Practical Lessons on Antimicrobial Therapy for Critically Ill Patients.

Sepsis stands as a formidable global health challenge, with persistently elevated mortality rates in recent decades. Each year, sepsis not only contributes to heightened morbidity but also imposes substantial healthcare costs on survivors. This narrative review aims to highlight the targeted measures that can be instituted to alleviate the incidence and impact of sepsis in intensive care. Here we discuss measures to reduce nosocomial infections and the prevention of equipment and patient colonisation by resilient pathogens. The overarching global crisis of bacterial resistance to newly developed antimicrobial agents intensifies the imperative for antimicrobial stewardship and de-escalation. This urgency has been accentuated in recent years, notably during the COVID-19 pandemic, as high-dose steroids and opportunistic infections presented escalating challenges. Ongoing research into airway colonisation's role in influencing disease outcomes among critically ill patients underscores the importance of tailoring treatments to disease endotypes within heterogeneous populations, which are important lessons for intensivists in training. Looking ahead, the significance of novel antimicrobial delivery systems and drug monitoring is poised to increase. This narrative review delves into the multifaceted barriers and facilitators inherent in effectively treating critically ill patients vulnerable to nosocomial infections. The future trajectory of intensive care medicine hinges on the meticulous implementation of vigilant stewardship programs, robust infection control measures, and the continued exploration of innovative and efficient technological solutions within this demanding healthcare landscape.

Endothelial dysfunction triggers acute respiratory distress syndrome in patients with sepsis: a narrative review.

Acute respiratory distress syndrome (ARDS) is a severe organ failure occurring mainly in critically ill patients as a result of different types of insults such as sepsis, trauma or aspiration. Sepsis is the main cause of ARDS, and it contributes to a high mortality and resources consumption both in hospital setting and in the community. ARDS develops mainly an acute respiratory failure with severe and often refractory hypoxemia. ARDS also has long term implications and sequelae. Endothelial damage plays an important role in the pathogenesis of ARDS. Understanding the mechanisms of ARDS presents opportunities for novel diagnostic and therapeutic targets. Biochemical signals can be used in concert to identify and classify patients into ARDS phenotypes allowing earlier effective treatment with personalised therapies. This is a narrative review where we aimed to flesh out the pathogenetic mechanisms and heterogeneity of ARDS. We examine the links between endothelium damage and its contribution to organ failure. We have also investigated future strategies for treatment with a special emphasis in endothelial damage.

Multi-Omics Endotypes in ICU Sepsis-Induced Immunosuppression.

It is evident that the admission of some patients with sepsis and septic shock to hospitals is occurring late in their illness, which has contributed to the increase in poor outcomes and high fatalities worldwide across age groups. The current diagnostic and monitoring procedure relies on an inaccurate and often delayed identification by the clinician, who then decides the treatment upon interaction with the patient. Initiation of sepsis is accompanied by immune system paralysis following "cytokine storm". The unique immunological response of each patient is important to define in terms of subtyping for therapy. The immune system becomes activated in sepsis to produce interleukins, and endothelial cells express higher levels of adhesion molecules. The proportions of circulating immune cells change, reducing regulatory cells and increasing memory cells and killer cells, having long-term effects on the phenotype of CD8 T cells, HLA-DR, and dysregulation of microRNA. The current narrative review seeks to highlight the potential application of multi-omics data integration and immunological profiling at the single-cell level to define endotypes in sepsis and septic shock. The review will consider the parallels and immunoregulatory axis between cancer and immunosuppression, sepsis-induced cardiomyopathy, and endothelial damage. Second, the added value of transcriptomic-driven endotypes will be assessed through inferring regulatory interactions in recent clinical trials and studies reporting gene modular features that inform continuous metrics measuring clinical response in ICU, which can support the use of immunomodulating agents.

Parallel Dysregulated Immune Response in Severe Forms of COVID-19 and Bacterial Sepsis via Single-Cell Transcriptome Sequencing.

Critically ill COVID-19 patients start developing single respiratory organ failure that often evolves into multiorgan failure. Understanding the immune mechanisms in severe forms of an infectious disease (either critical COVID-19 or bacterial septic shock) would help to achieve a better understanding of the patient's clinical trajectories and the success of potential therapies. We hypothesized that a dysregulated immune response manifested by the abnormal activation of innate and adaptive immunity might be present depending on the severity of the clinical presentation in both COVID-19 and bacterial sepsis. We found that critically ill COVID-19 patients demonstrated a different clinical endotype that resulted in an inflammatory dysregulation in mild forms of the disease. Mild cases (COVID-19 and bacterial non severe sepsis) showed significant differences in the expression levels of CD8 naïve T cells, CD4 naïve T cells, and CD4 memory T cells. On the other hand, in the severe forms of infection (critical COVID-19 and bacterial septic shock), patients shared immune patterns with upregulated single-cell transcriptome sequencing at the following levels: B cells, monocyte classical, CD4 and CD8 naïve T cells, and natural killers. In conclusion, we identified significant gene expression differences according to the etiology of the infection (COVID-19 or bacterial sepsis) in the mild forms; however, in the severe forms (critical COVID-19 and bacterial septic shock), patients tended to share some of the same immune profiles related to adaptive and innate immune response. Severe forms of the infections were similar independent of the etiology. Our findings might promote the implementation of co-adjuvant therapies and interventions to avoid the development of severe forms of disease that are associated with high mortality rates worldwide.

