Consortium
Hyperlactatemia is a frequent finding in critically ill patients and is traditionally interpreted as a marker of tissue hypoxia and anaerobic metabolism. However, in sepsis, septic shock, and other states of circulatory...Hyperlactatemia is a frequent finding in critically ill patients and is traditionally interpreted as a marker of tissue hypoxia and anaerobic metabolism. However, in sepsis, septic shock, and other states of circulatory failure - including post-cardiac arrest syndrome - elevated lactate concentrations often occur despite preserved arterial oxygenation and adequate oxygen delivery. Increasing evidence indicates that lactate is a central metabolic intermediate whose circulating concentration reflects the balance between stress-induced production, cellular utilization, and organ clearance. While hepatic metabolism has long been considered the dominant pathway for lactate disposal, the kidneys - particularly proximal tubular cells - play a major and often underappreciated role in lactate utilization and clearance. Acute kidney injury (AKI), a common complication of sepsis, directly alters systemic lactate homeostasis. In this narrative review, we synthesize current knowledge on lactate biology in critical illness and examine the contribution of renal metabolism to hyperlactatemia in patients with sepsis-induced AKI. We propose that lactate should be interpreted as an integrated metabolic signal reflecting systemic stress and impaired clearance - rather than as a surrogate for hypoxia alone - with important implications for the management of septic AKI. The potential of urinary lactate as a marker of proximal tubular metabolic dysfunction and the emerging role of protein lactylation in modulating the inflammatory-to-reparative phenotypic transition are also discussed.
BACKGROUND: Sepsis and shock are associated with high morbidity and mortality in critically ill patients. Oxidative stress contributes to endothelial dysfunction and multiorgan failure, but the prognostic value of total...BACKGROUND: Sepsis and shock are associated with high morbidity and mortality in critically ill patients. Oxidative stress contributes to endothelial dysfunction and multiorgan failure, but the prognostic value of total plasma antioxidant capacity, measured by the Ferric Reducing Antioxidant Power (FRAP) assay, has not been systematically evaluated in postoperative patients. METHODS: We conducted a prospective, multicentre observational study including 464 critically ill postoperative patients admitted to intensive care units at three Spanish hospitals (2021-2026). Plasma FRAP levels were measured within the first 24 h after surgery or after clinical diagnosis of sepsis or shock, according to patient status. Clinical severity was assessed using Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores. Associations between FRAP, shock, endothelial damage and 90-day mortality were analysed using survival and regression analyses. Endothelial-associated responses were evaluated in Human Umbilical Vein Endothelial Cells incubated with patient plasma. RESULTS: FRAP levels were significantly higher in patients with shock, particularly in those with septic shock and in non-survivors (p < 0.001). FRAP positively correlated with Acute Physiology and Chronic Health Evaluation II scores and was independently associated with 90-day mortality (HR = 4.69; p < 0.05). Elevated FRAP was associated with endothelial damage and with increased FRAP levels in HUVEC supernatants. FRAP showed good discrimination for 90-day mortality (Area Under the Curve = 0.881; 95% CI: 0.775-0.987). Comparative analyses demonstrated slightly higher discriminative performance for FRAP compared with APACHE II within the present cohort, while combined FRAP-APACHE II models showed improved performance in precision-recall analyses. CONCLUSIONS: Elevated plasma Ferric Reducing Antioxidant Power levels in postoperative critically ill patients are associated with shock severity, endothelial injury and increased mortality, particularly in those with septic shock. This biomarker may serve as an early prognostic marker and a rapid, inexpensive and reproducible tool for risk stratification in critical care settings.
