Plasma components to protect the endothelial barrier after shock: A role for sphingosine 1-phosphate.

BACKGROUND: Hemorrhagic shock leads to endothelial glycocalyx shedding, endothelial cellular inflammation, and increased vascular permeability. Early plasma administration improves survival in severely injured patients; this may be due in part to its ability to ameliorate this trauma-induced endotheliopathy. The protective effect of early plasma administration may be due to its sphingosine 1-phosphate content. Principle carriers of plasma sphingosine 1-phosphate include apolipoprotein M and albumin. The relative roles of these carriers on sphingosine 1-phosphate protective effects are unknown and were studied in an in vitro model of microcirculation. METHODS: Endothelial cell monolayers were established in microfluidic perfusion devices and exposed to control or biomimetic shock conditions. Sphingosine 1-phosphate, albumin + sphingosine 1-phosphate, or apolipoprotein M + sphingosine 1-phosphate were added later to the perfusate. Biomarkers of endothelial and glycocalyx activation and damage were then determined. RESULTS: Sphingosine 1-phosphate preserved endothelial and glycocalyx barrier function after exposure to conditions of shock in the microcirculation. The protective effect was related to sphingosine 1-phosphate chaperones; the apolipoprotein M loaded with sphingosine 1-phosphate had the most profound effect. CONCLUSION: Carrier-based sphingosine 1-phosphate may be a useful adjunct in early hemorrhagic shock resuscitation.

Shock Index in the early assessment of febrile children at the emergency department: a prospective multicentre study.

OBJECTIVE: (1) To derive reference values for the Shock Index (heart rate/systolic blood pressure) based on a large emergency department (ED) population of febrile children and (2) to determine the diagnostic value of the Shock Index for serious illness in febrile children. DESIGN/SETTING: Observational study in 11 European EDs (2017-2018). PATIENTS: Febrile children with measured blood pressure. MAIN OUTCOME MEASURES: Serious bacterial infection (SBI), invasive bacterial infection (IBI), immediate life-saving interventions (ILSIs) and intensive care unit (ICU) admission. The association between high Shock Index (>95th centile) and each outcome was determined by logistic regression adjusted for age, sex, referral, comorbidity and temperature. Additionally, we calculated sensitivity, specificity and negative/positive likelihood ratios (LRs). RESULTS: Of 5622 children, 461 (8.2%) had SBI, 46 (0.8%) had IBI, 203 (3.6%) were treated with ILSI and 69 (1.2%) were ICU admitted. High Shock Index was associated with SBI (adjusted OR (aOR) 1.6 (95% CI 1.3 to 1.9)), ILSI (aOR 2.5 (95% CI 2.0 to 2.9)), ICU admission (aOR 2.2 (95% CI 1.4 to 2.9)) but not with IBI (aOR: 1.5 (95% CI 0.6 to 2.4)). For the different outcomes, sensitivity for high Shock Index ranged from 0.10 to 0.15, specificity ranged from 0.95 to 0.95, negative LRs ranged from 0.90 to 0.95 and positive LRs ranged from 1.8 to 2.8. CONCLUSIONS: High Shock Index is associated with serious illness in febrile children. However, its rule-out value is insufficient which suggests that the Shock Index is not valuable as a screening tool for all febrile children at the ED.

IL-18R-mediated HSC quiescence and MLKL-dependent cell death limit hematopoiesis during infection-induced shock.

Severe infection can dramatically alter blood production, but the mechanisms driving hematopoietic stem and progenitor cell (HSC/HSPC) loss have not been clearly defined. Using Ixodes ovatus Ehrlichia (IOE), a tick-borne pathogen that causes severe shock-like illness and bone marrow (BM) aplasia, type I and II interferons (IFNs) promoted loss of HSPCs via increased cell death and enforced quiescence. IFN-αß were required for increased interleukin 18 (IL-18) expression during infection, correlating with ST-HSC loss. IL-18 deficiency prevented BM aplasia and increased HSC/HSPCs. IL-18R signaling was intrinsically required for ST-HSC quiescence, but not for HSPC cell death. To elucidate cell death mechanisms, MLKL- or gasdermin D-deficient mice were infected; whereas Mlkl-/- mice exhibited protected HSC/HSPCs, no such protection was observed in Gsdmd-/- mice during infection. MLKL deficiency intrinsically protected HSCs during infection and improved hematopoietic output upon recovery. These studies define MLKL and IL-18R signaling in HSC loss and suppressed hematopoietic function in shock-like infection.

