Substantial heterogeneity of inflammatory cytokine production and its inhibition by a triple cocktail of toll-like receptor blockers in early sepsis.

Introduction: Early sepsis is a life-threatening immune dysregulation believed to feature a "cytokine storm" due to activation of pattern recognition receptors by pathogen and danger associated molecular patterns. However, treatments with single toll-like receptor (TLR) blockers have shown no clinical benefit. We speculated that sepsis patients at the time of diagnosis are heterogeneous in relation to their cytokine production and its potential inhibition by a triple cocktail of TLR blockers. Accordingly, we analyzed inflammatory cytokine production in whole blood assays from early sepsis patients and determined the effects of triple TLR-blockade. Methods: Whole blood of 51 intensive care patients sampled within 24h of meeting Sepsis-3 criteria was incubated for 6h without or with specific TLR2, 4, and 7/8 stimuli or suspensions of heat-killed S. aureus or E. coli bacteria as pan-TLR challenges, and also with a combination of monoclonal antibodies against TLR2 and 4 and chloroquine (endosomal TLR inhibition), subsequent to dose optimization. Concentrations of tumor necrosis factor (TNF), Interleukin(IL)-6, IL-8, IL-10, IL-1α and IL-1ß were measured (multiplex ELISA) before and after incubation. Samples from 11 sex and age-matched healthy volunteers served as controls and for dose-finding studies. Results: Only a fraction of sepsis patient samples revealed ongoing cytokine production ex vivo despite sampling within 24 h of first meeting Sepsis-3 criteria. In dose finding studies, inhibition of TLR2, 4 and endosomal TLRs reliably suppressed cytokine production to specific TLR agonists and added bacteria. However, inflammatory cytokine production ex vivo was only suppressed in the high cytokine producing samples but not in the majority. The suppressive response to TLR-blockade correlated both with intraassay inflammatory cytokine production (r=0.29-0.68; p<0.0001-0.04) and cytokine baseline concentrations (r=0.55; p<0.0001). Discussion: Upon meeting Sepsis-3 criteria for less than 24 h, a mere quarter of patient samples exhibits a strong inflammatory phenotype, as characterized by increased baseline inflammatory cytokine concentrations and a stark TLR-dependent increase upon further ex vivo incubation. Thus, early sepsis patient cohorts as defined by Sepsis-3 criteria are very heterogeneous in regard to inflammation. Accordingly, proper ex vivo assays may be useful in septic individuals before embarking on immunomodulatory treatments.

Blood Lactate Level and the Predictor of Death in Non-shock Septic Patients.

Objective: To evaluate the association of initial blood lactate with mortality and subsequent septic shock in non-shock septic patients. Materials and methods: A retrospective cohort study was conducted at Maharaj Nakorn Chiang Mai Hospital, Chiang Mai University, Muang, Chiang Mai, Thailand. Inclusion criteria included septic patients admitted to a non-critical medical ward and had initial serum lactate at the emergency department (ED). Shock and other causes of hyperlactatemia were excluded. Results: A total of 448 admissions were included with median age [interquartile range (IQR)] of 71 (59, 87) years and 200 males (44.6%). Pneumonia was the most common cause of sepsis (47.5%). The median systemic inflammatory response syndrome (SIRS) and quick sequential organ failure assessment (qSOFA) scores were 3 (2, 3) and 1 (1, 2), respectively. The median initial blood lactate was 2.19 (1.45, 3.23) mmol/L. The high blood lactate (≥2 mmol/L) group; N = 248, had higher qSOFA and other predictive scores and had significantly higher 28 days mortality (31.9% vs 10.0%; p < 0.001) and subsequent 3 days septic shock (18.1% vs 5.0%; p < 0.001) than the normal blood lactate group; N = 200. A combination of blood lactate above or equal to 2 mmol/L plus the national early warning score (NEWS) above or equal to 7 showed the highest prediction of 28 days mortality with the area under receiver-operating characteristic curve (AUROC) of 0.70 [95% confidence interval (CI): 0.65-0.75]. Conclusions: An initial blood lactate level above or equal to 2 mmol/L is associated with high mortality and subsequent septic shock among non-shock septic patients. The composite of blood lactate levels and other predictive scores yields better accuracy to predict mortality. How to cite this article: Noparatkailas N, Inchai J, Deesomchok A. Blood Lactate Level and the Predictor of Death in Non-shock Septic Patients. Indian J Crit Care Med 2023;27(2):93-100.

