The glycocalyx is a gel-like layer covering the luminal surface of vascular endothelial cells. It is comprised of membrane-attached proteoglycans, glycosaminoglycan chains, glycoproteins, and ...adherent plasma proteins. The glycocalyx maintains homeostasis of the vasculature, including controlling vascular permeability and microvascular tone, preventing microvascular thrombosis, and regulating leukocyte adhesion.During sepsis, the glycocalyx is degraded via inflammatory mechanisms such as metalloproteinases, heparanase, and hyaluronidase. These sheddases are activated by reactive oxygen species and pro-inflammatory cytokines such as tumor necrosis factor alpha and interleukin-1beta. Inflammation-mediated glycocalyx degradation leads to vascular hyper-permeability, unregulated vasodilation, microvessel thrombosis, and augmented leukocyte adhesion. Clinical studies have demonstrated the correlation between blood levels of glycocalyx components with organ dysfunction, severity, and mortality in sepsis.Fluid resuscitation therapy is an essential part of sepsis treatment, but overaggressive fluid therapy practices (leading to hypervolemia) may augment glycocalyx degradation. Conversely, fresh frozen plasma and albumin administration may attenuate glycocalyx degradation. The beneficial and harmful effects of fluid and plasma infusion on glycocalyx integrity in sepsis are not well understood; future studies are warranted.In this review, we first analyze the underlying mechanisms of glycocalyx degradation in sepsis. Second, we demonstrate how the blood and urine levels of glycocalyx components are associated with patient outcomes. Third, we show beneficial and harmful effects of fluid therapy on the glycocalyx status during sepsis. Finally, we address the concept of glycocalyx degradation as a therapeutic target.
A recent randomised trial showed that recombinant thrombomodulin did not benefit patients who had sepsis with coagulopathy and organ dysfunction. Several recent studies suggested presence of clinical ...phenotypes in patients with sepsis and heterogenous treatment effects across different sepsis phenotypes. We examined the latent phenotypes of sepsis with coagulopathy and the associations between thrombomodulin treatment and the 28-day and in-hospital mortality for each phenotype.
This was a secondary analysis of multicentre registries containing data on patients (aged ≥ 16 years) who were admitted to intensive care units for severe sepsis or septic shock in Japan. Three multicentre registries were divided into derivation (two registries) and validation (one registry) cohorts. Phenotypes were derived using k-means with coagulation markers, platelet counts, prothrombin time/international normalised ratios, fibrinogen, fibrinogen/fibrin-degradation-products (FDP), D-dimer, and antithrombin activities. Associations between thrombomodulin treatment and survival outcomes (28-day and in-hospital mortality) were assessed in the derived clusters using a generalised estimating equation.
Four sepsis phenotypes were derived from 3694 patients in the derivation cohort. Cluster dA (n = 323) had severe coagulopathy with high FDP and D-dimer levels, severe organ dysfunction, and high mortality. Cluster dB had severe disease with moderate coagulopathy. Clusters dC and dD had moderate and mild disease with and without coagulopathy, respectively. Thrombomodulin was associated with a lower 28-day (adjusted risk difference RD: - 17.8% 95% CI - 28.7 to - 6.9%) and in-hospital (adjusted RD: - 17.7% 95% CI - 27.6 to - 7.8%) mortality only in cluster dA. Sepsis phenotypes were similar in the validation cohort, and thrombomodulin treatment was also associated with lower 28-day (RD: - 24.9% 95% CI - 49.1 to - 0.7%) and in-hospital mortality (RD: - 30.9% 95% CI - 55.3 to - 6.6%).
We identified four coagulation marker-based sepsis phenotypes. The treatment effects of thrombomodulin varied across sepsis phenotypes. This finding will facilitate future trials of thrombomodulin, in which a sepsis phenotype with high FDP and D-dimer can be targeted.
Intravenous fluids, an essential component of sepsis resuscitation, may paradoxically worsen outcomes by exacerbating endothelial injury. Preclinical models suggest that fluid resuscitation degrades ...the endothelial glycocalyx, a heparan sulfate-enriched structure necessary for vascular homeostasis. We hypothesized that endothelial glycocalyx degradation is associated with the volume of intravenous fluids administered during early sepsis resuscitation.