Association between prehospital field to emergency department delta shock index and in-hospital mortality in patients with torso and extremity trauma: A multinational, observational study.

Hemorrhage, a main cause of mortality in patients with trauma, affects vital signs such as blood pressure and heart rate. Shock index (SI), calculated as heart rate divided by systolic blood pressure, is widely used to estimate the shock status of patients with hemorrhage. The difference in SI between the emergency department and prehospital field can indirectly reflect urgency after trauma. We aimed to determine the association between delta SI (DSI) and in-hospital mortality in patients with torso or extremity trauma. Patients with DSI >0.1 are expected to be associated with high mortality. This retrospective, observational study used data from the Pan-Asian Trauma Outcomes Study. Patients aged 18-85 years with abdomen, chest, upper extremity, lower extremity, or external injury location were included. Patients from China, Indonesia, Japan, Philippines, Thailand, and Vietnam; those who were transferred from another facility; those who were transferred without the use of emergency medical service; those with prehospital cardiac arrest; those with unknown exposure and outcomes were excluded. The exposure and primary outcome were DSI and in-hospital mortality, respectively. The secondary and tertiary outcome was intensive care unit (ICU) admission and massive transfusion, respectively. Multivariate logistic regression analysis was performed to test the association between DSI and outcome. In total, 21,534 patients were enrolled according to the inclusion and exclusion criteria. There were 3,033 patients with DSI >0.1. The in-hospital mortality rate in the DSI >0.1 and ≤0.1 groups was 2.0% and 0.8%, respectively. In multivariate logistic regression analysis, the DSI ≤0.1 group was considered the reference group. The unadjusted and adjusted odds ratios of in-hospital mortality in the DSI >0.1 group were 2.54 (95% confidence interval [CI] 1.88-3.42) and 2.82 (95% CI 2.08-3.84), respectively. The urgency of traumatic hemorrhage can be determined using DSI, which can help hospital staff to provide proper trauma management, such as early trauma surgery or embolization.

A case of chronic systemic capillary leak syndrome (SCLS) exacerbated during SARS-CoV2 infection.

Systemic capillary leak syndrome (SCLS) is a very rare and lethal disease characterized by hemoconcentration and hypoalbuminemia caused by reversible plasma extravasation. The underlying cause for SCLS remains largely unknown and acute treatment has remained mainly supportive. Prophylaxis with intravenous immunoglobulin (IVIG) has been shown to successfully prevent further episodes in affected patients. We reported a case of SCLS in a patient who presented to our hospital with COVID-19 and developed profound shock.

Relation of Magnetic Resonance Elastography to Fontan Circulatory Failure in a Cohort of Pediatric and Adult Patients.

Elevated magnetic resonance elastography (MRE)-derived liver stiffness may be associated with worse outcomes in people with Fontan circulation. We sought to evaluate the association between liver stiffness and Fontan failure or portal hypertension. Single center cross-sectional retrospective study of people with Fontan circulation who underwent MRE between 2011 and 2020. The cohort was divided into adult (age ≥ 21 years) and pediatric (< 21 years) groups. Fontan circulatory failure (FF) was defined as any of the following: death, transplantation, ventricular assist device, heart failure symptoms requiring escalation of diuretics. Radiologic portal hypertension was defined as the presence of one or more of the following: splenomegaly, ascites, or gastrointestinal varices. 128 patients were included (average age = 22.6 ± 8.7 years) and 58 (45%) were children. Median liver stiffness was 4.3 kPa (interquartile range (IQR) 3.8-5.8) for the entire cohort. Thirty patients (23%) developed FF (16 adults, 14 children). Liver stiffness was higher in adults with FF compared to those without FF (4.9 (IQR 4.0-6.0) vs. 4.2 (IQR 3.8-4.7) kPa, p = 0.04). There was no difference in liver stiffness between pediatric patients with and without FF (4.4 (IQR 4.1-5.4) vs. 4.4 (IQR 3.8-5.0), p = 0.5). Adults with radiologic portal hypertension and adults with moderate or severe atrioventricular valve regurgitation had higher liver stiffness than adults without. MRE-derived liver stiffness is associated with atrioventricular valve regurgitation, portal hypertension, and poor clinical outcomes in adults with Fontan circulation. There was no association between liver stiffness and FF in pediatric patients. This difference may be due to the progressive nature of Fontan-associated liver disease.

Endothelial Dysfunction as a Component of Severe Acute Respiratory Syndrome Coronavirus 2-Related Multisystem Inflammatory Syndrome in Children With Shock.