Blood Lactate in Early Sepsis: A Predictor to "Keep Up" Rather than "Catch Up".

How to cite this article: Renuka MK, Sailaja B. Blood Lactate in Early Sepsis: A Predictor to "Keep Up" Rather than "Catch Up". Indian J Crit Care Med 2023;27(2):83-84.

Whetting the Rapid Diagnostic Tools for Sepsis.

How to cite this article: Krishna B. Whetting the Rapid Diagnostic Tools for Sepsis. Indian J Crit Care Med 2023;27(3):159-160.

FedSepsis: A Federated Multi-Modal Deep Learning-Based Internet of Medical Things Application for Early Detection of Sepsis from Electronic Health Records Using Raspberry Pi and Jetson Nano Devices.

The concept of the Internet of Medical Things brings a promising option to utilize various electronic health records stored in different medical devices and servers to create practical but secure clinical decision support systems. To achieve such a system, we need to focus on several aspects, most notably the usability aspect of deploying it using low-end devices. This study introduces one such application, namely FedSepsis, for the early detection of sepsis using electronic health records. We incorporate several cutting-edge deep learning techniques for the prediction and natural-language processing tasks. We also explore the multimodality aspect for the better use of electronic health records. A secure distributed machine learning mechanism is essential to building such a practical internet of medical things application. To address this, we analyze two federated learning techniques. Moreover, we use two different kinds of low-computational edge devices, namely Raspberry Pi and Jetson Nano, to address the challenges of using such a system in a practical setting and report the comparisons. We report several critical system-level information about the devices, namely CPU utilization, disk utilization, process CPU threads in use, process memory in use (non-swap), process memory available (non-swap), system memory utilization, temperature, and network traffic. We publish the prediction results with the evaluation metrics area under the receiver operating characteristic curve, the area under the precision-recall curve, and the earliness to predict sepsis in hours. Our results show that the performance is satisfactory, and with a moderate amount of devices, the federated learning setting results are similar to the single server-centric setting. Multimodality provides the best results compared to any single modality in the input features obtained from the electronic health records. Generative adversarial neural networks provide a clear superiority in handling the sparsity of electronic health records. Multimodality with the generative adversarial neural networks provides the best result: the area under the precision-recall curve is 96.55%, the area under the receiver operating characteristic curve is 99.35%, and earliness is 4.56 h. FedSepsis suggests that incorporating such a concept together with low-end computational devices could be beneficial for all the medical sector stakeholders and should be explored further.

Evaluation of Immature Granulocyte Count as the Earliest Biomarker for Sepsis.

Background: Diagnosing sepsis early is important for its successful management. Various biomarkers are being used currently, but mostly they are either expensive or not readily available. This study aims to evaluate usefulness of automated immature granulocyte count (IG#) and immature granulocyte percentage (IG%) as early diagnostic markers of sepsis and compares it to other established predictive markers. Patients and methods: In this prospective observational study, 137 eligible, critically ill, nonseptic intensive care unit patients were analyzed for automated IG#, IG%, serum procalcitonin (PCT), and blood lactate (Lac), daily for 7 days after recruitment. Patients were followed for the development of sepsis, defined by the new Sepsis-3 criteria. The study was divided into four time periods of 24 hours each with respect to the day of developing organ dysfunction. Using area under receiver operator characteristic and diagnostic odds ratio (DOR) methods, the best biomarker for the prediction of sepsis in each time period was calculated. Results: IG# and IG% were the earliest biomarkers to have a significant discriminating value with area under the curve of 0.81 and 0.82, respectively, as early as 24 hours before clinical sepsis is diagnosed by Sepsis-3 criteria. Both IG# and IG% have a high DOR of 34.91 and 18.11, respectively, when compared to others like PCT and Lac having a DOR of 27.06 and 4.78, respectively. Conclusion: IG# and IG% are easily available, rapid, and inexpensive tools to differentiate between septic and nonseptic patients with high specificity and sensitivity. It is the earliest biomarker to show a significant rise in patients developing sepsis. How to cite this article: Bhansaly P, Mehta S, Sharma N, Gupta E, Mehta S, Gupta S. Evaluation of Immature Granulocyte Count as the Earliest Biomarker for Sepsis. Indian J Crit Care Med 2022;26(2):216-223.

