Causal inference can lead us to modifiable mechanisms and informative archetypes in sepsis.

Medical progress is reflected in the advance from broad clinical syndromes to mechanistically coherent diagnoses. By this metric, research in sepsis is far behind other areas of medicine-the word itself conflates multiple different disease mechanisms, whilst excluding noninfectious syndromes (e.g., trauma, pancreatitis) with similar pathogenesis. New technologies, both for deep phenotyping and data analysis, offer the capability to define biological states with extreme depth. Progress is limited by a fundamental problem: observed groupings of patients lacking shared causal mechanisms are very poor predictors of response to treatment. Here, we discuss concrete steps to identify groups of patients reflecting archetypes of disease with shared underlying mechanisms of pathogenesis. Recent evidence demonstrates the role of causal inference from host genetics and randomised clinical trials to inform stratification analyses. Genetic studies can directly illuminate drug targets, but in addition they create a reservoir of statistical power that can be divided many times among potential patient subgroups to test for mechanistic coherence, accelerating discovery of modifiable mechanisms for testing in trials. Novel approaches, such as subgroup identification in-flight in clinical trials, will improve efficiency. Within the next decade, we expect ongoing large-scale collaborative projects to discover and test therapeutically relevant sepsis archetypes.

Immune biomarkers and secondary hemophagocytic lymphohistiocytosis: a scoping review protocol.

OBJECTIVE: To identify immunological pathways and markers of severity of illness associated with clinical outcomes that may represent potential therapeutic targets in the management of secondary hemophagocytic lymphohistiocytosis. INTRODUCTION: A broad range of immunomodulatory therapies is used to manage hemophagocytic lymphohistiocytosis, however the supporting evidence for these therapies is scarce. Identifying patients likely to experience more severe disease, or die, is currently extremely difficult, if not impossible. The identification of implicated cytokines in secondary disease can provide further support for the identification of high-risk patients and the development of targeted therapies. INCLUSION CRITERIA: Studies reporting immune biomarker and cytokine measurement in adult patients (age >18 years) with secondary hemophagocytic lymphohistiocytosis. METHODS: The proposed review will be conducted in line with the JBI methodology for scoping reviews. The MEDLINE (Ovid) and Embase (Ovid) databases will be searched, without date limitations. Data will be extracted using a data extraction tool developed by the reviewers. Relevant sources will be retrieved, and their citation details imported into the JBI System for the Unified Management, Assessment and Review of Information.

Risk assessment with gene expression markers in sepsis development.

Infection is a commonplace, usually self-limiting, condition but can lead to sepsis, a severe life-threatening dysregulated host response. We investigate the individual phenotypic predisposition to developing uncomplicated infection or sepsis in a large cohort of non-infected patients undergoing major elective surgery. Whole-blood RNA sequencing analysis was performed on preoperative samples from 267 patients. These patients developed postoperative infection with (n = 77) or without (n = 49) sepsis, developed non-infectious systemic inflammatory response (n = 31), or had an uncomplicated postoperative course (n = 110). Machine learning classification models built on preoperative transcriptomic signatures predict postoperative outcomes including sepsis with an area under the curve of up to 0.910 (mean 0.855) and sensitivity/specificity up to 0.767/0.804 (mean 0.746/0.769). Our models, confirmed by quantitative reverse-transcription PCR (RT-qPCR), potentially offer a risk prediction tool for the development of postoperative sepsis with implications for patient management. They identify an individual predisposition to developing sepsis that warrants further exploration to better understand the underlying pathophysiology.

Taming hemoglobin chemistry-a new hemoglobin-based oxygen carrier engineered with both decreased rates of nitric oxide scavenging and lipid oxidation.

