The purpose of this narrative review is to describe the mechanisms for gut dysfunction during critical illness, outline hypotheses of gut-derived inflammation, and identify nutrition and non-nutritional therapies that have direct and indirect effects on preserving both epithelial barrier function and gut microbiota during critical illness.

Clinical and animal model studies have demonstrated that critical illness pathophysiology and interventions breach epithelial barrier function and convert a normally commensal gut microbiome into a pathobiome. As a result, the gut has been postulated to be the "motor" of critical illness and numerous hypotheses have been put forward to explain how it contributes to systemic inflammation and drives multiple organ failure. Strategies to ameliorate gut dysfunction have focused on maintaining gut barrier function and promoting gut microbiota commensalism. The trajectory of critical illness may be closely related to gut epithelial barrier function, the gut microbiome and interventions that may contribute towards a deleterious pathobiome with immune dysregulation.

Evidence suggests that the intestinal microbiome may play an important role in the pathogenesis and progression of acute critical illness in humans and other mammals, although evidence in small animal medicine is sparse. Moreover, the intestinal microbiota plays many important metabolic roles (production of short-chain fatty acids, trimethylamine-N-oxide, and normal bile acid metabolism) and is crucial for immunity as well as defense against enteropathogens. The use of probiotics and fecal microbiota transplantation as instruments to modulate the intestinal microbiota seems to be safe and effective in studies on critically ill dogs with acute gastrointestinal diseases.

Traumatic brain injury (TBI) remains a leading cause of mortality and disability worldwide, characterized by complex pathophysiological processes that extend beyond the initial trauma. The inflammatory response following TBI plays a crucial role in patient outcomes, presenting both protective and potentially detrimental effects. This narrative review examines the current evidence regarding the role of nutritional supplements in modulating the inflammatory response after TBI. Recent research has demonstrated that various nutritional interventions, including probiotics, immunonutrition formulas, vitamin D, and taurine supplementation, can significantly influence inflammatory markers and clinical outcomes. Probiotics have shown particular promise in reducing inflammatory mediators and infection rates, while also decreasing hospital and ICU length of stay. Immunonutrition, especially through vitamin D supplementation, demonstrates significant effects on consciousness levels and ventilation requirements. The timing of nutritional intervention emerges as critical, with the early post-injury period (24-72 h) representing a crucial window for therapeutic intervention. The gut-brain axis appears central to these effects, with nutritional supplements potentially modulating both central and systemic inflammatory responses. While these interventions show promising results in reducing inflammatory markers and improving short-term outcomes, their impact on mortality rates remains limited. Future research should focus on optimizing nutritional protocols, understanding individual patient factors, and investigating long-term functional outcomes. This review supports a paradigm shift in approaching nutritional support in TBI, transitioning from viewing it as merely supportive care to recognizing it as an active therapeutic intervention that can significantly influence patient outcomes.

As the incessant emergence of drug-resistant bacterial strains, bacterial pneumonia poses a serious threat to the public health worldwide. There is an urgent need to explore unconventional therapeutic strategies. Carbon dots are usually designed to directly kill bacteria, however, carbon dots that enhance the anti-infection function of immune cells are rarely reported. In the present study, CDots were synthesized with ascorbic acid and polyethyleneimine, exhibiting outstanding biocompatibility. Functionally, the CDots exhibited a well therapeutic impact on bacterial pneumonia induced by gram-positive multidrug-resistant Staphylococcus aureus (MRSA) or gram-negative Klebsiella pneumoniae (K. pneumoniae) in mice. Utilizing in vitro models of macrophages infected with MRSA and K. pneumoniae, we discovered that CDots augmented the M1 polarization of macrophages, subsequently enhancing their survival and activity of phagocytosis and bactericidal. Further investigations through molecular dynamics simulations and in vitro experiments validated that CDots directly bind to the catalytic subunit (PIK3CD) of phosphoinositide 3-kinase (PI3K), resulting in the inhibition of the PI3K/AKT/mTOR signaling pathway. Moreover, the crucial domain for the binding was located in amino acids 752-787 of PIK3CD. In summary, CDots exerted a protective effect on bacterial pneumonia by targeting the PIK3CD and fostering the PI3K-mediated M1 polarization of macrophages. These findings not only reveal a new role of CDots in the treatment of bacterial pneumonia, but also provide potential targets for future treatment strategies.

In recent years, the study of the interaction between gut microbiota and distant organs such as the heart, lungs, brain, and liver has become a hot topic in the field of gut microbiology. With a deeper understanding of its immune regulation and mechanisms of action, these findings have increasingly highlighted their guiding value in clinical practice. The gut is not only the largest digestive organ in the human body but also the habitat for most microorganisms. Imbalances in gut microbial communities have been associated with various lung diseases, such as allergic asthma and cystic fibrosis. Furthermore, gut microbial communities have significant impacts on metabolic function and immune responses. Their metabolites not only regulate gastrointestinal immune systems but may also affect distant organs such as the lungs and brain. As one of the most common types of respiratory system diseases worldwide, pulmonary infections have high morbidity and mortality rates. Pulmonary infections caused by immune dysfunction can lead to gastrointestinal problems like diarrhea, further resulting in imbalances within complex interactions that are associated with abnormal manifestations under disequilibrium conditions. Meanwhile, clinical interventions can significantly modulate the composition of gut microbiota, and alteration in gut microbiota may subsequently indicate susceptibility to pulmonary infections and even contribute to the prevention or regulation of their progression. This review delves into the interaction between gut microbiota and pulmonary infections, elucidating the latest advancements in gut-lung axis research and providing a fresh perspective for the treatment and prevention of pneumonia.