Predictors of Requirement of Inotrope Among Patients With Early Sepsis: Special Reference to Microcirculatory Parameters.

Introduction The management of septic shock and refractory septic shock is essential in preventing sepsis-related death. The handheld vital microscope is a new modality of investigation for sepsis for microcirculatory assessment. This study aimed to identify predictors of inotrope requirements among patients with early sepsis and impending septic shock with particular reference to sublingual microcirculation assessment parameters. Methodology We conducted an observational cross-sectional hospital-based study in central India. The formal sample size was calculated to be 52 patients using a convenient sampling technique. The study was initiated with ethics approval (IHEC-LOP/2019/ MD0090) with consent from the patients. We used the MicroScan (MicroVision Medical, Netherlands) Video Microscope System (No.16A00102) to obtain sidestream dark-field imaging along with the AVA 4.3C software (MicroVision Medical). Results Of 51 cases, 60.8% were women, and 39.2% were men, and the study population had a mean age of 41.0 ± 14.9 years. Patients were recruited from medical wards (64.7%) and emergency departments (35.3%). The most common site of infection was gastrointestinal (33.3%), followed by respiratory infections (25.5%) and genitourinary infections (11.8%). The quick sequential organ failure assessment score was 2.0 ± 0.1. Eight patients required inotropes, and six patients died. High respiratory rates and lactate levels were important predictors of inotrope requirements in patients with early sepsis. Sublingual microcirculatory parameters at baseline did not significantly affect the requirement of inotropes consequently. Conclusions Sublingual microscopy is a suggested tool for the management of sepsis. However, without clearly defined cut-off values, handheld vital microscopy could not predict fluid responsiveness among patients with early sepsis. Also, it would be difficult to incorporate this technology into regular practice without equipment upgrades and image acquisition software.

Esculetin protects against early sepsis via attenuating inflammation by inhibiting NF-κB and STAT1/STAT3 signaling.

Esculetin, a natural derivative from the traditional and widely-used Chinese medicinal herb Cortex Fraxini, has a variety of pharmacological effects, especially in anti-inflammation. However, it is not clear whether esculetin has a therapeutic effect on sepsis. This study aimed to investigate the anti-inflammatory and protective effects of esculetin on early sepsis. The results showed that the lung injury was significantly relieved with the treatment of esculetin, accompanied with the restrained production of inflammatory factors including IL-1ß, IL-6, TNF-α, CCL2 and iNOS during the early phase of E.coli-induced sepsis. Of note, activation of NF-κB and STAT1/STAT3 signals, the main upstream signals of many inflammatory factors, were attenuated by esculetin in both lung tissues from septic mice and LPS-stimulated macrophage. These findings suggested that the protection of esculetin against early sepsis should be related to its anti-inflammatory effect, which was at least partly due to its inhibition on NF-κB and STAT1/STAT3 signaling pathway in macrophage. Thus, esculetin could serve as a potential therapeutic agent by rebalancing innate immune response in macrophage for the treatment of early sepsis.

HeMA: A hierarchically enriched machine learning approach for managing false alarms in real time: A sepsis prediction case study.

