Clinical effectiveness of high-flow nasal therapy (HFNT) over conventional oxygen therapy (COT) in patients with mild COVID-19-related acute hypoxaemic respiratory failure (AHRF) remains uncertain. The COVID-HIGH trial did not demonstrate statistically significant benefits of HFNT over COT. However, the trial was slightly underpowered, and the event rate lower-than-expected. Bayesian methods provide deeper insight by incorporating prior knowledge and quantifying uncertainty intuitively. This analysis aimed to quantify the probability of benefit or harm associated with HFNT, adopting a Bayesian approach. We performed a Bayesian reanalysis of the COVID-HIGH trial (NCT, which randomised 364 patients with PaO₂/FiO₂ between 200–300 mmHg to receive HFNT or COT. The primary outcome was escalation of respiratory support (continuous positive airway pressure, noninvasive ventilation or invasive mechanical ventilation) within 28 days. A key secondary outcome was clinical recovery at day 14. Bayesian logistic models with noninformative and informative priors were used to estimate the posterior probability of treatment effects. Escalation of respiratory support occurred in 23.6

BACKGROUND:Arginine vasopressin (AVP) is used as an adjunct to catecholamine vasopressors, but its role as a sole agent in high-risk non-cardiac surgery remains poorly defined. OBJECTIVES:To characterize the integrated hemodynamic effects of AVP when used as the primary intraoperative vasopressor. METHODS:In a propensity-matched physiological analysis, high-risk patients receiving AVP as the sole intraoperative vasopressor were matched to contemporaneous controls managed with catecholamine-based vasopressors. Serial hemodynamic data were analyzed, including arterial pressure, cardiac index, central venous pressure (CVP), venous return determinants, efficiency measures, and intraoperative fluid administration. RESULTS:Fifteen AVP-treated patients were matched to 13 controls, with all covariates balanced (SMDs <0.10). Mean AVP infusion rate was 0.023 (0.005) IU min-1. AVP patients received lower intraoperative fluids (p = 0.03) and had reduced net positive fluid balance (p = 0.02). Mean arterial pressure targets were maintained in both groups (AVP: 72-78 mmHg; controls: 70-76 mmHg). Cardiac index remained preserved with AVP (2.2-2.5 L min-1 m-2), comparable to controls (2.1-2.4 L min-1 m-2), despite lower CVP (AVP: 6-7 mmHg vs. 8-10 mmHg), consistent with effective recruitment of stressed volume and preserved cardiac function. Resistance to venous return remained stable over time, with no between-group differences (p > 0.05). AVP-treated patients demonstrated patterns consistent with improved circulatory efficiency compared with controls. CONCLUSION:In high-risk non-cardiac surgery, AVP-based hemodynamic management was associated with stable circulatory dynamics, preserved venous return, and reduced fluid exposure. These findings provide a physiological rationale for considering AVP as an alternative hemodynamic strategy in selected surgical patients.

Abstract Septic shock is a life-threatening syndrome characterized by profound circulatory dysfunction and disordered cellular metabolism, necessitating precise physiologic monitoring to guide resuscitation. In this context, sepsis-induced hemodynamic derangements range from early vasoplegia and hyperdynamic circulation to later-stage myocardial depression and microcirculatory failure. These dynamic changes create a heterogeneous perfusion landscape that challenges traditional approaches to oxygen transport assessment. Central venous oxygen saturation (ScvO2) has long been used as a surrogate marker of cardiac output and global tissue oxygenation; however, in sepsis, impaired cellular oxygen utilization may result in paradoxically normal or elevated ScvO2 despite ongoing tissue hypoxia. In contrast, the oxygen extraction ratio (O2ER) offers a more integrative assessment of oxygen transport by reflecting the balance between oxygen delivery and consumption. Unlike ScvO2, O2ER may remain informative in the presence of microcirculatory and mitochondrial dysfunction and may demonstrate greater sensitivity to changes in oxygen delivery, based on physiological reasoning and observational data. Accordingly, O2ER may provide complementary physiological insight in complex shock states, although this approach has not been validated in randomized interventional trials. This narrative review synthesizes foundational and contemporary evidence to propose a physiologically grounded framework for oxygen transport monitoring, delineating the strengths, limitations, and clinical utility of ScvO2, O2ER, and metabolic markers in guiding resuscitation strategies for patients with septic shock.

