Critical Care Explorations

BackgroundEarly lactate is widely used to risk-stratify septic shock, yet clinically actionable cut-offs for 28-day mortality remain uncertain. MethodsIn a single-centre study conducted across two intensive care units, we analysed 84 adults with septic shock identified within 24 hours of intensive care unit admission. The primary endpoint was 28-day mortality. Four lactate metrics obtained during the first 24 hours were evaluated: first (admission) lactate, last lactate, peak lactate, and lactate clearance from first to last. Associations were tested using logistic regression with and without adjustment for the Simplified Acute Physiology Score 3; discrimination was assessed by area under the receiver-operating characteristic curve (AUROC), and optimal cut-offs were defined by the Youden index. ResultsThirty-nine of 84 patients (46.4%) died by day 28. Higher absolute lactate values were independently associated with death (adjusted odds ratio (OR) per 1 mmol/L increase: First 1.47, p<0.001; Last 1.41, p=0.002; Peak 1.39, p<0.001), whereas Lactate clearance was not (OR 0.65, p=0.202). Discrimination was moderate to good for peak (AUROC 0.817), first (0.791), and last (0.757) lactate, and poor for clearance (0.577). Youden-derived thresholds provided pragmatic trade-offs: First 3.55 mmol/L (sensitivity 0.821, specificity 0.689), Last 3.15 mmol/L (0.567, 0.864), and Peak 3.55 mmol/L (0.973, 0.556). Kaplan-Meier curves using these cut-offs showed early and sustained separation. ConclusionsIn adults with septic shock, simple early lactate thresholds around 3.3- 3.6 mmol/L (first/peak) and approximately 3.15 mmol/L (last) identify 28-day mortality risk and outperform lactate clearance.

RationaleAutonomic dysfunction is a hallmark of sepsis pathophysiology, yet its quantification remains challenging. Multiscale entropy (MSE) derived from heart rate variability (HRV) offers a dynamic measure of physiological complexity and may serve as a biomarker of early deterioration associated with subsequent organ failure, vasopressor escalation, or mortality. ObjectiveTo determine whether MSE computed across multiple temporal scales during the first 24 hours of Intensive Care Unit (ICU) admission is associated with short-term mortality and longer-term organ dysfunction in patients with sepsis, and whether these relationships vary across vasopressor exposure. Unlike prior studies that focused on short-term HRV metrics, we applied MSE across multiple temporal scales and incorporated these features into machine learning models to evaluate their prognostic utility in septic shock. MethodsThis retrospective cohort study included adult ICU sepsis patients at Emory University Hospital from January 2016 to December 2019. Of 2,076 eligible patients, 958 were propensity matched into two cohorts: fluids-only and fluids-plus-vasopressor, with norepinephrine as the primary vasopressor. High-resolution electrocardiogram (ECG) waveforms were analyzed to compute MSE across 20 temporal scales. Machine learning models using (1) MSE features alone and (2) MSE combined with demographic and vital sign data (MSE-DV) were compared against traditional HRV measures based model and severity of illness scores for predicting outcomes. Model performance was assessed using the area under the receiver operating characteristic curve (AUROC), with a primary outcome of mortality at day 7 and secondary outcome of persistent organ dysfunction at day 28. ResultsIn the fluids-plus-vasopressor cohort, MSE-based models demonstrated superior predictive performance for 7-day mortality (AUROC 0.84) compared to severity of illness scores (AUROC 0.64). MSE-DV models also predicted organ dysfunction including 28-day renal (AUROC 0.75), neurological (AUROC 0.79), and respiratory (AUROC 0.71) dysfunction. Patients receiving second-line and third-line vasopressors and corticosteroids exhibited progressively lower MSE values, particularly at mid-range and long-range scales. ConclusionMSE features in the first 24 hours of ICU stay predict mortality and organ dysfunction with higher discrimination than traditional severity of illness scores. Future work should validate these findings, assess longitudinal MSE trends, and race-specific autonomic patterns to refine predictive models.

IntroductionSepsis-induced organ failure is caused by a dysregulated host response characterized by mitochondrial and microcirculatory abnormalities. Early detection of perfusion deficits is critical to preventing progression to shock and organ failure. While capillary refill time (CRT) and other single-parameter assessments are used, a comprehensive, multimodal evaluation of peripheral perfusion has not yet been applied in clinical settings. The purpose of the MAP-SEPS trial is to ascertain whether such a multimodal approach can enhance early identification of sepsis and organ dysfunction in critically ill ICU patients. Methods and analysisMAP-SEPS is a prospective observational study enrolling a minimum of 50 adult ICU patients without sepsis on admission. Patients will be monitored over 72 hours using a multimodal protocol that includes clinical (CRT, skin temperature, mottling score, urine output), biochemical (lactate, ScvO{square}, Pv- aCO{square}, arterial/interstitial glucose), and near-infrared spectroscopy assessments. Standardized macrohemodynamic monitoring and echocardiography will be performed, along with advanced calculations of venous return dynamics, cardiac efficiency, and arterial/venous resistance. Data will be collected at predefined intervals and analyzed using mixed-effects linear regression models. The primary objective is to assess the predictive value of these hemodynamic and perfusion parameters for early detection of sepsis and organ failure. Secondary outcomes include ICU and hospital length of stay, mechanical ventilation duration, and mortality at 28 and 90 days. Ethics and disseminationThe study has been approved by the Ethics Committee of the General Hospital Tzaneio and complies with the Declaration of Helsinki. Peer-reviewed papers, conference presentations, and clinical seminars will all be used to disseminate the findings, contributing to better bedside evaluation techniques for septic patients.