Background: Critical illness induces profound metabolic alterations, characterized by a hypermetabolic state, insulin resistance, protein catabolism, and gut barrier dysfunction, which contribute to increased morbidity and mortality. Emerging evidence highlights the role of the gut microbiome and its metabolites in modulating systemic inflammation and immune responses during critical illness. This narrative review explores the metabolic evolution of critically ill patients, the impact of gut dysbiosis on disease progression, and the potential role of nutrition in modulating metabolism and improving patient outcomes. Methods: A comprehensive literature search was conducted across PubMed and Google Scholar for articles published up to February 2025. Search terms included "critical illness", "metabolism", "gut microbiota", "nutrition", and related keywords. Articles published in English addressing metabolic alterations, microbiome changes, and nutritional strategies in critically ill patients were included. After screening for eligibility, relevant articles were synthesized to outline current knowledge and identify gaps. Results: Metabolic changes in critical illness progress through distinct phases, from catabolism-driven hypermetabolism to gradual recovery. Gut dysbiosis, characterized by a loss of microbial diversity and increased gut permeability, contributes to systemic inflammation and organ dysfunction. Nutritional strategies, including enteral nutrition, probiotics, prebiotics, and metabolomics-driven interventions, may help restore microbial balance, preserve gut barrier integrity, and modulate immune and metabolic responses. Future nutrition therapy should focus on metabolic modulation rather than solely addressing nutrient deficits. Conclusions: Advances in gut microbiome research and metabolomics offer new avenues for personalized nutrition strategies tailored to the metabolic demands of critically ill patients. Integrating these approaches may improve clinical and functional recovery while mitigating the long-term consequences of critical illness.

Ventilator-associated pneumonia (VAP) remains a significant concern in intensive care units (ICUs), contributing to increased morbidity, mortality, and healthcare costs. Probiotics and synbiotics have been explored as potential preventive measures due to their ability to modulate gut microbiota, reduce pathogenic colonization, enhance immune responses, and maintain intestinal barrier integrity. While some randomized controlled trials (RCTs) suggest that specific strains, such as Lactobacillus rhamnosus GG and Bifidobacterium breve, may reduce VAP incidence, larger trials have not confirmed significant benefits. Systematic reviews and meta-analyses indicate a potential 28-38% relative risk reduction in VAP, but evidence quality remains low due to methodological limitations and study heterogeneity. Economic evaluations also question the cost effectiveness of probiotic use in ICU settings. Future research should focus on large-scale, multicenter RCTs to determine the optimal strains, dosages, and administration methods, along with standardized diagnostic criteria. Until stronger evidence emerges, probiotics should be considered an adjunctive rather than a primary VAP prevention strategy.

This review explores the evolving understanding of gut microbiota's role in critical illness, focusing on how acute illness and exposures in intensive care unit (ICU) environment negatively impact the gut microbiota and the implications of these changes on host responses in critically-ill patients. Focusing on recent findings from clinical and preclinical studies, we discuss the effects of inflammation, enteral nutrient deprivation, and antibiotics on gut microbial dynamics. This review aims to enhance comprehension of microbial dynamics in the ICU and their implications for clinical outcomes and therapeutic strategies.

This narrative review discusses the mechanisms connecting gut dysbiosis to adverse clinical outcomes in critically ill patients and explores potential therapeutic strategies.

In recent years, the study of microbiota in ICUs has gained attention because of its potential effects on patient outcomes. Critically ill patients often face severe conditions, which can compromise their immune systems and lead to opportunistic infections from bacteria typically harmless to healthy individuals. The relationship between aggressive medical treatments and microbiota composition remains unclear. Dysbiosis, characterized by reduced microbial diversity and the loss of beneficial bacteria, can lead to prolonged immunosuppression and increased pathogenic risks, contributing to infections and organ failure. Recent advancements in multiomics technologies have enhanced the understanding of host-microbe interactions and their implications in critical care.

The microbiota plays an important role in shaping outcomes for critically ill patients. According to evidence, alterations in the gut and lung microbiota are associated with disease severity, mortality, and overall patient recovery. Evolving research opens possibilities for personalized medicine by tailoring treatments based on individual microbiota profiles, though clinical applications are still developing.

Nutrition therapy is important in the management of critically ill patients and is continuously evolving as new evidence emerges. The Japanese Critical Care Nutrition Guideline 2024 (JCCNG 2024) is specific to Japan and is the latest set of clinical practice guidelines for nutrition therapy in critical care that was revised from JCCNG 2016 by the Japanese Society of Intensive Care Medicine. An English version of these guidelines was created based on the contents of the original Japanese version. These guidelines were developed to help health care providers understand and provide nutrition therapy that will improve the outcomes of children and adults admitted to intensive care units or requiring intensive care, regardless of the disease. The intended users of these guidelines are all healthcare professionals involved in intensive care, including those who are not familiar with nutrition therapy. JCCNG 2024 consists of 37 clinical questions and 24 recommendations, covering immunomodulation therapy, nutrition therapy for special conditions, and nutrition therapy for children. These guidelines were developed in accordance with the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system by experts from various healthcare professionals related to nutrition therapy and/or critical care. All GRADE-based recommendations, good practice statements (GPS), future research questions, and answers to background questions were finalized by consensus using the modified Delphi method. Strong recommendations for adults include early enteral nutrition (EN) within 48 h and the provision of pre/synbiotics. Weak recommendations for adults include the use of a nutrition protocol, EN rather than parenteral nutrition, the provision of higher protein doses, post-pyloric EN, continuous EN, omega-3 fatty acid-enriched EN, the provision of probiotics, and indirect calorimetry use. Weak recommendations for children include early EN within 48 h, bolus EN, and energy/protein-dense EN formulas. A nutritional assessment is recommended by GPS for both adults and children. JCCNG 2024 will be disseminated through educational activities mainly by the JCCNG Committee at various scientific meetings and seminars. Since studies on nutritional treatment for critically ill patients are being reported worldwide, these guidelines will be revised in 4 to 6 years. We hope that these guidelines will be used in clinical practice for critically ill patients and in future research.

The gut has long been hypothesized to be the "motor" of critical illness, propagating inflammation and playing a key role in multiple organ dysfunction. However, the exact mechanisms through which impaired gut integrity potentially contribute to worsened clinical outcome remain to be elucidated. Critical elements of gut dysregulation including intestinal hyperpermeability and a perturbed microbiome are now recognized as potential therapeutic targets in critical care.