The syndromic convergence of septic shock and acute respiratory distress syndrome represents a critical nexus of pathophysiological complexity, marked by profoundly elevated mortality and governed by multifaceted, temporally dynamic cardiorespiratory interactions. Conventional hemodynamic management paradigms frequently fail to achieve optimal outcomes, owing to their insufficient accommodation of the bidirectional and nonlinear interdependence between respiratory system derangements and cardiovascular stress responses. This review systematically re-examines the underlying mechanistic architecture of these interactions, commencing with a reappraisal of the canonical Guyton model of circulatory equilibrium, followed by an in-depth delineation of the respiratory cycle's modulatory influence on cardiac preload, afterload, and ventricular interdependence. Central to the analysis is the contention that acute respiratory distress syndrome should be mechanistically phenotyped into "pulmonary" and "extra-pulmonary" subtypes, a nosological distinction with direct implications for divergent hemodynamic trajectories under mechanical ventilation. Emerging integrative models-synthesizing respiratory mechanics with advanced circulatory physiology-are presented to conceptualize and visualize these complex feedback loops. This framework converges upon the pivotal determinant of hemodynamic stability: the coupling ratio between right ventricular contractile performance, quantified by end-systolic elastance, and the imposed pulmonary arterial load, represented by effective arterial elastance. The overarching aim is to advance an integrative, mechanistically anchored, and clinically actionable schema capable of enhancing diagnostic granularity, guiding individualized hemodynamic optimization, and ultimately improving survival in this uniquely unstable and high-acuity patient cohort.

Circulatory shock remains difficult to manage because fluid resuscitation and catecholamines may exacerbate vascular dysfunction and tissue hypoperfusion. This prospective physiological analysis, embedded within a multicentre phase IV study, examined whether selectively targeting the venous circulation with centhaquine improves circulatory dynamics in spontaneously breathing patients with mixed hypovolaemic-vasodilatory shock (MHVS). Fifteen spontaneously breathing adults with MHVS received centhaquine (0.01 mg kg-1) in addition to standard care. Over 300 min, mean circulatory filling pressure analogue increased from 6.03 ± 0.22 to 7.28 ± 0.21 mmHg and driving pressure for venous return from 5.88 ± 0.22 to 7.16 ± 0.21 mmHg (adjusted P < 0.001 for both), while estimated central venous pressure remained near atmospheric pressure and resistance to venous return remained unchanged. Cardiac output increased from 5.62 ± 0.22 to 6.80 ± 0.24 L min-1 and mean arterial pressure from 56.8 ± 1.5 to 69.8 ± 2.0 mmHg (adjusted P < 0.001 for both). Effective arterial elastance and systemic vascular resistance did not significantly change over time. Patients received 677 ± 79 mL of crystalloids during the study period, and no drug-related adverse events were observed. The findings of this preliminary physiological study suggest that selective venoconstriction may augment venous return and systemic haemodynamics in spontaneously breathing patients with MHVS without evidence of major adverse haemodynamic effects.