BACKGROUND: Frailty is an independent predictor of worse outcomes after critical illness, yet intensive care trials almost invariably omit reporting frailty distribution in the investigated cohort. This study investigate...BACKGROUND: Frailty is an independent predictor of worse outcomes after critical illness, yet intensive care trials almost invariably omit reporting frailty distribution in the investigated cohort. This study investigated the magnitude and prevalence of imbalanced baseline distribution in frailty using the ordinal Clinical Frailty Scale that could contribute to clinically significant differences in apparent mortality. METHODS: A database of 6968 patients admitted to intensive care unit was used to simulate enrolment of between 100 and up to 1000 patients into each of the control and interventional arms of a hypothetical two-arm trial. Both 1:1 randomisation and block randomisation using permuted blocks of variable sizes were simulated 100 times and referred to as 'trials'. The observed relationship between the Clinical Frailty Scale and observed in-hospital mortality was used to determine thresholds for frailty imbalance sufficient to generate ≥2% and ≥5% differences in mortality. The proportions of 'trials' meeting these criteria are reported as percentages and 95%CI. RESULTS: Imbalanced frailty generated a ≥2% mortality difference in 36 [95%CI 31-42]% of 'trials' with 100 patients/arm that was reduced to 9 [95%CI 6-13]% of 'trials' with 400 patients/arm. An imbalance in frailty associated with a ≥5% mortality difference occurred in 3 [95%CI 1-5]% of 'trials' with 100 patients/arm and reduced to 0% [95%CI 0-1.3]% in all 'trials' using larger sample sizes. 'Trials' with a binary balance between non-frail vs frail patients still retained an ordinal frailty imbalance to generate a ≥2% mortality difference in 10 [95%CI 7-14]% with 100 patients/arm. Block randomisation only reduced the proportion of 'trials' with mortality differences related to frailty to a minor and variable degree. CONCLUSIONS: Baseline distributional imbalance in frailty may create clinically significant differences in apparent mortality estimates. The hypothesis-generating findings in this study suggest that intensive care trials should report complete frailty distributions and consider frailty in study designs and analyses.
PURPOSE: The sequential organ failure assessment (SOFA) score was recently updated to better reflect contemporary intensive care. This study compares the predictive validity of the updated SOFA-2 and the previous SOFA-1...PURPOSE: The sequential organ failure assessment (SOFA) score was recently updated to better reflect contemporary intensive care. This study compares the predictive validity of the updated SOFA-2 and the previous SOFA-1 for 30-day mortality over the first week in ICU, overall and in subgroups with distinct age and comorbidity profiles. METHODS: We conducted a retrospective observational study of adult patients admitted to four ICUs in Sweden from 2010 to 2021. Predictive validity for 30-day mortality was assessed on day 1-7 using the area under the receiver operating characteristic curve (AUROC). RESULTS: We included 29,820 admissions (mean age 60 years, 64.8% males, median Charlson comorbidity index [CCI] 1). Reclassification between SOFA-1 and SOFA-2 occurred in 75-79% of admissions across days 1-7. On day 1, the AUROC for 30-day mortality was 0.81 (95% CI 0.80-0.81) for SOFA-2 and 0.80 (95% CI 0.79-0.81) for SOFA-1 (p < 0.001). From day 2 onward, AUROCs declined for both scores and were largely similar. Among trauma patients (mean age 50 years; median CCI 0), day-1 AUROC for SOFA-2 was 0.81 (95% CI 0.79-0.83), while among sepsis patients (mean age 61 years; median CCI 3) it was 0.72 (95% CI 0.70-0.74), with comparable performance for SOFA-1. CONCLUSIONS: SOFA-2 provided modestly better discrimination for 30-day mortality on ICU-day 1 compared with SOFA-1. Predictive validity diminished over subsequent days for both scores and varied across subgroups with different age and comorbidity distributions, underscoring the context-dependence of organ dysfunction scoring. TRIAL REGISTRATION: https://doi.org/10.5281/zenodo.17651826 , registration date November 19, 2025.