Early detection of sepsis can be life-saving. Machine learning models have shown great promise in early sepsis prediction when applied to patient physiological data in real-time. However, these existing models often under-perform in terms of positive predictive value, an important metric in clinical settings. This is especially the case when the models are applied to data with less than 50% sepsis prevalence, reflective of the incidence rate of sepsis on the floor or in the ICU. In this study, we develop HeMA, a hierarchically enriched machine learning approach for managing false alarms in real time, and conduct a case study for early sepsis prediction. Specifically, we develop a two-stage framework, where a first stage machine learning model is paired with statistical tests, particularly Kolmogorov-Smirnov tests, in the second stage, to predict whether a patient would develop sepsis. Compared with machine learning models alone, the framework results in an increase in specificity and positive predictive value, without compromising F1 score. In particular, the framework shows improved performance when applied to data with 50% and 25% sepsis prevalence, collected from a large hospital system in the US, resulting in up to 18% and 7% increase in specificity and positive predictive value, respectively. Despite the significant improvements observed, and although F1 score is not negatively affected, because of the up to 6% decrease in sensitivity, further improvements and pilot studies may be necessary before deploying the framework in a clinical setting. Finally, external validation conducted using a publicly available dataset produces similar results, validating that the proposed framework is generalizable.

Effect of enos gene polymorphism on the course of early onset bacterial infections in premature infants.

OBJECTIVE: The aim of the study was to analyze the associations between 4a/4b polymorphism of the eNOS gene and impaired systemic hemodynamics in premature infants with early neonatal sepsis. PATIENTS AND METHODS: Materials and methods: We conducted a prospective cohort study, which included 120 premature babies with early neonatal sepsis, in 57 children the course of the disease was accompanied by arterial hypotension (AH) and in 61 children - not. In children of both groups, genotyping was performed to determine 4a/4b polymorphism of the eNOS gene. RESULTS: Results: It was shown that the heart rate, blood pressure, hourly diuresis, the level of total nitrates and nitrites in the urine, as well as a number of echocardioscopic and dopplerometric indicators in children with different eNOS gene genotypes are not different. CONCLUSION: Conclusions: There is no effect of 4a/4b polymorphism of the eNOS gene on the occurrence of hemodynamic disturbances in premature infants with sepsis.

Dynamical modeling of pro- and anti-inflammatory cytokines in the early stage of septic shock.

A dynamical model of the pathophysiological behaviors of IL18 and IL10 cytokines with their receptors is tested against data for the case of early sepsis. The proposed approach considers the surroundings (organs and bone marrow) and the different subsystems (cells and cyctokines). The interactions between blood cells, cytokines and the surroundings are described via mass balances. Cytokines are adsorbed onto associated receptors at the cell surface. The adsorption is described by the Langmuir model and gives rise to the production of more cytokines and associated receptors inside the cell. The quantities of pro and anti-inflammatory cytokines present in the body are combined to give global information via an inflammation level function which describes the patient's state. Data for parameter estimation comes from the Sepsis 48 H database. Comparisons between patient data and simulations are presented and are in good agreement. For the IL18/IL10 cytokine pair, 5 key parameters have been found. They are linked to pro-inflammatory IL18 cytokine and show that the early sepsis is driven by components of inflammatory character.

Comparison of 'time to detection' values between BacT/ALERT VIRTUO and BacT/ALERT 3D instruments for clinical blood culture samples.

OBJECTIVES: The early detection of bacteraemia and fungemia is of paramount importance to guide antimicrobial therapy in septic patients. In this study the 'time to detection' (TTD) value for the new blood culture system BacT/ALERT VIRTUO (VIRTUO) was evaluated in 1462 positive clinical bottles and compared with the TTD for 1601 positive clinical bottles incubated in the BacT/ALERT 3D system (BTA-3D). METHODS: The most representative microorganisms isolated from bottles incubated in both blood culture systems were divided into eight categories (in order of frequency): coagulase-negative staphylococci (CoNS), Escherichia coli, Enterobacteriaceae (other than E. coli), Staphylococcus aureus, Enterococcus spp, viridans group streptococci, Pseudomonas aeruginosa, and Candida spp. RESULTS: The comparison of TTD values for the two blood culture systems strongly indicated that growth of the first five groups listed above was detected earlier with VIRTUO than with BTA-3D (p < 0.05). CONCLUSIONS: The new VIRTUO blood culture system can reduce the TTD for more than 75% of isolated microorganisms.

Prognostic utility of plasma lactate measured between 24 and 48 h after initiation of early goal-directed therapy in the management of sepsis, severe sepsis, and septic shock.

