A Review on the Chemical Properties, Plant Sources, Anti-shock Effects, Pharmacokinetics, Toxicity, and Clinical Applications of Anisodamine.

Alkaloids are natural products that occur widely in many herbal plants. Anisodamine, widely present in the Solanaceae family, is an alkaloid extracted from the roots of the Anisodus tanguticus Maxim. It is an antagonist to M-choline receptors and exhibits diverse pharmacological effects, such as cholinolytic effect, calcium antagonist effect, anti-oxygenation effect. Anisodamine, a prominent constituent of the tropine alkaloid family, exhibits a range of pharmacological effects akin to those of atropine and scopolamine. owing to its low toxicity and moderate efficacy in clinical to wide applications, especially for varieties of shock treatment. However, there remains a dearth of research regarding the in vivo pharmacokinetics, mechanism of action, and toxicity of anisodamine. Consequently, this paper provides a comprehensive review of the anti-shock effects, toxicity, and pharmacokinetic characteristics of anisodamine to increase the understanding of its medicinal value, and provide reference and inspiration for the clinical application and further in-depth research of anisodamine.

A simulation of skin mitochondrial Po2 in circulatory shock.

Circulatory shock is the inadequacy to supply mitochondria with enough oxygen to sustain aerobic energy metabolism. A novel noninvasive bedside measurement was recently introduced to monitor the mitochondrial oxygen tension in the skin (mitoPo2). As the most downstream marker of oxygen balance in the skin, mitoPo2 may provide additional information to improve shock management. However, a physiological basis for the interpretation of mitoPo2 values has not been established yet. In this paper, we developed a mathematical model of skin mitoPo2 using a network of parallel microvessels, based on Krogh's cylinder model. The model contains skin blood flow velocity, heterogeneity of blood flow, hematocrit, arteriolar oxygen saturation, and mitochondrial oxygen consumption as major variables. The major results of the model show that normal physiological mitoPo2 is in the range of 40-60 mmHg. The relationship of mitoPo2 with skin blood flow velocity follows a logarithmic growth curve, reaching a plateau at high skin blood flow velocity, suggesting that oxygen balance remains stable while peripheral perfusion declines. The model shows that a critical range exists where mitoPo2 rapidly deteriorates if skin perfusion further decreases. The model intuitively shows how tissue hypoxia could occur in the setting of septic shock, due to the profound impact of microcirculatory disturbance on mitoPo2, even at sustained cardiac output. MitoPo2 is the result of a complex interaction between all factors of oxygen delivery and microcirculation. This mathematical framework can be used to interpret mitoPo2 values in shock, with the potential to enhance personalized clinical trial design.NEW & NOTEWORTHY This is the first paper to simulate mitochondrial oxygen tension in skin in circulatory shock. The relationships of mitoPo2 with parameters of (microcirculatory) oxygen delivery aid in the understanding of noninvasive bedside measurement of mitoPo2 values and show that mitochondrial oxygen tension is two orders of magnitude higher than classically assumed. The model can be used to enhance clinical trial design investigating mitoPo2 as a resuscitation target in circulatory shock.

Shock-Driven Endotheliopathy in Trauma Patients Is Associated with Leucocyte Derived Extracellular Vesicles.

Endotheliopathy following trauma is associated with poor outcome, but the underlying mechanisms are unknown. This study hypothesized that an increased extracellular vesicle (EV) concentration is associated with endotheliopathy after trauma and that red blood cell (RBC) transfusion could further enhance endotheliopathy. In this post hoc sub study of a multicentre observational trial, 75 trauma patients were stratified into three groups based on injury severity score or shock. In patient plasma obtained at hospital admission and after transfusion of four RBC transfusions, markers for endotheliopathy were measured and EVs were labelled with anti CD41 (platelet EVs), anti CD235a (red blood cell EVs), anti CD45 (leucocyte EVs), anti CD144 (endothelial EVs) or anti CD62e (activated endothelial EVs) and EV concentrations were measured with flow cytometry. Statistical analysis was performed by a Kruskall Wallis test with Bonferroni correction or Wilcoxon rank test for paired data. In patients with shock, syndecan-1 and von Willebrand Factor (vWF) were increased compared to patients without shock. Additionally, patients with shock had increased red blood cell EV and leucocyte EV concentrations compared to patients without shock. Endotheliopathy markers correlated with leucocyte EVs (ρ = 0.263, p = 0.023), but not with EVs derived from other cells. Injury severity score had no relation with EV release. RBC transfusion increased circulating red blood cell EVs but did not impact endotheliopathy. In conclusion, shock is (weakly) associated with EVs from leucocytes, suggesting an immune driven pathway mediated (at least in part) by shock.