BACKGROUND: Spontaneous breathing trial (SBT) is the standard test of readiness for liberation from invasive mechanical ventilation, but some patients who successfully complete SBT still experience early post-extubation...BACKGROUND: Spontaneous breathing trial (SBT) is the standard test of readiness for liberation from invasive mechanical ventilation, but some patients who successfully complete SBT still experience early post-extubation failure. Inspiratory effort during SBT has emerged as an important physiological determinant of weaning tolerance and extubation outcome because it reflects the balance between ventilatory load and respiratory muscle capacity, yet its assessment often requires airway occlusions, dedicated ventilator algorithms, or intermittent measurements. We therefore evaluated whether an electrical impedance tomography (EIT)-derived flow index (EFI) measured during SBT was associated with SBT outcome and with reintubation within 48 h after extubation. METHODS: In this prospective multicenter observational study, mechanically ventilated adults receiving invasive ventilation for at least 48 h underwent a standardized 30-min pressure support SBT with continuous EIT monitoring. EFI was calculated breath by breath from EIT-derived inspiratory flow-time profiles. The primary endpoint was SBT outcome. A prespecified key secondary endpoint was reintubation within 48 h after planned extubation among patients who successfully completed the SBT and underwent extubation according to routine care. EFI discrimination for SBT failure was assessed using receiver operating characteristic analysis. For the post-extubation analysis, 48-h freedom from reintubation was evaluated using Kaplan-Meier analysis and Cox proportional hazards models. RESULTS: A total of 150 patients were enrolled, of whom 107 successfully completed the SBT and underwent planned extubation. EFI showed excellent discrimination for the primary endpoint of SBT outcome (AUC 0.980) and provided early physiological warning of evolving SBT intolerance. Reintubation within 48 h occurred in 7 of 107 extubated patients. Using the EFI threshold of 1.333 derived from the primary endpoint analysis, patients with EFI < 1.333 had significantly lower 48-h freedom from reintubation than those with EFI ≥ 1.333, and all reintubation events occurred in the EFI < 1.333 group. In univariable Cox analyses, EFI, RSBI, MIP, and P0.1 were each associated with reintubation within 48 h after extubation. Because of severe multicollinearity among these indices and the very small number of events, a combined multivariable model was not pursued. CONCLUSIONS: EFI measured during SBT was strongly associated with SBT outcome and showed an exploratory association with reintubation within 48 h after extubation. Beyond identifying SBT intolerance, EFI may help identify patients with residual physiological vulnerability after a successful SBT; however, this secondary finding requires cautious interpretation and external validation. TRIAL REGISTRATION: ClinicalTrials.gov NCT06876792. Registered on March 10, 2025.
White KC, Neto AS, Laupland KB
… +13 more, Gatton M, Ramanan M, Chaba A, Whebell S, Tabah A, Shekar K, McCullough J, Kumar A, Garrett P, Attokaran A, Luke S, Blank S, Queensland Critical Care Research Network (QCCRN)#
PURPOSE: To estimate the effect of restrictive fluid management on renal function and mortality in critically ill patients with acute kidney injury (AKI) at high risk of developing positive fluid balance. METHODS: We con...PURPOSE: To estimate the effect of restrictive fluid management on renal function and mortality in critically ill patients with acute kidney injury (AKI) at high risk of developing positive fluid balance. METHODS: We conducted a target trial emulation using data from 12 intensive care units in Queensland, Australia (2015-2021). Adults with AKI within 72 h of intensive care unit (ICU) admission and an AKI-Fluid Balance Risk Score ≥ 32 were included. The intervention comprised conservative crystalloid administration, restricted nutritional fluid intake, and diuretic use for 72 h. We estimated per-protocol effects using a sequential doubly robust estimator for longitudinal modified treatment policies. The primary outcome was AKI Rank at day 7; secondary outcomes included 30-day mortality. RESULTS: Among 8,685 patients, the intervention was associated with substantial reduction in fluid balance (- 2,304 mL at 72 h; 95% CI, - 2,465 to - 2,144) and modest improvement in AKI Rank (mean difference - 0.8; 95% confidence interval (CI), - 1.3 to - 0.3). Heterogeneity by AKI stage was observed: the intervention was associated with improved renal function in stage 1 AKI (mean difference - 3.1; 95% CI, - 3.8 to - 2.5) but worse outcomes in stage 2 AKI (mean difference 4.5; 95% CI, 3.8 to 5.1) and stage 3 AKI (mean difference 6.3; 95% CI, 4.7 to 7.9) with increased 30-day mortality (relative risk 1.20; 95% CI, 1.09 to 1.33). Effective sample sizes were limited (7-16%), indicating reliance on extrapolation. CONCLUSIONS: Restrictive fluid management was associated with improved renal function in early AKI but potentially harmful effects in stages 2 and 3 AKI. These hypothesis-generating findings suggest any future trial should incorporate safety criteria for patients with advanced renal injury.
