Why anticoagulant studies on sepsis fail frequently --- start with SCARLET.

The Sepsis Coagulopathy Asahi Recombinant LE Thrombomodulin (SCARLET) trial has many defects, and thus cannot be the terminator of recombinant thrombomodulin (rTM). On the contrary, it provides sufficient evidence for further research. Based on analysis focusing on the failure of SCARLET and several previous anticoagulant studies, it is most important for new studies to grasp the following two points: (1) The enrolled cases should have sufficient disease severity and a clear standard for disseminated intravascular coagulation; (2) Heparin should not be used in combination with the investigated drugs. Multiple post-hoc analyses show that no combination of heparin will not increase the risk of thromboembolism. In fact, the combination of heparin can mask the true efficacy of the investigated drug. Due to the complexity of sepsis treatment and the limitations of clinical studies, the results of all treatment studies should be repeatedly verified, rather than be determined at one stroke. Some research conclusions contrary to disease physiology, pharmacology and clinical practice may be deceptive, and should be cautious rather than be simply accepted. On the other hand, the dissenting voices in the "consensus" scene are often well discussed by the authors and should be highly valued.

The severe COVID-19: A sepsis induced by viral infection? And its immunomodulatory therapy.

COVID-19 is known for its magical infectivity, fast transmission and high death toll based on the large number of infected people. From the perspective of the clinical manifestation, autopsy examination and pathophysiology, the essence of COVID-19 should be viewed as a sepsis induced by viral infection, and has the essential characteristics as sepsis induced by other pathogens. Therefore, in addition to etiological and supportive treatment, immunomodulatory therapy is also appropriate to severe COVID-19. Although there is still a lack of consensus on immunotherapy for sepsis so far, relatively rich experiences have been accumulated in the past decades, which will help us in the treatment of severe COVID-19. This article will elaborate immunotherapy of sepsis, though it may not be consistent.

Pyruvate oral rehydration solution improved visceral function and survival in shock rats.

BACKGROUND: Recent findings showed advantages of a novel pyruvate-enriched oral rehydration solution (Pyr-ORS) in resuscitation of burns. This study focused on effects of Pyr-ORS on the visceral blood perfusion (VBP), gastrointestinal function, and survival rate, compared with the bicarbonate-based World Health Organization-guided oral rehydration solution (WHO-ORS), during intragastric rehydration of lethal hemorrhagic shock in rats. METHODS: Sixty adult rats were subjected to 45% total blood volume loss and were randomly allocated to the following three groups (n = 20): group NR (no fluid resuscitation), group PORS (oral Pyr-ORS rehydration), and group BORS (oral WHO-ORS rehydration), respectively. Other 10 rats were served as group NH (the sham group). Enteral rehydration lasted for 4 h after hemorrhage. The mean arterial pressure (MAP), VBP, and plasma enzymes activities of heart, liver, and kidney, and intestinal fatty acid binding protein were measured. Liver, kidney, and ileum were harvested for the evaluation of activities of oxidative enzymes and intestinal barrier protein (ZO-1). Other 84 rats with identical procedures without sampling were observed for their 24-h survival rates. RESULTS: Pyr-ORS was more effective in enhancing the MAP and VBP, inhibiting tissue oxidative damage, and improving organ function, compared with WHO-ORS. Hypoxic lactic acidosis was fully corrected in group PORS in 4 h, whereas it worsened in group BORS, and the 24-h survival rate was twice higher in group PORS than in group BORS (45.8 versus 20.8%, P < 0.05). CONCLUSIONS: A small amount of pyruvate in Pyr-ORS was more therapeutically beneficial than equivalent bicarbonate in WHO-ORS and greatly raised survival in enteral rehydration of lethal hemorrhagic shock. The Pyr-ORS may be an ideal oral fluid in resuscitation of hypovolemic shock, especially in prehospital and resource-poor settings.

Nonvolatile Modulation of Bi2O2Se/Pb(Zr,Ti)O3 Heteroepitaxy.