We used mass spectrometry to measure plasma heparan sulfate (a highly sensitive and specific index of systemic endothelial glycocalyx degradation) after 6 h of intravenous fluids in 56 septic shock patients, at presentation and after 24 h of intravenous fluids in 100 sepsis patients, and in two groups of non-infected patients. We compared plasma heparan sulfate concentrations between sepsis and non-sepsis patients, as well as between sepsis survivors and sepsis non-survivors. We used multivariable linear regression to model the association between volume of intravenous fluids and changes in plasma heparan sulfate.
Consistent with previous studies, median plasma heparan sulfate was elevated in septic shock patients (118 IQR, 113-341 ng/ml 6 h after presentation) compared to non-infected controls (61 45-79 ng/ml), as well as in a second cohort of sepsis patients (283 155-584 ng/ml) at emergency department presentation) compared to controls (177 144-262 ng/ml). In the larger sepsis cohort, heparan sulfate predicted in-hospital mortality. In both cohorts, multivariable linear regression adjusting for age and severity of illness demonstrated a significant association between volume of intravenous fluids administered during resuscitation and plasma heparan sulfate. In the second cohort, independent of disease severity and age, each 1 l of intravenous fluids administered was associated with a 200 ng/ml increase in circulating heparan sulfate (p = 0.006) at 24 h after enrollment.
Glycocalyx degradation occurs in sepsis and septic shock and is associated with in-hospital mortality. The volume of intravenous fluids administered during sepsis resuscitation is independently associated with the degree of glycocalyx degradation. These findings suggest a potential mechanism by which intravenous fluid resuscitation strategies may induce iatrogenic endothelial injury.
Age-based bodyweight estimation is commonly used in pediatric settings, but pediatric ICU patients often have preexisting comorbidity and resulting failure to thrive, hence their anthropometric ...measures may be small-for-age. Accordingly, age-based methods could overestimate bodyweight in such settings, resulting in iatrogenic complications. We performed a retrospective cohort study using pediatric data (aged < 16 years) registered in the Japanese Intensive Care Patient Database from April 2015 to March 2020. All the anthropometric data were overlaid on the growth charts. The estimation accuracy of 4 age-based and 2 height-based bodyweight estimations was evaluated by the Bland-Altman plot analysis and the proportion of estimates within 10% of the measured weight (ρ10%). We analyzed 6616 records. The distributions of both bodyweight and height were drifted to the lower values throughout the childhood while the distribution of BMI was similar to the general healthy children. The accuracy in bodyweight estimation with age-based formulae was inferior to that with height-based methods. These data demonstrated that the pediatric patients in the Japanese ICU were proportionally small-for-age, suggesting a special risk of using the conventional age-based estimation but supporting the use of height-based estimation of the bodyweight in the pediatric ICU.
A recent randomised controlled trial failed to demonstrate a beneficial effect of recombinant human thrombomodulin (rhTM) on sepsis. However, there is still controversy in the effects of rhTM for ...sepsis due to the heterogeneity of the study population. We previously identified patients with a distinct phenotype that could be a potential target of rhTM therapy (rhTM target phenotype). However, for application in the clinical setting, a simple tool for determining this target is necessary. Thus, using three multicentre sepsis registries, we aimed to develop and validate a machine learning model for predicting presence of the target phenotype that we previously identified for targeted rhTM therapy. The predictors were platelet count, PT-INR, fibrinogen, fibrinogen/fibrin degradation products, and D-dimer. We also implemented the model as a web-based application. Two of the three registries were used for model development (n = 3694), and the remaining registry was used for validation (n = 1184). Approximately 8-9% of patients had the rhTM target phenotype in each cohort. In the validation, the C statistic of the developed model for predicting the rhTM target phenotype was 0.996 (95% CI 0.993-0.998), with a sensitivity of 0.991 and a specificity of 0.967. Among patients who were predicted to have the potential target phenotype (predicted target patients) in the validation cohort (n = 142), rhTM use was associated with a lower in-hospital mortality (adjusted risk difference, - 31.3% - 53.5 to - 9.1%). The developed model was able to accurately predict the rhTM target phenotype. The model, which is available as a web-based application, could profoundly benefit clinicians and researchers investigating the heterogeneity in the treatment effects of rhTM and its mechanisms.