BACKGROUND: Discomfort of noninvasive respiratory supports remain controversial. In the present study, the discomfort of high flow nasal cannula oxygen, noninvasive ventilation, and conventional oxygen therapy were evalu...BACKGROUND: Discomfort of noninvasive respiratory supports remain controversial. In the present study, the discomfort of high flow nasal cannula oxygen, noninvasive ventilation, and conventional oxygen therapy were evaluated in the post-extubation period. METHODS: Noninvasive ventilation alternating with high flow nasal cannula oxygen or conventional oxygen therapy were implemented for 48 h following extubation in patients free of chronic obstructive pulmonary disease. Using a 10-cm visual analog scale, the discomfort of the interface (oxygen mask, nasal prongs or facial mask), was self-evaluated by 264 patients after extubation whereas the discomfort of the respiratory support (conventional oxygen therapy or high flow nasal cannula oxygen alternating with noninvasive ventilation) was evaluated by the nurses in 306 patients. Evaluations were performed in patients at high (n = 127) and low (n = 179) risk of postextubation respiratory failure, 6, 24 and 48 h after extubation. RESULTS: Facial mask was the source of a significant and persisting self-evaluated discomfort. Nasal prongs and oxygen mask were less uncomfortable, with a progressive reduction of the discomfort with time. High flow nasal cannula oxygen alternating with noninvasive ventilation caused a significant and persisting nurse-reported discomfort. Conventional oxygen therapy was significantly less uncomfortable, and the degree of discomfort was not different in patients at high and low risk of extubation failure. CONCLUSIONS: Noninvasive ventilation was associated with a significant and persisting discomfort whereas high flow nasal cannula oxygen-induced discomfort remained limited. After 48 h, discomfort resulting from high flow nasal cannula oxygen and conventional oxygen therapy was similar and negligible.
Mühlhaus M, Dyck B, Witowski A
… +30 more, Unterberg M, Wolf A, Haberl H, von Busch A, Ziehe D, Thon P, Palmowski L, Westhus B, Ehrentraut SF, Bracht T, Bayer M, Sitek B, Marcus K, Eisenacher M, Ellger B, Wappler F, Schwier E, Henzler D, Köhler T, Zarbock A, Putensen C, Frey UH, Anft M, Babel N, Nowak H, Rahmel T, Adamzik M, Rump K, Koos B, SepsisDataNet.NRW research group
BACKGROUND: Sepsis is a life-threatening condition characterized by a dysregulated immune response to infection. Toll-like receptor 4 plays a central role in pathogen recognition and inflammatory signalling and has been...BACKGROUND: Sepsis is a life-threatening condition characterized by a dysregulated immune response to infection. Toll-like receptor 4 plays a central role in pathogen recognition and inflammatory signalling and has been considered a key driver of sepsis pathophysiology. Pharmacological inhibition of this receptor showed beneficial effects in experimental models but failed in clinical trials. We therefore aimed to quantify in vivo activation of Toll-like receptor 4 in patients with sepsis and to determine its association with 30-day survival. METHODS: Peripheral blood mononuclear cells were obtained from 100 patients with sepsis enrolled in the SepsisDataNet.NRW cohort. Samples were collected on day 1 (within 36 h after diagnosis) and day 4. Activation of TLR4 was quantified by measuring receptor phosphorylation using a validated proximity ligation assay. Survival analyses were performed using Kaplan-Meier curves and Cox proportional hazards regression models to assess the association between receptor activation and 30-day mortality. RESULTS: Overall activation of TLR4 was low, with median values below one signal per cell at both day 1 and day 4. Despite the generally low levels, a subgroup of patients showed increased receptor activation. Higher activation was associated with significantly reduced 30-day survival. Patients with elevated activation had a higher risk of death both at day 1 (HR 2.03, 95% CI 1.01-4.07, p = 0.048) and day 4 (HR 2.77, 95% CI 1.14-6.73, p = 0.025). This association remained significant after adjustment for SOFA score at admission, age, infection focus and sex in multivariable Cox regression analysis (p = 0.006). CONCLUSIONS: In vivo activation of TLR4 is not uniformly present in patients with sepsis but occurs only in a subset of individuals. In those patients, increased activation is strongly associated with mortality. These findings suggest the presence of a distinct high-risk sepsis endotype characterized by enhanced receptor activation. This may help explain the failure of previous clinical trials of TLR4 inhibitors and supports the concept of biomarker-guided precision medicine approaches in sepsis. TRIAL REGISTRATION: German Clinical Trials Register (DRKS), DRKS00018871, retrospectively registered on 14 November 2019.
