Alda-1 alleviates brain injury after cardiopulmonary resuscitation by regulating acyl-CoA synthetase long-chain family member 4/glutathione peroxidase 4 pathway-mediated ferroptosis in swine / 中华危重病急救医学

OBJECTIVE@#To investigate whether the acetaldehyde dehydrogenase 2 specific activator, Alda-1, can alleviate brain injury after cardiopulmonary resuscitation (CPR) by inhibiting cell ferroptosis mediated by acyl-CoA synthetase long-chain family member 4/glutathione peroxidase 4 (ACSL4/GPx4) pathway in swine.@*METHODS@#Twenty-two conventional healthy male white swine were divided into Sham group (n = 6), CPR model group (n = 8), and Alda-1 intervention group (CPR+Alda-1 group, n = 8) using a random number table. The swine model of CPR was reproduced by 8 minutes of cardiac arrest induced by ventricular fibrillation through electrical stimulation in the right ventricle followed by 8 minutes of CPR. The Sham group only experienced general preparation. A dose of 0.88 mg/kg of Alda-1 was intravenously injected at 5 minutes after resuscitation in the CPR+Alda-1 group. The same volume of saline was infused in the Sham and CPR model groups. Blood samples were collected from the femoral vein before modeling and 1, 2, 4, 24 hours after resuscitation, and the serum levels of neuron specific enolase (NSE) and S100 β protein were determined by enzyme-linked immunosorbent assay (ELISA). At 24 hours after resuscitation, the status of neurologic function was evaluated by neurological deficit score (NDS). Thereafter, the animals were sacrificed, and brain cortex was harvested to measure iron deposition by Prussian blue staining, malondialdehyde (MDA) and glutathione (GSH) contents by colorimetry, and ACSL4 and GPx4 protein expressions by Western blotting.@*RESULTS@#Compared with the Sham group, the serum levels of NSE and S100β after resuscitation were gradually increased over time, and the NDS score was significantly increased, brain cortical iron deposition and MDA content were significantly increased, GSH content and GPx4 protein expression in brain cortical were significantly decreased, and ACSL4 protein expression was significantly increased at 24 hours after resuscitation in the CPR model and CPR+Alda-1 groups, which indicated that cell ferroptosis occurred in the brain cortex, and the ACSL4/GPx4 pathway participated in this process of cell ferroptosis. Compared with the CPR model group, the serum levels of NSE and S100 β starting 2 hours after resuscitation were significantly decreased in the CPR+Alda-1 group [NSE (μg/L): 24.1±2.4 vs. 28.2±2.1, S100 β (ng/L): 2 279±169 vs. 2 620±241, both P < 0.05]; at 24 hours after resuscitation, the NDS score and brain cortical iron deposition and MDA content were significantly decreased [NDS score: 120±44 vs. 207±68, iron deposition: (2.61±0.36)% vs. (6.31±1.66)%, MDA (μmol/g): 2.93±0.30 vs. 3.68±0.29, all P < 0.05], brain cortical GSH content and GPx4 expression in brain cortical was significantly increased [GSH (mg/g): 4.59±0.63 vs. 3.51±0.56, GPx4 protein (GPx4/GAPDH): 0.54±0.14 vs. 0.21±0.08, both P < 0.05], and ACSL4 protein expression was significantly decreased (ACSL4/GAPDH: 0.46±0.08 vs. 0.85±0.13, P < 0.05), which indicated that Alda-1 might alleviate brain cortical cell ferroptosis through regulating ACSL4/GPx4 pathway.@*CONCLUSIONS@#Alda-1 can reduce brain injury after CPR in swine, which may be related to the inhibition of ACSL4/GPx4 pathway mediated ferroptosis.