The pursuit of high-performance electronic devices has driven the research focus toward 2D semiconductors with high electron mobility and suitable band gaps. Previous studies have demonstrated that quasi-2D Bi2O2Se (BOSe) has remarkable physical properties and is a promising candidate for further exploration. Building upon this foundation, the present work introduces a novel concept for achieving nonvolatile and reversible control of BOSe's electronic properties. The approach involves the epitaxial integration of a ferroelectric PbZr0.2Ti0.8O3 (PZT) layer to modify BOSe's band alignment. Within the BOSe/PZT heteroepitaxy, through two opposite ferroelectric polarization states of the PZT layer, we can tune the Fermi level in the BOSe layer. Consequently, this controlled modulation of the electronic structure provides a pathway to manipulate the electrical properties of the BOSe layer and the corresponding devices.

Network pharmacology and molecular docking prediction, combined with experimental validation to explore the potential mechanism of Qishen Yiqi pills against HF-related cognitive dysfunction.

ETHNOPHARMACOLOGICAL RELEVANCE: Qishen Yiqi Pills (QSYQ) is a classical herbal formula for treating heart failure (HF) and has potential efficacy in improving cognitive function. The latter is one of the most common complications in patients with HF. However, there is no study on treating HF-related cognitive dysfunction by QSYQ. AIMS OF THE STUDY: The study aims to investigate the effect and mechanism of QSYQ on treating post-HF cognitive dysfunction based on network pharmacology and experimental validation. MATERIALS AND METHODS: Network pharmacology analysis and molecular docking was used to explore endogenous targets of QSYQ in treating cognitive impairment. Ligation of the anterior descending branch of the left coronary artery and sleep deprivation (SD) were used to induce HF-related cognitive dysfunction in rats. The efficacy and potential signal targets of QSYQ were then verified by functional evaluation, pathological staining, and molecular biology experiments. RESULTS: 384 common targets were identified by intersecting QSYQ 'compound targets' and 'cognitive dysfunction' disease targets. KEGG analysis showed these targets were enriched to the cAMP signal, and four marks responsible for regulating the cAMP signal were successfully docked with core compounds of QSYQ. Animal experiments demonstrated that QSYQ significantly ameliorated cardiac function and cognitive function in rats suffering from HF and SD, inhibited the reduction of cAMP and BDNF content, reversed the upregulation of PDE4 and downregulation of CREB, suppressed the loss of neurons, and restored the expression of synaptic protein PSD95 in the hippocampus. CONCLUSION: This study clarified that QSYQ could improve HF-related cognitive dysfunction by modulating cAMP-CREB-BDNF signals. It provides a rich basis for the potential mechanism of QSYQ in the treatment of heart failure with cognitive dysfunction.

[Sedation with stimulative circadian rhythm in mechanically ventilation patients in intensive care unit].

OBJECTIVE: To sedate the mechanically ventilation patients in intensive care unit (ICU) with stimulative circadian rhythm, and evaluate whether the protocol has advantages in recovering natural circadian rhythm, duration of mechanical ventilation, and length of ICU stay after weaning of sedation. METHODS: A prospective random control trial was conducted. One hundred and twenty ventilated patients in ICU were randomly assigned to four groups: circadian rhythm (CR), daily interruption (DI), continuous sedation (CS) or demand sedation (DS) group, each n = 30. Given more complications, DS group was deleted after recruiting 10 cases and 90 patients were admitted ultimately. Patients' age, gender, body weight, acute physiology and chronic health evaluation II (APACHE II) scores, sedatives dosages, daily arousal time, duration of mechanical ventilation, length of ICU stay, complications (ventilator-associated pneumonia, barotrauma with intrathoracic drain tube) and untoward reactions (accidental extubation, reintubation, tracheotomy, death) were recorded, the biochemical indicators were determined, as well as number of nurses on duty at 10:00 and 22:00. RESULTS: The patients' sex ratio, age, body weight, APACHEII scores, duration of mechanical ventilation, length of ICU stay showed no difference among CR, DI and CS groups. The total sedatives dosages (mg: 5466.7 ± 620.4) and average sedatives dosages [mg×h(-1) ×kg(-1): 2.19 ± 0.61] in CS group were significantly higher than those in CR group (4344.5 ± 816.0, 1.00 ± 0.51) and DI group (4154.3 ± 649.4, 1.23 ± 0.62, all P < 0.01), and there was no difference between CR group and DI group. Daily arousal time in the CR group (hours: 4.40 ± 1.30) was significantly lengthened compared with that in DI group (0.59 ± 0.26) and CS group (0.15 ± 0.02, both P < 0.05). The complications showed no differences in each group, but incidences of the untoward reactions in DI group (2 cases) were significantly increased compared with that in CR group (1 case) and CS group (0 case, P = 0.0477). After weaning of sedation, patients with normal circadian rhythm were significantly more in CR group than that in CS group (19 vs. 9, P = 0.0339). Among CR group, DI group and CS group, there were significant differences in the numbers of nurses on duty in the daytime (1.65, 1.41, 1.14, all P < 0.01), but there was no difference in the night. The biochemistry index showed no difference in each group. CONCLUSIONS: It demonstrated that sedation with stimulative circadian rhythm be helpful to create circadian rhythm after weaning of sedation. While complications and untoward reactions did not increase, as well as duration of mechanical ventilation and length of ICU stay. Therefore, the clinical applicability of this sedative strategy was highlighted.

