Proteomic Characterization of Plasma in Lemierre's Syndrome.

BACKGROUND: The underlying mechanisms of thrombosis in Lemierre's syndrome and other septic thrombophlebitis are incompletely understood. Therefore, in this case control study we aimed to generate hypotheses on its pathogenesis by studying the plasma proteome in patients with these conditions. METHODS: All patients with Lemierre's syndrome in the Skåne Region, Sweden, were enrolled prospectively during 2017 to 2021 as cases. Age-matched patients with other severe infections were enrolled as controls. Patient plasma samples were analyzed using label-free data-independent acquisition liquid chromatography tandem mass spectrometry. Differentially expressed proteins in Lemierre's syndrome versus other severe infections were highlighted. Functions of differentially expressed proteins were defined based on a literature search focused on previous associations with thrombosis. RESULTS: Eight patients with Lemierre's syndrome and 15 with other severe infections were compared. Here, 20/449 identified proteins were differentially expressed between the groups. Of these, 14/20 had functions previously associated with thrombosis. Twelve of 14 had a suggested prothrombotic effect in Lemierre's syndrome, whereas 2/14 had a suggested antithrombotic effect. CONCLUSION: Proteins involved in several thrombogenic pathways were differentially expressed in Lemierre's syndrome compared to other severe infections. Among identified proteins, several were associated with endothelial damage, platelet activation, and degranulation, and warrant further targeted studies.

Utility of heparin-binding protein following cardiothoracic surgery using cardiopulmonary bypass.

Cardiothoracic surgery using cardiopulmonary bypass (CPB) triggers an inflammatory state that may be difficult to differentiate from infection. Heparin-binding protein (HBP) is a candidate biomarker for sepsis. As data indicates that HBP normalizes rapidly after cardiothoracic surgery, it may be a suitable early marker of postoperative infection. We therefore aimed to investigate which variables influence postoperative HBP levels and whether elevated HBP concentration is associated with poor surgical outcome. This exploratory, prospective, observational study enrolled 1475 patients undergoing cardiothoracic surgery using CPB, where HBP was measured at ICU arrival. Patients with HBP in the highest tercile were compared to remaining patients. Multivariable logistic regressions were performed to identify factors predictive of elevated HBP and 30-day mortality. Overall median HBP was 30.0 ng/mL. Patients undergoing isolated CABG or surgery with CPB-duration ≤ 60 min had a median HBP of 24.9 ng/mL and 23.2 ng/mL, respectively. Independent predictors of elevated postoperative HBP included increased EuroSCORE, prolonged CPB-duration and high intraoperative temperature. Increased HBP was an independent predictor of 30-day mortality. This study confirms the promising characteristics of HBP as a biomarker for identification of postoperative sepsis, especially after routine procedures. Further studies are required to investigate whether HBP may detect postoperative infections.

Understanding Post-Sepsis Syndrome: How Can Clinicians Help?

Sepsis is a global health challenge, with over 49 million cases annually. Recent medical advancements have increased in-hospital survival rates to approximately 80%, but the escalating incidence of sepsis, owing to an ageing population, rise in chronic diseases, and antibiotic resistance, have also increased the number of sepsis survivors. Subsequently, there is a growing prevalence of "post-sepsis syndrome" (PSS). This syndrome includes long-term physical, medical, cognitive, and psychological issues after recovering from sepsis. PSS puts survivors at risk for hospital readmission and is associated with a reduction in health- and life span, both at short and long term, after hospital discharge. Comprehensive understanding of PSS symptoms and causative factors is vital for developing optimal care for sepsis survivors, a task of prime importance for clinicians. This review aims to elucidate our current knowledge of PSS and its relevance in enhancing post-sepsis care provided by clinicians.

Interpreting biologically informed neural networks for enhanced proteomic biomarker discovery and pathway analysis.