Hurtado-Navarro L, Flores-Cabeza E, Mata-Martínez P
… +15 more, Sánchez-Sánchez M, Terrón-Arcos V, Martín-Flórez C, Cachafeirio L, Vejo-Gutiérrez J, Fernández-Felipe J, Lozano-Rodríguez R, Córdoba L, de Santa María-Diez GS, Del Prado-Montero J, Rigor-Pérez JG, de Diego RP, Del Fresno C, Cueto FJ, López-Collazo E
Rehn P, Hölzl K, Seidlitz S
… +12 more, von Garrel A, Hölle T, von der Forst M, Studier-Fischer A, Fiedler-Kalenka M, Fischer D, Schmitt FC, Lichtenstern C, Weigand MA, Maier-Hein L, Dietrich M, Katzenschlager S
BACKGROUND: Despite stabilizing macrocirculatory blood pressure, vasopressors may deleteriously affect microcirculatory perfusion in critically ill patients. As microcirculatory dysfunction is associated with adverse out...BACKGROUND: Despite stabilizing macrocirculatory blood pressure, vasopressors may deleteriously affect microcirculatory perfusion in critically ill patients. As microcirculatory dysfunction is associated with adverse outcomes and objective bedside monitoring remains limited, hyperspectral imaging (HSI) has emerged as a promising noninvasive method to assess tissue oxygenation. This study investigated the association between load of vasoactive medication and microcirculatory impairment using HSI in critically ill patients. METHODS: In this secondary analysis of the prospective HySpec-ICU study, 502 surgical ICU patients were included. HSI measurements of the hand were performed on the day of admission to determine tissue oxygenation (StO₂) and other HSI variables. Multivariable linear regression and mediation analysis were employed to investigate the association between Norepinephrine Equivalent (NEE) and StO₂ and its impact on serum lactate levels. RESULTS: Higher NEE was independently associated with significantly lower StO₂ (B = - 0.0931, β=-0.193, p = 0.001), while MAP showed no significant correlation with StO₂. Patients in the highest NEE quartile (> 0.28) exhibited the lowest StO₂ and the highest 30-day mortality (41.8%). StO₂ partially mediated the relationship between vasopressor load and arterial lactate. StO₂ generally improved after shock reversal defined as NEE ≤ 0.05, lactate < 2mmol/l, MAP ≥ 65mmHg for at least 24 h (+ 5.8%, p < 0.001). CONCLUSION: High vasopressor requirements are associated with impaired microcirculatory oxygenation of the hand regardless of systemic blood pressure. HSI provides an objective bedside tool to monitor these alterations, potentially identifying patients with persistent microcirculatory shock who require intensified therapy beyond macrohemodynamic targets.
BACKGROUND: Immune checkpoint inhibitors (ICIs) are increasingly used as first-line therapy for various malignancies and are associated with a growing spectrum of immune-related adverse events. While many toxicities are...BACKGROUND: Immune checkpoint inhibitors (ICIs) are increasingly used as first-line therapy for various malignancies and are associated with a growing spectrum of immune-related adverse events. While many toxicities are managed in the outpatient setting, a clinically significant subset progresses to life-threatening multisystem disease requiring intensive care. Among these, the Triple M overlap syndrome, characterized by concurrent myasthenia gravis-like disease, inflammatory myositis, and myocarditis, represents the most severe and lethal phenotype encountered in critical care. MAIN TEXT: Triple M overlap syndrome presents unique diagnostic and management challenges in critically ill patients. Clinical features frequently overlap with sepsis, pneumonia, thromboembolism, and cardiopulmonary disease, creating significant diagnostic uncertainty. In addition, traditional diagnostic tools such as myasthenia gravis antibody testing and early cardiac imaging may be normal or nondiagnostic early in the disease course. This review focuses on the recognition and management of Triple M overlap syndrome in the intensive care unit. We highlight key diagnostic pitfalls, including the frequent under-recognition of occult myocarditis and the limitations of electrophysiologic and serologic testing. A structured ICU-oriented approach is proposed, emphasizing early multisystem evaluation with creatine kinase, serial troponins, electrocardiography, and cardiac imaging, alongside concurrent assessment for infection. Management strategies include prompt discontinuation of ICIs, early initiation of corticosteroids, and escalation to intravenous immunoglobulin or plasma exchange for severe neuromuscular involvement. Cardiac complications require close monitoring and early immunosuppression. Targeted therapies such as abatacept are discussed in the context of myocarditis, with current evidence limited primarily to cardiac involvement. This review emphasizes a practical ICU-oriented framework incorporating parallel evaluation for immune-mediated toxicity and infection in critically ill patients. CONCLUSION: Triple M overlap syndrome represents a high-risk and often underrecognized manifestation of ICI toxicity in critically ill patients. Early recognition, parallel evaluation for infection and immune-mediated disease, and coordinated multisystem management are essential to improving outcomes. Greater awareness and structured diagnostic approaches may reduce delays in treatment and associated mortality.