The clinical utility of hemoglobin-based oxygen carriers (HBOC) is limited by adverse heme oxidative chemistry. A variety of tyrosine residues were inserted on the surface of the γ subunit of recombinant fetal hemoglobin to create novel electron transport pathways. This enhanced the ability of the physiological antioxidant ascorbate to reduce ferryl heme and decrease lipid peroxidation. The γL96Y mutation presented the best profile of oxidative protection unaccompanied by loss of protein stability and function. N-terminal deletions were constructed to facilitate the production of recombinant hemoglobin by fermentation and phenylalanine insertions in the heme pocket to decrease the rate of NO dioxygenation. The resultant mutant (αV1del. αL29F, γG1del. γV67F, γL96Y) significantly decreased NO scavenging and lipid peroxidation in vitro. Unlike native hemoglobin or a recombinant control (αV1del, γG1del), this mutation showed no increase in blood pressure immediately following infusion in a rat model of reperfusion injury, suggesting that it was also able to prevent NO scavenging in vivo. Infusion of the mutant also resulted in no meaningful adverse physiological effects apart from diuresis, and no increase in oxidative stress, as measured by urinary isoprostane levels. Following PEGylation via the Euro-PEG-Hb method to increase vascular retention, this novel protein construct was compared with saline in a severe rat reperfusion injury model (45% blood volume removal for 90 minutes followed by reinfusion to twice the volume of shed blood). Blood pressure and survival were followed for 4 h post-reperfusion. While there was no difference in blood pressure, the PEGylated Hb mutant significantly increased survival.

Challenging management dogma where evidence is non-existent, weak, or outdated: part II.

Many dogmas influence daily clinical practice, and critical care medicine is no exception. We previously highlighted the weak, questionable, and often contrary evidence base underpinning four established medical managements-loop diuretics for acute heart failure, routine use of heparin thromboprophylaxis, rate of sodium correction for hyponatremia, and 'every hour counts' for treating bacterial meningitis. We now provide four further examples in this "Dogma II" piece (a week's course of antibiotics, diabetic ketoacidosis algorithms, sodium bicarbonate to improve ventricular contractility during severe metabolic acidosis, and phosphate replacement for hypophosphatemia) where routine practice warrants re-appraisal.

Definition and Epidemiology of Sepsis.

Here we review the epidemiology of sepsis, focusing on its definition, incidence, and mortality, as well as the demographic insights and risk factors that influence its occurrence and outcomes. We address how age, sex, and racial/ethnic disparities impact upon incidence and mortality rates. Sepsis is more frequent and severe among the elderly, males, and certain racial and ethnic groups. Poor socioeconomic status, geographic location, and pre-existing comorbidities also elevate the risk of developing and dying from sepsis. Seasonal variations, with an increased incidence during winter months, is also apparent. We delve into the predictive value of disease severity scores such as the Sequential Organ Failure Assessment score. We also highlight issues relating to coding and administrative data that can generate erroneous and misleading information, and the need for greater consistency. The Sepsis-3 definitions, offering more precise clinical criteria, are a step in the right direction. This overview will, we hope, facilitate understanding of the multi-faceted epidemiological characteristics of sepsis and current challenges.

A randomised controlled trial of plasma exchange compared to standard of care in the treatment of severe COVID-19 infection (COVIPLEX).

COVID-19 disease is associated with a hyperinflammatory, pro-thrombotic state and a high mortality. Our primary objective was to assess the change in inflammatory and thrombotic markers associated with PEX, and secondary objectives were to assess the effects of PEX on progression of respiratory failure and incidence of acute thrombotic events. We conducted a prospective, phase II, non-blinded randomised control trial of plasma exchange compared to standard of care in critically ill adults with severe COVID-19 associated respiratory failure, requiring supplemental oxygen or ventilatory support and elevated thrombo-inflammatory markers (LDH, CRP, ferritin, and D-Dimer). Patients randomised to receive PEX were treated with a daily single volume plasma exchange for a minimum of five days. Twenty-two patients were randomised of who 11 received PEX. Demographic and clinical characteristics were similar between groups at presentation. PEX was associated with a significant reduction in pro-thrombotic markers FVIII, VWF and VWF Ag: ADAMTS 13 ratio (p < 0.001). There were no differences in the reduction of inflammatory markers, severity of respiratory failure (p = 0.7), thrombotic events (p = 0.67), or mortality (p > 0.99) at 28 days. PEX successfully reduced pro-thrombotic markers, although was not associated with reduction in inflammatory markers, respiratory failure, or thrombotic events.Trial registration: (NCT04623255); first posted on 10/11/2020.