The incorporation of machine learning methods into proteomics workflows improves the identification of disease-relevant biomarkers and biological pathways. However, machine learning models, such as deep neural networks, typically suffer from lack of interpretability. Here, we present a deep learning approach to combine biological pathway analysis and biomarker identification to increase the interpretability of proteomics experiments. Our approach integrates a priori knowledge of the relationships between proteins and biological pathways and biological processes into sparse neural networks to create biologically informed neural networks. We employ these networks to differentiate between clinical subphenotypes of septic acute kidney injury and COVID-19, as well as acute respiratory distress syndrome of different aetiologies. To gain biological insight into the complex syndromes, we utilize feature attribution-methods to introspect the networks for the identification of proteins and pathways important for distinguishing between subtypes. The algorithms are implemented in a freely available open source Python-package ( https://github.com/InfectionMedicineProteomics/BINN ).

Estimating Sepsis Incidence Using Administrative Data and Clinical Medical Record Review.

Importance: Despite the large health burden, reliable data on sepsis epidemiology are lacking; studies using International Statistical Classification of Diseases and Related Health Problems (ICD)-coded hospital discharge diagnosis for sepsis identification suffer from limited sensitivity. Also, ICD data do not allow investigation of underlying pathogens and antimicrobial resistance. Objectives: To generate reliable epidemiological estimates by linking data from a population-based database to a reference standard of clinical medical record review. Design, Setting, and Participants: This was a retrospective, observational cohort study using a population-based administrative database including all acute care hospitals of the Scania region in Sweden in 2019 and 2020 to identify hospital-treated sepsis cases by ICD codes. From this database, clinical medical records were also selected for review within 6 strata defined by ICD discharge diagnosis (both with and without sepsis diagnosis). Data were analyzed from April to October 2022. Main outcomes and measures: Hospital and population incidences of sepsis, case fatality, antimicrobial resistance, and temporal dynamics due to COVID-19 were assessed, as well as validity of ICD-10 case identification methods compared with the reference standard of clinical medical record review. Results: Out of 295 531 hospitalizations in 2019 in the Scania region of Sweden, 997 patient medical records were reviewed, among which 457 had sepsis according to clinical criteria. Of the patients with clinical sepsis, 232 (51%) were female, and 357 (78%) had at least 1 comorbidity. The median (IQR) age of the cohort was 76 (67-85) years. The incidence of sepsis in hospitalized patients according to the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) criteria in 2019 was 4.1% (95% CI, 3.6-4.5) by medical record review. This corresponds to an annual incidence rate of 747 (95% CI, 663-832) patients with sepsis per 100 000 population. No significant increase in sepsis during the COVID-19 pandemic nor a decrease in sepsis incidence when excluding COVID-19 sepsis was observed. Few sepsis cases caused by pathogens with antimicrobial resistance were found. The validity of ICD-10-based case identification in administrative data was low. Conclusions and Relevance: In this cohort study of sepsis epidemiology, sepsis was a considerable burden to public health in Sweden. Supplying administrative data with information from clinical medical records can help to generate reliable data on sepsis epidemiology.

Design of a national patient-centred clinical pathway for sepsis in Sweden.

BACKGROUND: The World Health Organization has adopted a resolution on sepsis and urged member states to develop national processes to improve sepsis care. In Sweden, sepsis was selected as one of the ten first diagnoses to be addressed, when the Swedish government in 2019 allocated funds for patient-centred clinical pathways in healthcare. A national multidisciplinary working group, including a patient representative, was appointed to develop the patient-centred clinical pathway for sepsis. METHODS: The working group mapped challenges and needs surrounding sepsis care and included a survey sent to all emergency departments (ED) in Sweden, and then designed a patient-centred clinical pathway for sepsis. RESULTS: The working group decided to focus on the following four areas: (1) sepsis alert for early detection and management optimisation for the most severely ill sepsis patients in the ED; (2) accurate sepsis diagnosis coding; (3) structured information to patients at discharge after sepsis care and (4) structured telephone follow-up after sepsis care. A health-economic analysis indicated that the implementation of the clinical pathway for sepsis will most likely not drive costs. An important aspect of the clinical pathway is implementing continuous monitoring of performance and process indicators. A national working group is currently building up such a system for monitoring, focusing on extraction of this information from the electronic health records systems. CONCLUSION: A national patient-centred clinical pathway for sepsis has been developed and is currently being implemented in Swedish healthcare. We believe that the clinical pathway and the accompanying monitoring will provide a more efficient and equal sepsis care and improved possibilities to monitor and further develop sepsis care in Sweden.