PURPOSE: Evidence on inhaled sedation in neurocritically ill patients remains limited, mainly due to concerns about potential increases in intracranial pressure (ICP). We aimed to evaluate the efficacy and safety of earl...PURPOSE: Evidence on inhaled sedation in neurocritically ill patients remains limited, mainly due to concerns about potential increases in intracranial pressure (ICP). We aimed to evaluate the efficacy and safety of early isoflurane sedation compared with propofol in invasively monitored neurocritical patients without intracranial hypertension. METHODS: NEURO-CONDA is a phase IV, randomized, open-label, parallel-group pilot trial conducted in a tertiary ICU (May 2024-October 2025). Adult neurocritical patients requiring ICP monitoring and without intracranial hypertension were randomized to receive either propofol or isoflurane. The primary endpoints were efficacy (assessed with RASS and BIS™) and safety, defined as the occurrence of serious adverse drug reactions (ADRs), including sustained ICP elevation or cerebral perfusion pressure (CPP) < 60 mmHg requiring increased vasopressor support. Nociception (NOL®) and other systemic parameters were recorded for up to 72 h. Analyses were performed according to the intention-to-treat principle. RESULTS: Thirty patients were included (15 per group), and baseline characteristics were comparable; 19 had traumatic brain injury. Sedation efficacy was 100% in both groups throughout the study period. No serious ADRs occurred. ICP and CPP remained stable throughout the study period without requiring higher doses of vasopressors in the isoflurane sedated group. CONCLUSIONS: In this randomized pilot trial, early sedation with isoflurane was feasible and achieved reliable deep sedation without compromising intracranial or cerebral perfusion parameters in invasively monitored neurocritical patients without intracranial hypertension. Larger randomized studies are warranted to confirm these findings and assess long-term neurological outcomes.
INTRODUCTION: Prognostic assessment in critically ill patients traditionally relies on severity scores or single biomarkers, each with limited ability to capture the biological heterogeneity of critical illness. OBJECTIV...INTRODUCTION: Prognostic assessment in critically ill patients traditionally relies on severity scores or single biomarkers, each with limited ability to capture the biological heterogeneity of critical illness. OBJECTIVE: To compare the prognostic performance of multiple biomarkers, individually and in combination with clinical variables, using machine learning approaches for the prediction of mortality and kidney-related outcomes. MATERIALS AND METHODS: We performed a post-hoc analysis of the FROG-ICU cohort, a prospective observational study of patients admitted to ICUs. The study included critically ill patients who required invasive mechanical ventilation or a vasoactive agent for more than 24 h. The primary outcome was day-90 mortality, secondary outcome was major adverse kidney event (MAKE) in ICU. A total of 15 plasma biomarkers were evaluated using multiparametric approach. ML models involved Random Forest (RF) and LASSO regression. Mean decrease in accuracy was used to determine variable importance in RF model. External validation was performed in the MARS cohort which involved ICU patients admitted for sepsis and septic shock. RESULTS: Among 2,061 patients in the FROG-ICU day-90 mortality was 30.1%. Machine learning models achieved AUCs of 0.74, outperforming severity scores (AUC 0.64, p < 0.001). Variable importance analysis consistently identified sTREM-1 as the strongest predictor. When evaluated alone, sTREM-1 demonstrated high prognostic performance (AUC 0.72), comparable to ML models. These findings were confirmed in the MARS cohort. Similar results were observed for MAKE prediction. CONCLUSION: sTREM-1 is a robust biomarker associated with mortality and kidney-related outcomes in critically ill patients. Its predictive performance were comparable to multiparametric machine learning models and superior to severity scores.