Model-interpreted outcomes of artificial neural networks classifying immune biomarkers associated with severe infections in ICU.

Introduction: Millions of deaths worldwide are a result of sepsis (viral and bacterial) and septic shock syndromes which originate from microbial infections and cause a dysregulated host immune response. These diseases share both clinical and immunological patterns that involve a plethora of biomarkers that can be quantified and used to explain the severity level of the disease. Therefore, we hypothesize that the severity of sepsis and septic shock in patients is a function of the concentration of biomarkers of patients. Methods: In our work, we quantified data from 30 biomarkers with direct immune function. We used distinct Feature Selection algorithms to isolate biomarkers to be fed into machine learning algorithms, whose mapping of the decision process would allow us to propose an early diagnostic tool. Results: We isolated two biomarkers, i.e., Programmed Death Ligand-1 and Myeloperoxidase, that were flagged by the interpretation of an Artificial Neural Network. The upregulation of both biomarkers was indicated as contributing to increase the severity level in sepsis (viral and bacterial induced) and septic shock patients. Discussion: In conclusion, we built a function considering biomarker concentrations to explain severity among sepsis, sepsis COVID, and septic shock patients. The rules of this function include biomarkers with known medical, biological, and immunological activity, favoring the development of an early diagnosis system based in knowledge extracted from artificial intelligence.

Novel investigational treatments for ventilator-associated pneumonia and critically ill patients in the intensive care unit.

INTRODUCTION: Ventilator-associated pneumonia (VAP) is common; its prevalence has been highlighted by the Covid-19 pandemic. Even young patients can suffer severe nosocomial infection and prolonged mechanical ventilation. Multidrug-resistant bacteria can spread alarmingly fast around the globe and new antimicrobials are struggling to keep pace; hence physicians must stay abreast of new developments in the treatment of nosocomial pneumonia and VAP. AREAS COVERED: This narrative review examines novel antimicrobial investigational drugs and their implementation in the ICU setting for VAP. This paper highlights novel approaches such as monoclonal antibody treatments for P. aeruginosa and S. aureus and phage antibiotic synthesis. This paper also examines mechanisms of resistance in Gram-negative bacteria, virulence factors, and inhaled antibiotics and questions what may be on the horizon in terms of emerging treatment strategies. EXPERT OPINION: The postantibiotic era is rapidly approaching, and the need for personalized medicine, point-of-care microbial sensitivity testing, and development of biomarkers for severe infections is clear. Results from emerging and new antibiotics are encouraging, but infection control measures and de-escalation protocols must be employed to prolong their usefulness in critical illness.

Effects of Fluids on the Sublingual Microcirculation in Sepsis.

Sepsis is one of the most common and deadly syndromes faced in Intensive Care settings globally. Recent advances in bedside imaging have defined the changes in the microcirculation in sepsis. One of the most advocated interventions for sepsis is fluid therapy. Whether or not fluid bolus affects the microcirculation in sepsis has not been fully addressed in the literature. This systematic review of the evidence aims to collate studies examining the microcirculatory outcomes after a fluid bolus in patients with sepsis. We will assimilate the evidence for using handheld intra vital microscopes to guide fluid resuscitation and the effect of fluid bolus on the sublingual microcirculation in patients with sepsis and septic shock. We conducted a systematic search of Embase, CENTRAL and Medline (PubMed) using combinations of the terms "microcirculation" AND "fluid" OR "fluid resuscitation" OR "fluid bolus" AND "sepsis" OR "septic shock". We found 3376 potentially relevant studies. Fifteen studies published between 2007 and 2021 fulfilled eligibility criteria to be included in analysis. The total number of participants was 813; we included six randomized controlled trials and nine non-randomized, prospective observational studies. Ninety percent used Sidestream Dark Field microscopy to examine the microcirculation and 50% used Hydroxyethyl Starch as their resuscitation fluid. There were no clear effects of fluid on the microcirculation parameters. There was too much heterogeneity between studies and methodology to perform meta-analysis. Studies identified heterogeneity of affect in the sepsis population, which could mean that current clinical classifications were not able to identify different microcirculation characteristics. Use of microcirculation as a clinical endpoint in sepsis could help to define sepsis phenotypes. More research into the effects of different resuscitation fluids on the microcirculation is needed.

Endothelial Damage and the Microcirculation in Critical Illness.