Generalized precursor prediction boosts identification rates and accuracy in mass spectrometry based proteomics.

Data independent acquisition mass spectrometry (DIA-MS) has recently emerged as an important method for the identification of blood-based biomarkers. However, the large search space required to identify novel biomarkers from the plasma proteome can introduce a high rate of false positives that compromise the accuracy of false discovery rates (FDR) using existing validation methods. We developed a generalized precursor scoring (GPS) method trained on 2.75 million precursors that can confidently control FDR while increasing the number of identified proteins in DIA-MS independent of the search space. We demonstrate how GPS can generalize to new data, increase protein identification rates, and increase the overall quantitative accuracy. Finally, we apply GPS to the identification of blood-based biomarkers and identify a panel of proteins that are highly accurate in discriminating between subphenotypes of septic acute kidney injury from undepleted plasma to showcase the utility of GPS in discovery DIA-MS proteomics.

A pharmacoproteomic landscape of organotypic intervention responses in Gram-negative sepsis.

Sepsis is the major cause of mortality across intensive care units globally, yet details of accompanying pathological molecular events remain unclear. This knowledge gap has resulted in ineffective biomarker development and suboptimal treatment regimens to prevent and manage organ dysfunction/damage. Here, we used pharmacoproteomics to score time-dependent treatment impact in a murine Escherichia coli sepsis model after administering beta-lactam antibiotic meropenem (Mem) and/or the immunomodulatory glucocorticoid methylprednisolone (Gcc). Three distinct proteome response patterns were identified, which depended on the underlying proteotype for each organ. Gcc enhanced some positive proteome responses of Mem, including superior reduction of the inflammatory response in kidneys and partial restoration of sepsis-induced metabolic dysfunction. Mem introduced sepsis-independent perturbations in the mitochondrial proteome that Gcc counteracted. We provide a strategy for the quantitative and organotypic assessment of treatment effects of candidate therapies in relationship to dosing, timing, and potential synergistic intervention combinations during sepsis.

Heparin-binding protein as a marker of ventriculostomy related infection and central nervous system inflammation in neuro-intensive care.

OBJECTIVE: Diagnosis of ventriculostomy related infections (VRI) in the neuro-intensive care unit remains challenging and current biomarkers lack adequate precision. The aim of this study was to explore the potential of Heparin-binding protein (HBP) in cerebrospinal fluid (CSF) as a diagnostic biomarker of VRI. METHODS: All patients treated with an external ventricular drain (EVD) between January 2009 and March 2010 at Skåne university hospital in Lund, Sweden, were consecutively included. CSF samples obtained during routine care were analyzed for HBP. VRI was defined as a positive bacterial microbiology test result on a CSF sample with an erythrocyte-corrected leukocyte count of > 50 × 106/l. HBP levels at VRI diagnosis was compared to peak HBP levels in non-VRI controls. RESULTS: In total, 394 CSF samples from 103 patients were analyzed for HBP. Seven patients (6.8%) fulfilled VRI criteria. Levels of HBP were significantly higher in VRI subjects (31.7 ng/mL [IQR 26.9-40.7 ng/mL]) compared to non-VRI controls (7.7 ng/mL [IQR 4.1-24.5 ng/mL]) (p = 0.024). The AUC of the receiver operating characteristic (ROC) curve was 0.76 (95% confidence interval [CI], 0.62-0.90). Among non-VRI patients, HBP was highest in patients with acute bacterial meningitis. Patients with subarachnoid hemorrhage displayed higher HBP levels than those with traumatic brain injury or shunt dysfunction. CONCLUSIONS: HBP levels were higher in VRI subjects and varied between patients and different diagnoses. To validate the clinical usefulness and added value of HBP as a biomarker for VRI, the results need to be confirmed in larger studies with head-to-head comparisons to current biomarkers.

Protocolised reduction of non-resuscitation fluids versus usual care in patients with septic shock (REDUSE): a protocol for a multicentre feasibility trial.