BackgroundSepsis-related organ dysfunction results from complex interactions between systemic hemodynamics, microcirculatory alterations, and cellular metabolic failure. Conventional resuscitation strategies guided by global parameters may miss persistent tissue hypoperfusion, a phenomenon termed "hemodynamic incoherence." The PRISM trial was designed to determine whether individualized management guided by advanced multimodal circulatory and perfusion monitoring improves outcomes in septic shock. MethodsThe PRISM trial is a multicenter, randomized, controlled, open-label study with blinded outcome assessment. Adults with septic shock (Sepsis-3 criteria) are randomized (1:1) to structured multimodal monitoring versus standard care. The intervention integrates advanced systemic hemodynamic indices --including mean circulatory filling pressure analogue and other determinants of venous return, heart efficiency, cardiac power output, power efficiency, and volume efficiency-- with a comprehensive perfusion panel (capillary refill time, mottling score, temperature gradients, lactate kinetics, central venous oxygen saturation, venous-arterial carbon dioxide difference, near-infrared spectroscopy-derived skeletal muscle tissue oxygen saturation, and arterial-interstitial glucose gradients). A predefined treatment algorithm links abnormal thresholds to therapeutic interventions. The primary endpoint is change in SOFA and SAPS II scores from baseline to 72 hours. Secondary endpoints include 28-day mortality, ICU and hospital length of stay, ventilator- and vasopressor-free days, lactate clearance, and safety outcomes. DiscussionBy combining advanced hemodynamic physiology with structured multimodal perfusion monitoring, the PRISM trial tests whether individualized, pathophysiology-guided resuscitation can overcome hemodynamic incoherence and improve patient-centered outcomes in septic shock.

BackgroundProgressive hypoxemia is the predominant mode of deterioration in COVID-19. Among hypoxemia measures, the ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (P/F ratio) has optimal construct validity but poor availability because it requires arterial blood sampling. Pulse oximetry reports oxygenation continuously, but occult hypoxemia can occur in Black patients because the technique is affected by skin color. Oxygen dissociation curves allow non-invasive estimation of P/F ratios (ePFR) but this approach remains unproven. Research QuestionCan ePFRs measure overt and occult hypoxemia? Study Design and methodsWe retrospectively studied COVID-19 hospital encounters (n=5319) at two academic centers (University of Virginia [UVA] and Emory University). We measured primary outcomes (death or ICU transfer within 24 hours), ePFR, conventional hypoxemia measures, baseline predictors (age, sex, race, comorbidity), and acute predictors (National Early Warning Score (NEWS) and Sepsis-3). We updated predictors every 15 minutes. We assessed predictive validity using adjusted odds ratios (AOR) and area under receiver operating characteristics curves (AUROC). We quantified disparities (Black vs non-Black) in empirical cumulative distributions using the Kolmogorov-Smirnov (K-S) two-sample test. ResultsOvert hypoxemia (low ePFR) predicted bad outcomes (AOR for a 100-point ePFR drop: 2.7 [UVA]; 1.7 [Emory]; p<0.01) with better discrimination (AUROC: 0.76 [UVA]; 0.71 [Emory]) than NEWS (AUROC: 0.70 [UVA]; 0.70 [Emory]) or Sepsis-3 (AUROC: 0.68 [UVA]; 0.65 [Emory]). We found racial differences consistent with occult hypoxemia. Black patients had better apparent oxygenation (K-S distance: 0.17 [both sites]; p<0.01) but, for comparable ePFRs, worse outcomes than other patients (AOR: 2.2 [UVA]; 1.2 [Emory], p<0.01). InterpretationThe ePFR was a valid measure of overt hypoxemia. In COVID-19, it may outperform multi-organ dysfunction models like NEWS and Sepsis-3. By accounting for biased oximetry as well as clinicians real-time responses to it (supplemental oxygen adjustment), ePFRs may enable statistical modelling of racial disparities in outcomes attributable to occult hypoxemia.