Novel heat shock protein 90 inhibitor improves cardiac recovery in a rodent model of donation after circulatory death.

OBJECTIVE: Organ donation after circulatory death (DCD) is a potential solution for the shortage of suitable organs for transplant. Heart transplantation using DCD donors is not frequently performed due to the potential myocardial damage following warm ischemia. Heat shock protein (HSP) 90 has recently been investigated as a novel target to reduce ischemia/reperfusion injury. The objective of this study is to evaluate an innovative HSP90 inhibitor (HSP90i) as a cardioprotective agent in a model of DCD heart. METHODS: A DCD protocol was initiated in anesthetized Lewis rats by discontinuation of ventilation and confirmation of circulatory death by invasive monitoring. Following 15 minutes of warm ischemia, cardioplegia was perfused for 5 minutes at physiological pressure. DCD hearts were mounted on a Langendorff ex vivo heart perfusion system for reconditioning and functional assessment (60 minutes). HSP90i (0.01 µmol/L) or vehicle was perfused in the cardioplegia and during the first 10 minutes of ex vivo heart perfusion reperfusion. Following assessment, pro-survival pathway signaling was evaluated by western blot or polymerase chain reaction. RESULTS: Treatment with HSP90i preserved left ventricular contractility (maximum + dP/dt, 2385 ± 249 vs 1745 ± 150 mm Hg/s), relaxation (minimum -dP/dt, -1437 ± 97 vs 1125 ± 85 mm Hg/s), and developed pressure (60.7 ± 5.6 vs 43.9 ± 4.0 mm Hg), when compared with control DCD hearts (All P = .001). Treatment abrogates ischemic injury as demonstrated by a significant reduction of infarct size (2,3,5-triphenyl-tetrazolium chloride staining) of 7 ± 3% versus 19 ± 4% (P = .03), troponin T release, and mRNA expression of Bax/Bcl-2 (P < .05). CONCLUSIONS: The cardioprotective effects of HSP90i when used following circulatory death might improve transplant organ availability by expanding the use of DCD hearts.

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.

Assessment of Tissue Perfusion Using the Peripheral Perfusion Index and Lactate Clearance in Shock in Pediatric Patients.

BACKGROUND: Pediatric shock has a high mortality rate because many of the early clinical signs are subtle and have poor sensitivity and specificity. Pediatric shock was categorized either: compensated with normal blood pressure, poor skin perfusion (CRT >2 s, mottled, cool peripheries, peripheral cyanosis), weak peripheral pulse, age specific tachycardia, tachypnoea, and oliguria or decompensated with hypotension (SBP < 70 + (2× age in years) mm Hg and decreased mental status. The perfusion index is a non-invasive method for assessing peripheral perfusion and may be a useful marker for identifying shock early in pediatric patients. OBJECTIVE: This prospective cohort study (November 2019 to August 2020) evaluated whether the perfusion index, lactate, and/or lactate clearance could predict mortality among pediatric shock patients. METHODS: Fifty children (68% male) with shock underwent assessments at presentation to the emergency room to evaluate their heart rate, blood pressure, capillary refill time, central venous pressure, perfusion index, cardiac index, systemic vascular resistance, central venous oxygen saturation, and lactate clearance. RESULTS: The perfusion index range was 0.03 to 2.2 and ≤0.18 as the cut-off for mortality prediction providing 74% sensitivity and 78% specificity. The serum lactate concentration range was 0 to 16 mmol/L and >5.7 mmol/L as the cut-off for mortality prediction provided 70% sensitivity and 96% specificity at presentation to the emergency room. The lactate clearance range was 3% to 75% and >10% as the cut-off for survival prediction after resuscitation and at 6 h later. CONCLUSION: Perfusion index (PI), lactate, and lactate clearance provided comparable sensitivity and specificity for predicting outcomes among pediatric patients with shock Therefore, we suggest that the PI is an inexpensive, rapid, and non-invasive tool that can be used to predict illness severity and mortality in busy pediatric intensive care units and emergency departments. This tool may guide better patient triage and an earlier diagnosis of shock in this setting.