The gut is a finely tuned ecosystem comprising ~ 40 trillion microorganisms, a single cell layer intestinal epithelia that separates the host from the microbiome and its products, and the mucosal immune system that actively communicates in a bidirectional manner. Under basal conditions, these elements cooperate to maintain a finely balanced homeostasis benefitting both the host and its internal microbial community. Tight junctions between adjacent epithelial cells selectively transport essential molecules while preventing translocation of pathogens. However, critical illness disrupts gut barrier function leading to increased gut permeability, epithelial apoptosis, and immune activation. This disruption is further exacerbated by a shift in the microbiome toward a "pathobiome" dominated by pathogenic microbes with increased expression of virulence factors, which intensifies systemic inflammation and accelerates organ dysfunction. Research has highlighted several potential therapeutic targets to restore gut integrity in the host, including the regulation of epithelial cell function, modulation of tight junction proteins, and inhibition of epithelial apoptosis. Additionally, microbiome-targeted therapies, such as prebiotics, probiotics, fecal microbiota transplantation, and selective decontamination of the digestive tract have also been extensively investigated to promote restoration of gut homeostasis in critically ill patients. Future research is needed to validate the potential efficacy of these interventions in clinical settings and to determine if the gut can be targeted in an individualized fashion.

Increased gut permeability and a disrupted microbiome are common in critical illness, potentially driving dysregulated systemic inflammation and organ dysfunction. Therapeutic strategies to modulate gut permeability and restore the composition of microbiome hold promise as novel treatments for critically ill patients.

Diarrhea is usually observed in newborn Hu lambs, while severe diarrhea may lead to the stunted growth and even death in lambs, necessitating the common practice of antibiotic administration to newborns. In order to explore the application of the effective probiotics and/or prebiotic treatment in animal feed to lessen the recline on antibiotics, 27 newborn of Hu lambs were equally allocated into three groups: control group (Con), probiotics group (Pro) receiving Lactiplantibacillus plantarum N-1 (LPN-1), and synbiotics group (Syn) receiving LPN-1 combined with isomaltose-oligosaccharide (IMO), and raised till 60 days of age.

Compared with the Con, the incidence of severe diarrhea was lower in both two treatment groups, accompanied by a significant reduction in terramycin administration frequency (P < 0.05). The daily feed intake in newborns significantly increased after probiotics or synbiotics treatment (P < 0.05), leading to the substantial increment in average daily gain by 48.28% and heart girth (P < 0.05), as well as enhancements in height (P < 0.01) at 60 days of the age in synbiotics treatment group. Applying probiotics and synbiotics exhibited the enhanced rumen weight (P < 0.05), and synbiotics further promoted the spleen development (P < 0.05). The inclusion of probiotics and synbiotics significantly modified the gut microbial composition of Hu lambs (P < 0.01), with an increase in Butyrivibrio proteoclasticus and Pseudoruminococcus massiliensis, which were associated with starch and sucrose metabolism. Additionally, the Syn group exhibited an upsurge in the number of species associated with amino acid metabolism and cellulolysis, as well as the raised short-chain fatty acids levels in the newborn gut (P < 0.05).

This study demonstrated that LPN-1 and IMO had an enhanced effect to improve the growth performance and decrease the reliance on antibiotics by promoting the feed intake, balancing the gut microbiota and increasing the short-chain fatty acids content in Hu lambs.

Enteral nutrition (EN) has been reported to have some physiological importance for critically ill patients. However, the advantage of EN over parenteral nutrition remains controversial in recent paradigms. To maximize the benefits and efficiency of EN, implementing measures based on comprehensive evidence is essential. Here, we systematically reviewed EN-related studies and integrated them into the best and most up-to-date EN practices. We extracted studies from 13 systematic reviews during the development of Japanese Critical Care Nutrition Guidelines, summarizing findings on the assessment of enteral feeding intolerance (EFI), the timing of EN, formula composition and nutrients, and method of administration in critically ill adult patients. Multifaceted EFI assessment may be needed in patients for high-risk patients. Early EN may reduce infectious complications, and initiating EN even earlier may offer an additional advantage. High protein intake (≥1.2 g/kg/day) could maintain muscle mass and physical function without increasing gastrointestinal complications. Probiotics, prebiotics, and synbiotics may serve as beneficial options for preventing infection and gastrointestinal complications, although their efficacy depends on the strains, types, and combinations used. For patients with EFI, post-pyloric feeding could be an effective approach, while intermittent feeding may be a safer approach. Both methods should be utilized to achieve nutritional targets. Integrating these nutritional interventions into EN strategies may help maximize their effectiveness and minimize complications. However, careful consideration regarding timing, dosage, nutrient selection, administration methods, and patient selection is required.

In critical illness, all elements of gut function are perturbed. Dysbiosis develops as the gut microbial community loses taxonomic diversity and new virulence factors appear. Intestinal permeability increases, allowing for translocation of bacteria and/or bacterial products. Epithelial function is altered at a cellular level and homeostasis of the epithelial monolayer is compromised by increased intestinal epithelial cell death and decreased proliferation. Gut immunity is impaired with simultaneous activation of maladaptive pro- and anti-inflammatory signals leading to both tissue damage and susceptibility to infections. Additionally, splanchnic vasoconstriction leads to decreased blood flow with local ischemic changes. Together, these interrelated elements of gastrointestinal dysfunction drive and then perpetuate multi-organ dysfunction syndrome. Despite the clear importance of maintaining gut homeostasis, there are very few reliable measures of gut function in critical illness. Further, while multiple therapeutic strategies have been proposed, most have not been shown to conclusively demonstrate benefit, and care is still largely supportive. The key role of the gut in critical illness was the subject of the tenth Perioperative Quality Initiative meeting, a conference to summarize the current state of the literature and identify key knowledge gaps for future study. This review is the product of that conference.

Perioperative neurocognitive dysfunction is a significant concern for population health, impacting postoperative recovery and increasing the financial burden on patients. With an increasing number of surgical procedures being performed, the prevention and management of perioperative neurocognitive dysfunction have garnered significant attention. While factors such as age, lifestyle, genetics, and education are known to influence the development of cognitive dysfunction, recent research has highlighted the role of the gut microbiota in neurological health. An increased abundance of pro-inflammatory gut microbiota can trigger and worsen neuroinflammation, neuronal cell damage, and impaired cellular autophagy. Moreover, the inflammation-promoting gut microbiota can disrupt immune function, impair neuroautophagy, and affect the production and circulation of extracellular vesicles and neurotransmitters. These factors collectively play a role in the onset and advancement of cognitive impairment. This narrative review delves into the molecular mechanisms through which gut microbiota and their derivatives contribute to cognitive impairment, focusing on the impact of anesthesia surgery, changes in gut microbial populations, and perioperative cognitive impairment associations. The study suggests that alterations in the abundance of various bacterial species and their metabolites pre- and post-surgery may be linked to postoperative cognitive impairment. Furthermore, the potential of probiotics or prebiotics in addressing cognitive impairment is discussed, offering a promising avenue for investigating the treatment of perioperative neurocognitive disorders.