TRIAL REGISTRATION: NCT04420468. OBJECTIVES: Severe acute respiratory syndrome coronavirus 2-related multisystem inflammatory syndrome in children is frequently associated with shock; endothelial involvement may be one of the underlying mechanisms. We sought to describe endothelial dysfunction during multisystem inflammatory syndrome in children with shock and then assess the relationship between the degree of endothelial involvement and the severity of shock. DESIGN: Observational study. SETTING: A PICU in a tertiary hospital. PATIENTS: Patients aged under 18 (n = 28) with severe acute respiratory syndrome coronavirus 2-related multisystem inflammatory syndrome in children and shock, according to the Centers for Disease Control and Prevention criteria. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Correlations between endothelial marker levels and shock severity were assessed using Spearman coefficient. The median (interquartile range) age was 9 years (7.5-11.2 yr). Sixteen children presented with cardiogenic and distributive shock, 10 presented with cardiogenic shock only, and two presented with distributive shock only. The median left ventricular ejection fraction, troponin level, and lactate level were, respectively, 40% (35-45%), 261 ng/mL (131-390 ng/mL), and 3.2 mmol/L (2-4.2 mmol/L). Twenty-five children received inotropes and/or vasopressors; the median Vasoactive and Inotropic Score was 8 (5-28). Plasma levels of angiopoietin-2 (6,426 pg/mL [2,814-11,836 pg/mL]), sE-selectin (130,405 pg/mL [92,987-192,499 pg/mL]), von Willebrand factor antigen (344% [288-378%]), and the angiopoietin-2/angiopoietin-1 ratio (1.111 [0.472-1.524]) were elevated and significantly correlated with the Vasoactive and Inotropic Score (r = 0.45, p = 0.016; r = 0.53, p = 0.04; r = 0.46, p = 0.013; and r = 0.46, p = 0.012, respectively). CONCLUSIONS: Endothelial dysfunction is associated with severe acute respiratory syndrome coronavirus 2-related multisystem inflammatory syndrome in children with shock and may constitute one of the underlying mechanisms.

Applying the RE-AIM framework in a process evaluation of the introduction of the Non-Pneumatic Anti-Shock Garment in a rural district of Zimbabwe.

The Non-Pneumatic Anti-Shock Garment (NASG) is a first aid tool that can halt and reverse hypovolemic shock secondary to obstetric hemorrhage. The World Health Organization recommended the NASG for use as a temporizing measure in 2012, but uptake of the recommendation has been slow, partially because operational experience is limited. The study is a process evaluation of the introduction of NASG in a public sector health facility network in rural Zimbabwe utilizing an adapted RE-AIM, categorizing observations into the domains of: reach, effectiveness, adoption, implementation and maintenance. The location of the study was Hurungwe district, where staff members of 34 health facilities at primary (31), secondary (2) and tertiary (1) levels of care participated. We found that all facilities became skilled in using the NASG, and that the NASG was used in 10 of 11 instances of severe hemorrhage. In the cases of hypovolemic shock where the NASG was used, there were no maternal deaths and no extreme adverse outcomes related to obstetric hemorrhage in the study period. Among the 10 NASG uses, the garment was used correctly in each case. Fidelity to processes was high, especially in regard to training and cascading skills, but revisions of the NASG rotation and replacement operating procedures were required to keep clean garments stocked. Clinical documentation was also a key challenge. NASG introduction dovetailed very well with pre-existing systems for obstetric emergency response, and improved clinical outcomes. Scale-up of the NASG in the Zimbabwean public health system can be undertaken with careful attention to mentorship, drills, documentation and logistics.

Rapid Response System Should Be Enhanced at Non-general Ward Locations: a Retrospective Multicenter Cohort Study in Korea.

BACKGROUND: A rapid response system (RRS) contributes to the safety of hospitalized patients. Clinical deterioration may occur in the general ward (GW) or in non-GW locations such as radiology or dialysis units. However, there are few studies regarding RRS activation in non-GW locations. This study aimed to compare the clinical characteristics and outcomes of patients with RRS activation in non-GW locations and in the GW. METHODS: From January 2016 to December 2017, all patients requiring RRS activation in nine South Korean hospitals were retrospectively enrolled and classified according to RRS activation location: GW vs non-GW RRS activations. RESULTS: In total, 12,793 patients were enrolled; 222 (1.7%) were non-GW RRS activations. There were more instances of shock (11.6% vs. 18.5%) and cardiac arrest (2.7% vs. 22.5%) in non-GW RRS activation patients. These patients also had a lower oxygen saturation (92.6% ± 8.6% vs. 88.7% ± 14.3%, P < 0.001) and a higher National Early Warning Score 2 (7.5 ± 3.4 vs. 8.9 ± 3.8, P < 0.001) than GW RRS activation patients. Although non-GW RRS activation patients received more intubation (odds ratio [OR], 3.135; P < 0.001), advanced cardiovascular life support (OR, 3.912; P < 0.001), and intensive care unit transfer (OR, 2.502; P < 0.001), their hospital mortality (hazard ratio, 0.630; P = 0.013) was lower than GW RRS activation patients upon multivariate analysis. CONCLUSION: Considering that there were more critically ill but recoverable cases in non-GW locations, active RRS involvement should be required in such locations.