Effect of Alda-1 on ferroptosis in cardiomyocytes after cardiac arrest and cardiopulmonary resuscitation in swine / 中华麻醉学杂志

Objective:To evaluate the effect of Alda-1 on ferroptosis in cardiomyocytes after cardiac arrest and cardiopulmonary resuscitation in swine.Methods:Twenty-two healthy male white swine, weighing 35-43 kg, were divided into 3 groups using a random number table method: sham operation group (group S, n=6), cardiac arrest-cardiopulmonary resuscitation group (group CA-CPR, n=8) and Alda-1 group ( n=8). The animals only underwent the general preparation in group S, and the swine model of cardiac arrest and cardiopulmonary resuscitation was developed by 8 min of electrically induced cardiac arrest through the pacing catheter in the right ventricle followed by 8 min of cardiopulmonary resuscitation in CA-CPR and Alda-1 groups.Alda-1 0.88 mg/kg was intravenously injected at 5 min after resuscitation in group Alda-1, and the equal volume of vehicle was administered instead in the other two groups.Stroke volume (SV) and global ejection fraction (GEF) were measured using PiCCO before developing the model and at 1, 2 and 4 h after resuscitation (T 0-3). Venous blood samples were collected from the femoral vein to measure the concentrations of serum cardiac troponin (cTnI) by enzyme-linked immunosorbent assay at T 0-3, and at 24 h after resuscitation (T 4). The animals were then sacrificed, and myocardial tissues in the left ventricle were harvested to measure the expression of acyl-CoA synthetase long-chain family member 4 (ACSL4) and glutathione peroxidase 4 (GPX4) (by Western blot), iron deposition (by Prussian blue staining), 4-hydroxy-2-nonenal (4-HNE) content (by enzyme-linked immunosorbent assay), and malondialdehyde (MDA) and glutathione (GSH) contents (by colorimetry). Results:Compared with group S, SV and GEF were significantly decreased at T 1-3, the serum concentrations of cTnI were increased at T 1-4, myocardial ACSL4 expression was up-regulated, GPX4 expression was down-regulated, iron deposition and contents of 4-HNE and MDA were increased, and the content of GSH was decreased in CA-CPR and Alda-1 groups ( P<0.05). Compared with group CA-CPR, SV and GEF were significantly increased at T 2-3, the serum concentrations of cTnI were decreased at T 3-4, myocardial ACSL4 expression was down-regulated, GPX4 expression was up-regulated, iron deposition and contents of 4-HNE and MDA were decreased, and the content of GSH was increased in group Alda-1 ( P<0.05). Conclusions:Alda-1 can alleviate myocardial injury after cardiac arrest and cardiopulmonary resuscitation in swine and further improve cardiac dysfunction, and the mechanism may be related to inhibition of cell ferroptosis.

Correlation of transcutaneous oxygen pressure and blood lactate in patients with septic shock / 中华内科杂志

To analyze the correlation between transcutaneous oxygen pressure (PtcO2) and blood lactate in patients with septic shock. Fifty-sixpatients with septic shock were prospectively investigated. PtcO2 was monitored continuously for 6 hours, and arterial blood gas was measured at baseline (T0) and 6 hours (T6). Records of PtcO2, were analyzed for the correlation with lactate level and lactate clearance rate. PtcO2 valuesin the high lactate clearance group and the low one were compared.The lowest value of PtcO2 at T6 and duration of PtcO2<40 mmHg (1 mmHg=0.133 kPa) were both correlated with lactate level and lactate clearance rateat T6. The low predictive value of PtcO2 was 29 mmHg of lactate clearance under 20％with a sensitivity 85.2％and a specificity 65.5％. The low predictive value of PtcO2 in high lactate clearance group was significantly higher than that in low lactate clearance group, while the duration of PtcO2<40 mmHg was shorter than the latter. During 6 h continuous monitoring, patients with a significant low PtcO2 or prolonged duration of low PtcO2 have relatively high lactate or low lactate clearance after resuscitation.

