Anders Aneman

Background: Fibrinolysis resistance is associated with adverse outcomes in sepsis and can be quantified at the bedside by tissue plasminogen activator–enhanced viscoelastometric testing, using the fibrin-adjusted (FIBA10) clot lysis time (TPA-LT) expressed as the TPA-LT/FIBA10 ratio. In this study of adults admitted to intensive care with sepsis, plasma tissue plasminogen activator activity, plasminogen activator inhibitor-1 activity (PAI-1), plasminogen and α2-antiplasmin were measured serially alongside TPA-LT/FIBA10 and Sequential Organ Failure Assessment (SOFA-2) scores. Whether the bedside TPA-LT/FIBA10 measure of fibrinolysis resistance reflects the underlying plasma fibrinolytic protein environment, and whether it tracks organ-failure severity, has not been established. Results: This prospective observational study included 283 paired observations in 69 septic patients admitted with a median Acute Physiology and Chronic Health Evaluation III score 81, median SOFA-2 score 13 and a 38% ICU mortality. PAI-1 increased and plasminogen decreased with increasing fibrinolysis resistance (1.77 [1.50-2.09]-fold increase and 0.81 [0.76-0.87]-fold decrease, respectively, per e-fold increase in TPA-LT/FIBA10). Increasing organ-failure severity was also associated with increased PAI-1 and decreased plasminogen (1.23 [1.17–1.29]-fold increase and 0.95 [0.93–0.96]-fold decrease, respectively, per point increase in SOFA-2). In contrast, tissue plasminogen activator activity and absolute α2-antiplasmin did not relate to fibrinolysis resistance or organ failure. Principal component analysis of the fibrinolysis proteins, organ-failure severity and fibrinolysis resistance identified a dominant axis explaining 35% of the variance, on which PAI-1, SOFA-2 and TPA-LT/FIBA10 loaded together in opposition to plasminogen. Unsupervised clustering of the dataset, performed without reference to patient outcomes, separated a fibrinolysis inhibitor-high, substrate-depleted group with 61% mortality compared to 29% in the preserved-fibrinolysis group. During the ICU stay, PAI-1 decreased within 72 hours in survivors but remained unchanged in non-survivors (interaction p<0.001). A trend was observed for plasminogen levels increasing in survivors but remaining static in non-survivors. Conclusions: Changes in key fibrinolysis proteins, organ-failure severity and fibrinolysis resistance measured by viscoelastometry were coupled facets of the response to sepsis dominated by fibrinolysis inhibitor excess and substrate depletion rather than by reduced activator availability. These findings provide biological validation for bedside viscoelastometric quantification of fibrinolysis resistance and support prospective evaluation of substrate-directed profibrinolytic strategies. ESSENTIALS: Fibrinolysis resistance (FR) in sepsis associates with organ failure and poor outcomes Repeat FR assays in 69 septic ICU cases using viscoelastometry, clinical and protein evaluation FR linked to organ failure via joint decrease in fibrinolysis substrate and increased inhibition Grading fibrinolysis resistance by viscoelastometry in sepsis quantifies clinical risk