Expert consensus on the monitoring and treatment of sepsis-induced immunosuppression.

Emerged evidence has indicated that immunosuppression is involved in the occurrence and development of sepsis. To provide clinical practice recommendations on the immune function in sepsis, an expert consensus focusing on the monitoring and treatment of sepsis-induced immunosuppression was developed. Literature related to the immune monitoring and treatment of sepsis were retrieved from PubMed, Web of Science, and Chinese National Knowledge Infrastructure to design items and expert opinions were collected through an online questionnaire. Then, the Delphi method was used to form consensus opinions, and RAND appropriateness method was developed to provide consistency evaluation and recommendation levels for consensus opinions. This consensus achieved satisfactory results through two rounds of questionnaire survey, with 2 statements rated as perfect consistency, 13 as very good consistency, and 9 as good consistency. After summarizing the results, a total of 14 strong recommended opinions, 8 weak recommended opinions and 2 non-recommended opinions were produced. Finally, a face-to-face discussion of the consensus opinions was performed through an online meeting, and all judges unanimously agreed on the content of this consensus. In summary, this expert consensus provides a preliminary guidance for the monitoring and treatment of immunosuppression in patients with sepsis.

[Effect of endothelial nitric oxide synthase gene polymorphisms upon disease severity and outcome in septic patients].

OBJECTIVE: To investigate the association of eNOS 894G-->T, -786T-->C gene polymorphisms with disease severity and outcome in septic patients. METHODS: A total of 117 patients with severe sepsis were randomly selected from ICUs at 9 academic hospitals in Beijing during April 2007 to May 2009. PCR-RFLP and PCR-SSCP were used to analyze the alleles and genotypes in eNOS 894G-->T and -786T--> C gene polymorphisms. Recorded clinical data included demographics, pathogens, APACHE II score within 24 hours and SOFA score within 7 days after ICU admission, percentage of shock patients, days to shock onset (from infection to shock onset), duration of shock and the mortality at Days 7 and 28. RESULTS: In comparison with genotype GT carriers, the patients with genotype GT in eNOS 894G-->T polymorphism had a incremental trend in frequency of shock (87% vs 68.1%, P = 0.071) and a significantly shortened days to shock onset [1.0 (0.1 - 6.5) vs 2.0 (0.10 - 27.0) days, median (range), P < 0.05]. Those patients had been shown to have a significantly high APACHE II score (23.61 +/- 7.00 vs 19.50 +/- 6.99, P < 0.05), SOFA score (9.43 +/- 3.42 vs 5.26 +/- 2.94, P < 0.001) and mortality at Day 7 (34.8% vs 0%, P < 0.001) and Day 28 (78.3% vs 23.4%, P < 0.001). Multivariate analyses revealed that age in years, SOFA score and genotype GT in eNOS 894G-->T polymorphism were independent high-risk factors for the outcome in septic patients. However, eNOS -786T-->C gene polymorphism was not associated with disease severity and outcome in septic patients. CONCLUSION: Carriage of genotype GT in eNOS 894G-->T polymorphism is associated with the occurrence of shock and impaired organ function.

[The potential role of high mobility group box 1 protein in immune dysfunction and its regulatory mechanism after major trauma].