BACKGROUND:Hemodynamic failure remains a major determinant of mortality in critical illness, yet its detection is often delayed because conventional monitoring relies predominantly on Eulerian measurements that quantify pressure and flow magnitude without resolving the spatial and temporal organization of circulation. Consequently, clinically significant states of dysfunction may persist despite apparently stable hemodynamic indices. The Geometry of Shock is a conceptual and hypothesis-generating multi-scale framework intended to integrate established cardiovascular physiology with emerging computational approaches for the analysis of circulatory dysfunction. FRAMEWORK:The proposed framework combines Guytonian venous return physiology and cardiopulmonary interactions with Lagrangian flow topology, geometric representations of circulatory equilibrium, topological data analysis, and physics-constrained inverse modeling. Rather than focusing exclusively on static thresholds of pressure and flow, the framework proposes a structural interpretation of circulation centered on the dynamic organization and coherence of blood transport across cardiovascular domains. Within this paradigm, under-recognized hemodynamic phenotypes-including stressed volume failure, oscillatory shock during spontaneous breathing, macro-microcirculatory decoupling, and pulmonary vascular pressure-flow dissociation-may emerge from disrupted coupling between vascular, cardiac, pulmonary, and microcirculatory systems. These states may represent reversible structural transitions in venous return geometry and cardiopulmonary interaction preceding overt circulatory collapse. CONCLUSIONS:By reframing shock as a disorder of circulatory structure and coherence rather than solely a deficit in flow, this framework proposes a mechanistic foundation that may support future approaches aimed at earlier recognition of instability, improved physiological characterization of hemodynamic phenotypes, and future development and prospective validation of physiology-informed computational decision-support strategies in critical care. These concepts remain exploratory and hypothesis-generating rather than clinically validated.

Objectives: To investigate the correlation between varying doses of norepinephrine (NE) and the incidence of pressure injuries (PIs) in COVID-19 patients in intensive care units (ICUs). Design: A retrospective multicenter study was conducted on 1,078 COVID-19 patients admitted to ICUs with acute respiratory distress syndrome (ARDS) requiring mechanical ventilation. The research spanned from March 2020 to April 2021 across five university-affiliated hospitals in Iran. Univariate and multivariate binary logistic regression analyses, along with linear and non-linear dose-response assessments, were utilized to evaluate the relationship between NE dosages and the probability of PI development. Findings: The multivariate analysis revealed a significant association between higher doses of NE administered over 24 h (OR: 1.832,95% CI: 1.218-2.754, P=0.004) and cumulative doses (OR: 1.408,95% CI: 1.204-1.975, P=0.048) with the occurrence of PIs. Moreover, patients receiving high NE doses had a nearly fourfold increased risk of developing PIs, regardless of PIs stage, compared to those on low or moderate doses (>15 mu g/min vs. <= 15 mu g/min; OR: 4.401, 95 % CI: 3.339-5.801, P=0.001). Although the linear dose-response analysis did not show a significant correlation between NE doses and PI development (P>0.05), the non-linear analysis indicated that NE doses <= 9 mu g/min were associated with a reduced risk of PI development. Conclusion: Maintaining NE infusion within the range of 1-9 mu g/min appears to be most effective in reducing the likelihood of PIs in ICU patients with COVID-19. Lower NE doses (<= 9 mu g/min) were associated with a lower risk of PI development, suggesting that factors beyond NE dosage or the use of other vasopressors may play a crucial role in PI formation in this patient cohort. Implications for Clinical Practice: Rather than suggesting a specific threshold, clinicians should consider further studies to determine the optimal dose that balances microvascular perfusion and patient outcomes. It is crucial to comprehensively evaluate additional factors and selectively use vasopressors. Individualized care, including regular monitoring and personalized treatment plans, is essential for achieving the best outcomes in this patient population.

AbstractThe gastrointestinal tract can be deranged by ailments including sepsis, trauma and haemorrhage. Ischaemic injury provokes a common constellation of microscopic and macroscopic changes that, together with the paradoxical exacerbation of cellular dysfunction and death following restoration of blood flow, are collectively known as ischaemia–reperfusion injury (IRI). Although much of the gastrointestinal tract is normally hypoxemic, intestinal IRI results when there is inadequate oxygen availability due to poor supply (pathological hypoxia) or abnormal tissue oxygen use and metabolism (dysoxia). Intestinal oxygen uptake usually remains constant over a wide range of blood flows and pressures, with cellular function being substantively compromised when ischaemia leads to a >50% decline in intestinal oxygen consumption. Restoration of perfusion and oxygenation provokes additional injury, resulting in mucosal damage and disruption of intestinal barrier function. The primary cellular mechanism for sensing hypoxia and for activating a cascade of cellular responses to mitigate the injury is a family of heterodimer proteins called hypoxia‐inducible factors (HIFs). The HIF system is connected to numerous biochemical and immunologic pathways induced by IRI and the concentration of those proteins increases during hypoxia and dysoxia. Activation of the HIF system leads to augmented transcription of specific genes in various types of affected cells, but may also augment apoptotic and inflammatory processes, thus aggravating gut injury.Key points During intestinal ischaemia, mitochondrial oxygen uptake is reduced when cellular oxygen partial pressure decreases to below the threshold required to maintain normal oxidative metabolism. Upon reperfusion, intestinal hypoxia may persist because microcirculatory flow remains impaired and/or because available oxygen is consumed by enzymes, intestinal cells and neutrophils.