INTRODUCTION: Administration of large volumes of fluids is associated with poor outcome in septic shock. Recent data suggest that non-resuscitation fluids are the major source of fluids in the intensive care unit (ICU) patients suffering from septic shock. The present trial is designed to test the hypothesis that a protocol targeting this source of fluids can reduce fluid administration compared with usual care. METHODS AND ANALYSIS: The design will be a multicentre, randomised, feasibility trial. Adult patients admitted to ICUs with septic shock will be randomised within 12 hours of admission to receive non-resuscitation fluids either according to a restrictive protocol or to receive usual care. The healthcare providers involved in the care of participants will not be blinded. The participants, outcome assessors at the 6-month follow-up and statisticians will be blinded. Primary outcome will be litres of fluids administered within 3 days of randomisation. Secondary outcomes will be proportion of randomised participants with outcome data on all-cause mortality; days alive and free of mechanical ventilation within 90 days of inclusion; any acute kidney injury and ischaemic events in the ICU (cerebral, cardiac, intestinal or limb ischaemia); proportion of surviving randomised patients who were assessed by European Quality of Life 5-Dimensions 5-Level questionnaire and Montreal Cognitive Assessment; proportion of all eligible patients who were randomised and proportion of participants experiencing at least one protocol violation. ETHICS AND DISSEMINATION: Ethics approval has been obtained in Sweden. Results of the primary and secondary outcomes will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT05249088.

Use of healthcare before and after sepsis in Sweden: a case-control study.

OBJECTIVES: The aim of this study was to compare readmissions and death between sepsis and non-sepsis hospitalisations the first year after discharge, and to investigate what diagnoses patients with sepsis present with at readmission. The aim was also to evaluate to what degree patients hospitalised for sepsis seek medical attention prior to hospitalisation. DESIGN: Retrospective case-control study with data validated through clinical chart review. A disproportionate stratified sampling model was used to include a relatively larger number of sepsis hospitalisations. SETTING: All eight public hospitals in region Scania, Sweden (1 January to 3 December 2019). PARTICIPANTS: There were 447 patients hospitalised for sepsis (cases), and 541 hospitalised for other causes (control) identified through clinical chart review. OUTCOME MEASURES: Cox regression was used to analyse readmission and death the year after discharge, and logistic regression was used to analyse healthcare the week prior to hospitalisation. Both analyses were made unadjusted, and adjusted for age, sex and comorbidities. RESULTS: Out of patients who survived a sepsis hospitalisation, 48% were readmitted the year after discharge, compared with 39% for patients without sepsis (HR 1.50, 95% CI 1.03 to 2.19), p=0.04. The majority (52%) of readmissions occurred within 90 days and 75% within 180 days. The readmissions were most often caused by infection (32%), and 18% by cardiovascular disease. Finally, 34% of patients with sepsis had sought prehospital contact with a physician the week before hospitalisation, compared with 22% for patients without sepsis (OR 1.80, 95% CI 1.06 to 3.04), p=0.03. CONCLUSION: Patients hospitalised for sepsis had a higher risk of readmission the year after discharge compared with patients without sepsis. The most common diagnoses at readmission were infection followed by cardiovascular disease. With better follow-up, some of these readmissions could potentially be prevented. Patients hospitalised for sepsis had sought prehospital contact the week prior to hospitalisation to a greater extent than patients without sepsis.

Cystatin C and derived measures of renal function as risk factors for mortality and acute kidney injury in sepsis - A post-hoc analysis of the FINNAKI cohort.