Diarrhea is one of the most common complications among patients in the Intensive Care Unit (ICU). Alongside common medical products for managing diarrhea, attention has been directed toward natural approaches, such as the use of probiotics or synbiotics supplements. The purpose of this review is to evaluate the effectiveness of probiotics or synbiotics in the prevention and treatment of diarrhea, mortality, and length of ICU stay.

In adherence to the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) statement, a systematic review and meta-analysis was conducted. Relevant articles were identified by searching PubMed, SpringerLink, and ScienceDirect databases. Quality assessment was done using Cochrane Collaboration's tool for randomized-controlled trials (ROB2).

6305 articles were identified, of which 14 papers were included. Probiotics reduced the risk of diarrhea by 10 %; however, the result was not statistically significant [Risk Ratio (RR) = 0.90; 95 % Confidence Interval (CI): 0.77 to 1.05; P = 0.16; I2 = 29 %; 13 studies]. No statistical significance was found among studies regarding reducing the duration of diarrhea, with considerable heterogeneity [RR = - 0.53; 95 % CI: -1.46 to 0.41; P = 0.27; I2 = 71 %, 5 studies]. Neither the length of ICU stays nor the mortality rate was affected by the use of probiotics or synbiotics.

Probiotics or synbiotics appear to slightly reduce the incidence of diarrhea among ICU patients. However, this effect is considered statistically significant only after conducting sensitivity and subgroup analyses. Further high-quality clinical trials are required to evaluate the potential of probiotics or synbiotics in the treatment of diarrhea among critically ill patients.

The mucosal immune system, as the most extensive peripheral immune network, serves as the frontline defense against a myriad of microbial and dietary antigens. It is crucial in preventing pathogen invasion and establishing immune tolerance. A comprehensive understanding of mucosal immunity is essential for developing treatments that can effectively target diseases at their entry points, thereby minimizing the overall impact on the body. Despite its importance, our knowledge of mucosal immunity remains incomplete, necessitating further research. The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has underscored the critical role of mucosal immunity in disease prevention and treatment. This systematic review focuses on the dynamic interactions between mucosa-associated lymphoid structures and related diseases. We delve into the basic structures and functions of these lymphoid tissues during disease processes and explore the intricate regulatory networks and mechanisms involved. Additionally, we summarize novel therapies and clinical research advances in the prevention of mucosal immunity-related diseases. The review also addresses the challenges in developing mucosal vaccines, which aim to induce specific immune responses while maintaining tolerance to non-pathogenic microbes. Innovative therapies, such as nanoparticle vaccines and inhalable antibodies, show promise in enhancing mucosal immunity and offer potential for improved disease prevention and treatment.

Eligibility criteria for randomized clinical trials (RCTs) are designed to select clinically relevant patient populations. However, not all eligibility criteria are strongly justified, potentially excluding marginalized groups, and limiting the generalizability of trial findings.

To summarize and evaluate the justification of exclusion criteria in published RCTs in critical care medicine.

A systematic sampling review of parallel-group RCTs published in the top 5 general internal medicine journals by impact factor (The Lancet, New England Journal of Medicine, Journal of the American Medical Association, British Medical Journal, and Annals of Internal Medicine) between January 1, 2018, and February 23, 2023, was conducted. RCTs enrolling adults in intensive care units (ICUs) and RCTs enrolling critically ill patients who required life-sustaining interventions typically initiated in the ICU were included. All study exclusion criteria were categorized as either poorly justified, potentially justified, or strongly justified, adapting previously established criteria, independently and in duplicate.

In total, 225 studies were identified, 75 of which were included. The median (IQR) number of exclusion criteria per trial was 19 (14-24), with 1455 total exclusion criteria. Common exclusion criteria were related to the risk of adverse reaction to interventions (302 criteria [20.8%]), followed by inability to obtain consent (120 criteria [8.2%]), and treatment limitation decisions (97 criteria [6.7%]). Most exclusion criteria were either strongly justified (1080 criteria [74.2%]) or potentially justified (297 criteria [20.4%]), whereas 5.4% (78 criteria) were poorly justified. Of the 78 poorly justified exclusion criteria, the most common were pregnancy (19 criteria [24.4%]), communication barriers (11 criteria [14.1%]), lactation (10 criteria [12.8%]), and lack of health insurance (10 criteria [12.8%]). Overall, 45 of 75 studies (60.0%) had at least 1 poorly justified exclusion criteria.

Most exclusion criteria in critical care medicine RCTs were strongly justifiable. Across poorly justified criteria, the most common exclusions were pregnant or lactating persons, those with communication barriers, and individuals without health insurance. This highlights the need to carefully consider exclusion criteria when designing trials to minimize the inappropriate exclusion of participants and enhance generalizability.

Sepsis, a common acute and critical disease, leads to 11 million deaths annually worldwide. Probiotics are living microorganisms that are beneficial to the host and may benefit sepsis outcomes, but their effects are still inconclusive. This study aimed to evaluate the overall effect of probiotics on the prognosis of patients with sepsis.

We searched several sources for published/presented studies, including PubMed, EMBASE, Web of Science, the Cochrane Library and the US National Library of Medicine Clinical Trials Register (www.clinicaltrials.gov) updated through July 30, 2023, to identify all relevant randomized controlled trials (RCTs) or observational studies that assessed the effectiveness of probiotics or synbiotics in patients with sepsis and reported mortality. We focused primarily on mortality during the study period and analyzed secondary outcomes, including 28-day mortality, in-intensive care unit (ICU) mortality and other outcomes.

Data from 405 patients in five RCTs and 108 patients in one cohort study were included in the analysis. The overall quality of the studies was satisfactory, but clinical heterogeneity existed. All adult studies reported a tendency for probiotics to reduce the mortality of patients with sepsis, and most studies reported a decreasing trend in the incidence of infectious complications, length of ICU stay and duration of antibiotic use. There was only one RCT involving children.