Sex differences in the SOFA score of ICU patients with sepsis or septic shock: a nationwide analysis.

BACKGROUND: The Sequential Organ Failure Assessment (SOFA) score is an important tool in diagnosing sepsis and quantifying organ dysfunction. However, despite emerging evidence of differences in sepsis pathophysiology between women and men, sex is currently not being considered in the SOFA score. We aimed to investigate potential sex-specific differences in organ dysfunction, as measured by the SOFA score, in patients with sepsis or septic shock and explore outcome associations. METHODS: Retrospective analysis of sex-specific differences in the SOFA score of prospectively enrolled ICU patients with sepsis or septic shock admitted to one of 85 certified Swiss ICUs between 01/2021 and 12/2022. RESULTS: Of 125,782 patients, 5947 (5%) were admitted with a clinical diagnosis of sepsis (2244, 38%) or septic shock (3703, 62%). Of these, 5078 (37% women) were eligible for analysis. A statistically significant difference of the total SOFA score on admission was found between women (mean 7.5 ± SD 3.6 points) and men (7.8 ± 3.6 points, Wilcoxon rank-sum p < 0.001). This was driven by differences in the coagulation (p = 0.008), liver (p < 0.001) and renal (p < 0.001) SOFA components. Differences between sexes were more prominent in younger patients < 52 years of age (women 7.1 ± 4.0 points vs men 8.1 ± 4.2 points, p = 0.004). No sex-specific differences were found in ICU length of stay (women median 2.6 days (IQR 1.3-5.3) vs men 2.7 days (IQR 1.2-6.0), p = 0.13) and ICU mortality (women 14% vs men 15%, p = 0.17). CONCLUSION: Sex-specific differences exist in the SOFA score of patients admitted to a Swiss ICU with sepsis or septic shock, particularly in laboratory-based components. Although the clinical meaningfulness of these differences is unclear, a reevaluation of sex-specific thresholds for SOFA score components is warranted in an attempt to make more accurate and individualised classifications.

Hormesis as an adaptive response to infection.

Hormesis is a phenomenon whereby low-level stress can improve cellular, organ, or organismal fitness in response to a subsequent similar or other stress insult. Whereas hormesis is thought to contribute to the fitness benefits arising from symbiotic host-microbe interactions, the putative benefits of hormesis in host-pathogen interactions have yet to be explored. Hormetic responses have nonetheless been reported in experimental models of infection, a common feature of which is regulation of host mitochondrial function. We propose that these mitohormetic responses could be harnessed therapeutically to limit the severity of infectious diseases.

From ICU Syndromes to ICU Subphenotypes: Consensus Report and Recommendations for Developing Precision Medicine in the ICU.

Critical care uses syndromic definitions to describe patient groups for clinical practice and research. There is growing recognition that a "precision medicine" approach is required and that integrated biologic and physiologic data identify reproducible subpopulations that may respond differently to treatment. This article reviews the current state of the field and considers how to successfully transition to a precision medicine approach. To impact clinical care, identification of subpopulations must do more than differentiate prognosis. It must differentiate response to treatment, ideally by defining subgroups with distinct functional or pathobiological mechanisms (endotypes). There are now multiple examples of reproducible subpopulations of sepsis, acute respiratory distress syndrome, and acute kidney or brain injury described using clinical, physiological, and/or biological data. Many of these subpopulations have demonstrated the potential to define differential treatment response, largely in retrospective studies, and that the same treatment-responsive subpopulations may cross multiple clinical syndromes (treatable traits). To bring about a change in clinical practice, a precision medicine approach must be evaluated in prospective clinical studies requiring novel adaptive trial designs. Several such studies are underway, but there are multiple challenges to be tackled. Such subpopulations must be readily identifiable and be applicable to all critically ill populations around the world. Subdividing clinical syndromes into subpopulations will require large patient numbers. Global collaboration of investigators, clinicians, industry, and patients over many years will therefore be required to transition to a precision medicine approach and ultimately realize treatment advances seen in other medical fields.