The influence of left ventricular-arterial coupling on the prognosis of elderly patients with septic shock / 中华内科杂志

Objective To investigate the influence of left ventricular-arterial coupling(VAC) on clinical prognosis of elderly patients with septic shock.Methods A total of 56 elderly septic shoek patients were enrolled in this study,all of whom were admitted to Department of Intensive Care Unit in Zhejiang Hospital from August 2014 to October 2015.The patients were divided into two groups according to the status of left ventricular-arterial coupling when septic shock was diagnosed,which were left ventricular-arterial uncoupling group(UC group) and left ventricular-arterial coupling group(C group).Various parameters were recorded,including blood lactate level,central venous oxygen saturation(ScvO2),serum level of N-terminal pro-brain natriuretic peptide(NT-proBNP) and cardiac troponin Ⅰ (cTN Ⅰ),dose of vasoactive drugs,the total fluid volume and urine volume per hour within 24 hours.The 28-day survival rate was a key index of prognosis.Multivariate logistic regression was taken to analyze risk factors related to death within 28 day.Results Compared with C group,UC group had lower values of left ventricular ejection fraction[(42.43 ±4.76)％ vs (53.17±3.01)％;P＜0.01] and cardiac index[(2.36±0.68) L· min-1 · m 2vs (2.93±0.45)L · min-1 · m-2;P ＜0.01].Yet serum levels of NT-proBNP[lg NT-proBNP 3.93 ±0.53 vs 3.40 ±0.63;P =0.004] and cTN Ⅰ [lg cTN Ⅰ-0.16 ± 0.68 vs-1.03 ± 0.69;P ＜ 0.001] in UC group were higher than those in C group.Moreover,the total fluid volume within 24 hours [(3 806.3 ± 831.4) ml vs (3 142.0±770.0) ml;P =0.016],blood lactate level[(5.61 ±2.68) mmol/L vs (3.93 ± 1.59)mmol/L;P =0.043] and dose of norepinephrine[(0.630 ±0.300) μg · kg-1 · min-1 vs (0.292 ±0.234)μg · kg-1 · min-1;P =0.001] in UC group were greater than those in C group,while ScvO2 [(60.75 ±2.91)％ vs (64.42 ±2.19)％;P＜0.001] and urine volume per hour[(0.518 ±0.358) ml vs (0.926 ±0.678) ml;P =0.007] were less than those in C group.Compared with C group,UC group had a lower 28-day survival rate [43.2％ (19/44) vs 9/12;P =0.049].Ea/Ees ratio was negatively correlated with LVEF,ScvO2 (r =-0.686,P ＜ 0.001;r =-0.411,P =0.002),positively correlated with NT-proBNP,cTN Ⅰ (r =0.294,P =0.028;r =0.363,P =0.006),yet no obvious correlation was noticed with blood lactate level (r =0.170,P =0.21).Multiple logistic regression analysis showed that VAC(OR =11.187,95％ CI 2.489-50.285;P =0.002),lactate level (OR =1.727,95 ％ CI 1.164-2.563;P =0.007) and lg cTN Ⅰ (OR =0.247,95 ％ CI 0.079-0.779;P =0.017) were independent risk factors affecting 28-day mortality.Conclutions In elderly patients with septic shock,left ventricular-arterial uncoupling indicates a lower 28-day survival rate,worse cardiac function and tissue perfusion.Ea/Ees ratio might sever as a predictive indicator of 28-day mortality.

Association of poly(ADP-ribose) polymerase activity in circulating mononuclear cells with myocardial dysfunction in patients with septic shock / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Severe sepsis and septic shock are the leading causes of morbidity and mortality in hospitalized patients. This study aimed to investigate the association of poly (ADP-ribose) polymerase-1 (PARP-1) activity in circulating mononuclear cells with myocardial dysfunction in patients with septic shock.</p><p><b>METHODS</b>A total of 64 patients with septic shock were divided into the survival group (n = 41) and the nonsurvival group (n = 23) according to mortality at 28 days after enrollments. PARP-1 activity in circulating mononuclear cells, brain natriuretic peptide, Acute Physiology and Chronic Health Evaluation II score, the cardiac index (CI), the cardiac function index (CFI), global ejection fraction (GEF), and the left ventricular contractility index (dp/dt max) were measured after admission to the intensive care unit.</p><p><b>RESULTS</b>PARP-1 activity in circulating mononuclear cells of nonsurvival patients with septic shock was significantly higher than that in survival patients. PARP-1 activity in circulating mononuclear cells was strongly, negatively correlated with the CI, the CFI, GEF, and dp/dt max. Multiple Logistic regression analysis showed that PARP-1 activity in circulating mononuclear cells was an independent risk factor of myocardial dysfunction. The optimal cutoff point of PARP-1 activity for predicting 28-day mortality was 942 nmol/L with a sensibility of 78.2% and specificity of 65.1%.</p><p><b>CONCLUSION</b>PARP-1 activity in circulating mononuclear cells is significantly associated with myocardial dysfunction and may have prognostic value in patients with septic shock.</p>