Non-steroidal anti-inflammatory drugs (NSAIDs) are integral to multimodal analgesic strategies after non-cardiac surgery, aimed at minimizing opioid exposure. Although their analgesic and anti-inflammatory efficacy is well established, emerging evidence raises concerns that perioperative NSAID use may increase the risk of postoperative atrial fibrillation (POAF). Mechanistic studies suggest multiple pathways for this association, including cyclooxygenase inhibition, renin–angiotensin–aldosterone system activation, oxidative stress, and autonomic dysregulation. In this context, perioperative clinicians face the challenge of optimizing pain control while mitigating cardiovascular risk. This review synthesizes preclinical, translational, and clinical data to delineate the potential impact of NSAIDs on POAF risk after non-cardiac surgery, providing a framework for evidence-informed perioperative management.

Objectives: To evaluate the survival rates with favorable neurological outcomes among patients who experienced in-hospital cardiac arrest (IHCA) and out-of-hospital cardiac arrest (OHCA). Design: This prospective cohort study assessed 554 adult patients with IHCA or OHCA referred to Hamad General Hospital, Qatar, between February 2015 and November 2021. Neurologic outcomes were measured using the Cerebral Performance Category (CPC) score. Survival rate and neurologic status were re-evaluated at 28 days, hospital discharge, and one year after cardiac arrest (CA). Findings: For all participants, the hospital discharge and one-year survival rates with a favorable neurological outcome (CPC <= 2) were 18.5% and 19.5%, respectively. Specifically, among patients with IHCA, the rates were 20.5 % and 19 %, while in patients with OHCA, the rates were 16.4 % and 19.9 %, respectively. Multivariate regression analysis indicated that factors male sex (OR: 2.129, 95 % CI: 1.168-3.881, P = 0.014), initial shockable rhythm (OR: 1.691, 95 % CI: 1.024-2.788, P = 0.041), and the use of ECPR (OR: 1.944, 95 % CI: 1.178-3.209, P = 0.009) were associated with increased likelihood of survival with favorable neurological outcomes at 28 days. Conversely, older age, presence of comorbidities, infection, higher APACHE II score, longer hospital stays, and undergoing tracheostomy were linked to decreased chances of survival with favorable neurological outcomes at different time points. Conclusion: Survival with good neurological outcomes after OHCA was 20.3 %, 16.4 %, and 19.9 % at 28 days, hospital discharge, and one year, respectively. Among patients with IHCA, survival with good neurological outcomes was 20.5 %, 20.5 %, and 19 % at 28 days, hospital discharge, and one year, respectively.

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 [PaO2/FiO2] 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, inter- quartile 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.

Sepsis-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. The 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. By 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.

The gastrointestinal tract is affected by multiple ailments that manifest with similar chemical, subcellular, and cellular changes, such as those in intestinal ischemia–reperfusion injury (IRI). The main chemical changes that are described under IRI conditions include the depletion of oxygen available for normal metabolism and the abundant production and increase in intracellular and extracellular concentrations of hydrogen peroxide and other reactive oxygen species (ROS). The enzymes causing this accumulation are xanthine dehydrogenase turning into xanthine oxidase, nicotinamide adenine dinucleotide phosphate oxidase, and nitric oxide synthase. The cellular changes revolve around an oxygen-sensing system that is responsive to varying oxygen levels, which has Hypoxia-Inducible Factors (HIFs) at its base. HIFs are transcription factors, the intracellular concentrations of which significantly increase under hypoxic conditions. Upon activation, they alter the expression of gene sets to ensure appropriate cellular adjustment to the hypoxic and IRI environment. Despite the primary regulation of the system involving oxygen, it is interconnected with multiple other subcellular and cellular functions. Thus, it represents a linchpin control mechanism of cellular adaptation. The effect of HIF activation in intestinal cells aims at preserving the structural integrity of the intestinal lining. The effect in different subtypes of leucocytes aims at immune system activation to protect against previously luminally located and subsequently invading pathogens and toxins. All in all, the HIF system is an integral part of cellular and tissue compensation against intestinal IRI.