Development and translation of thiometallate sulfide donors using a porcine model of coronary occlusion and reperfusion.

Sulfide-releasing compounds reduce reperfusion injury by decreasing mitochondria-derived reactive oxygen species production. We previously characterised ammonium tetrathiomolybdate (ATTM), a clinically used copper chelator, as a sulfide donor in rodents. Here we assessed translation to large mammals prior to clinical testing. In healthy pigs an intravenous ATTM dose escalation revealed a reproducible pharmacokinetic/pharmacodynamic (PK/PD) relationship with minimal adverse clinical or biochemical events. In a myocardial infarction (1-h occlusion of the left anterior descending coronary artery)-reperfusion model, intravenous ATTM or saline was commenced just prior to reperfusion. ATTM protected the heart (24-h histological examination) in a drug-exposure-dependent manner (r2 = 0.58, p < 0.05). Blood troponin T levels were significantly (p < 0.05) lower in ATTM-treated animals while myocardial glutathione peroxidase activity, an antioxidant selenoprotein, was elevated (p < 0.05). Overall, our study represents a significant advance in the development of sulfides as therapeutics and underlines the potential of ATTM as a novel adjunct therapy for reperfusion injury. Mechanistically, our study suggests that modulating selenoprotein activity could represent an additional mode of action of sulfide-releasing drugs.

Early dynamic changes to monocytes following major surgery are associated with subsequent infections.

Background: Post-operative infections are a common cause of morbidity following major surgery. Little is understood about how major surgery perturbs immune function leading to heightened risk of subsequent infection. Through analysis of paired blood samples obtained immediately before and 24 h following surgery, we evaluated changes in circulating immune cell phenotype and function across the first 24 h, to identify early immune changes associated with subsequent infection. Methods: We conducted a prospective observational study of adult patients undergoing major elective gastrointestinal, gynecological, or maxillofacial surgery requiring planned admission to the post-anesthetic care unit. Patients were followed up to hospital discharge or death. Outcome data collected included mortality, length of stay, unplanned intensive care unit admission, and post-operative infections (using the standardized endpoints in perioperative medicine-core outcome measures for perioperative and anesthetic care criteria). Peripheral blood mononuclear cells were isolated prior to and 24 h following surgery from which cellular immune traits including activation and functional status were assessed by multi-parameter flow cytometry and serum immune analytes compared by enzyme-linked immunosorbent assay (ELISA). Results: Forty-eight patients were recruited, 26 (54%) of whom developed a post-operative infection. We observed reduced baseline pre- and post-operative monocyte CXCR4 and CD80 expression (chemokine receptors and co-stimulation markers, respectively) in patients who subsequently developed an infection as well as a profound and selective post-operative increase in CD4+ lymphocyte IL-7 receptor expression in the infection group only. Higher post-operative monocyte count was significantly associated with the development of post-operative infection (false discovery rate < 1%; adjusted p-value = 0.001) with an area under the receiver operating characteristic curve of 0.84 (p < 0.0001). Conclusion: Lower monocyte chemotaxis markers, higher post-operative circulating monocyte counts, and reduced co-stimulatory signals are associated with subsequent post-operative infections. Identifying the underlying mechanisms and therapeutics to reverse defects in immune cell function requires further exploration.