Thermodynamic interference with bile acid demicelleization reduces systemic entry and injury during cholestasis.

Bile acids (BA), with their large hydrophobic steroid nucleus and polar groups are amphipathic molecules. In bile, these exist as micelles above their critical micellar concentration (CMC). In blood at low concentrations, these exist as monomers, initiating cellular signals. This micellar to monomer transition may involve complex thermodynamic interactions between bile salts alone or with phospholipids, i.e. mixed micelles and the aqueous environment. We therefore went on to test if therapeutically relevant changes in temperature could influence micellar behavior of bile salts, and in turn whether this affected the biological responses in cells, and in vivo. Sodium taurocholate (STC) belongs to a major class of bile salts. STC has a CMC in the 5-8 mM range and its infusion into the pancreatic duct is commonly used to study pancreatitis. We thus studied micellar breakdown of STC using isothermal titration calorimetry (ITC), dynamic light scattering and cryogenic transmission electron microscopy. Under conditions relevant to the in vivo environment (pH 7.4, Na 0.15 M), ITC showed STC to have a U shaped reduction in micellar breakdown between 37 °C and 15 °C with a nadir at 25 °C approaching ≈90% inhibition. This temperature dependence paralleled pancreatic acinar injury induced by monomeric STC. Mixed micelles of STC and 1-palmitoyl, 2-oleyl phosphatidylcholine, a phospholipid present in high proportions in bile, behaved similarly, with ≈75% reduction in micellar breakdown at 25 °C compared to 37 °C. In vivo pancreatic cooling to 25 °C reduced the increase in circulating BAs after infusion of 120 mM (5%) STC into the pancreatic duct, and duct ligation. Lower BA levels were associated with improved cardiac function, reduced myocardial damage, shock, lung injury and improved survival independent of pancreatic injury. Thus micellar breakdown of bile salts is essential for their entry into the systemic circulation, and thermodynamic interference with this may reduce their systemic entry and consequent injury during cholestasis, such as from biliary pancreatitis.

Reverse shock index multiplied by Glasgow Coma Scale (rSIG) predicts mortality in severe trauma patients with head injury.

The reverse shock index (rSI), a ratio of systolic blood pressure (SBP) to heart rate (HR), is used to identify prognosis in trauma patients. Multiplying rSI by Glasgow Coma Scale (rSIG) can possibly predict better in-hospital mortality in patients with trauma. However, rSIG has never been used to evaluate the mortality risk in adult severe trauma patients (Injury Severity Score [ISS] ≥ 16) with head injury (head Abbreviated Injury Scale [AIS] ≥ 2) in the emergency department (ED). This retrospective case control study recruited adult severe trauma patients (ISS ≥ 16) with head injury (head AIS ≥ 2) who presented to the ED of two major trauma centers between January 01, 2014 and May 31, 2017. Demographic data, vital signs, ISS scores, injury mechanisms, laboratory data, managements, and outcomes were included for the analysis. Logistic regression and receiver operating characteristic analysis were used to evaluate the accuracy of rSIG score in predicting in-hospital mortality. In total, 438 patients (mean age: 56.48 years; 68.5% were males) were included in this study. In-hospital mortality occurred in 24.7% patients. The median (interquartile range) ISS score was 20 (17-26). Patients with rSIG ≤ 14 had seven-fold increased risks of mortality than those without rSIG ≤ 14 (odds ratio: 7.64; 95% confidence interval: 4.69-12.42). Hosmer-Lemeshow goodness-of-fit test and area under the curve values for rSIG score were 0.29 and 0.76, respectively. The sensitivity, specificity, positive predictive value, and negative predictive values of rSIG ≤ 14 were 0.71, 0.75, 0.49, and 0.89, respectively. The rSIG score is a prompt and simple tool to predict in-hospital mortality among adult severe trauma patients with head injury.