RationaleThe blood pressure value below which the benefits of vasopressors clearly outweigh their disadvantages is uncertain. ObjectivesThe main objective of this analysis was to investigate the statistical properties and potential utility of indices estimating the vasopressor dose-rates as a function of blood pressure values over time. MethodsIn this single-center observational study, we collected blood pressure values from intensive care unit (ICU) monitors and norepinephrine dose-rates from infusion pumps corresponding to a derivation and a validation cohort. Patients included in each cohort were 18 years or older and received norepinephrine in the ICU. We defined and derived indices corresponding to vasopressor therapy above (>65 mmHg) and below (<60 mmHg) targets. We report the distribution of both indices over time from both cohorts as well as their associations with hospital mortality using logistic regression models adjusted for baseline variables. ResultsBetween July 30 2020 and March 28 2022, 283 patients were included in the derivation cohort. The median ICU stay was 5 days (interquartile range [IQR] 2-10.5) and the median duration of norepinephrine therapy was 27.3 hours (IQR 13.9-54.2). The median cumulative time with a MAP below 60 mmHg was 0.9 hours (IQR 0.2-3.1), whereas the cumulative time with a MAP above 65 mmHg was 22.5 hours (IQR 10.9-40.4). Adjusting for prespecified baseline variables, the above target index was associated with hospital mortality (OR 1.6, 95% CI 1.2 -2.3) but not the below target index (OR 1.1 95% CI 0.8 - 1.5). Between May 5 2022 and December 16 2022, 83 patients were included in the validation cohort. The duration of ICU stay and the proportion of norepinephrine exposure above MAP target were consistent with the derivation cohort. The point estimates of the associations between each index and mortality were also consistent with the derivation cohort, but not statistically significant. ConclusionIndices of vasopressor administration as a function of blood pressure suggest that during most of vasopressor therapy episodes, patients are treated above target. The association of these indices with patient outcomes remains uncertain but could be explored in larger datasets, and future clinical trials of target MAPs may consider measurement of these indices to adjust results for treatment adherence.

ImportanceEarly identification of fever or hypothermia is crucial for diagnosing sepsis. Despite their increased use across healthcare systems, concerns have been raised about the accuracy of temporal thermometers among Black patients. ObjectiveTo study the performance of temporal thermometry across race and ethnicity, and its impact on the initiation of the sepsis management bundle (SEP-1). DesignIn this retrospective cohort study, records from 2008-2024 in 123 U.S. hospitals were analyzed, including electronic health records from Duke, MIMIC-IV, eICU-CRD-1, and eICU-CRD-2. Patients were included if they had a temporal measurement within one hour of an oral/core measurement (esophageal, bladder, rectal). Main Outcomes and MeasuresHidden Fever was defined when the temporal thermometer read [&le;] 38{degrees}C but oral/core measurement > 38{degrees}C and Hidden Hypothermia as temporal temperature [&ge;] 36{degrees}C but oral/core < 36{degrees}C. The primary outcome was Hidden Hyper/Hypothermia (HHH) when either Hidden Fever or Hidden Hypothermia happened. Observed Hyper/Hypothermia (OHH) corresponded to an agreement between both measurements, used as a control. To study the impact of temporal thermometry underperformance on SEP-1 bundle initiation, we assessed time to culture ordering, antibiotics administration, and lactate measurement. A composite of these three, whichever happened first, was defined as our secondary outcome. Results6,921 paired temperature measurements were studied for the primary outcome analysis, corresponding to 4,248 hospitalizations (2.6% Asian; 12.4% Black; 2.6% Hispanic/Latino; 83.4% White; 44.9% female; 7.7% with HHH) from 115 hospitals. After adjusting for confounders, Black [OR (95% CI): 1.760 (1.219, 2.541), p=0.003] and Hispanic/Latino [OR (95% CI): 2.183 (1.226, 3.888), p=0.008] patients were significantly more likely to present with HHH than White patients. For the study of the secondary outcome, 434 patients had either OHH or HHH. Compared to patients with OHH, patients with HHH had significantly delayed secondary outcomes, with log-rank p-value of 0.002. Conclusions and RelevanceSolely relying on temporal thermometry can lead to missed hyper/hypothermia events, especially among Asian, Black, and Hispanic patients. This has been associated with delays in the initiation of the SEP-1 bundle, which may hamper health systems compliance with reimbursement programs. Key PointsO_ST_ABSQuestionC_ST_ABSAre there racial differences in temporal thermometry that result in missed hyper/hypothermia, and are these associated with delays in sepsis bundle care (SEP-1) initiation? FindingsIn this multicenter retrospective cohort study of 4,248 hospitalizations, Asian, Black, and Hispanic patients were more likely to have hidden hyper/hypothermia when using temporal thermometers, as compared to oral/core measurements. These missed events were associated with delayed SEP-1 interventions (three out of four were studied: culture orders, antibiotic administration, and lactate measurements). MeaningReliance on temporal thermometry could exacerbate health disparities and hamper hospital systems compliance with reimbursement programs. Temporal thermometers should therefore be routinely validated with contact thermometers.

