Yun Long

Acute renal failure during sepsis: potential role of cell cycle regulation.

OBJECTIVES This study aimed to evaluate cell cycle regulation in acute kidney injury after intraperitoneal sepsis in rats. METHODS Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) in rats. At 0, 6, 12, 24, 48, and 72 h after CLP, serum creatinine was evaluated. DNA content of isolated kidney cells was analyzed using flow cytometer. Furthermore, the expression of p21, p53, cyclin D1, cyclin E, CDK2, CDK4 and P-pRb was also measured by western blot. RESULTS After sepsis-induced by CLP, kidney injury of rat was associated with G1 cell cycle arrest, however, recovery of renal function related to cell cycle progression 48h after CLP. Results also showed that the upregulation of p53 and p21 was correlated with G1 cell arrest in 48h after CLP. Nevertheless, upregulation of cyclin D1/CDK4 and cyclin E/CDK2 induced pRb phosphorylation, which resulted in the G1/S transition 48 h after CLP. CONCLUSION The data suggest that G1 cell cycle arrest may play a role in the initiation of kidney injury, whereas, through regulating cell cycle, p53, p21, CDKs, cyclins and P-pRb may be involved in the injury or recovery of renal function after intraperitoneal sepsis.

Melatonin improved rat cardiac mitochondria and survival rate in septic heart injury

The pathogenesis of septic myocardial depression is complicated. Mitochondrial dysfunction has been suggested to be one of the main reasons for the reduced cardiac function. As melatonin is an antioxidant with the potential to scavenge radicals in mitochondria, we therefore employed a sepsis model, that is, cecal ligation and double puncture (CLP) in rats, to study the melatonin effects on: (i), myocardial mitochondrial function; (ii), heart systolic function; and (iii), prognosis of septic rats. We demonstrate that melatonin treatment (30 mg/kg, 3, 6, 12, 18, 24 hr after CLP) (i) improved myocardial cytochrome c oxidase (CcOX) activity and blood lactate level, (ii) attenuated heart dysfunction with a higher left ventricular ejection fraction (EF), and (iii) promoted 48‐h survival of the rats compared to CLP animals with no melatonin treatment. In conclusion, our results show that rat myocardial mitochondrial CcOX activity was depressed during severe sepsis accompanied by myocardial depression characterized by the decline of EF. In septic rats, melatonin increased the CcOX activity, improved heart systolic function, and lowered mortality rate. The clinical use of melatonin in septic myocardial depression should be tested in the future.

Restriction of third-generation cephalosporin use decreases infection-related mortality.

ObjectiveTo determine the effect of restriction of third-generation cephalosporin use on antibiotic resistance and the outcome of patients with infection. DesignA prospective, before–after comparative study. SettingA general intensive care unit with 14 beds at a university-affiliated teaching hospital. PatientsAll patients admitted to the intensive care unit within 2 yrs. InterventionsA new antibiotic treatment strategy was implemented during phase II. All patients with confirmed or suspected Gram-negative bacterial infections were treated mainly with antibiotics other than third-generation cephalosporins. Measurements and Main ResultsAntibiotic resistance among common Gram-negative bacilli and infection-related hospital mortality during phase I were compared with phase II. A 26.6% reduction in third-generation cephalosporin use (from 168.2 ± 48.0 to 123.5 ± 39.3 g/month, p = .021), accompanied by a 277.7% increase in cefepime use (from 10.3 ± 19.2 to 38.9 ± 31.7 g/month, p = .014) occurred in phase II compared with phase I. This was accompanied by a significant decrease in reduced susceptibility of Gram-negative bacilli to third-generation cephalosporins (p < .05), mainly because of the improved susceptibility of Escherichia coli and Klebsiella species (p < .05). Infection-related hospital mortality was significantly lower in phase II (19.3% vs. 36.3%, p = .014). Multiple logistic regression analysis demonstrated lower respiratory tract infection, the status of immunocompromise, and continuous veno-venous hemofiltration as independent risk factors for infection-related hospital mortality (p < .05), whereas infection with E. coli or Klebsiella species (p = .039) and restriction of third-generation cephalosporin use (p = .025) were associated with a significantly lower mortality rate. ConclusionsRestriction of third-generation cephalosporin use may improve the antibiotic susceptibility and reduce infection-related hospital mortality in critically ill patients.