OBJECTIVE: To investigate the potential effect of high mobility group box 1 protein (HMGB1) on host immune response and its molecular regulation mechanism as well as its interventional pathway following major burns/trauma. METHODS: With both animal experiments and clinical investigation, serial studies were conducted to observe the effects of HMGB1 on changes in immune function of T lymphocytes, dendritic cells, and macrophages both in vivo and in vitro. RESULTS: It was found that thermal injury or trauma induced a delayed and persistent increase in HMGB1 expression as well as its release in various tissues. HMGB1 formation could markedly influence the cell-mediated immunity, including the changes in T lymphocytes, dendritic cells, and macrophages following major trauma or burns. These effects were closely related with dysfunction of various organs in the course of sepsis. CONCLUSION: These data proved that HMGB1 not only acts as a novel "late" inflammatory mediator but is also closely associated with immunosuppression after acute insults. HMGB1 might play an important role in inducing systemic inflammatory response together with host immunological dissonance, resulting in the development of septic complications. Intervention of HMGB1 expression and release presumably provides a potentially effective way to regulate both excessive inflammatory and immune response, thereby as a measure to improve the prognosis of severe sepsis secondary to major trauma.

[Epidemiology of unpleasant experiences in conscious critically ill patients during intensive care unit stay].

OBJECTIVE: To survey the incidences of psychological and physiological unpleasant experiences in conscious critically ill patients during their intensive care unit (ICU) stay, and investigate the inducing factors. METHODS: A two-month consecutive nationwide investigation was prospectively performed in 31 academic hospital ICUs. An in-person questionnaire interview to each conscious patient was performed by specific trained staff from RMC-ROMIT Healthcare Consulting Company within 2 days after the patient was transferred from ICU. RESULTS: Two hundred and thirty-four cases were interviewed in this survey. One hundred and sixty-three of the 234 patients (69.6%) appeared psychological unpleasant experience. The ratio of patients with physiological unpleasant experience was as high as 97.0%, and 74.8% of whom were with serious physiological unpleasant experiences. The incidence of serious physiological unpleasant experiences was markedly higher in patients with than without psychological unpleasant experience (46.5% vs. 86.5%). The difference was shown to be statistical significant (P < 0.01). The percentage of patients complained of ICU noise and medical or nursing manipulations not tolerable was 65.8% and 74.8%, respectively. Compared with the tolerable cases, the incidences of psychological and physiological unpleasant experiences were significantly increased in those patients (P < 0.05 or P < 0.01). Acute physiology and chronic health evaluation II (APACHE II) score was the independent high risk factor inducing psychological unpleasant experience through multiple factor analysis [odds ratio (OR) = 1.070, 95% confidence interval (CI) = 1.020-1.130, P < 0.05]. Age was the high risk factor inducing physiological unpleasant experience (OR = 0.936, 95% CI = 0.879-0.998, P < 0.05). In addition, adequate sedation significantly reduced the incidence of the psychological and physiological unpleasant experiences. CONCLUSION: A high incidence of unpleasant experience is found in conscious critically ill patients during their ICU stay. Patients with psychological unpleasant experiences are with higher possibility of occurring physiological unpleasant experiences. The data show that APACHE II score is the independent high risk factor inducing psychological unpleasant experiences. ICU environment, noise for instance, and medical or nursing manipulations are closely related with the incidence of psychological and physiological unpleasant experiences. Meanwhile, adequate sedation is one of the effective methods to reduce the incidences of them.

[Clinical trial with a new immunomodulatory strategy: treatment of severe sepsis with Ulinastatin and Maipuxin].