The protective role of estrogen on endothelial and glycocalyx barriers after shock conditions: A microfluidic study.

BACKGROUND: Sexual dimorphism has been demonstrated after major trauma and hemorrhage shock with protective effects related to female sex or estrogen. Traumatic endotheliopathy is an important component of trauma-induced coagulopathy. Components of endothelial barrier dysfunction include degradation of the endothelial glycocalyx and endothelial cellular injury. Estrogen modulates endothelial function via its membrane and cellular receptors. The effects of estrogen on the vascular endothelial barrier after trauma and hemorrhage shock are, however, unknown. This topic was studied in an in vitro model under flow conditions. METHODS: Monolayers of human umbilical vein endothelial cells were established in microfluidic flow devices. After overnight perfusion, cell monolayers were subjected to normoxic or hypoxic perfusion and then treated with either estrogen (as estradiol), testosterone (as dihydrotestosterone), or media alone. Endothelial activation/injury was indexed by soluble thrombomodulin and glycocalyx degradation by syndecan-1 and hyaluronic acid shedding as well as measurement of the thickness of the glycocalyx layer. The coagulation phenotype of the human umbilical vein endothelial cells was indexed by the relative values of the activities of tissue plasminogen activator and plasminogen activator inhibitor-1. Vascular endothelial growth factor was measured in cell culture supernatants using a solid-phase enzyme-linked immunosorbent assay. RESULTS: Treatment with estrogen but not testosterone mitigated the adverse effect of shock on endothelial and glycocalyx barrier properties. Our biomimetic model suggests a beneficial effect of estrogen administration after trauma and hemorrhage shock on the glycocalyx and endothelial barriers. CONCLUSION: Early estrogen treatment after trauma and hemorrhage shock may be a useful adjunct to mitigating the development of traumatic endotheliopathy.

Cardiovascular Manifestations and Mechanisms in Patients with COVID-19.

Coronavirus disease 2019 (COVID-19) patients with pre-existing cardiovascular disease (CVD) or with cardiovascular complications have a higher risk of mortality. The main cardiovascular complications of COVID-19 include acute cardiac injury, acute myocardial infarction (AMI), myocarditis, arrhythmia, heart failure, shock, and venous thromboembolism (VTE)/pulmonary embolism (PE). COVID-19 can cause cardiovascular complications or deterioration of coexisting CVD through direct or indirect mechanisms, including viral toxicity, dysregulation of the renin-angiotensin-aldosterone system (RAAS), endothelial cell damage and thromboinflammation, cytokine storm, and oxygen supply-demand mismatch. We systematically review cardiovascular manifestations, histopathology, and mechanisms of COVID-19, to help to formulate future research goals and facilitate the development of therapeutic management strategies.

Vitamin B6 prevents excessive inflammation by reducing accumulation of sphingosine-1-phosphate in a sphingosine-1-phosphate lyase-dependent manner.

Vitamin B6 is necessary to maintain normal metabolism and immune response, especially the anti-inflammatory immune response. However, the exact mechanism by which vitamin B6 plays the anti-inflammatory role is still unclear. Here, we report a novel mechanism of preventing excessive inflammation by vitamin B6 via reduction in the accumulation of sphingosine-1-phosphate (S1P) in a S1P lyase (SPL)-dependent manner in macrophages. Vitamin B6 supplementation decreased the expression of pro-inflammatory cytokines by suppressing nuclear factor-κB and mitogen-activated protein kinases signalling pathways. Furthermore, vitamin B6-reduced accumulation of S1P by promoting SPL activity. The anti-inflammatory effects of vitamin B6 were inhibited by S1P supplementation or SPL deficiency. Importantly, vitamin B6 supplementation protected mice from lethal endotoxic shock and attenuated experimental autoimmune encephalomyelitis progression. Collectively, these findings revealed a novel anti-inflammatory mechanism of vitamin B6 and provided guidance on its clinical use.