Background: Suppressed fibrinolysis (fibrinolysis resistance) is increasingly recognised as a driver of organ failure in sepsis, yet trials in sepsis-induced coagulopathy have largely targeted coagulation rather than fibrinolysis. This study combined an observational ICU cohort with nested analyses of plasma fibrinolysis proteins and ex vivo reversibility, modelling the potential mortality reduction from restoring fibrinolytic capacity to inform trial design. Methods: In 188 adults admitted to ICU with sepsis, repeated tissue plasminogen activator (tPA)-enhanced viscoelastometric testing quantified fibrinolysis resistance as the fibrin-adjusted lysis time (TPA-LT/FIBA10) and as ordinal Grades 1–3 of worsening resistance. Adjusted logistic regression and time-varying Cox models related fibrinolysis resistance to death within 28 days of admission, with unmeasured confounding assessed by E-values. In nested sub-studies, plasma fibrinolysis proteins were measured and whole blood was tested ex vivo for reversal of resistance by supplemental tPA, plasminogen, or an inhibitory antibody to α2-antiplasmin (α2AP iAb). Ex vivo effects were modelled onto the observed fibrinolysis resistance–mortality relationship using a hypothetical intervention distribution framework. Results: Each e-fold (∼2.72×) increase in TPA-LT/FIBA10 was associated with a 2.2-fold (95% CI 1.5–3.3) increase in the odds of death in the fully adjusted logistic model and a 2.3-fold (1.6–3.2) increased hazard in the time-varying Cox model. Comparing the least (Grade 1) with the worst (Grade 3) resistance state, the odds ratio was 7.4 (2.4–23) and the hazard ratio 6.7 (3.0–15). Associations were robust to unmeasured confounding, with E-values of 3–13. Grade 3 resistance showed the highest PAI-1/tPA and α2AP/plasminogen ratios. Ex vivo supplementation with plasminogen or α2AP iAb reversed fibrinolysis resistance from Grade 3 to Grade 1. Modelling these effects yielded hypothetical absolute mortality reductions of 18-21% across Grades 2 and 3, and 32-36% in Grade 3. Conclusions: Fibrinolysis resistance measured at the bedside in sepsis reflects mechanistically reversible changes in fibrinolytic balance ex vivo . Modelling reversal by plasminogen supplementation or α2AP inhibition yielded hypothetical absolute mortality reductions of up to 32% in the most severe resistance state. These hypothesis-generating estimates identify candidate interventions and provide a rationale for a clinical trial. Trial registration: NCT06680180, Registration Date 2024-11-08

Background: Sepsis‐induced coagulopathy is characterised by consumptive coagulation abnormalities and resistance to fibrinolysis, which is increasingly recognised as a driver of microvascular thrombosis, organ dysfunction and mortality. The molecular determinants of the fibrinolysis‐resistant phenotype remain incompletely defined. Objective: To present a pre‐specified statistical analysis plan for a plasma proteomic investigation of fibrinolysis resistance in 89 samples collected serially from 32 critically ill patients with sepsis, using the Olink Explore HT platform (approximately 5400 proteins). The plan is designed to characterise protein associations with a validated bedside measure of fibrinolysis resistance, the ratio of tissue plasminogen activator‐induced lysis time to fibrin clot amplitude (TPA‐LT/FIBA10). The associations will be examined across the fibrinolysis resistance severity continuum and between three ordinal severity grades, and over time within individual patients. Methods: The analytic framework combines five complementary approaches: (i) limit‐of‐detection‐based data filtering, (ii) continuous‐variable modelling of protein abundance against TPA‐LT/FIBA10 using limma‐trend regression, (iii) categorical comparison across severity grades using empirical Bayes moderated statistics, (iv) linear mixed‐effects modelling of longitudinal intra‐patient trajectories and (v) pathway‐level enrichment analysis to translate statistical associations into mechanistic hypotheses. A semi‐supervised pathway clustering analysis will describe how proteins change by fibrinolysis resistance in eight a priori defined domains. Discussion: This multi‐model design is intended to define genuine biological signals in a high‐dimensional dataset while remaining transparent about the exploratory nature of several components. The statistical reasoning behind each method is discussed alongside anticipated limitations. Trial Registration: ClinicalTrials.gov : NCT06680180

Purpose: This pilot study evaluated the real-world accuracy of a novel wearable morphic sensor system for unobtrusive, continuous heart rate (HR) and respiratory rate (RR) monitoring in critically ill patients within an intensive care unit (ICU). Methods: A hybrid piezoresistive/piezoelectric disk-shaped sensor was placed on patients’ backs to capture cardiorespiratory activity via forcecardiographic principles. Data were acquired from 15 ICU patients using a custom wireless recorder. The piezoelectric channel was processed using discrete wavelet transform and an adaptive peak detection algorithm. Derived HR and RR were compared against reference measurements from clinical patient monitors and a ventilator. Results: Bland–Altman analysis showed a mean bias of −0.39 ± 1.99 beats per minute for HR and 0.06 ± 0.90 breaths per minute for RR. Linear regression revealed strong correlation with clinical monitors (HR R-squared = 0.982; RR R-squared = 0.966). The device’s RR performance matched the agreement between two independent clinical reference devices. Conclusion: The proposed system met the pre-specified bias and standard deviation criteria for HR and RR monitoring in bed-bound ICU patients. Its skin-adhesive-free design enables unobtrusive, continuous vital sign surveillance without direct skin contact. These findings support ICU monitoring. Step-down ward and ambulatory applications remain to be validated in future studies.