The Sequential Organ Failure Assessment (SOFA)-2 score was recently validated for ICU mortality prediction across more than 3 million admissions but was not evaluated across demographic subgroups. We assessed the discrimination and calibration of the SOFA-2 score for ICU mortality across subgroups defined by age, sex, race and ethnicity, primary language, and insurance status. We conducted a retrospective cohort study of adult patients (aged 18 years or older) admitted to ICUs at Beth Israel Deaconess Medical Center between 2008 and 2022 (MIMIC-IV, version 3.1), selecting the first ICU admission per patient. First-day SOFA-2 scores (range, 0-24) were calculated using worst recorded values across 6 organ systems. Discrimination was assessed using AUROC, calibration using intercepts and slopes, and subgroup differences using bootstrap resampling. Among 64,015 ICU admissions (median age, 66 years [IQR, 54-78]; 56.1% male; 66.1% White), overall ICU mortality was 7.2% (n=4,596). Overall AUROC was acceptable at 0.77 (95% CI, 0.76-0.77). Notably, discrimination declined significantly with age: AUROC was 0.85 (95% CI, 0.83-0.87) for ages 18-44 and 0.72 (95% CI, 0.70-0.73) for ages 75 and older (difference in AUROC, -0.14; 95% CI, -0.16 to -0.11), with systematic underprediction of mortality in older patients (calibration intercept, 0.39). Discrimination was also significantly lower among non-English speakers (difference in AUROC, -0.04; 95% CI, -0.07 to -0.01) but did not differ significantly across documented racial and ethnic groups. Patients with unknown race/ethnicity (14.3% of the cohort) had nearly double the overall mortality rate and poor calibration. SOFA-2 demonstrated good overall performance for ICU mortality prediction but with clinically meaningful variation across demographic subgroups, particularly a substantial decline in discrimination with advancing age. These findings underscore the need for routine equity evaluation of clinical prediction tools before widespread implementation.

ObjectivesThis study aims to evaluate the association between pre-Extracorporeal Membrane Oxygenation (ECMO) markers of impaired oxygen delivery, as quantified by the iDO2 predictive analytics platform, and neurologic outcomes in infants supported on ECMO. The goal is to determine whether these markers can inform decision-support systems for optimizing ECMO initiation timing. Materials & MethodsWe performed a single-center retrospective cohort study of infants <1 year supported on ECMO from 2013-2017, excluding cases with congenital diaphragmatic hernia or post-cardiac surgery ECMO. Data included demographics, clinical variables, and iDO2 estimates retroactively calculated in 120-minute intervals prior to ECMO initiation. Primary outcomes included mortality, EEG abnormalities, and head imaging findings; secondary outcomes included MRI abnormalities and Functional Status Scores (FSS). ResultsOf 219 patients, 47 met inclusion criteria. Median age and weight at ECMO initiation were 16 days [IQR 6-112] and 3.3 kg [IQR 2.8-4.8], with an overall mortality rate of 55%. Non-survivors had higher rates of congenital heart disease (77% vs. 42%, p=0.03) and pre-ECMO cardiac arrest (53% vs. 14%, p=0.006). Time spent above iDO2 thresholds of 25%, 50%, and 75% increased closer to ECMO initiation. Higher iDO2 dose correlated with adverse neurologic outcomes, including EEG abnormalities and abnormal imaging, and predicted poor composite functional outcomes (p<0.05). Discussion & ConclusionMarkers of impaired oxygen delivery, such as iDO2, may inform the development of decision-support systems to optimize ECMO timing, potentially improving neurologic outcomes. Further research is needed to validate these findings and develop decision-support systems for clinical practice.

BACKGROUNDThe use of resuscitative endovascular balloon occlusion of the aorta (REBOA) for control of noncompressible torso hemorrhage remains controversial. We aimed to utilize a novel and transparent/interpretable artificial intelligence (AI) method called Optimal Policy Trees (OPT), to improve the appropriate use and decrease the misuse of REBOA in hemodynamically unstable blunt trauma patients. METHODSWe trained then validated OPTs that "prescribe" REBOA in a 50:50 split on all hemorrhagic shock blunt trauma patients in the 2010-2019 ACS-TQIP database based on rates of survival. Hemorrhagic shock was defined as a systolic blood pressure [&le;] 90 on arrival or transfusion requirement of [&ge;] 4 units of blood in the first 4 hours of presentation. The expected 24-hour mortality rate following OPT prescription was compared to the observed 24-hour mortality rate in patients who were or were not treated with REBOA. RESULTSOut of 4.5 million patients, 100,615 were included and 803 underwent REBOA. REBOA patients had a higher rate of pelvic fracture, femur fracture, hemothorax, pneumothorax, and thoracic aorta injury (p<0.001). The 24-hour mortality rate for the REBOA vs. non-REBOA group was 47% vs. 21%, respectively (p<0.001). OPTs resulted in an 18% reduction in 24-hour mortality for REBOA and 0.8% reduction in non-REBOA patients. CONCLUSIONInterpretable AI models can improve mortality in unstable blunt trauma patients by optimizing the use and decreasing the misuse of REBOA. These models to date have been used to predict outcomes, but their groundbreaking use will be prescribing interventions and changing outcomes. LEVEL OF EVIDENCELevel IV, Prognostic