Antibiotics, Sedatives, and Catecholamines Further Compromise Sepsis-Induced Immune Suppression in Peripheral Blood Mononuclear Cells.

OBJECTIVES: We hypothesized that the immunosuppressive effects associated with antibiotics, sedatives, and catecholamines amplify sepsis-associated immune suppression through mitochondrial dysfunction, and there is a cumulative effect when used in combination. We thus sought to determine the impact of the exemplar drugs ciprofloxacin, propofol, and norepinephrine, used alone and in combination, at clinically relevant concentrations, on the ex vivo functionality of peripheral blood mononuclear cells (PBMCs) drawn from healthy, infected, and septic individuals. DESIGN: In vitro/ex vivo investigation. SETTING: University laboratory. SUBJECTS: Healthy volunteers, infected (nonseptic) patients in the emergency department, and septic ICU patients. INTERVENTIONS: PBMCs were isolated from these subjects and treated with ciprofloxacin (100 µg/mL), propofol (50 µg/mL), norepinephrine (10 µg/mL), or all three drugs combined, with and without lipopolysaccharide (100 ng/mL) for 6 or 24 hours. Comparison was made between study groups and against untreated cells. Measurements were made of cell viability, cytokine production, phagocytosis, human leukocyte antigen-DR (HLA-DR) status, mitochondrial membrane potential, mitochondrial reactive oxygen species production, and oxygen consumption. Gene expression in immune and metabolic pathways was investigated in PBMCs sampled from healthy volunteers coincubated with septic serum. MEASUREMENTS AND RESULTS: Coincubation with each of the drugs reduced cytokine production and phagocytosis in PBMCs isolated from septic patients, and healthy volunteers coincubated with septic serum. No effect was seen on HLA-DR surface expression. No cumulative effects were seen with the drug combination. Sepsis-induced changes in gene expression and mitochondrial functionality were not further affected by addition of any of the drugs. CONCLUSION: Drugs commonly used in critical care lead to significant immune dysfunction ex vivo and enhance sepsis-associated immunosuppression. Further studies are required to identify underlying mechanisms and potential impact on patient outcomes.

How far back do we need to look to capture diagnoses in electronic health records? A retrospective observational study of hospital electronic health record data.

OBJECTIVES: Analysis of routinely collected electronic health data is a key tool for long-term condition research and practice for hospitalised patients. This requires accurate and complete ascertainment of a broad range of diagnoses, something not always recorded on an admission document at a single point in time. This study aimed to ascertain how far back in time electronic hospital records need to be interrogated to capture long-term condition diagnoses. DESIGN: Retrospective observational study of routinely collected hospital electronic health record data. SETTING: Queen Elizabeth Hospital Birmingham (UK)-linked data held by the PIONEER acute care data hub. PARTICIPANTS: Patients whose first recorded admission for chronic obstructive pulmonary disease (COPD) exacerbation (n=560) or acute stroke (n=2142) was between January and December 2018 and who had a minimum of 10 years of data prior to the index date. OUTCOME MEASURES: We identified the most common International Classification of Diseases version 10-coded diagnoses received by patients with COPD and acute stroke separately. For each diagnosis, we derived the number of patients with the diagnosis recorded at least once over the full 10-year lookback period, and then compared this with shorter lookback periods from 1 year to 9 years prior to the index admission. RESULTS: Seven of the top 10 most common diagnoses in the COPD dataset reached >90% completeness by 6 years of lookback. Atrial fibrillation and diabetes were >90% coded with 2-3 years of lookback, but hypertension and asthma completeness continued to rise all the way out to 10 years of lookback. For stroke, 4 of the top 10 reached 90% completeness by 5 years of lookback; angina pectoris was >90% coded at 7 years and previous transient ischaemic attack completeness continued to rise out to 10 years of lookback. CONCLUSION: A 7-year lookback captures most, but not all, common diagnoses. Lookback duration should be tailored to the conditions being studied.