Probiotics show promise for improving the prognosis of patients with sepsis, including reducing mortality and the incidence of infectious complications, particularly in adult patients. Despite the limited number of studies, especially in children, these findings will be encouraging for clinical practice in the treatment of sepsis and suggest that gut microbiota-targeted therapy may improve the prognosis of patients with sepsis.

Understanding site-related factors that influence enrolment within multicenter randomized controlled trials (RCT) may help reduce trial delays and cost over-runs and prevent early trial discontinuation. In this analysis of PROSPECT (Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial), we describe patient enrolment patterns and examine factors influencing site-based monthly enrolment.

Retrospective analysis of a multicenter RCT.

The PROSPECT multicenter RCT enrolled patients in the main trial from July 2015 to March 2019. We documented site characteristics and trial metrics including data from the methods center tracking documents, site-level data at trial initiation, screening logs submitted by research coordinators, and prospectively collected case report forms. In this retrospective analysis of trial data, we analyzed enrolment patterns across sites using negative binomial regression to explore the association between monthly enrolment rate accounting for number of ICU beds, site characteristics, and trial metrics.

Overall, 41 sites enrolling 2365 patients in the PROSPECT main trial were analyzed. After accounting for number of beds in each ICU, site launch early in the trial was associated with higher monthly enrolment rates, but time to first enrolment and research coordinator experience was not. We observed considerable variability in the number of active screening months and enrolment rates across sites.

These findings highlight the complexity of recruitment dynamics in critical care RCTs and emphasize the need for tailored approaches to trial planning and execution.

PROSPECT (Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial): NCT02462590 (registered June 2, 2015).

Therapeutic antibodies (Ab) have revolutionized the management of multiple illnesses including respiratory tract infections (RTIs). However, anti-infectious Ab displayed several limitations including antigen restrictiveness, narrowed therapeutic windows, and limited dose in the vicinity of the target when delivered by parenteral routes. Strategies enhancing further Ab-dependent containment of infection are currently needed. Here we showed that a combination of inhaled anti-infectious Ab and probiotics is an efficient formulation to protect against lung infection. Using a mouse model of Pseudomonas aeruginosa-induced pneumonia, we demonstrated a synergistic effect reducing both bacterial burden and pro-inflammatory response affording protection against primary and secondary infections. This is the first study showing that the local combination in the airways of anti-infective Ab and probiotics subverts suboptimal potency of Ab monotherapy and provides protection against respiratory pathogen.

Background Cerebrovascular accidents (CVAs), or strokes, are major global health concerns associated with oxidative stress, inflammation, and gastrointestinal complications. This study aimed to explore the impact of postbiotic supplementation in CVA patients, specifically in terms of oxidative stress, inflammation, and clinical outcomes, as an alternative to probiotics with potential advantages. Method A prospective, single-center, randomized, controlled trial was conducted with 120 CVA patients in Iran. These patients were admitted to the ICU to assess the severity of their strokes. Patients were randomly assigned to receive either postbiotic supplementation (n = 60) or a placebo (n = 60). Various biomarkers related to oxidative stress, inflammation, and clinical outcomes were assessed. Data on demographic characteristics, nosocomial infections, and laboratory measurements were collected. Gut microbiota analysis was also performed on fecal samples. Results After the 7-day intervention, postbiotic supplementation resulted in significant improvements in inflammatory markers, oxidative stress, and a reduced incidence of pneumonia compared with those in the control group, with the postbiotic group demonstrating notable decreases in the serum IL-1β levels (-1.79; 95% CI: = -2.9 to -0.64, p = 0.002 ), MDA levels (-30.5; 95% CI: -54.8 to -6.1, p = 0.015), Hs-CRP levels (-0.67; 95% CI:-1.1 to -0.26 mg/dl, p = 0.001) and TAC levels (62.5; 95%CI: 34.1 to 90.9, p < 0.001) compared with those in the placebo group. However, no significant differences in other clinical outcomes, including the NIHSS score, NUTRIC score, and APACHE II score, or the gut microbiota profile, were observed between the two groups. Conclusion Postbiotic supplementation improved the levels of inflammatory factors and oxidative stress markers and reduced the risk of pneumonia in CVA patients. Trial registration This trial is registered in the Iranian Registry of Clinical Trials (registration code IRCT20180712040438N7), Registration date 06122022.

Sepsis is a complex clinical syndrome characterized by an uncontrolled inflammatory response to an infection that may result in septic shock and death. Recent research has revealed a crucial link between sepsis and alterations in the gut microbiota, showing that the microbiome could serve an essential function in its pathogenesis and prognosis. In sepsis, the gut microbiota undergoes significant dysbiosis, transitioning from a beneficial commensal flora to a predominance of pathobionts. This transformation can lead to a dysfunction of the intestinal barrier, compromising the host's immune response, which contributes to the severity of the disease. The gut microbiota is an intricate system of protozoa, fungi, bacteria, and viruses that are essential for maintaining immunity and metabolic balance. In sepsis, there is a reduction in microbial heterogeneity and a predominance of pathogenic bacteria, such as proteobacteria, which can exacerbate inflammation and negatively influence clinical outcomes. Microbial compounds, such as short-chain fatty acids (SCFAs), perform a crucial task in modulating the inflammatory response and maintaining intestinal barrier function. However, the role of other microbiota components, such as viruses and fungi, in sepsis remains unclear. Innovative therapeutic strategies aim to modulate the gut microbiota to improve the management of sepsis. These include selective digestive decontamination (SDD), probiotics, prebiotics, synbiotics, postbiotics, and fecal microbiota transplantation (FMT), all of which have shown potential, although variable, results. The future of sepsis management could benefit greatly from personalized treatment based on the microbiota. Rapid and easy-to-implement tests to assess microbiome profiles and metabolites associated with sepsis could revolutionize the disease's diagnosis and management. These approaches could not only improve patient prognosis but also reduce dependence on antibiotic therapies and promote more targeted and sustainable treatment strategies. Nevertheless, there is still limited clarity regarding the ideal composition of the microbiota, which should be further characterized in the near future. Similarly, the benefits of therapeutic approaches should be validated through additional studies.

To date, age, frailty, and multimorbidity have been used primarily to inform prognosis in older adults. It remains uncertain, however, whether these patient factors may also predict response to critical care interventions or treatment outcomes.