Background: Many patients in the ICU receive oxygen to secure blood and tissue oxygenation. Increasing evidence shows exposure to high fractions of inhaled oxygen (FiO2) being associated with adverse effects. In patients with severe ARDS, veno-venous Extracorporeal Membrane Oxygenation (VV-ECMO) can be implemented as a rescue therapy and PaO2 levels can be controlled by the blood flow of the VV-ECMO. Yet, optimal oxygenation targets in ARDS patients treated with VV-ECMO are unknown. Methods: Retrospective analysis of 443 patients with severe ARDS treated with VV-ECMO. Regression analyses were performed for mortality and time-weighted averages of PaO2 and FiO2. Furthermore, considering a possible non-linear relationship, a restricted cubic spline (RCS) model was performed for PaO2. Results: A simple logistic regression for mean PaO2 and ICU mortality showed a significant positive association (per mmHg OR 0.99 [95%CI 0.98-1.00], p=0.002). RCS analysis showed a U-shaped association of mortality and mean paO2 (paO2 69.70-90.24mmHg: OR 0.92 [95%CI 0.89-0.94], p<0.001; paO2 90.24-123.40mmHg: OR 1.09 [95%CI 1.06-1.13], p<0.001). A model including PaO2 as RCS variable and FiO2 showed significant associations of mortality with both variables (PaO2 69.70-90.24mmHg: OR 0.94 [95%CI 0.91-0.97], p<0.001; paO2 90.24-123.40 mmHg: OR 1.07 [95%CI 1.04-1.11], p<0.001; FiO2: OR 35.98 [95%CI 8.67-158.60], p<0.001, VIF<1.11). Conclusions: PaO2-levels in patients with ARDS and VV-ECMO have a U-shaped association with mortality. Optimal outcomes are observed in the 90-123 mmHg range, which is higher compared to non-ECMO settings. Whether this is explainable by increased tissue oxygenation with concurrent avoidance of pulmonary hypoxia should be subject of future research.

PurposeEndostatin is a promising biomarker for predicting acute kidney injury (AKI) and mortality in the intensive care unit (ICU). We investigated plasma endostatin upon ICU admission as a predictor of AKI, renal replacement therapy (RRT), and 30-day mortality. MethodsA retrospective multicenter study was performed with admissions (ICU length of stay [&ge;]24 hours) to four ICUs. KDIGO criteria defined AKI. Endostatin on ICU admission was compared to creatinine, cystatin C, and the Simplified Acute Physiology Score 3 (SAPS-3). Admissions with sepsis and creatinine <100 mol/L on ICU admission underwent subgroup analyses. Regression models and the area under the receiver operating characteristic curve (AUC) were assessed. ResultsIn total, 4449 admissions were included (43% sepsis and 61% AKI). Endostatin was associated with AKI (odds ratio [OR] 1.6, 95% confidence interval [CI] 1.4-1.7), future AKI (OR 1.5, 95% CI 1.4-1.7), future AKI stage 3 (OR 1.4, 95% CI 1.2-1.6), and RRT (OR 1.2, 95% CI 1.1-1.4) independently of creatinine and cystatin C, with similar results in sepsis. Endostatin was also associated with time to AKI (hazard ratio 1.2, 95% CI 1.1-1.2). For admissions with creatinine <100 mol/L, endostatin (AUC 0.62, 95% CI 0.59-0.65) outperformed creatinine (AUC 0.51, 95% CI 0.49-0.54) and cystatin C (AUC 0.53, 95% CI 0.50-0.56) in predicting future AKI (p<0.001). Endostatin was not associated with 30-day mortality after adjusting for SAPS-3. ConclusionEndostatin is an early and potentially clinically useful biomarker for predicting AKI and RRT needs at ICU admission, especially in patients with low to mildly elevated creatinine.

BackgroundPulse oximeters are typically validated on cohorts of 200-500 subjects under controlled conditions. Whether these cohorts capture the demographic heterogeneity of national clinical practice -- and whether measurement error is associated with patient outcomes -- has not been established at scale. MethodsWe analyzed paired SpO2/SaO2 readings from three independent sources spanning 209 U.S. hospitals: MIMIC-IV (1 hospital; 12,934 ICU stays), eICU-CRD (208 hospitals; 55,178 stays), and the Open Oximetry Repository (PhysioNet; 52.4 million readings with continuous melanin and perfusion indices). Bias was defined as SpO2 - SaO2. Hidden hypoxemia (SpO2 [&ge;] 94% with SaO2 < 88%) was assessed per ICU stay. Mortality was compared between hidden-hypoxemia-positive and -negative stays with multivariable logistic regression adjusting for age, sex, race, and four laboratory severity markers (cluster-robust SEs by hospital). Sensitivity analyses included landmark restriction (first 48 hours), lactate stratification, alternate thresholds, and patient-level aggregation. PPG signal quality was assessed in 125 ICU patients with demographic-linked waveform data. ResultsBias was minimal at normal perfusion but amplified under low perfusion in high-melanin patients, consistent with known optics: at very low perfusion x high melanin x severe hypoxia, mean bias reached +12.8% (n = 458,571), with 47% of readings constituting hidden severe hypoxemia. National bias in African American patients was +2.76% (n = 529,541; 208 hospitals), 62% higher than academic estimates. Across 55,178 eICU stays, hidden hypoxemia was associated with approximately doubled mortality after adjustment for age, sex, race, and illness severity (adjusted OR 1.86, 95% CI 1.69-2.04, p < 0.001), consistent across all racial groups. Hidden hypoxemia was not a pre-terminal phenomenon: 63% of events occurred >48 hours before death (median first event: 15.3 hours; mean time to death: 151 hours), and the association persisted in landmark analysis (first 48 hours only), in patients with normal lactate (adjusted OR 1.87, 95% CI 1.61-2.16), and when both restrictions were applied simultaneously (16.5% vs. 11.1%). Waveform analysis (n = 125) showed no fixed racial difference in baseline PPG AC/DC ratio (Black: 0.299, White: 0.273), suggesting the signal deficit is conditional on perfusion state. Full extraction (n = 1,545) is in progress. ConclusionsIn this multicenter retrospective analysis, national pulse oximetry variance exceeded published benchmarks and was associated with approximately doubled ICU mortality, replicated across 209 U.S. hospitals. Hidden hypoxemia was not a pre-terminal artifact: events occurred throughout the ICU stay at a constant rate, and mortality associations persisted in landmark and lactate-stratified analyses. These findings suggest that current regulatory validation standards may underestimate the real-world prevalence of demographic bias in pulse oximetry, and that perfusion-dependent mechanisms may offer a target for algorithmic correction.