Combining central venous-to-arterial partial pressure of carbon dioxide difference and central venous oxygen saturation to guide resuscitation in septic shock

PURPOSE Central venous oxygen saturation (Scvo2) is a useful therapeutic target when treating septic shock. We hypothesized that combining Scvo2 and central venous-to-arterial partial pressure of carbon dioxide difference (△Pco2) may provide additional information about survival. MATERIALS AND METHODS We performed a retrospective analysis of 172 patients treated for septic shock. All patients were treated using goal-directed therapy to achieve Scvo2 ≥ 70%. After 6 hours of treatment, we divided patients into 4 groups based on Scvo2 (<70% or ≥ 70%) and △Pco2 (<6 mm Hg or ≥ 6 mm Hg). RESULTS Overall, 28-day mortality was 35.5%. For patients in whom the Scvo2 target was not achieved at 6 hours, mortality was 50.0%, compared with 29.5% in those in whom Scvo2 exceeded 70% (P = .009). In patients with Scvo2 ≥ 70%, mortality was lower if △Pco2 was <6 mm Hg than if △Pco2 was ≥ 6 mm Hg (56.1% vs 16.1%, respectively; P < .001) and 6-hour lactate clearance was superior (0.01 ± 0.61 vs 0.21 ± 0.31, respectively; P = .016). CONCLUSIONS The combination of Scvo2 and △Pco2 appears to predict outcome in critically ill patients resuscitated from septic shock better than Scvo2 alone. Patients who meet both targets appear to clear lactate more efficiently.

The peripheral perfusion index and transcutaneous oxygen challenge test are predictive of mortality in septic patients after resuscitation.

IntroductionThe peripheral perfusion index (PI) is a noninvasive numerical value of peripheral perfusion, and the transcutaneous oxygen challenge test (OCT) is defined as the degree of transcutaneous partial pressure of oxygen (PtcO2) response to 1.0 FiO2. The value of noninvasive monitoring peripheral perfusion to predict outcome remains to be established in septic patients after resuscitation. Moreover, the prognostic value of PI has not been investigated in septic patients.MethodsForty-six septic patients, who were receiving PiCCO-Plus cardiac output monitoring, were included in the study group. Twenty stable postoperative patients were studied as a control group. All the patients inspired 1.0 of FiO2 for 10 minutes during the OCT. Global hemodynamic variables, traditional metabolic variables, PI and OCT related-variables were measured simultaneously at 24 hours after PiCCO catheter insertion. We obtained the 10min-OCT ((PtcO2 after 10 minutes on inspired 1.0 oxygen) - (baseline PtcO2)), and the oxygen challenge index ((10min-OCT)/(PaO2 on inspired 1.0 oxygen - baseline PaO2)) during the OCT.ResultsThe PI was significantly correlated with baseline PtcO2, 10min-OCT and oxygen challenge index (OCI) in all the patients. The control group had a higher baseline PtcO2, 10min-OCT and PI than the septic shock group. In the sepsis group, the macro hemodynamic parameters and ScvO2 showed no differences between survivors and nonsurvivors. The nonsurvivors had a significantly lower PI, 10min-OCT and OCI, and higher arterial lactate level. The PI, 10min-OCT and OCI predicted the ICU mortality with an accuracy that was similar to arterial lactate level. A PI <0.2 and a 10min-OCT <66mmHg were related to poor outcome after resuscitation.ConclusionsThe PI and OCT are predictive of mortality for septic patients after resuscitation. Further investigations are required to determine whether the correction of an impaired level of peripheral perfusion may improve the outcome of septic shock patients.