PURPOSE: To assess the association between cystatin C-derived estimates of kidney function and mortality and acute kidney injury (AKI) in sepsis. MATERIALS AND METHODS: Post-hoc analysis of sepsis patients in the FINNAKI-cohort (n = 802). Primary outcome was 90-day mortality. We measured plasma cystatin C and creatinine at intensive care unit (ICU) admission and estimated glomerular filtration rates (eGFRcys, eGFRcrea) and shrunken pore syndrome (SPS; defined as eGFRcys/eGFRcrea ratio < 0.7). Associations were assessed using Cox- or logistic regression. RESULTS: Increased cystatin C and decreased eGFRcys were associated with mortality in unadjusted analyses and in analyses adjusted for illness severity and creatinine. Hazard ratios (HRs) in unadjusted analyses were 3.30 (95% CI; 2.12-5.13, p < 0.001) and 3.26 (95% CI; 2.12-5.02, p < 0.001) respectively. SPS was associated with mortality in an unadjusted- (HR 1.78, 95% CI; 1.33-2.37, p < 0.001) and in an adjusted analysis (HR 1.54, 95% CI; 1.07-2.22, p = 0.021). All cystatin C-derived measures were associated with mortality also after adjustment for AKI development. Cystatin C was associated with AKI in unadjusted analyses but not in analyses adjusted for creatinine. CONCLUSION: Cystatin C and derived measures of kidney function at ICU admission are associated with an increased 90-day mortality. Increased AKI incidence does not fully explain this association.

New, Useful Criteria for Assessing the Evidence of Infection in Sepsis Research.

OBJECTIVES: The Sepsis-3 definition states the clinical criteria for sepsis but lacks clear definitions of the underlying infection. To address the lack of applicable definitions of infection for sepsis research, we propose new criteria, termed the Linder-Mellhammar criteria of infection (LMCI). The aim of this study was to validate these new infection criteria. DESIGN: A multicenter cohort study of patients with suspected infection who were admitted to emergency departments or ICUs. Data were collected from medical records and from study investigators. SETTING: Four academic hospitals in Sweden, Switzerland, the Netherlands, and Germany. PATIENTS: A total of 934 adult patients with suspected infection or suspected sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Agreement of infection site classification was measured using the LMCI with Cohen κ coefficient, compared with the Calandra and Cohen definitions of infection and diagnosis on hospital discharge as references. In one of the cohorts, comparisons were also made to adjudications by an expert panel. A subset of patients was assessed for interobserver agreement. MEASUREMENTS AND MAIN RESULTS: The precision of the LMCI varied according to the applied reference. LMCI performed better than the Calandra and Cohen definitions (κ = 0.62 [95% CI, 0.59-0.65] vs κ = 0.43 [95% CI, 0.39-0.47], respectively) and the diagnosis on hospital discharge (κ = 0.57 [95% CI, 0.53-0.61] vs κ = 0.43 [95% CI, 0.39-0.47], respectively). The interobserver agreement for the LMCI was evaluated in 91 patients, with agreement in 77%, κ = 0.72 (95% CI, 0.60-0.85). When tested with adjudication as the gold standard, the LMCI still outperformed the Calandra and Cohen definitions (κ = 0.65 [95% CI, 0.60-0.70] vs κ = 0.29 [95% CI, 0.24-0.33], respectively). CONCLUSIONS: The LMCI is useful criterion of infection that is intended for sepsis research, in and outside of the ICU. Useful criteria for infection have the potential to facilitate more comparable sepsis research and exclude sepsis mimics from clinical studies, thus improving and simplifying sepsis research.

Factors influencing stone-free rate of Extracorporeal Shock Wave Lithotripsy (ESWL); a cohort study.

OBJECTIVE: To evaluate the success rate of Extracorporeal Shock Wave Lithotripsy (ESWL) therapy and identify relevant treatment-specific factors affecting stone-free rate (SFR) after ESWL. MATERIALS AND METHODS: All ESWL treatments in the years 2016-2019, in Ängelholm Hospital, Skåne, Sweden were analysed retrospectively. Primary outcome was stone-free rate (SFR) at 3 months. Univariate logistic regression was used followed by multivariable regression. Lasso analysis was made to adjust for treatment-specific factors such as age, stone size, skin-to-stone distance (SSD), stone attenuation, number of treatments, stone location and presence of a urinary stent. RESULTS: Factors affecting successful ESWL treatment were lower age (p < 0.001), smaller stone size and volume (both p = 0.001). SSD, stone attenuation, sex, laterality and drainage did not have an effect on SFR in this study. After the first ESWL treatment session, 46.7% of the patients were stone-free. CONCLUSION: Results indicate that stone size and age are the most predictive factors for ESWL outcome. Based on this, we present a simple model for prediction of SFR after ESWL, to be used when counseling patients before ESWL treatment.