OBJECTIVE: To evaluate the efficacy of treatment of severe sepsis by combining anti-inflammatory and immune-enhancing agents. METHODS: Multiple-center, prospective, randomized, controlled designs. Cases were from surgical or general ICU of 26 university teaching hospitals. Totally, 433 adult patients developing severe sepsis with Marshall score 5-20 were enrolled. Patients received either standard treatment based on SSC direction (as group control), or additional Ulinastatin (urinary trypsin inhibitor) 300 K units per day+thymosin alpha1 (Maipuxin) 1.6 mg per day for 7 days (as treatment group 1, adopted in the first trial), or double dosage of the above agents (as treatment group 2, adopted in the second trial). The outcome of 28 and 90 days, APACHEII and Marshall score, monocyte HLA-DR/CD14+ at several points until 28 days, and the lengths of ICU stay, antibiotics usage and mechanical ventilation were determinated. RESULTS: In the first trial (91 cases), there was no significant difference in variables between treatment group 1 and control at 28 days. In the second trial (342 cases), the mortality of treatment group 2 decreased from 38.32% to 25.14% (P=0.0088), compared with group control at 28 days, and from 52.10% to 37.14% (P=0.0054) on 90 days. APACHEIIalso decreased from 14.32 to 12.70 (P=0.0384) and monocyte HLA-DR/CD14+ increased from 40.13% to 51.65% (P=0.0092) on 28 days in treatment group 2. Other variables had no significant differences between two groups. CONCLUSION: Treatment by the combining anti-inflammatory and immune enhancing agents can significantly improve the outcome of severe sepsis. The efficacy of this therapy seems to be dose dependent on.

[Highlighting the potential of heparin in the treatment of sepsis in view of failure of KyberSept and OPTIMIST projects].

Systemic inflammation can induce blood hypercoagulability, even disseminated intravascular coagulation (DIC), and "cross talk" exists between inflammatory and coagulation system. So anticoagulation should be helpful in the treatment of systemic inflammatory response syndrome (SIRS) or sepsis. The success in the use of recombinant human activated protein C (rhAPC) is a strong evidence to support anticoagulation strategy in the treatment of sepsis. Unexpectedly, other two anticoagulation studies, KyberSept and OPTIMIST, respectively with antithrombin and tissue factor pathway inhibitor (TFPI) failed to show improvement in 28-day survival rate. Blame had been laid on the combined use of heparin or low molecular weight heparin (LMWH), as it might interfere with efficacy of antithrombin and TFPI. However, no compelling evidence was found to support this hypothesis, as there was no significant difference in result between the patients with and without heparin or LMWH in the treatment groups in these two studies. Contrarily, significant differences in outcome were found between patients with and without heparin or LMWH in control groups, and the survival rate of patients with heparin or LMWH in control groups was higher than that of the treatment groups. These results strongly suggested heparin or LMWH could be effective in the treatment of sepsis. It is our understanding that any anticoagulant should have some potential effect in treatment of sepsis. Therefore, it seems to be necessary to explore the efficacy of traditional anticoagulant, and compare the effects between the new and old drugs.

[Prospective, multi-center investigation on safety of critical patients in intensive care units].

OBJECTIVE: To perform a prospective, multi-center investigation of the incidence and causes of medical errors happened in intensive care unit (ICU). METHODS: This investigation was performed in eight ICUs in level A, grade 3 teaching hospitals from October 23 to December 23, 2006. One attending physician and the head nurse in each center were entrusted with the responsibility for this project. Medical errors were identified as (1) type of errors (happened in diagnosis, medication, caring procedures or monitoring etc.); (2)characteristics of errors (related to complications, emergency intervention, low ability or carelessness of care givers and others); (3) consequence of errors (resulted in non-serious influence, vital signs fluctuation, alternation of respiratory or circulatory function, organ injury or death). Besides the medical errors, data included ICU beds, numbers of doctors or nurses, numbers of critical patients receiving intensive care during the investigation period and their acute physiology and chronic health evaluation II (APACHE II) scores, the academic degree and title and years of ICU working experience of doctors or nurses who made medical errors. RESULTS: Data from three of eight centers were excluded due to lack of objectivity. A total number of 232 critical patients were surveyed in 1 319 ICU patient x days. Two hundred and ninety-six ICU errors were found. One error occurred in average of 4.46 patient x days. Medical errors happened in 157 patients (67.6%). The percentage of error related to nursing (74.3%) was significantly higher than that made by doctor's caring (25.7%). Two hundred and twelve errors (71.6%) were devoid of serious effects to patients. However, Eighty-two errors were followed by vital signs instability. Medical errors occurred more frequently in patients with the higher (greater than 20) than the lower (less than 20) APACHE II score. The frequency of nursing oriented errors was closely positively correlated with the rates of shortage of working force, low educational level and working years less than 3 years respectively. CONCLUSION: Our survey indicates that critical patients are facing high medical error risk in the higher level Chinese teaching hospitals. There is a close relationship between ICU errors and severity of patient's disease, inadequate training and less working experience.