Artificial intelligence or AI has been heralded as the most transformative technology in healthcare, including critical care medicine. Globally, healthcare specialists and health ministries are being ...pressured to create and implement a roadmap to incorporate applications of AI into care delivery. To date, the majority of Japan's approach to AI has been anchored in industry, and the challenges that have occurred therein offer important lessons for nations developing new AI strategies. Notably, the demand for an AI-literate workforce has outpaced training programs and knowledge. This is particularly observable within medicine, where clinicians may be unfamiliar with the technology. National policy and private sector involvement have shown promise in developing both workforce and AI applications in healthcare. In combination with Japan's unique national healthcare system and aggregable healthcare and socioeconomic data, Japan has a rich opportunity to lead in the field of medical AI.
The trajectory of glomerular filtration rate (GFR) in relation to glomerular hyperfiltration (GHF) has been unknown. It was evaluated retrospectively in 23,982 GHF-free health examinees who were ...followed for 2-10 yr (mean: 5.1 yr). GFR was estimated by the serum creatinine concentration, and GHF was defined as age- and sex-specific estimated GFR (eGFR) ≥ 95% of the Japanese general population. The temporal profile of eGFR was plotted in a GHF-centered way, which was fitted to a random coefficient linear mixed model. Of the 23,982 subjects, 797 and 23,185 subjects developed or did not develop GHF, respectively, so that they were termed as the GHF
and GHF
groups. At baseline, median eGFR was significantly elevated in the GHF
group compared with in the GHF
group: 94.1 versus 77.3 mL/min/1.73 m
(
< 0.001). Elevation of basal eGFR lasted for a mean (SD) of 3.3 (1.9) yr in the GHF
group; mean eGFR then rose to the GHF range, which was 108.5 mL/min/1.73 m
. The eGFR decline after the peak was steeper in the GHF
group than in the GHF
group: -0.984 versus -0.497 mL/min/1.73 m
/yr (
< 0.001). Baseline eGFR, but no other variable, well predicted incident GHF, with an area under the receiver operating characteristic curve of 0.87 (95% confidence interval: 0.86-0.88). In conclusion, GHF occurs as a chronic, multiphasic phenomenon: initially with a sustained GFR elevation for years, followed by a GFR surge to the GHF range, which was accompanied by accelerated GFR declining.
Advanced Life Support (ALS) is regarded to be associated with improved survival in pre-hospital trauma care when compared to Basic Life Support (BLS) irrespective of lack of evidence. The aim of this ...study is to ascertain ALS improves survival for trauma in prehospital settings when compared to BLS.
We searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials for published controlled trials (CTs), and observational studies that were published until Aug 2017. The population of interest were adults (>18 years old) trauma patients who were transported by ground transportation and required resuscitation in prehospital settings. We compared outcomes between the ALS and BLS groups. The primary outcome was in-hospital mortality and secondary outcomes were neurological outcome and time spent on scene.
We identified 2,502 studies from various databases and 10 studies were included in the analysis (two CTs, and eight observational studies). The outcomes were not statistically significant between the ALS and BLS groups (pooled OR 1.14; 95% CI 0.95 to 1.36 for mortality, pooled OR 1.12; 95% CI 0.88 to 1.42 for good neurological outcomes, pooled mean difference -0.96; 95% CI-6.64 to 4.72 for on-scene time) in CTs. In observational studies, ALS prolonged on-scene time and increased mortality (pooled OR 1.56; 95% CI: 1.31 to 1.86 for mortality, and pooled mean difference, 1.26; 95% CI: 0.07 to 2.45 for on-scene time).
In prehospital settings, the present study showed no advantages of ALS on the outcomes in patients with trauma compared to BLS.
It is unclear whether initial infection control or anticoagulant therapy exerts a greater effect on early changes in the Sequential Organ Failure Assessment (SOFA) score among patients with ...sepsis-induced disseminated intravascular coagulation (DIC). This retrospective propensity score cohort study aimed to evaluate whether adequacy of infection control or anticoagulation therapy had a greater effect on early changes in the SOFA scores among 52 patients with sepsis-induced DIC. Inadequate initial infection control was associated with a lower 28-day survival rate among patients with sepsis-induced DIC (odds ratio OR: 0.116, 95% confidence interval CI: 0.022-0.601; P = .010); however, the adequacy was not associated with an early improvement in the SOFA score. However, despite adjusting for inadequate initial infection control, administration of recombinant human soluble thrombomodulin was associated with an early improvement in the SOFA score (OR: 5.058, 95% CI: 1.047-24.450; P = .044). Therefore, early changes in the SOFA score within 48 hours after the DIC diagnosis were more strongly affected by the administration of recombinant human soluble thrombomodulin than the adequacy of initial infection control.
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