We conducted a systematic search of top general medicine and critical care journals for randomized controlled trials (RCTs) examining critical care interventions published between January 1, 2011, and December 31, 2021.

We included RCTs of critical care interventions that examined any one of three subgroups-age, frailty, or multimorbidity. We excluded cluster RCTs, studies that did not report interventions in an ICU, and studies that did not report data examining subgroups of age, frailty, or multimorbidity.

We collected study characteristics (single vs. multicountry enrollment, single vs. multicenter enrollment, funding, sample size, intervention, comparator, primary outcome and secondary outcomes, length of follow-up), study population (inclusion and exclusion criteria, average age in intervention and comparator groups), and subgroup data. We used the Instrument for assessing the Credibility of Effect Modification Analyses instrument to evaluate the credibility of subgroup findings.

Of 2037 unique citations, we included 48 RCTs comprising 50,779 total participants. Seven (14.6%) RCTs found evidence of statistically significant effect modification based on age, whereas none of the multimorbidity or frailty subgroups found evidence of statistically significant subgroup effect. Subgroup credibility ranged from very low to moderate.

Most critical care RCTs do not examine for subgroup effects by frailty or multimorbidity. Although age is more commonly considered, the cut-point is variable, and relative effect modification is rare. Although interventional effects are likely similar across age groups, shared decision-making based on individual patient preferences must remain a priority. RCTs focused specifically on critically ill older adults or those living with frailty and/or multimorbidity are crucial to further address this research question.

Serum anion gap (AG) can potentially be applied to the diagnosis of various metabolic acidosis, and a recent study has reported the association of AG with the mortality of patients with coronavirus disease 2019 (COVID-19). However, the relationship of AG with the short-term mortality of patients with ventilator-associated pneumonia (VAP) is still unclear. Herein, we aimed to investigate the association between AG and the 30-day mortality of VAP patients, and construct and assess a multivariate predictive model for the 30-day mortality risk of VAP.

This retrospective cohort study extracted data of 477 patients with VAP from the Medical Information Mart for Intensive Care III (MIMIC-III) database. Data of patients were divided into a training set and a testing set with a ratio of 7:3. In the training set, variables significantly associated with the 30-day mortality of VAP patients were included in the multivariate predictive model through univariate Cox regression and stepwise regression analyses. Then, the predictive performance of the multivariate predictive model was assessed in both training set and testing set, and compared with the single AG and other scoring systems including the Sequential Organ Failure Assessment (SOFA) score, the confusion, urea, respiratory rate (RR), blood pressure, and age (≥65 years old) (CURB-65) score, and the blood urea nitrogen (BUN), altered mental status, pulse, and age (>65 years old) (BAP-65) score. In addition, the association of AG with the 30-day mortality of VAP patients was explored in subgroups of gender, age, and infection status. The evaluation indexes were hazard ratios (HRs), C-index, and 95% confidence intervals (CIs).

A total of 70 patients died within 30 days. The multivariate predictive model consisted of AG (HR =1.052, 95% CI: 1.008-1.098), age (HR =1.037, 95% CI: 1.019-1.055), duration of mechanical ventilation (HR =0.998, 95% CI: 0.996-0.999), and vasopressors use (HR =1.795, 95% CI: 1.066-3.023). In both training set (C-index =0.725, 95% CI: 0.670-0.780) and testing set (C-index =0.717, 95% CI: 0.637-0.797), the multivariate model had a relatively superior predictive performance to the single AG value. Moreover, the association of AG with the 30-day mortality was also found in patients who were male (HR =1.088, 95% CI: 1.029-1.150), and whatever the pathogens they infected (bacterial infection: HR =1.059, 95% CI: 1.011-1.109; fungal infection: HR =1.057, 95% CI: 1.002-1.115).

The AG-related multivariate model had a potential predictive value for the 30-day mortality of patients with VAP. These findings may provide some references for further exploration on simple and robust predictors of the short-term mortality risk of VAP, which may further help clinicians to identify patients with high risk of mortality in an early stage in the intensive care units (ICUs).

Ventilator-associated pneumonia (VAP) increases the length of hospitalization and mortality rate. This study aimed to determine the effect of propolis mouthwash on the incidence of VAP in intensive care unit (ICU) patients.

Triple-blind, comparative randomized, controlled clinical trial was conducted over one year, with 110 ICU patients at Imam-Hossein and Bahar hospitals (Shahroud) and Kowsar Hospital (Semnan) in Iran. The intervention group used 15 cc of 0.06% propolis mouthwash solution twice daily at 8 AM and 4 PM for seven days. The control group used 15 cc of 0.2% chlorhexidine mouthwash at the same times and duration. Data were collected using a demographic questionnaire, APACHE II, Beck Oral Assessment Scale, and Modified Clinical Pulmonary Infection Score (MCPIS).

There was no significant difference in demographic information, disease severity, and oral health between the two groups before and after intervention (P > 0.05). The incidence of VAP in the intervention group compared to the control group was 10.9% vs. 30.9% on the third day (P = 0.0166, 95% CI: 0.53-0.83 and RR = 0.35), 23.6% vs. 43.6% on the fifth day (P = 0.0325 and 95% CI: 0.31-0.95 and RR = 0.54), and 25.5% vs. 47.3% on the seventh day (P = 0.0224, 95% CI: 0.32-0.92, and RR = 0.54). The Mann-Whitney indicated the incidence of VAP was significantly lower in the intervention group on the third, fifth, and seventh days.

Propolis mouthwash can be considered as an alternative to chlorhexidine mouthwash for ICU patients.

Propolis mouthwash serves as a simple, economical intervention to potentially reduce incidence of VAP.

(IRCT20110427006318N12, date 02.04.2019).

Ventilator associated pneumonia (VAP) leads to an increase in morbidity, mortality, and healthcare costs. In addition to increased evidence from the latest European and American guidelines (published in 2017 and 2022, respectively), in the last two years, several important clinical experiences have added new prevention tools to be included to improve the management of VAP.

This paper is a narrative review of new evidence on VAP prevention. We divided VAP prevention measures into pharmacological, non-pharmacological, and ventilator care bundles.

Most of the effective strategies that have been shown to decrease the incidence of complications are easy to implement and inexpensive. The implementation of care bundles, accompanied by educational measures and a multidisciplinary team should be part of optimal management. In addition to ventilator care bundles for the prevention of VAP, it could possibly be beneficial to use ventilator care bundles for the prevention of noninfectious ventilator associated events.