Value of stroke volume variation in guiding fluid resuscitation therapy in the elderly septic patients / 中华老年医学杂志

Objective To investigate the clinical values of central venous pressure (CVP) versus stroke volume variation (SVV) in patients with severe sepsis after early goal-directed therapy (EGDT).Methods Totally 30 mechanically ventilated patients with severe sepsis who underwent goal-achieved EGDT were enrolled and randomly divided into CVP group (study group) and SVV group (control group) according to the data detected by pulse contour continuous cardiac output (PiCCO) analysis device.The differences in 28-day survival,3-day APACHE Ⅱ score,time of ICU stay,duration of mechanical ventilation,number that need CRRT,entral venous pressure (CVP),heart end-diastolic volume index (GEDVI),intrathoracic blood volume index (ITBVI),extravascular lung water index (EVLWI),cardiac index (CI),central venous oxygen saturation (ScvO2),lactate clearance rate and APACHE Ⅱ score were compared between the 2 groups.Results The death rate had no difference between the 2 groups(x2=0.240,P=0.624).Among survival patients in the CVP group,the time of ICU stay and duration of mechanical ventilation were shorter in study group than in control group(t=2.166,P=0.041;t=2.104,P=0.046),APACHE Ⅱ score at 3th day was decreased(t=2.20,P =0.038).The values of ITBVI,GEDVI,CI,lactate clearance rate were higher in study group than in control group (t=2.759,2.146,2.199,2.654,3.362,P=0.011,0.043,0.038,0.014,0.003).EVLWI and APACHE Ⅱ score were not different (P＞0.05) between the two groups.Conclusions SVV as a recovery target for fluid resuscitation can reach a better recovery results and improvement of prognosis than CVP goal-achieved EGDT.

Role of damaged mitochondria in cardiocyte apoptosis in septic rats / 中华急诊医学杂志

Objective To investigate the role of damaged mitochondria in cardiac cell apoptosis in septic rats and the possible mechanism involved.Methods Seventy-two Sprague-Dawley rats were randomly (random number) divided into negative control group (n =18) and septic group (further divided into three groups as per rats sacrificed 6 h,12 h,and 24 h after endotoxin injection intra-peritoneally,n =18).The hearts of rats were taken.The changes of cardiac morphology were observed under light microscope and scanning electron microscope.Cell apoptosis in situ were examined by using terminal transferase-mediated dUTP nick end-labeling assay and nuclear factor-kappa B (NF-κB) activation in myocardium was detected by using Western blotting to estimate myocardial cell apoptosis.Mitochondrial lipid and protein oxidation were measured to assess oxidative stress,and mitochondrial superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities were determined to estimate antioxidant defense.Results Septic induced inflammatory cells infiltration,myocardium degeneration and effusion in a time-dependent manner.A remarkable expansion of capillaries could be observed in the hearts of infected rats at post-challenge of 24 h.Compared with sham-treated rats,the percentage of apoptosis increased in a time-dependent manner in the hearts of infected rats at 6 h,12 h,24 h of post-injection (P ＜0.05).The concentration of NF-κB p65 in the cytosol decreased gradually and increased in the nucleus during sepsis in a time-dependent manner (P ＜0.05),indicating that septic challenge provoked progressive activation of NF-κB.Mitochondrial cristae disappeared in 6 h of challenge,and significant mitochondrial cristae disappearance,vacuolization,and rupture of mitochondria membrane became markedly obvious 12 and 24 h later.Both SOD and GPx activities decreased,while mitochondrial lipid and protein oxidation increased in a time-dependent manner after 6-24 h of challenge (P ＜ 0.05).Conclusions Septic challenge induced myocardial apoptosis and mitochondrial damage.Further,damaged mitochondria might play an important role by means of alteration of defenses against reactive oxygen species in myocardial cell apoptosis during sepsis.