Postoperative delirium is a prevalent complication in cardiac surgery patients, highlighting the importance of early risk factor identification for optimal management. This study aimed to pinpoint risk factors and devise a novel screening tool, the Screening Tool for Delirium After Cardiac Surgery (SDACS), to predict postoperative delirium in cardiac surgery patients after the first day. This study employed a multiphase design consisting of three phases. In the first phase, through a scoping review of 38 finally selected published papers, 136 potential risk factors for identifying delirium after cardiac surgery were identified. These risk factors were then incorporated into three Delphi rounds of expert panels to develop a screening tool for postoperative delirium. Finally, 76 potential risk factors were examined on 920 cardiac surgery patients at three academic institutions between 2020 and 2023 (third phase of the study). All predictors were included into a screening instrument (SDACS), and the regression coefficient of each predictor was transformed into a risk score. Delirium was diagnosed in 53

Background: Severe traumatic brain injury (TBI) frequently disrupts cerebral auto-regulation, rendering cerebral perfusion pressure highly dependent on systemic he-modynamics. Vasopressors are a cornerstone of TBI management, yet norepineph-rine and vasopressin may exert divergent effects on cerebral autoregulation and sys-temic cardiovascular function. Their comparative impact in this population remains poorly defined. Objective: The REGULATE trial is a randomized, controlled study designed to in-vestigate the effects of norepinephrine, vasopressin, and their combination on cere-bral autoregulation and advanced systemic hemodynamics in patients with severe TBI. Methods: This quadruple-blinded, parallel-group trial will enroll 450 adults with se-vere TBI (Glasgow Coma Scale ≤ 8) requiring vasopressor support. Participants will be randomized (1:1:1) to norepinephrine, vasopressin, or combination therapy. Con-tinuous multimodal monitoring will include intracranial pressure, arterial pressure, near-infrared spectroscopy, and advanced cardiac output assessment. Co-primary outcomes are (1) cerebral autoregulation, quantified as the area under the curve of the pressure reactivity index over 48 hours, and (2) systemic hemodynamics, defined as the area under the curve of cardiac output and effective arterial elastance over 48 hours. A prespecified interaction analysis will evaluate treatment effects on the rela-tionship between cerebral autoregulation and systemic hemodynamics. Secondary outcomes include cerebral oxygenation indices, intracranial pressure burden, vaso-pressor dose exposure, organ perfusion markers, adverse events, and clinical out-comes (mortality, ICU length of stay, neurological recovery at 3 months). Conclusions: REGULATE is the first adequately powered trial to systematically compare norepinephrine, vasopressin, and their combination on cerebral autoregula-tion and systemic cardiovascular performance in severe TBI. Results are expected to inform individualized vasopressor strategies to optimize cerebral and systemic phys-iology while minimizing secondary injury. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial The study will be registered at ClinicalTrials.gov ### Funding Statement This study did not receive any funding. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approval will be provided by the Ethics Committee of the Tzaneio General Hospital. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data will be made available upon request after publication through a collaborative process. Researchers should provide a methodically sound proposal with specific objectives in an approval proposal.