Hospital-acquired pneumonia (HAP) is associated with high mortality and costs, and frequently caused by multidrug-resistant (MDR) bacteria. Although prior antimicrobial therapy is a major risk factor for HAP, the underlying mechanism remains incompletely understood. Here, we demonstrate that antibiotic therapy in hospitalized patients is associated with decreased diversity of the gut microbiome and depletion of short-chain fatty acid (SCFA) producers. Infection experiments with mice transplanted with patient fecal material reveal that these antibiotic-induced microbiota perturbations impair pulmonary defense against MDR Klebsiella pneumoniae. This is dependent on inflammatory monocytes (IMs), whose fatty acid receptor (FFAR)2/3-controlled and phagolysosome-dependent antibacterial activity is compromized in mice transplanted with antibiotic-associated patient microbiota. Collectively, we characterize how clinically relevant antibiotics affect antimicrobial defense in the context of human microbiota, and reveal a critical impairment of IM´s antimicrobial activity. Our study provides additional arguments for the rational use of antibiotics and offers mechanistic insights for the development of novel prophylactic strategies to protect high-risk patients from HAP.

Critical care research in Canada is conducted primarily in academically affiliated intensive care units (ICUs) with established research infrastructure. Efforts are made to engage community hospital ICUs in research, although the impacts of their inclusion in clinical research have never been explicitly quantified. We therefore sought to determine the number of additional eligible patients that could be recruited into critical care trials and the change in time to study completion if community ICUs were included in clinical research.

We conducted a decision tree analysis using 2018 Alberta Health Services data. Patient demographics and clinical characteristics for all ICU patients were compared against eligibility criteria from ten landmark, randomized, multicentre critical care trials. Individual patients from academic and community ICUs were assessed for eligibility in each of the ten studies, and decision tree analysis models were built based on prior inclusion and exclusion criteria from those trials.

The number of potentially eligible patients for the ten trials ranged from 2,082 to 10,157. Potentially eligible participants from community ICUs accounted for 40.0% of total potentially eligible participants. The recruitment of community ICU patients in trials would have increased potential enrolment by an average of 64.0%. The inclusion of community ICU patients was predicted to decrease time to trial completion by a mean of 14 months (43% reduction).

Inclusion of community ICU patients in critical care research trials has the potential to substantially increase enrolment and decrease time to trial completion.

Many meta-analyses have assessed the efficacy of preventive interventions against ventilator-associated pneumonia (VAP) in critically ill patients. However, there has been no comprehensive analysis of the strength and quality of evidence to date. Systematic reviews of randomized and quasi-randomized controlled trials, which evaluated the effect of preventive strategies on the incidence of VAP in critically ill patients receiving mechanical ventilation for at least 48 h, were included in this article. We identified a total of 34 interventions derived from 31 studies. Among these interventions, 19 resulted in a significantly reduced incidence of VAP. Among numerous strategies, only selective decontamination of the digestive tract (SDD) was supported by highly suggestive (Class II) evidence (risk ratio (RR)=0.439, 95% CI: 0.362-0.532). Based on data from the sensitivity analysis, the evidence for the efficacy of non-invasive ventilation in weaning from mechanical ventilation (NIV) was upgraded from weak (Class IV) to highly suggestive (Class II) (RR=0.32, 95% CI: 0.22-0.46). All preventive interventions were not supported by robust evidence for reducing mortality. Early mobilization exhibited suggestive (Class III) evidence in shortening both intensive length of stay (LOS) in the intensive care unit (ICU) (mean difference (MD)=-0.85, 95% CI: -1.21 to -0.49) and duration of mechanical ventilation (MD=-1.02, 95% CI: -1.41 to -0.63). In conclusion, SDD and NIV are supported by robust evidence for prevention against VAP, while early mobilization has been shown to significantly shorten the LOS in the ICU and the duration of mechanical ventilation. These three strategies are recommendable for inclusion in the ventilator bundle to lower the risk of VAP and improve the prognosis of critically ill patients.

Ventilator-associated pneumonia (VAP) remains a significant clinical entity with reported incidence rates of 7% to 15%. Given the considerable adverse consequences associated with this infection, VAP prevention became a core measure required in most US hospitals. Many institutions took pride in implementing effective VAP prevention bundles that combined at least head of bed elevation, hand hygiene, chlorhexidine oral care, and subglottic drainage. Spontaneous breathing and awakening trials have also consistently been shown to shorten the duration of mechanical ventilation and secondarily reduce the occurrence of VAP.

The lung microbiota is a complex community of microorganisms that colonize the respiratory tract of individuals from, or even before, birth. Although the lungs were traditionally believed to be sterile, recent research has shown that there is a diversity of bacterial species in the respiratory system. Knowledge about the lung microbiota in newborns and its relationship with bacterial infections is of vital importance to understand the pathogenesis of respiratory diseases in neonatal patients undergoing mechanical ventilation. In this article, the current evidence on the composition of the lung microbiota in newborns will be reviewed, as well as the risks that an altered microbiota can impose on premature newborns. Although advances in neonatal intensive care units have significantly improved the survival rate of preterm infants, the diagnosis and treatment of ventilator-associated pneumonia has not progressed in recent decades. Avoiding dysbiosis caused by inappropriate use of antibiotics around birth, as well as avoiding intubation of patients or promoting early removal of endotracheal tubes, are among the most important preventive measures for ventilator-associated pneumonia. The potential benefit of probiotics and prebiotics in preventing infectious, allergic or metabolic complications in the short or long term is not clearly established and constitutes a very important field of research in perinatal medicine.

Dysbiosis of the gut microbiome is frequent in the intensive care unit (ICU), potentially leading to a heightened risk of nosocomial infections. Enhancing the gut microbiome has been proposed as a strategic approach to mitigate potential adverse outcomes. While prior research on select probiotic supplements has not successfully shown to improve gut microbial diversity, fermented foods offer a promising alternative. In this open-label phase I safety and feasibility study, we examined the safety and feasibility of kefir as an initial step towards utilizing fermented foods to mitigate gut dysbiosis in critically ill patients.