Peripheral Oxygen Saturation Facilitates Assessment of Respiratory Dysfunction in the Sequential Organ Failure Assessment Score With Implications for the Sepsis-3 Criteria.

OBJECTIVES: Sequential Organ Failure Assessment score is the basis of the Sepsis-3 criteria and requires arterial blood gas analysis to assess respiratory function. Peripheral oxygen saturation is a noninvasive alternative but is not included in neither Sequential Organ Failure Assessment score nor Sepsis-3. We aimed to assess the association between worst peripheral oxygen saturation during onset of suspected infection and mortality. DESIGN: Cohort study of hospital admissions from a main cohort and emergency department visits from four external validation cohorts between year 2011 and 2018. Data were collected from electronic health records and prospectively by study investigators. SETTING: Eight academic and community hospitals in Sweden and Canada. PATIENTS: Adult patients with suspected infection episodes. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The main cohort included 19,396 episodes (median age, 67.0 [53.0-77.0]; 9,007 [46.4%] women; 1,044 [5.4%] died). The validation cohorts included 10,586 episodes (range of median age, 61.0-76.0; women 42.1-50.2%; mortality 2.3-13.3%). Peripheral oxygen saturation levels 96-95% were not significantly associated with increased mortality in the main or pooled validation cohorts. At peripheral oxygen saturation 94%, the adjusted odds ratio of death was 1.56 (95% CI, 1.10-2.23) in the main cohort and 1.36 (95% CI, 1.00-1.85) in the pooled validation cohorts and increased gradually below this level. Respiratory assessment using peripheral oxygen saturation 94-91% and less than 91% to generate 1 and 2 Sequential Organ Failure Assessment points, respectively, improved the discrimination of the Sequential Organ Failure Assessment score from area under the receiver operating characteristics 0.75 (95% CI, 0.74-0.77) to 0.78 (95% CI, 0.77-0.80; p < 0.001). Peripheral oxygen saturation/Fio2 ratio had slightly better predictive performance compared with peripheral oxygen saturation alone, but the clinical impact was minor. CONCLUSIONS: These findings provide evidence for assessing respiratory function with peripheral oxygen saturation in the Sequential Organ Failure Assessment score and the Sepsis-3 criteria. Our data support using peripheral oxygen saturation thresholds 94% and 90% to get 1 and 2 Sequential Organ Failure Assessment respiratory points, respectively. This has important implications primarily for emergency practice, rapid response teams, surveillance, research, and resource-limited settings.

The Dynamics of Circulating Heparin-Binding Protein: Implications for Its Use as a Biomarker.

Heparin-binding protein (HBP) is a promising biomarker for the development and severity of sepsis. To guide its use, it is important to understand the factors that could lead to false-positive or negative results, such as inappropriate release and inadequate clearance of HBP. HBP is presumably released only by neutrophils, and the organs responsible for its elimination are unknown. In this study, we aimed to determine whether non-neutrophil cells can be a source of circulating HBP and which organs are responsible for its removal. We found that in two cohorts of neutropenic patients, 12% and 19% of patients in each cohort, respectively, had detectable plasma HBP levels. In vitro, three leukemia-derived monocytic cell lines and healthy CD14+ monocytes constitutively released detectable levels of HBP. When HBP was injected intravenously in rats, we found that plasma levels of HBP decreased rapidly, with a distribution half-life below 10 min and an elimination half-life of 1-2 h. We measured HBP levels in the liver, spleen, kidneys, lungs, and urine using both ELISA and immunofluorescence quantitation, and found that the majority of HBP was present in the liver, and a small amount was present in the spleen. Immunofluorescence imaging indicated that HBP is associated mainly with hepatocytes in the liver and monocytes/macrophages in the spleen. The impact of hematologic malignancies and liver diseases on plasma HBP levels should be explored further in clinical studies.

Non-corticosteroid adjuvant therapies for acute bacterial meningitis.