A Novel Peptide Antibiotic, Pro10-1D, Designed from Insect Defensin Shows Antibacterial and Anti-Inflammatory Activities in Sepsis Models.

Owing to the challenges faced by conventional therapeutics, novel peptide antibiotics against multidrug-resistant (MDR) gram-negative bacteria need to be urgently developed. We had previously designed Pro9-3 and Pro9-3D from the defensin of beetle Protaetia brevitarsis; they showed high antimicrobial activity with cytotoxicity. Here, we aimed to develop peptide antibiotics with bacterial cell selectivity and potent antibacterial activity against gram-negative bacteria. We designed 10-meric peptides with increased cationicity by adding Arg to the N-terminus of Pro9-3 (Pro10-1) and its D-enantiomeric alteration (Pro10-1D). Among all tested peptides, the newly designed Pro10-1D showed the strongest antibacterial activity against Escherichia coli, Acinetobacter baumannii, and MDR strains with resistance against protease digestion. Pro10-1D can act as a novel potent peptide antibiotic owing to its outstanding inhibitory activities against bacterial film formation with high bacterial cell selectivity. Dye leakage and scanning electron microscopy revealed that Pro10-1D targets the bacterial membrane. Pro10-1D inhibited inflammation via Toll Like Receptor 4 (TLR4)/Nuclear factor-κB (NF-κB) signaling pathways in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Furthermore, Pro10-1D ameliorated multiple-organ damage and attenuated systemic infection-associated inflammation in an E. coli K1-induced sepsis mouse model. Overall, our results suggest that Pro10-1D can potentially serve as a novel peptide antibiotic for the treatment of gram-negative sepsis.

The ratio of shock index to pulse oxygen saturation predicting mortality of emergency trauma patients.

OBJECTIVE: To test the following hypothesis: the ratio of shock index to pulse oxygen saturation can better predict the mortality of emergency trauma patients than shock index. METHODS: 1723 Patients of trauma admitted to the Emergency Department of the First Affiliated Hospital of Soochow University from 1 November 2016 to 30 November 2019 were retrospectively evaluated. We defined SS as the ratio of SI to SPO2, and the mortality of trauma patients in the emergency department as end-point of outcome. We calculated the crude HR of SS and adjusted HR with the adjustment for risk factors including sex, age, revised trauma score (RTS) by Cox regression model. ROC curve analyses were performed to compare the area under the curve (AUC) of SS and SI. RESULTS: The crude HR of SS was: 4.31, 95%CI (2.89-6.42) and adjusted HR: 3.01, 95%CI(1.86-4.88); ROC curve analyses showed that AUC of SS was higher than that of shock index (SI), and the difference was statistically significant: 0.69, 95%CI(0.55-0.83) vs 0.65, 95%CI (0.51-0.79), P = 0.001. CONCLUSION: The ratio of shock index to pulse oxygen saturation is good predictor for emergency trauma patients, which has a better prognostic value than shock index.

A Combination of Kidney Ischemia and Injection of Isolated Mitochondria Leads to Activation of Inflammation and Increase in Mortality Rate in Rats.

We studied the development of acute kidney injury and animal death in the model of combined injury caused by kidney ischemia/reperfusion with simultaneous systemic administration of mitochondria. It was found that intraperitoneal injection of isolated mitochondria led to the appearance of mitochondrial DNA in the peripheral blood that could activate innate immunity. After administration of mitochondria, as well as after renal ischemia/reperfusion, proinflammatory changes were observed, primarily leukocytosis and granulocytosis. The combination of ischemia/reperfusion with injection of mitochondria caused a sharp increase in animal death, which may indicate a direct link between activation of TLR-signaling and high mortality of patients with combined injuries and multiple-organ failure in intensive care units. Treatment with mitochondria-targeted antioxidant increased animal survival, which indicated the participation of mitochondrial ROS in the development of systemic inflammatory response and death caused by acute renal failure.

Reevaluation of Lung Injury in TNF-Induced Shock: The Role of the Acid Sphingomyelinase.