[Clinical study on bacterial translocation in severe multiple trauma patients].

OBJECTIVE: To investigate bacterial translocation in severe multiple trauma patients using polymerase chain reaction (PCR) to detect the presence of bacteria in the blood. METHODS: Sixteen severe multiple trauma patients [injury severity score (ISS)>20] in surgery intensive care unit (SICU) were selected. Blood samples were collected 2, 24 and 48 hours after trauma for bacterial culture and microbial DNA detection. Meanwhile, plasma levels of D-lactate and lipopolysaccharide (LPS) in systemic circulation were determined. PCR was performed after DNA extraction, with target beta-lactosidase gene of E. coli and 16SrRNA gene of most pathogenic bacteria. All patients were observed within 30 days for infectious complications. D-lactate and LPS levels were determined in 63 patients before selective operation. RESULTS: Microbial DNA could be detected in blood as early as 2 hours following severe trauma, and altogether positive results were found in 10 patients (62.50%). All PCR-positive patients manifested sepsis, but none of the PCR-negative patients did (P<0.01). Bacterial DNA was discovered in 100.00% of sepsis patients and none in non-sepsis patients (P<0.01). Seventy percent of PCR-positive patients developed infectious complications, while none of PCR-negative patients did (P<0.01). The blood culture was positive only in 3 patients (18.75%), all of them were PCR-positive. E.coli DNA was found in 70.00% of all the PCR positive blood specimens. Systemic plasma concentration of D-lactate and LPS of all patients was significantly higher than that in control group, which consisted of 63 inpatients waiting for elective operations. Systemic plasma level of D-lactate showed a positive correlation with that of LPS (r=0.94, P<0.01). CONCLUSION: Intestinal bacterial translocation (most commonly E. coli) might occur early (2 hours) after severe trauma. Infection and sepsis have a close relationship with bacterial translocation. Detection of blood microbial DNA using PCR could reflect bacteria translocation and forecast imminent infection and sepsis.

[Changes in tumor necrosis factor-alpha mRNA expression in peripheral polymorphonuclear leukocyte and tissues during posttraumatic sepsis].

OBJECTIVE: To evaluate the changes in tumor necrosis factor-alpha (TNF-alpha) mRNA expression in peripheral polymorphonuclear leukocyte (PMNs) and tissues after cecal ligation puncture (CLP) in rats. METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect TNF-alpha mRNA expression in peripheral PMNs and tissues. RESULTS: The TNF-alpha mRNA expression in peripheral PMNs rose gradually after CLP, and it began to decrease after reaching the peak at 48 hours, but it was still higher than normal. The elevation of TNF-alpha mRNA expression was first limited in the regional tissues (P<0.01 at 12 hours after CLP and peaked at 24 hours in the intestine), then it entered the blood circulation later to affect the sensitive organs--lungs and livers (P<0.01 at 24 hours after CLP and peaked at 48 hours in the lung; P<0.05 at 24 hours after CLP and peaked at 48 hours in the liver). CONCLUSION: The rise of TNF-alpha mRNA expression plays an important role in pathogenesis of sepsis.

[Dynamic change in interleukin-18 and its relationships with multiple organ dysfunction syndrome].

OBJECTIVE: To determine interleukin-18 (IL-18) in plasma after trauma, and evaluate its relationship with multiple organ dysfunction syndromes. METHODS: A total of 54 patients were enrolled and divided into low injury seriousness score (L-ISS) and high injury seriousness score (H-ISS) groups. Blood IL-18 levels were determined on admission, day 4, day 7 and day 14 after trauma using enzyme-linked immunoadsorbent assay (ELISA), and the relationship between its level and organ dysfunction was analyzed. RESULTS: Plasma IL-18 concentration was significantly increased on posttrauma day 4 and day 7. Also, plasma IL-18 concentration was significantly higher in patients with organ dysfunction. CONCLUSION: This study suggests that major trauma can lead to a marked elevation of IL-18, which might be associated with organ dysfunction.