Corticosteroids decrease the duration of organ dysfunction in a range of infectious critical illnesses, but their risk and benefit are not fully defined using this construct. This retrospective multicenter study aimed to evaluate the association between usage of corticosteroids and mortality of patients with infectious critical illness by emulating a target trial framework. The study employed a novel stratification method with predictive machine learning (ML) subphenotyping based on organ dysfunction trajectory. Our analysis revealed that corticosteroids effectiveness varied depending on the stratification method. The ML-based approach identified four distinct subphenotypes, two of which had a large enough sample size in our patient cohorts for further evaluation: "Rapidly Improving" (RI) and "Rapidly Worsening," (RW) which showed divergent responses to corticosteroid treatment. Specifically, the RW group either benefited or were not harmed from corticosteroids, whereas the RI group appeared to derive harm. In the development cohort, which comprised of a combination of patients from the eICU and MIMIC-IV datasets, hazard ratio estimates for the primary outcome, 28-day mortality, in the RW group was 1.05 (95% CI: 0.96 - 1.04) whereas for the RW group, it was 1.40 (95% CI: 1.28 - 1.54). For the validation cohort, which comprised of patients from the Critical carE Database for Advanced Research, estimates for 28-day mortality for the RW and RI groups were 1.24 (95% CI: 1.05 - 1.46) and 1.34 (95% CI: 1.14 - 1.59), respectively. For secondary outcomes, the RW group had a shorter time to ICU discharge and time to cessation of mechanical ventilation with corticosteroid treatment, where the RI group again demonstrated harm. The findings support matching treatment strategies to empirically observed pathobiology and offer a more nuanced understanding of corticosteroid utility. Our results have implications for the design and interpretation of both observational studies and randomized controlled trials (RCTs), suggesting the need for stratification methods that account for the differential response to standard of care.

BACKGROUNDEarly identification of patients at risk for sepsis, mortality, and clinical deterioration is essential for improving outcomes, but existing diagnostic and predictive tools have limited accuracy. The objective was to evaluate the performance of an FDA-authorized AI tool, the Sepsis ImmunoScore, compared to widely available biomarkers and clinical tools for diagnosis of sepsis and prediction of in-hospital mortality and intensive care unit (ICU) admission. METHODSThis multicenter observational study included 6,027 adult patients suspected of infection across 7 U.S. hospital sites. The Sepsis ImmunoScores predictive performance was compared to the sequential organ failure assessment (SOFA) score, procalcitonin (PCT), C-reactive protein (CRP), Systemic Inflammatory Response Syndrome (SIRS) score, National Early Warning Score (NEWS), and quick SOFA (qSOFA). Primary outcomes included sepsis as defined by Sepsis-3 criteria, in-hospital mortality, and ICU admission. Predictive accuracy was assessed using area under the receiver operating characteristic curve (AUC), and 95% confidence intervals were generated and hypothesis testing conducted using the bootstrap method. RESULTSThe Sepsis ImmunoScore demonstrated statistically significant superior performance across all outcomes. For sepsis prediction, the Sepsis ImmunoScore achieved an AUC of 0.82, compared to SOFA (0.72), procalcitonin (PCT) (0.70),C-reactive protein (CRP) (0.61), SIRS (0.59), NEWS (0.69), and qSOFA (0.67). For in-hospital mortality prediction, the Sepsis ImmunoScore achieved an AUC of 0.80, outperforming SOFA (0.72), PCT (0.67), CRP (0.58), SIRS (0.60), NEWS (0.72), and qSOFA (0.69). For ICU admission, the Sepsis ImmunoScore reached an AUC of 0.74, superior to SOFA (0.63), PCT (0.64), CRP (0.54), SIRS (0.60), NEWS (0.70), and qSOFA (0.65). All differences between the Sepsis ImmunoScore and comparators were statistically significant. CONCLUSIONSThe Sepsis ImmunoScore significantly improved predictive accuracy for sepsis, in-hospital mortality, and ICU admission compared to six conventional clinical scores and biomarkers. This AI-based tool may enhance risk stratification and clinical decision-making, potentially leading to more timely sepsis interventions and improved outcomes. KEY POINTSO_ST_ABSQuestionC_ST_ABSHow does the FDA-authorized Sepsis ImmunoScore compare to conventional sepsis tools at diagnosing and predicting sepsis, clinical deterioration, and in-hospital mortality? FindingsIn a multicenter observational cohort of 6,027 patients with suspected infection, the Sepsis ImmunoScore demonstrated statistically superior performance compared to PCT, CRP, SOFA, qSOFA, SIRS, and NEWS in predicting all outcomes: sepsis diagnosis, ICU admission, and in-hospital mortality. MeaningBecause the Sepsis ImmunoScore outperforms existing sepsis diagnostics, it could potentially enhance risk stratification and clinical decision-making for patients with suspected infection, enabling more appropriate and timely interventions.