Endothelial integrity maintains microcirculatory flow and tissue oxygen delivery. The endothelial glycocalyx is involved in cell signalling, coagulation and inflammation. Our ability to treat critically ill and septic patients effectively is determined by understanding the underpinning biological mechanisms. Many mechanisms govern the development of sepsis and many large trials for new treatments have failed to show a benefit. Endothelial dysfunction is possibly one of these biological mechanisms. Glycocalyx damage is measured biochemically. Novel microscopy techniques now mean the glycocalyx can be indirectly visualised, using sidestream dark field imaging. How the clinical visualisation of microcirculation changes relate to biochemical laboratory measurements of glycocalyx damage is not clear. This article reviews the evidence for a relationship between clinically evaluable microcirculation and biological signal of glycocalyx disruption in various diseases in ICU. Microcirculation changes relate to biochemical evidence of glycocalyx damage in some disease states, but results are highly variable. Better understanding and larger studies of this relationship could improve phenotyping and personalised medicine in the future. Damage to the glycocalyx could underpin many critical illness pathologies and having real-time information on the glycocalyx and microcirculation in the future could improve patient stratification, diagnosis and treatment.

An artificial neural network classification method employing longitudinally monitored immune biomarkers to predict the clinical outcome of critically ill COVID-19 patients.

Background: The severe form of COVID-19 can cause a dysregulated host immune syndrome that might lead patients to death. To understand the underlying immune mechanisms that contribute to COVID-19 disease we have examined 28 different biomarkers in two cohorts of COVID-19 patients, aiming to systematically capture, quantify, and algorithmize how immune signals might be associated to the clinical outcome of COVID-19 patients. Methods: The longitudinal concentration of 28 biomarkers of 95 COVID-19 patients was measured. We performed a dimensionality reduction analysis to determine meaningful biomarkers for explaining the data variability. The biomarkers were used as input of artificial neural network, random forest, classification and regression trees, k-nearest neighbors and support vector machines. Two different clinical cohorts were used to grant validity to the findings. Results: We benchmarked the classification capacity of two COVID-19 clinicals studies with different models and found that artificial neural networks was the best classifier. From it, we could employ different sets of biomarkers to predict the clinical outcome of COVID-19 patients. First, all the biomarkers available yielded a satisfactory classification. Next, we assessed the prediction capacity of each protein separated. With a reduced set of biomarkers, our model presented 94% accuracy, 96.6% precision, 91.6% recall, and 95% of specificity upon the testing data. We used the same model to predict 83% and 87% (recovered and deceased) of unseen data, granting validity to the results obtained. Conclusions: In this work, using state-of-the-art computational techniques, we systematically identified an optimal set of biomarkers that are related to a prediction capacity of COVID-19 patients. The screening of such biomarkers might assist in understanding the underlying immune response towards inflammatory diseases.

Hypotension during hip fracture surgery and postoperative morbidity.

BACKGROUND: Hip fracture is a growing healthcare challenge, with 6-8% 30-day mortality and 20-30% of patients incurring major morbidity, including impaired mobilisation and ability to live independently. While observational studies have shown no benefit of general versus spinal anaesthesia on 30-day mortality, intraoperative hypotension during hip fracture surgery is associated with increased 30-day mortality regardless of anaesthetic technique. Although a recent trial on younger patients demonstrated reduced postoperative complications by maintaining intraoperative arterial blood pressure close to preoperative baseline, there are no data correlating intraoperative hypotension during hip fracture surgery with postoperative morbidity. OBJECTIVE: We evaluated the hypothesis that duration and severity of intraoperative hypotension during hip fracture surgery is associated with increased postoperative morbidity. METHODS: A retrospective analysis was carried out on n = 52 patients undergoing hip fracture surgery between January and June 2017. Measurements of patients' intraoperative systolic arterial pressure (SAP) and mean arterial pressure (MAP) during anaesthesia, logged electronically through an anaesthesia information management system, were reviewed. We calculated the total duration of time where SAP or MAP were below pre-defined thresholds for hypotension (MAP < 75 mmHg, MAP < 55 mmHg, SAP ≤ 80% admission baseline or SAP ≤ 80% pre-induction baseline). Univariate and bivariate descriptive statistics were generated for all relevant variables. With multivariable regression models containing known predictors, cumulative duration of hypotension was correlated with postoperative comorbidities as quantified by the Clavien-Dindo and Comprehensive Complication Indices. RESULTS: Mean age (± SD) was 78 ± 13 years, 75% were female, 87% were ASA II or III and 60% underwent spinal anaesthesia. Mean Comprehensive Complication Index was 20.4 ± 19.2. Lowest absolute SAP and MAP values were 82 ± 18 mmHg and 55 ± 12 mmHg respectively. Cumulative time of SAP < 80% pre-induction value adjusted to gender, age and the Charlson Comorbidity Index was associated with progression to a higher Clavien-Dindo classification (odds ratio 1.020 per additional minute; 95% CI 1.008-1.035; P = 0.003). CONCLUSIONS: In this exploratory retrospective analysis, the cumulative time of hypotension during hip fracture surgery correlated with extensive postoperative morbidity when adjusting to other known predictors. Intraoperative cumulative time of hypotension may be a good candidate for larger prediction studies as a predictor of postoperative complications. A randomised controlled trial evaluating the effect of actively minimising intraoperative hypotension on postoperative morbidity in hip fracture patients seems warranted.