Background: The characteristics of hemodynamic coherence in healthy states and disease remain unknown. Capillary tortuosity is a morphologic variant of microcirculatory vessels, but its effects have generally not been considered in the assessment of tissue perfusion and oxygenation. We investigated the role of sublingual capillary tortuosity in the hemodynamic coherence of anesthetized adult individuals with steady-state physiology (ASA 1) and patients with septic shock requiring emergency abdominal surgery (ASA 4E and 5E). Methods: Sublingual macro and microcirculatory variables, oxygen transport, metabolic parameters, and the capillary tortuosity score (CTS) were assessed. Results: Mean (SD) CTS was 0.55 (0.76) and 3.31 (0.86) in the steady-state and septic shock group, respectively (p < 0.001). In patients with septic shock, CTS was significantly associated with alveolar-to-arterial oxygen gradient (r = 0.658, p = 0.015) and oxygen debt (r = −0.769, p = 0.002). Significant differences were also observed in Consensus Proportion of Perfused Vessels (PPV; p < 0.001), Consensus PPV (small) (p < 0.001), Microvascular Flow Index (p < 0.001), vessel diameter (p < 0.001) and length (p < 0.001), wall shear stress (p < 0.001), lactate (p < 0.001), oxygen extraction ratio (p = 0.001), arterial oxygen content (p < 0.001), venous oxygen content (p < 0.001), oxygen delivery (p < 0.001), oxygen consumption (p < 0.001), and oxygen debt (p = 0.002) between the two groups. Conclusions: Sublingual tortuosity was essentially absent in individuals with steady-state physiology. In contrast, it was significantly increased and associated with Alveolar-to-arterial oxygen gradient and oxygen debt in critically ill patients with septic shock.

Introduction: Sepsis-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 analysis: MAP-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, ScvO2, Pv-aCO2, 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 dissemination: The 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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study protocol has been approved by the Ethics Committee of the Tzaneio General Hospital, Piraeus, Greece (16974/22-11-2024). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data will be made available upon request after publication through a collaborative process. Researchers should provide a methodically sound proposal with specific objectives in an approval proposal. Please contact the corresponding author for more information.

Background: Capillary tortuosity is a morphological variant of microcirculation. However, the mechanisms by which tortuous vessels meet metabolic requirements in health and disease remain unknown. We recently reported that capillary tortuosity score (CTS) is significantly higher in patients with septic shock than in steady-state individuals, and that CTS is significantly associated with alveolar-to-arterial oxygen (A-a O2) gradient and oxygen debt in septic shock patients. Objective: We aimed to investigate the characteristics of the magnetic fields in the sublingual microcirculation of individuals with normal physiology and patients with septic shock. Methods: Systemic hemodynamics were recorded, and sublingual microcirculation was monitored using sidestream dark field (SDF+) imaging. The number of capillary red blood cells (NRBC), the intensity of the magnetic field of a red blood cell (HRBC), the intensity of the magnetic field of each capillary (HCAP), and the intensity with which the magnetic field of a capillary acts on an RBC (FCAP) were calculated. Results: Significant differences in macro- and microhemodynamic variables were observed between the two groups. Although NRBC was significantly higher in individuals with steady-state physiology [87.4 (87.12) vs. 12.23 (6.9)], HRBC was significantly stronger in patients with septic shock [5.9 × 10-16 (6.9 × 10-16) A m-1 vs. 1.6 × 10-15 (1.4 × 10-15) A m-1]. No significant difference was observed in HCAP [2.16 × 10-14 (2.17 × 10-14) A m-1 vs. 1.34 × 10-14 (1.23 × 10-14) A m-1] and FCAP [1.66 × 10-24 (3.36 × 10-24) A m-1 vs. 6.44 × 10-25 (1.1 × 10-24) A m-1] between the two groups. In patients with septic shock, HRBC was associated with De Backer score (rho = -0.608) and venous-arterial carbon dioxide difference (rho = 0.569). In the same group, HCAP was associated with convective oxygen flow (rho = 0.790) and oxygen extraction ratio (rho = -0.596). Also, FCAP was significantly associated with base deficit (rho = 0.701), A-a O2 gradient (rho = 0.658), and oxygen debt (rho = -0.769). Conclusions: Despite the microcirculatory impairment in patients with septic shock, HRBC was significantly stronger in that group than in steady-state individuals. Also, HCAP and FCAP were comparable between the two groups. Tortuous vessels may function as biomagnetic coils that amplify RBC-induced magnetic fields, enhancing perfusion and oxygenation of adjacent tissues.