We administered kefir in escalating doses (60 mL, followed by 120 mL after 12 h, then 240 mL daily) to 54 critically ill patients with an intact gastrointestinal tract. To evaluate kefir's safety, we monitored for gastrointestinal symptoms. Feasibility was determined by whether patients received a minimum of 75% of their assigned kefir doses. To assess changes in the gut microbiome composition following kefir administration, we collected two stool samples from 13 patients: one within 72 h of admission to the ICU and another at least 72 h after the first stool sample.

After administering kefir, none of the 54 critically ill patients exhibited signs of kefir-related bacteremia. No side effects like bloating, vomiting, or aspiration were noted, except for diarrhea in two patients concurrently on laxatives. Out of the 393 kefir doses prescribed for all participants, 359 (91%) were successfully administered. We were able to collect an initial stool sample from 29 (54%) patients and a follow-up sample from 13 (24%) patients. Analysis of the 26 paired samples revealed no increase in gut microbial α-diversity between the two timepoints. However, there was a significant improvement in the Gut Microbiome Wellness Index (GMWI) by the second timepoint (P = 0.034, one-sided Wilcoxon signed-rank test); this finding supports our hypothesis that kefir administration can improve gut health in critically ill patients. Additionally, the known microbial species in kefir were found to exhibit varying levels of engraftment in patients' guts.

Providing kefir to critically ill individuals is safe and feasible. Our findings warrant a larger evaluation of kefir's safety, tolerability, and impact on gut microbiome dysbiosis in patients admitted to the ICU.

NCT05416814; trial registered on June 13, 2022.

Critically ill patients are at high risk of acquiring ventilator-associated pneumonia (VAP), which occurs in approximately 20% of mechanically ventilated patients. VAP results either from aspiration of pathogen-contaminated oropharyngeal secretions or contaminated biofilms that form on endotracheal tubes (ETTs) after intubation. VAP results in increased duration of mechanical ventilation, increased intensive care unit and hospital length of stay, increased risk of death and increased healthcare costs. Because of its impact on patient outcomes and the healthcare system, VAP is regarded as an important patient safety issue and there is an urgent need for better evidence on the efficacy of prevention strategies. Modified ETTs that reduce aspiration of oropharyngeal secretions with subglottic secretion drainage or reduce the occurrence of biofilm with a coating of ceragenins (CSAs) are available for clinical use in Canada. In this implementation study, we will evaluate the efficacy of these two types of Health Canada-licensed ETTs on the occurrence of VAP, and impact on patient-centred outcomes.

In this ongoing, pragmatic, prospective, longitudinal, interrupted time, cross-over implementation study, we will compare the efficacy of a CSA-coated ETT (CeraShield N8 Pharma) with an ETT with subglottic secretion drainage (Taper Guard, Covidien). The study periods consist of four alternating time periods of 11 or 12 weeks or a total of 23 weeks for each ETT. All patients intubated with the study ETT in each time period will be included in an intention-to-treat analysis. Outcomes will include VAP incidence, mortality and health services utilisation including antibiotic use and length of stay.

This study has been approved by the Health Sciences Research Ethics Board at Queen's University. The results of this study will be actively disseminated through manuscript publication and conference presentations.

NCT05761613.

This latest systematic review and meta-analysis aim to examine the effects of probiotic and synbiotic supplementation in critically ill patients.

Relevant articles were retrieved from PubMed, Embase, the Cochrane Database, and the Web of Science. The primary output measure was the incident of ventilator-associated pneumonia, and the secondary outputs were diarrhea, Clostridium diffusion infection (CDI), incident of sepsis, incident of hospital acquired pneumonia, duration of mechanical exploitation, ICU mortality rate, length of ICU stay, in hospital mortality, and length of hospital stay. Data were pooled and expressed as Relative Risk(RR) and Standardized Mean Difference (SMD) with a 95 % confidence interval (CI).

33 studies were included in this systematic review and meta-analysis, with 4065 patients who received probiotics or synbiotics (treatment group) and 3821 patients who received standard care or placebo (control group). The pooled data from all included studies demonstrated that the treatment group has significantly reduced incidence of ventilation-associated pneumonia (VAP) (RR = 0.80; 95 % CI: 0.67-0.96; p = 0.021, I2 = 52.5 %) and sepsis (RR = 0.97; 95 % CI: 0.66-1.42; p = 0.032, I2 = 54.4 %), As well as significantly increased duration of mechanical exploitation (SMD = -0.47; 95 % CI: -0.74-0.20, p = 0.012, I2 = 63.4 %), ICU mobility (RR = 0.95; 95 % CI: 0.71-1.27; p = 0.004, I2 = 62.8 %), length of ICU stay (SMD = -0.29; 95 % CI: -0.58-0.01; p = 0.000, I2 = 82.3 %) and length of hospital stay (SMD = -0.33; 95 % CI: -0.57-0.08, p = 0.000, I2 = 74.2 %) than the control group. There were no significant differences in diarrhea, CDI, incidence of hospital acquired pneumonia, and in hospital mortality between the two groups.

Our meta-analysis showed that probiotic and synbiotic supplements are beneficial for critically ill patients as they significantly reduce the incidence of ventilator associated pneumonia and sepsis, as well as the duration of mechanical exploitation, length of hospital stay, length of ICU stay, and ICU mortality. However, this intervention has minimal impact on diarrhea, CDI, incidence of hospital acquired pneumonia, and in hospital mortality in critically ill patients.

With approximately 39 trillion cells and over 20 million genes, the human gut microbiome plays an integral role in both health and disease. Modern living has brought a widespread use of processed food and beverages, antimicrobial and immunomodulatory drugs, and invasive procedures, all of which profoundly disrupt the delicate homeostasis between the host and its microbiome. Of particular interest is the human gut microbiome, which is progressively being recognized as an important contributing factor in many aspects of critical illness, from predisposition to recovery. Herein, we describe the current understanding of the adverse impacts of standard intensive care interventions on the human gut microbiome and delve into how these microbial alterations can influence patient outcomes. Additionally, we explore the potential association between the gut microbiome and post-intensive care syndrome, shedding light on a previously underappreciated avenue that may enhance patient recuperation following critical illness. There is an impending need for future epidemiological studies to encompass detailed phenotypic analyses of gut microbiome perturbations. Interventions aimed at restoring the gut microbiome represent a promising therapeutic frontier in the quest to prevent and treat critical illnesses.