BACKGROUND: Based on the proven efficacy of lactate in predicting mortality and morbidity in sepsis when measured early in the resuscitative protocol, our group hypothesized that this utility extends later in the course of care. This study sought to investigate the prognostic potential of plasma lactate clearance measured 24-48 h after the initiation of treatment for nonsurgical patients with sepsis, severe sepsis, and septic shock. METHODS: Plasma lactate values, measured 24-48 h after the initiation of treatment, were collected in nonsurgical septic, severe septic, and septic shock patients. The primary outcome was 30-day mortality, while secondary outcomes included requirements for vasopressors and boluses of intravenous fluids. Analysis of these three outcomes was performed while controlling for clinical severity as measured by Sequential Organ Failure Assessment (SOFA), renal dysfunction, and hepatic dysfunction. Lactate clearance was defined as the percent change in plasma lactate levels measured after 24-48 h of treatment from the plasma lactate level at initial presentation. RESULTS: Two hundred twenty-nine nonsurgical patients were divided into two groups, clearers (above median lactate clearance [31.6 %]) and nonclearers (below median lactate clearance [31.6 %]). The adjusted odds ratio of mortality in clearers compared to nonclearers was 0.39 (CI 0.20-0.76) (p = 0.006). For vasopressor requirement, the adjusted odds ratio was 0.41 (CI 0.21-0.79) in clearers compared to nonclearers (p = 0.008). For intravenous fluid bolus requirement, the adjusted odds ratio was 0.81 (CI 0.48-1.39) in clearers compared to nonclearers (p = 0.45). CONCLUSIONS: Lower plasma lactate clearance 24-48 h after the initiation of treatment is associated with higher 30-day mortality and requirements for vasopressors in nonsurgical septic patients and may be a useful noninvasive measurement for guiding late-sepsis treatment. Further investigation looking at mechanisms and therapeutic targets to improve lactate clearance in late sepsis may improve patient mortality and outcomes.

Lactate kinetics in sepsis and septic shock: a review of the literature and rationale for further research.

Over the last two decades, there have been vast improvements in sepsis-related outcomes, largely resulting from the widespread adoption of aggressive fluid resuscitation and infection control. With increased understanding of the pathophysiology of sepsis, novel diagnostics and resuscitative interventions are being discovered. In recent years, few diagnostic tests like lactate have engendered more attention and research in the sepsis arena. Studies highlighting lactate's prognostic potential for mortality and other outcomes are ubiquitous and largely focus on the early stage of sepsis management, defined as the initial 6 h and widely referred to as the "golden hours." Additional investigations, although more representative of surgical and trauma patients, suggest that lactate measurements beyond 24 h from the initiation of resuscitation continue to have predictive and prognostic utility. This review summarizes the current research and evidence regarding lactate's utility as a prognosticator of clinical outcomes in both early and late sepsis management, defines the mechanism of lactate production and clearance, and identifies areas warranting further research.

lnterleukin-8 and procalcitonin in early diagnosis of early severe bacterial infection in critically ill neonates.

We studied the value of serum interleukin-8 (IL-8) and procalcitonin (PCT) in the early diagnosis of early severe bacterial infection in 58 critically ill ventilated neonates. ELISA was used for determining IL-8 and immunoluminometric assay for PCT. IL-8 and PCT were compared with routinely used serum C-reactive protein (CRP). Neonates were divided into four groups: Ia - proven severe bacterial infection (n = 9), Ib - clinical sepsis (n = 16), II - respiratory distress without bacterial infection (n = 12), and III - various types of neonatal distress (n = 21). Sera were collected on admission, at 24 h and 48 h after admission. There was no significant difference between groups Ia and Ib for either parameter at any time interval. Significant difference was found between group Ia+b (septic neonates) and group II for PCT and CRP at 24 and 48 h, but not for IL-8. There was no difference between group Ia+b and group III except for CRP at 24 h. Diagnostic accuracy was best for PCT on admission and for CRP at 24 h. Serum PCT and IL-8 are not specific markers for early severe bacterial infection in critically ill neonates and are not better than CRP.