High central venous-to-arterial CO2 difference/arterial-central venous O2 difference ratio is associated with poor lactate clearance in septic patients after resuscitation

OBJECTIVE Recently, the central venoarterial carbon dioxide difference/arterial-central venous oxygen difference (P(v-a)CO2/C(a-v)O2) ratio has been suggested as an additional indicator of anaerobic metabolism. We investigated the relationship between the P(v-a)CO2/C(a-v)O2 ratio and 8-hour lactate clearance (LC) in septic patients after resuscitation. METHODS AND RESULTS We prospectively obtained 168 sets of measurements from 84 septic patients. The arterial and central venous blood gases were measured simultaneously at enrollment and 8 hours after resuscitation. The P(v-a)CO2/C(a-v)O2 (r = -0.24, P = .028) at T8 was negatively correlated with 8-hour LC after resuscitation in all patients. The patients with 8-hour LC ≥ 10% exhibited significantly lower P(v-a)CO2/C(a-v)O2 ratios and intensive care unit mortality after resuscitation than the patients with 8-hour LC < 10%. The area under the receiver operating characteristic curve of the P(v-a)CO2/C(a-v)O2 ratio for the detection of LC ≥ 10% was the greatest and was significantly better than that of the central venous oxygen saturation and similar to that of the P(v-a)CO2. Moreover, a P(v-a)CO2/C(a-v)O2 < 1.23 at T8 is related to poor 8-hour LC rate (LC ≥ 10%) in the patients with normalized central venous oxygen saturation values (≥70%) after resuscitation. CONCLUSIONS The high P(v-a)CO2/C(a-v)O2 ratio is associated with poor LC after resuscitation. The P(v-a)CO2/C(a-v)O2 ratio may provide useful information for assessing the LC potential and optimizing the LC rate.

Role of sTREM-1 in predicting mortality of infection: a systematic review and meta-analysis

Objectives Several studies have investigated the prognostic value of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in patients with infection. However, the result was controversial. Thus, the purpose of the present meta-analysis was to determine the prognostic value of the sTREM-1 level in predicting mortality at the initial stage of infection. Methods The literature was searched in the PubMed, EMBASE, Web of Knowledge and Cochrane databases. A 2×2 contingency table was constructed on the basis of mortality and sTREM-1 levels in patients with infection. 2 authors independently judged study eligibility and extracted data. The prognostic value of sTREM-1 in predicting mortality was determined using a bivariate meta-analysis model. Q-test and I2 index were used to test heterogeneity. Results 9 studies were selected from 803 studies. An elevated sTREM-1 level was associated with a higher risk of death in infection, with pooled risk ratio (RR) was 2.54 (95% CI 1.77 to 3.65) using a random-effects model (I2=53.8%). With the bivariate random-effects regression model, the pooled sensitivity and specificity of sTREM-1 to predict mortality in infection were 0.75 (95% CI 0.61 to 0.86) and 0.66 (95% CI 0.54 to 0.75), respectively. The diagnostic OR was 6 (95% CI 3 to 10). The overall area under the summary receiver operator characteristic (SROC) curve was 0.76 (95% CI 0.72 to 0.79). When we calculated the sepsis subgroup, the pooled RR was 2.98 (95% CI 2.19 to 4.40). The pooled sensitivity and specificity were 0.74 (95% CI 0.58 to 0.85) and 0.72 (95% CI 0.62 to 0.80), respectively. The overall area under the SROC curve was 0.78 (95% CI 0.74 to 0.81). Conclusions Elevated sTREM-1 concentrations had a moderate prognostic significance in assessing the mortality of infection in adult patients. However, sTREM-1 alone is insufficient to predict mortality as a biomarker.

Dexamethasone Suppressed LPS-Induced Matrix Metalloproteinase and Its Effect on Endothelial Glycocalyx Shedding

The aim of this study is to determine the mechanism of sepsis-induced vascular hyperpermeability and the beneficial effect of glucocorticoid in protecting vascular endothelium. Male Sprague-Dawley rats were given either a bolus intraperitoneal injection of a nonlethal dose of LPS (Escherichia coli 055:B5, 10 mg/kg, Sigma) or vehicle (pyrogen-free water). Animals of treatment groups were also given either dexamethasone (4 mg/kg, 30 min prior to LPS injection) or the matrix metalloproteinases (MMPs) inhibitor doxycycline (4 mg/kg, 30 min after LPS injection). Both activities and protein levels of MMP-2 (p < 0.001) and MMP-9 (p < 0.001) were significantly upregulated in aortic homogenates from LPS-treated rats, associated with decreased ZO-1 (p < 0.001) and syndecan-1 (p = 0.011) protein contents. Both dexamethasone and doxycycline could significantly inhibit MMPs activity and reserve the expressions of ZO-1 and syndecan-1. The inhibition of MMPs by dexamethasone was significantly lower than that by doxycycline, while the rescue of syndecan-1 expression from LPS-induced endotoxemic rat thoracic aorta was significantly higher in the dexamethasone-treated compared to the doxycycline-treated (p = 0.03). In conclusion, activation of MMPs plays important role in regulating ZO-1 and syndecan-1 protein levels in LPS mediated endothelial perturbation. Both dexamethasone and doxycycline inhibit activation of MMPs that may contribute to the rescue of ZO-1 and syndecan-1 expression.