Overview: SeptiCyte RAPID is an FDA-cleared gene expression test that quantifies host immune response to aid in the diagnosis of sepsis. The test yields a score (the SeptiScore) ranging from 0-15, distributed across four bands (1-4) based on increased likelihood of sepsis. Each band can be characterized by average positive and negative likelihood ratios (LR+, LR- respectively) for the discrimination of sepsis versus the non-infectious systemic inflammatory response syndrome (SIRS). Methods: A retrospective analysis of prospectively collected data from a combined cohort of critically ill patients suspected of sepsis (N=889), recruited across 19 hospitals in the USA and Europe. The analysis quantified the LR+ and LR- parameters as a function of SeptiScore, for discrimination of sepsis vs. SIRS in patients admitted to ICU. Hypotheses: (1) The likelihood ratio (LR) framework provides a clinically useful interpretive approach that complements the previously used SeptiScore banding scheme; (2) Low Band 1 SeptiScores are associated with sufficiently small LR- to support the use of SeptiCyte RAPID as a rule-out test for sepsis; (3) High Band 4 SeptiScores are associated with sufficiently large LR+ to support the use of SeptiCyte RAPID as a rule-in test for sepsis; and (4) SeptiScore-derived LR+ and LR- values can be combined with estimates of pre-test probability (derived from patient characteristics and/or other diagnostic tests) to generate individualized, patient-specific post-test probabilities of sepsis. Results: The SeptiCyte RAPID test demonstrates strong diagnostic performance in distinguishing sepsis from SIRS. The likelihood ratios across different score bands provide clear clinical utility: the median LR+ was 3.26 (range 2.57-4.24) for Band 3, and 6.97 (range 4.35-15.57) for Band 4 providing evidence toward ruling in sepsis at high SeptiScores. Conversely, the median LR- was 0.16 (range 0.14-0.20) for Band 2 and 0.085 (range 0.014-0.16) for Band 1, providing evidence toward ruling out sepsis at low SeptiScores. A higher-resolution analysis of SeptiCyte RAPID performance confirmed these trends by evaluating LR+ and LR- at specific values within each band. The sepsis group was further stratified according to whether patients were classified as blood-culture positive (BC+) or blood culture negative (BC-), and the detailed LR+ and LR- analyses were repeated. A monotonic increase in likelihood ratio with increasing SeptiScore was consistently observed, independent of whether sepsis patients were culture-positive, culture-negative, or unstratified with respect to blood culture status. Conclusion: High SeptiScores have correspondingly high LR+ values, and low SeptiScores have correspondingly low LR- values, both of which may have clinical utility. High likelihood ratios for band 4 SeptiScores, which precede traditional microbiology results, may provide clinicians with early confidence of a sepsis diagnosis and microbiology diagnostic stewardship. Low likelihood ratios for band 1 SeptiScores may prompt clinicians to consider an alternate diagnosis to sepsis. Such results, obtained early in the diagnostic workup process, may lead to fewer missed diagnoses and more efficient use of hospital resources.

ObjectiveThe objective of this study was to examine the impact of timely treatment and identification of sepsis on patient outcomes at Sutter Health, a mixed-payer healthcare system in northern California, US. MethodsThis observational, retrospective analysis considered electronic health record (EHR) data for individuals who presented with sepsis during 2016-17 at any of Sutter Healths 22 emergency departments (ED). Impacts were assessed for the timing of broad-spectrum antibiotic and intravenous (IV) fluid initiation, first vital signs, sepsis screening, and lactate results. Outcomes were in-hospital mortality, hospital length of stay (LOS) and intensive care unit (ICU) hours for patients discharged alive. ResultsThe final sample size was 35,847 (N=9,638 severe sepsis, N=5,309 septic shock). Early fluid initiation had the largest estimated impacts: a mortality reduction of 2.85%[2.03%,3.68%] overall and 2.94%[1.44%,4.48%] for severe sepsis (within 1 hour of sepsis presentation), and 14.66%[9.23%,20.07%] for septic shock (within 3 hours); reduced LOS (days) 1.39[1.08,1.71] overall, 2.30[1.31,3.21] severe sepsis, 3.07[1.21,4.94] septic shock; and fewer ICU hours 25.93[16.95,34.66] overall, 35.06[14.7,56.99] severe sepsis, 41.99[15.70,70.68] septic shock (within 3 hours). Sepsis screening within 30 minutes was also associated with mortality reductions (3.88%[2.96%,4.90%] overall, 1.74%[0.08%,3.50%] severe sepsis, 6.78%[3.12%,10.33%] septic shock). The greatest improvement opportunity was estimated for joint initiation of antibiotics and IV fluids, with a modest additional mortality reduction of 0.80%[0.47%,1.17%] overall, 0.77%[0.34%,1.19%] severe sepsis, 2.94%[1.83%,3.97%] septic shock; LOS reduction of 0.37[0.28,0.46] overall, 0.29[0.17,0.43] severe sepsis, 0.25[0.01,0.51] septic shock (within 1 hour); ICU hours reduction of 4.85[3.26,6.57] overall, 5.07[2.55,7.67] severe sepsis, 3.85[1.69,6.24] septic shock (within 3 hours).