Significance of procalcitonin test for directing antibiotic therapy in elderly patients with ventilator associated pneumonia / 中华老年医学杂志

Objective To explore the significance of the plasma procalcitonin (PCT) level for directing antibiotic therapy in elderly patients with ventilator-associated pneumonia (VAP).Methods The 50 elderly patients with VAP were randomly separated into the regular therapy group and the PCT-directed therapy group. The regular therapy group was given regular antibiotic therapy, while the antibiotic therapy was decided according to the plasma level of PCT in the PCT-directed therapy group. The used time and utilization rate of antibiotics, as well as inflammatory indicators including white blood cells, neutrophils, C-reactive protein (CRP) and clinical pulmonary infection score (CPIS) were compared between the two groups. Results After treatment, there were no significant differences in white blood cells, neutrophils and CRP between the PCT-directed therapy group and regular therapy group [(8.9 ± 3.5 ) × 109/L vs. (9.4 ± 3.7) × 109/L, 0.62 ± 0.04 vs.0.60±0.04, (18.7±8.5) mg/Lvs. (21.6±6.0) mg/L, t=0.47, 1.84 and 1.37, allP＞0.05],but the CPIS was markedly lower in PCT-directed therapy group than in regular therapy group [(4.0± 1.4) scores vs. (4.7± 1.0) scores, t= 2. 18, P＜0.05]. The neutrophils, CRP and CPIS were significantly lower after treatment than before in the both groups. The concentration of PCT was decreased after treatment than before [(0.5 ± 0.9) mg/L vs. (1.7 ± 0.7) mg/L]. Meanwhile, the time using antibiotics was longer in regular treatment group than in PCT-directed therapy group [(8.72±1.32) d vs. (5.17±0.72) d, t=11.96, P＜0.01], the utilization rate of antibiotics was higher (95.2 % vs. 55.2 %, χ2 = 12.41, P＜0.01) in regular treatment group. Conclusions Using PCT levels for directing treatment in elderly patients with VAP can achieve better curative effect and reduce the use of antibiotics.

Prognostic value of stroke volume variation in septic patients / 中华急诊医学杂志

Objective To investigate the prognostic value of stroke volume variation (SVV) in patients with severe sepsis after early goal-directed therapy (EGDT). Method Thirty-eight mechanically ventilated patients with severe sepsis underwent EGTD were divided into high SVV (≥10%) group and low SW (< 10%) group according to the data obtained from pulse contour continuous cardiac output (PiCCO) analysis device. The differ-enees in the rate of 28-day survival, length of ICU stay, duration of meehanical ventilation and eomplieation of in-fection between two groups of patients were compared. The rate of 28-day survival of patients was analyzed by using Kaplain-Meier survival analysis, and the relationship between SVV and mortality within 28 days was analyzed by using logistic regression model. Results In comparison with low SVV group, the rate of 28-day survival of high SVV group was signifieantly increased (87.5 % vs. 57.1%, P = 0.032), the length of ICU stay was significantly shortened (27.1±9.2) vs. (41.6±10.0) (P = 0. 004) and duration of mechanical ventilation was significantly more brief (20.4±7.3) vs. (28.5±8.3) (P = 0.038). The rate of cumulative survival of patients in high SVV group was higher than that in low SVV group. In addition, logistie analysis showed SW < 10% increased the risk of 28-day mortality (OR = 3.97; 95% CI 1.63 - 9.21, P = 0. 014). Conclusions The SVV can be served as a prognostic indicator in patients with severe sepsis after EGDT.