BACKGROUND: Acute bacterial meningitis is a bacterial infection of the membranes that surround and protect the brain, known as the meninges. The primary therapy for bacterial meningitis is antibiotics and corticosteroids. Although these therapies significantly improve outcomes, bacterial meningitis still has a high risk of death and a high risk of neurological sequelae in survivors. New adjuvant therapies are needed to further reduce the risk of death and neurological sequelae in bacterial meningitis. OBJECTIVES: To assess the effects of non-corticosteroid adjuvant pharmacological therapies for mortality, hearing loss, and other neurological sequelae in people with acute bacterial meningitis. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, and LILACS databases and ClinicalTrials.gov and WHO ICTRP trials registers up to 30 September 2021, together with reference checking, citation searching, and contact with study authors to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of any pharmacological adjuvant therapy for acute bacterial meningitis. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed and extracted data on methods, participants, interventions, and outcomes. We assessed risk of bias of studies with the Cochrane risk of bias tool and the certainty of the evidence using the GRADE approach. We presented results using risk ratios (RR) and 95% confidence intervals (CI) when meta-analysis was possible. All other results are presented in a narrative synthesis. MAIN RESULTS: We found that five different adjuvant therapies have been tested in RCTs for bacterial meningitis. These include paracetamol (3 studies, 1274 participants who were children); immunoglobulins (2 studies, 49 participants; one study included children, and the other adults); heparin (1 study, 15 participants who were adults); pentoxifylline (1 study, 57 participants who were children); and a mixture of succinic acid, inosine, nicotinamide, and riboflavin mononucleotide (1 study, 30 participants who were children). Paracetamol may make little or no difference to mortality (paracetamol 35.2% versus placebo 37.4%, 95% CI 30.3% to 40.8%; RR 0.94, 95% CI 0.81 to 1.09; 3 studies, 1274 participants; I² = 0%; low certainty evidence); hearing loss (RR 1.04, 95% CI 0.80 to 1.34; 2 studies, 901 participants; I² = 0%; low certainty evidence); neurological sequelae other than hearing loss (RR 1.56, 95% CI 0.98 to 2.50; 3 studies, 1274 participants; I² = 60%; low certainty evidence); and severe hearing loss (RR 0.96, 95% CI 0.67 to 1.36; 2 studies, 901 participants; I² = 0%; low certainty evidence). Paracetamol may lead to slightly more short-term neurological sequelae other than hearing loss (RR 1.99, 95% CI 1.40 to 2.81; 2 studies, 1096 participants; I² = 0%; low certainty evidence) and slightly more long-term neurological sequelae other than hearing loss (RR 2.32, 95% CI 1.34 to 4.04; 2 studies, 901 participants; I² = 0%; low certainty evidence). No adverse events were reported in either group in any of the paracetamol studies (very low certainty evidence). Two paracetamol studies had a low risk of bias in most domains, and one had low or unclear risk of bias in all domains. We judged the certainty of evidence to be low for mortality due to limitations in study design (unclear risk of bias in at least one domain and imprecision (high level of uncertainty in absolute effects), and low for all other outcomes due to limitations in study design (unclear risk of bias in at least one domain), and imprecision (low sample size and few events) or inconsistency in effect estimates (heterogeneity). We were not able to perform meta-analysis for any of the other adjuvant therapies due to the limited number of included studies. It is uncertain whether immunoglobulins, heparin, or pentoxifylline improves mortality outcomes due to the very low certainty of the evidence. Zero adverse events were reported for immunoglobulins (very low certainty evidence), and allergic reactions occurred at a rate of 3.3% in participants receiving a mixture of succinic acid, inosine, nicotinamide, and riboflavin mononucleotide (intervention group) (very low certainty evidence). None of our other outcomes (hearing loss, neurological sequelae other than hearing loss, severe hearing loss, and short-term or long-term neurological sequelae other than hearing loss) were reported in these studies, and all of these studies were judged to have a high risk of bias. All reported outcomes for all included adjuvant therapies, other than paracetamol, were graded as very low certainty of evidence due to limitations in study design (unclear or high risk of bias in at least four domains) and imprecision (extremely low sample size and few events). AUTHORS' CONCLUSIONS: Few adjuvant therapies for bacterial meningitis have been tested in RCTs. Paracetamol may make little or no difference to mortality, with a high level of uncertainty in the absolute effects (low certainty evidence). Paracetamol may make little or no difference to hearing loss, neurological sequelae other than hearing loss, and severe hearing loss (all low certainty evidence). Paracetamol may lead to slightly more short-term and long-term neurological sequelae other than hearing loss (both outcomes low certainty evidence). There is insufficient evidence to determine whether any of the adjuvant therapies included in this review (paracetamol, immunoglobulins, heparin, pentoxifylline, or a mixture of succinic acid, inosine, nicotinamide, and riboflavin mononucleotide) are beneficial or detrimental in acute bacterial meningitis.