Purpose: Polypharmacy is highly prevalent among critically ill patients, yet it's independent impact on intensive care unit (ICU) outcomes in sepsis remains critically unexplored. We aimed to evaluate whether pre-admission polypharmacy independently predicts ICU mortality and provides incremental prognostic value using the medication reconciliation module of the MIMIC-IV-ED linked database. Materials and Methods: We conducted a retrospective cohort study of 3,347 adults admitted to the ICU who met Sepsis-3 criteria. Pre-admission polypharmacy was categorized as none (0-4), standard (5-9), or high (>=10 medications). Multivariable logistic regression, propensity score matching, and reclassification analyses (NRI/IDI) were performed. The primary outcome was in-hospital ICU mortality. Results: High polypharmacy was present in 58.9% of patients. Crude ICU mortality increased sequentially: 18.5% (none), 26.0% (standard), and 27.5% (high; p < 0.001). After multivariable adjustment, high polypharmacy independently predicted in-hospital ICU mortality (aOR 1.45, 95% CI (1.10-1.91)), and 28-day mortality (aOR 1.47). Drug-class analysis identified statins as significantly protective (aOR 0.56), whereas RAS blockers combined with diuretics increased acute kidney injury risk (aOR 1.49). Propensity matching confirmed the primary mortality association (matched aOR 1.28). Conclusions: By utilizing the ED medication reconciliation table, this study proves high polypharmacy represents a distinct 'pharmacologic frailty', independent of acute severity. Available instantly at triage, this zero-latency metric provides significant early prognostic value (SOFA NRI = 0.24) and identifies actionable high-risk interactions (e.g., RAS blockers plus diuretics) for immediate, targeted pharmacist-led intervention upon ICU admission.

Background: Patient matching in intensive care databases yields sample sizes too small for individualised outcome analysis. Current AI systems provide population-level guideline summaries but omit stratification variables that may invert therapy signals at the individual level. Methods: We developed the Therapeutic Distance framework, which computes the z-standardised distance between a patient's clinical parameters and the centroid of MIMIC-IV patients who received each therapy: d(P,T) = sum of wi(T) x |(Li - mui(T)) / sigmai|. We hypothesise that patients at the same distance to a therapy (same orbit) have comparable outcomes. Six validation experiments were performed on 11,627 sepsis patients (SAPS-II 30-80) from MIMIC-IV v3.1. Results: Echo-stratified vasopressin recipients showed mortality of 30.1% (n=146, 95% CI 22.6-37.7%) versus 53.9% without echo (n=2,426, 95% CI 51.9-55.9%). Confidence intervals did not overlap (bootstrap, 1,000 resamples). However, echo-stratified patients had lower general severity (SAPS-II 49.2 vs 53.9) but higher cardiac biomarkers (troponin 1.0 vs 0.51 ng/mL), indicating that the observed difference is compatible with both severity confounding and a possible cardiac-specific vasopressin effect. Leave-one-out prediction with uniform weights achieved AUC 0.61 as a structural baseline. Conclusions: Therapeutic Distance replaces patient matching with orbit matching, substantially increasing usable sample sizes. The echo-vasopressin finding is hypothesis-generating and mechanistically plausible but not causally proven. The framework is intended as a clinical decision support signal under uncertainty, not as a causal inference method.

ObjectivesTo elucidate the changes in cardiorespiratory dynamics during neuromuscular blockade and prone positioning and determine the associations between changes in cardiorespiratory dynamics following prone positioning and mortality. DesignSingle center retrospective cohort study of patients admitted to the medical ICU between June 1, 2020 and September 1, 2022 who received prone positioning while mechanically ventilated. ResultsOur final cohort consisted of 136 patients. Prone position was associated with an improvement in A-a gradient of 113 mmHg (95% CrI 78 - 149) between the pre-proning values and 10 hours post proning. Norepinephrine dose did not significantly change before and after prone positioning (Estimated difference: 0.04 mcg/min 95% CrI -1.00 - 1.07). For the outcome of 7-d mortality, there was a high probability that the baseline factors of increasing age, male sex, and higher baseline A-a gradient were associated with increased risk of death. Increased total vasopressor requirement and increased in PCO2 were associated with worse prognosis while a decrease in instantaneous heart rate and a decrease in heart rate variability were associated with improved prognosis. ConclusionThe immediate changes in prone positioning primarily impact respiratory physiology, with limited influence on circulatory parameters. Predictors of short-term mortality after prone positioning include both respiratory and cardiovascular parameters suggesting that extrapulmonary effects, such as improvement in right ventricular heart function, might also contribute to the benefit of prone positioning.