Fluid resuscitation in elderly patients with septic shock guided by right ventricular end-diastolic volume index / 中华急诊医学杂志

Objective To assess the effects of fluid resuscitation in elderly patients with septic shock by right ventricular end-diastolic volume index (RVEDVI). Method Thirty elderly patients with septic shock with-in 6 hours after onset, admired to intensive care unit of Zhejiang Hospital from January 2007 to October 2008, were randomly divided into control group (n = 15) and experimental group (n = 15). Homodynamic profile of the right ventricular was monitored by using modified Swan-Ganz catheter. Fluid resuscitation was given to the patients of control group monitored by right atria pressure (RAP). The expected efficacy of treatment was the RAP elevated to 8 ～ 12 mmHg. The goal of fluid resuscitation in patients of experimental group was 100～ 200 mL/m~2 RVEDVI corrected by right ventricular ejection fraction (RVEF). RAP, pulmonary artery occlusion pressure (PAOP), RVEF, RVEDVI, acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ) and mixed venous oxygen sat-uration (SvO_2) were recorded before and after the treatment for 6 hours in both groups. The concentration of lactate and the lactate clearance rate of patients in both groups after fluid resuscitation were detected. The relationship between lactate clearance rate and ARVEDVI was evaluated by using correlation analysis. Results The percentage of patients reaching goal of resuscitation in experimental group (86.7%) was higher than that in control group (80%), however, there was no significant difference statistically. In goals-achieving group, RVEDVI, △RVEDVI, RVEF(%), RAP and lactate clearance rate(%) of the patients in experimental group were signifi-cantly higher than those in control group [(119.92 ± 15.65) mL/m~2, (38.54 ± 6.63) mL/m~2, (36.08 ± 3.40), (14.46±1.13) mmHg,(58.31 ± 13.36) vs. (99.92±11.71) mL/m~2,(21.00±11.01) mL/m~2,(32.42± 2.47),(13.08±1.08) mmHg,(43.99±16.26); P <0.05]. However, there was no significant difference in PAOP, APACHE Ⅱ and SvO_2 between two groups (P >0.05). The lactate clearance rate in goals-achieving pa-tients with septic shock has a significant correlation with RVEDVI and △RVEDVI (P < 0.01). Conclusions Fluid resuscitation guided by RVEDVI in elderly patients with septic shock is safe and more effective than that guided by RAP.

Effects of plasma brain natriuretic peptide on prognosis of elderly patients with severe sepsis / 中华急诊医学杂志

Objective To evaluate the predictive value of brain natriuretic peptide (BNP) on mortality in elderly patient with severe sepsis or septic shock. Method Eighty-three elderly patients meeting with criteria of severe sepsis or septic shock by the American College of Chest Physicians and the Society of Critical Care Medicine (ACCP/SCCM) in 2001, admitted in Intensive Care Unit (ICU) of Zhejiang Hospital during May 2004 to June 2007, were enrolled, and patients with chronic renal failure were excluded. The patients were divided into survivor and non - survivor group according to whether they survived within 28 days staying in ICU, the difference of plasma BNP level,serum C-creative protein (CRP) concentration, APACHE II and SOFA scores on admission day and BNP level on the third day between the two groups were compared; thereafter, the relationship between muhiple variables including age, admission day, BNP, CRP, APACHE 11 and SOFA scores, the 3rd day BNP level and 28-day mortality were analyzed by Logistic regression, and meanwhile the independent predictors for ICU moaality among which were determined. Results BNP levels on both admission day and the 3rd day were significantly higher in nomurvivor group than those in survivor group[ ( 1056.38±676.34) pg/ml vs. (611.59±610.02) pg/ml,p =0.002 and (1448.48+891.11) pg/ml vs. (522.41±575.20) pg/ml, P<0.001, respectively]. By Logistic regression analysis, BNP level on the 3rd day and SOFA score on admission day were independent predictors of ICU mortality, The receiver operating characteristic (ROC) curves indicated that values of areas under the curve of the admission day and the 3rd day BNP levels for 28-days mortality were 0.735 (95% CI,0. 621～0. 848, P <0.001) andO.836 (95% CI, 0.746～0,926,P<0.001), respectively. Conclusions Plasma BNP inereaseds in majority of eldedy patients with severe sepsis or septic shock, which may serve as irdex for prognosis in elderly severe septic paients.

Assessment of fluid treatment in elderly patients with severe sepsis guided by monitoring the variation of stroke volume / 解放军医学杂志

0.05).Conclusions Fluid therapy guided by functional hemodynamic index SVV in elderly patients with severe sepsis under MV is safe and more effective than that guided by CVP.SVV is valuable in prodicting the response to fluid treatment in elderly patients with severe sepsis.