The transcutaneous oxygen challenge test: a noninvasive method for detecting low cardiac output in septic patients.

ABSTRACT The transcutaneous partial pressure of oxygen (PtcO2) index has been used to detect low-flow state in circulatory failure, but the value of the transcutaneous oxygen challenge test (OCT) to estimate low cardiac output has not been thoroughly evaluated. The prospective observational study examined 62 septic patients requiring PiCCO-Plus for cardiac output monitoring. Simultaneous basal blood gases from the arterial, central venous catheters were obtained. Cardiac indices were measured by the transpulmonary thermodilution technique at the same time, then the 10-min inspired 1.0 fractional inspired oxygen concentration (FIO2) defined as the OCT was performed. Transcutaneous partial pressure of oxygen was measured continuously by using a noninvasive transcutaneous monitor throughout the test. The values for arterial pressure of oxygen (PaO2) were examined on inspired of 1.0 FIO2. We calculated the PtcO2 index = (baseline PtcO2/baseline PaO2), 10-min OCT (10 OCT) = (PtcO2 after 10 min on inspired 1.0 O2) − (baseline PtcO2), and the oxygen challenge index = (10 OCT) / (PaO2 on inspired 1.0 O2 − baseline PaO2). Patients were divided into two groups: a normal cardiac index (CI) group with CI of greater than 3 L/min per m2 (n = 41) and a low CI group with CI of 3 L/min per m2 or less (n = 21). The 10 OCT and the oxygen challenge index predicted a low CI (⩽3 L/min per m2) with an accuracy that was similar to central venous oxygen saturation, which was significantly better than the PtcO2 index. For a 10 OCT value of 53 mmHg, sensitivity was 0.83; specificity, 0.86; a positive predictive value, 0.92; and a negative predictive value, 0.72 for detecting CI of 3 L/min per m2 or less. We propose that the OCT substituted for the PtcO2 index as an accurate alternative method of PtcO2 for revealing low CI in septic patients.

The Role of Uncoupling Protein 2 During Myocardial Dysfunction in a Canine Model of Endotoxin Shock.

ABSTRACT To explore the role of uncoupling protein 2 (UCP2) during myocardial dysfunction in a canine model of endotoxin shock, 26 mongrel canines were randomly divided into the following four groups: A (control group; n = 6), B2 (shock after 2 h; n = 7), B4 (shock after 4 h; n = 7), and B6 (shock after 6 h; n = 6). Escherichia coli endotoxin was injected into the canines via the central vein, and hemodynamics were monitored. Energy metabolism, UCP2 mRNA and protein expression, and UCP2 localization were analyzed, and the correlation between energy metabolism changes, and UCP2 expression was determined. After the canine endotoxin shock model was successfully established, the expression of UCP2 mRNA and protein was found to increase, with later time points showing significant increases (P < 0.05). Immunofluorescence assays of UCP2 in heart tissue showed that UCP2 was localized in the cytoplasm, and its expression pattern was the same as that found in the mRNA and protein analyses. The energy metabolism results revealed that the ADP levels increased, but the ATP and phosphocreatine (PCr) levels and ATP/ADP and PCr/ATP ratios decreased in the model. In particular, the PCr/ATP ratio was significantly different from that of the control group 6 h after shock (P < 0.05). Furthermore, correlation analysis showed that the UCP2 protein and mRNA levels were negatively correlated with myocardial energy levels. In summary, decreased energy synthesis can occur in the myocardium during endotoxin shock, and UCP2 may play an important role in this process. The negative correlation between UCP2 expression and energy metabolism requires further study, as the results might contribute to the treatment of sepsis with heart failure.