Impact of cardiopulmonary bypass and surgical complexity on plasma soluble urokinase-type plasminogen activator receptor levels after cardiac surgery.

BACKGROUND: Circulating soluble urokinase plasminogen activator receptor (suPAR) is a marker of inflammation with prognostic value for elevated risk of morbidity and mortality. It has not yet been shown how the inflammatory process induced by cardiac surgery affects suPAR concentrations postoperatively. METHODS: In a prospective observational study, plasma suPAR levels were measured in 30 patients undergoing cardiac surgery with cardiopulmonary bypass (CPB), pre-, peri, post-operatively, and 3-5 days after surgery. Fifteen patients underwent coronary artery bypass grafting (CABG) and 15 underwent complex procedures with longer CPB duration. Concentrations of suPAR at each time point were compared to the preoperative levels and compared between the two groups. RESULTS: In both groups, plasma suPAR concentrations were significantly higher on the first postoperative day (3.27 (interquartile range (IQR) 2.75-3.86) µg/L compared to baseline (2.62 (1.98-3.86)) µg/L, p < .001. There were no significant differences in suPAR concentrations between the groups at any time point. Preoperatively, the median suPAR concentration was 2.57 (2.01-3.60) µg/L in the CABG group versus 2.67 (1.89-3.97) µg/L in the complex group (p = .567). At ICU arrival 2.48 (2.34-3.23) µg/L versus 2.73 (2.28-3.44) µg/L in CABG and complex patients, respectively (p = .914). There was no difference in suPAR concentrations between the groups on postoperative day 1 (3.34 (2.89-3.89) versus 3.19 (2.57-3.62) p = .967) or 3-5 days after surgery (2.72 (1.98-3.16) versus 2.96 (2.39-4.28) p = .085. CONCLUSIONS: After a transient rise on the first postoperative day, the suPAR levels returned to the preoperative levels by the third postoperative day. There was no significant difference in suPAR levels between the routine CABG and complex group with longer CPB time.

DNase Treatment Prevents Cerebrospinal Fluid Block in Early Experimental Pneumococcal Meningitis.

OBJECTIVE: Streptococcus pneumoniae is the most common cause of bacterial meningitis, a disease that, despite treatment with antibiotics, still is associated with high mortality and morbidity worldwide. Diffuse brain swelling is a leading cause of morbidity in S pneumoniae meningitis. We hypothesized that neutrophil extracellular traps (NETs) disrupt cerebrospinal fluid (CSF) transport by the glymphatic system and contribute to edema formation in S pneumoniae meningitis. METHODS: We used DNase I treatment to disrupt NETs and then assessed glymphatic function by cisterna magna injections of CSF tracers in a rat model of S pneumoniae meningitis. RESULTS: Our analysis showed that CSF influx into the brain parenchyma, as well as CSF drainage to the cervical lymph nodes, was significantly reduced in the rat model of S pneumoniae meningitis. Degrading NETs by DNase treatment restored glymphatic transport and eliminated the increase in brain weight in the rats. In contrast, first-line antibiotic treatment had no such effect on restoring fluid dynamics. INTERPRETATION: This study suggests that CSF accumulation is responsible for cerebral edema formation and identifies the glymphatic system and NETs as possible new treatment targets in S pneumoniae meningitis. ANN NEUROL 2021;90:653-669.