Background: Acute kidney injury (AKI) is a common and serious complication after cardiac arrest, affecting more than 30% of initially successfully resuscitated patients, with around 10% receiving Kidney Replacement Therapy (KRT). Currently, treatment options to prevent renal complications are limited. In this predefined sub‐study of the Sedation, TEmperature and Pressure after Cardiac Arrest and REsuscitation (STEPCARE) trial, we evaluate the effects of sedation depth, fever management strategies, and mean arterial pressure (MAP) targets on the risk of major adverse kidney events (MAKE) in post‐cardiac arrest patients. Methods: STEPCARE‐MAKE is a predefined prospective sub‐study of the international, randomized clinical STEPCARE trial. The main trial will enroll 3500 patients and employs a 2 × 2 × 2 factorial design, randomizing participants across three interventions: (1) deep sedation for 36 h or minimal sedation, (2) fever management with or without a feedback‐controlled device, and (3) MAP target ≥ 65 mmHg or ≥ 85 mmHg. The primary outcome is the composite outcome MAKE, which includes death from any cause by day 30, initiation of KRT, or persistent renal dysfunction, defined as the final creatinine value ≥ 200% of the baseline at the time of discharge from the primary hospital or at day 30, whichever occurs first. Differences between baseline and the highest in‐hospital creatinine, baseline and the last measured in‐hospital creatinine, baseline and 72‐h creatinine, and baseline and the highest creatinine within 72 h will be reported as secondary outcomes. Conclusion: The findings of this sub‐study will provide new evidence on the renal effects of the STEPCARE trial interventions and may inform the future of individualized kidney‐protective treatment approaches.

Lucy A Coupland, Steven A Frost, Jessica Lin, Nguyen Pham, Matthew Self, Philip J Crispin, David J Rabbolini, Charithani B Keragala, Robert L Medcalf, Ande

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.

Background: Increased plasma renin concentrations have been reported in patients following cardiac surgery while correlations to clinical outcomes have varied. More evidence is needed to support the potential clinical utility of plasma renin as a biomarker guiding postoperative management, including the need for alternative pharmacotherapy when standard catecholaminergic cardiovascular support is insufficient. Methods: Plasma concentrations were determined by direct renin immunoassay (milli‐International Units per litre, mIU L ⁻¹ ) on admission to ICU and then six and 24 h later. Postoperative complications were assessed by the composite and separate incidence of acute kidney injury, acute myocardial infarction, shock, acute respiratory failure, new onset atrial flutter/fibrillation and cerebrovascular accident. Pharmacological support required to treat postoperative haemodynamic instability was quantified using the vasoactive‐inotropic score. Results: One hundred and four patients were studied and 54 (52%) met at least one diagnostic criterion for postoperative complications. Renin concentrations on admission (130 [34–445] mIU L ⁻¹ ) and six (119 [35–447] mIU L ⁻¹ ) and 24 h later (184 [54‐513] mIU L ⁻¹ ) were not significantly different with substantial inter‐individual variation. Cumulative renin concentrations over 24 h were higher in haemodynamically unstable patients (median difference 1296 [54–2943] mIU L ⁻¹ , p = 0.04) and in patients with any postoperative complication (median difference 1887 [908–6177] mIU L ⁻¹ , p = 0.04). Plasma renin increased by 11 mIU L ⁻¹ for each unit increase in the vasoactive‐inotropic score. A statistical model using all renin measurements predicted haemodynamic instability ( AUC 0.77 [0.55–0.95], p = 0.04) and shock ( AUC 0.95 [0.83–1.0], p = < 0.001), but not the composite or separate incidence of the other complications. Conclusions: Haemodynamic compromise, but not postoperative complications overall, were associated with serial plasma renin concentrations during the first 24 h of ICU admission following cardiac surgery. Additional prospective studies are warranted to elucidate the relationship between renin dynamics, postoperative complications and criteria for escalating vasopressor therapy. Editorial Comment: This prospective observational study tested whether postoperative increase in plasma renin in patients undergoing cardiac surgery was associated with postoperative complications. No such association was found, but an association between increase in plasma renin and haemodynamic compromise and need for pharmacological support was found. Larger studies are warranted to elucidate the role of plasma renin as a biomarker for postoperative complications. Trial Registration: ClinicalTrials.gov identifier: NCT043303455.