Tumor necrosis factor (TNF) is a well-known mediator of sepsis. In many cases, sepsis results in multiple organ injury including the lung with acute respiratory distress syndrome (ARDS). More than 20-year-old studies have suggested that TNF may be directly responsible for organ injury during sepsis. However, these old studies are inconclusive, because they relied on human rather than conspecific TNF, which was contaminated with endotoxin in most studies. In this study, we characterized the direct effects of intravenous murine endotoxin-free TNF on cardiovascular functions and organ injury in mice with a particular focus on the lungs. Because of the relevance of the acid sphingomyelinase in sepsis, ARDS, and caspase-independent cell death, we also included acid sphingomyelinase-deficient (ASM-/-) mice. ASM-/- and wild-type (WT) mice received 50 µg endotoxin-free murine TNF intravenously alone or in combination with the pan-caspase inhibitor carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone (zVAD) and were ventilated at low tidal volume while lung mechanics were followed. Blood pressure was stabilized by intra-arterial fluid support, and body temperature was kept at 37°C to delay lethal shock and to allow investigation of blood gases, lung histopathology, proinflammatory mediators, and microvascular permeability 6 hours after TNF application. Besides the lungs, also the kidneys and liver were examined. TNF elicited the release of inflammatory mediators and a high mortality rate, but failed to injure the lungs, kidneys, or liver of healthy mice significantly within 6 hours. Mortality in WT mice was most likely due to sepsis-like shock, as indicated by metabolic acidosis, high procalcitonin levels, and cardiovascular failure. ASM-/- mice were protected from TNF-induced hypotension and reflex tachycardia and also from mortality. In WT mice, intravenous exogenous TNF does not cause organ injury but induces a systemic inflammatory response with cardiovascular failure, in which the ASM plays a role.

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.

Improving the performance of the Revised Trauma Score using Shock Index, Peripheral Oxygen Saturation, and Temperature-a National Trauma Database study 2011 to 2015.

BACKGROUND: The Revised Trauma Score is the standard physiologic injury severity indicator used in trauma research and quality control. Shock index, peripheral oxygen saturation, and temperature have emerged as strong predictors for mortality and morbidity. We hypothesized that replacing systolic blood pressure and respiratory rate with age-adjusted shock index and peripheral oxygen saturation and adding temperature would generate a more accurate model, valid across all ages. METHODS: This is a retrospective database analysis using children and adults from the National Trauma Data Bank for years 2011 to 2015. Glasgow Coma Scale, systolic blood pressure, heart rate, respiratory rate, peripheral oxygen saturation, temperature, and shock index (calculated as heart rate/systolic blood pressure) were used as predictor variables, alone or in combination, in logistic models with survival as primary outcome. Bayesian information criterion and area under the receiver operator characteristic curve were used to compare models' performances. To adjust for age, models tested on the entire population (children and adults) used Z-scores derived on age-based homogenous intervals rather than the raw value. RESULTS: The analysis included 283,724 pediatric and 1,555,478 adult patients. Overall mortality was 0.7% and 2.7%, respectively. The Glasgow Coma Scale + shock index + peripheral oxygen saturation + temperature model outperformed the revised trauma score in both adults (Bayesian information criterion 296,345.94 vs 298,494.72; area under the receiver operator characteristic curve 0.831 vs 0.809, P < .001) and children (Bayesian information criterion 12,251.48 vs 12,283.48; area under the receiver operator characteristic curve 0.974 vs 0.968, P = .05) cohorts. On the merged (children and adults) cohort the Glasgow Coma Scale + Z-scores derived on age-based homogenous intervals + peripheral oxygen saturation + temperature model outperformed the Revised Trauma Score (Bayesian information criterion 313,814.78 vs 317,781.31; area under the receiver operator characteristic curve 0.852 vs 0.809, P < .001). CONCLUSIONS: Replacing systolic blood pressure and respiratory rate with shock index and peripheral oxygen saturation in the Revised Trauma Score model and adding temperature generated a more accurate model in both children and adults. Adjusting shock index for age rendered the model accurate across all ages. Calibration on population-derived nomograms of vital signs would further increase the model's accuracy and precision.